Jana Skřičková

Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial

PURPOSE This randomized, multicenter, phase III trial was conducted to compare the tolerability of gemcitabine plus cisplatin (GP) vs. gemcitabine plus carboplatin (GC) in chemonaive patients with stage IIIb and IV non-small cell lung carcinoma (NSCLC). Secondary objectives were to evaluate response, duration of response, time to progressive disease (TTPD), and survival. PATIENTS AND METHODS Eligible patients were required to have stage IIIb or IV NSCLC, no previous chemotherapy, Karnofsky performance status of at least 70, bidimensionally measurable disease, and age 18-75 years. Randomized patients in both arms were given gemcitabine 1200 mg/m(2) on days 1 and 8, followed on day 1 by cisplatin 80 mg/m(2) (GP) or carboplatin AUC=5 (GC). Treatment cycles were repeated every 21 days for a maximum of six cycles, or until disease progression or unacceptable toxicity occurred. RESULTS Enrolled patients in both arms, 87 in GP and 89 in GC, were well balanced for demographics and disease characteristics. Dose intensity was 93.8 and 92.7% for gemcitabine in GP/GC arms, respectively; 97.7% for cisplatin and 99.9% for carboplatin. Patients with at least one grade 3/4 toxicity excluding nausea, vomiting or alopecia, were 44% in GP arm and 54% in GC arm. The only significantly different toxicities were, nausea and vomiting in GP and thrombocytopenia in GC group. The overall response rates, median TTPD, response duration and survival were, 41/29%, 5.87/4.75 months, 7.48/5.15 months, and 8.75/7.97 months for GP and GC arms, respectively. CONCLUSION GP and GC are effective and feasible regimens for advanced NSCLC, and are comparable in efficacy and toxicity. GC may offer acceptable option to patients with advanced NSCLC, especially those who are unable to receive cisplatin.

Monitoring the ionic content of exhaled breath condensate in various respiratory diseases by capillary electrophoresis with contactless conductivity detection.

The analysis of an ionic profile of exhaled breath condensate (EBC) by capillary electrophoresis with contactless conductivity detection and double opposite end injection, is demonstrated. A miniature sampler made from a 2 ml syringe and an aluminium cooling cylinder was used for the fast collection of EBC (under one minute). Analysis of the collected EBC was performed in a 60 mM 2-(N-morpholino)ethanesulfonic acid, 60 mM L-histidine background electrolyte with 30 µM cetyltrimethylammonium bromide and 2 mM 18-crown-6 at pH 6, and excellent repeatability of migration times (RSD  <1.3% (n = 7)) and peak areas (RSD  <  7% (n = 7)) of 14 ions (inorganic anions, cations and organic acids) was obtained. It is demonstrated that the analysis of EBC samples obtained from patients with various respiratory diseases (chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, sarcoidosis, cystic fibrosis) is possible in less than five minutes and the ionic profile can be compared with the group of healthy individuals. The analysis of the ionic profile of EBC samples provides a set of data in which statistically significant differences among the groups of patients could be observed for several clinically relevant anions (nitrite, nitrate, acetate, lactate). The developed collection system and method provides a highly reproducible and fast way of collecting and analyzing EBC, with future applicability in point-of-care diagnostics.

Therapy of small cell lung cancer with emphasis on oral topotecan.

Systemic chemotherapy plays the major role in the management of patients with small cell lung cancer. Cisplatin plus etoposide is the most widely used regimen and is considered as standard in patients with limited disease. Cisplatin plus irinotecan improved survival compared to cisplatin plus etoposide in a Japanese trial but failed to do so in two trials in Caucasians. Cisplatin plus topotecan had similar efficacy compared to cisplatin plus etoposide in patients with extensive disease. In the second-line setting, topotecan showed similar efficacy but better tolerability compared to cyclophosphamide, doxorubin plus vincristine. Oral topotecan was as efficacious as its intravenous formulation and was shown to improve survival compared to best supportive care alone in patients previously treated with chemotherapy. Thus topotecan is considered as the standard second-line chemotherapy in patients with small cell lung cancer.

Double opposite end injection capillary electrophoresis with contactless conductometric detection for simultaneous determination of chloride, sodium and potassium in cystic fibrosis diagnosis

A novel approach for diagnosis of cystic fibrosis is presented. A simple and fast procedure to obtain sweat sample was developed. It consists of repeatedly wiping the skin of the forearm with deionized water moisturized cotton swab and extraction in 1mL of deionized water. Double opposite end injection capillary electrophoresis with contactless conductometric detection is used for the analysis of the extract. Chloride, sodium and potassium as the three target ions that participate in the ion transfer across the cellular membranes, and are affected by CF, are simultaneously determined in approximately 3min in a background electrolyte containing 20mM 2-(N-morpholino)ethanesulfonic acid, 20mM l-histidine and 2mM 18-crown-6. By using the target ion ratios rather than the concentrations of each individual ion combined with principal component analysis, the diagnosis of CF can be made more accurately and greatly reduce the number of false positive or negative results as is often the case when single ion (chloride) is analyzed.

Thyroid transcription factor 1 expression is associated with outcome of patients with non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy

Pemetrexed is an antifolate cytostatic agent targeting several folate-dependent enzymatic pathways, widely used in the treatment of locally advanced or metastatic stage non-small cell lung cancer. Aside from the non-squamous histology, there is still no available molecular biomarker predicting treatment efficacy of pemetrexed-based chemotherapy. The aim of our retrospective study was to evaluate the association of thyroid transcription factor 1 expression with outcome of a large cohort of patients with non-squamous non-small cell lung cancer treated with pemetrexed. We retrospectively analysed clinical data of 463 patients with advanced-stage non-small cell lung cancer (IIIB or IV) treated with pemetrexed-based chemotherapy. Thyroid transcription factor 1 expression was assessed using indirect immunohistochemical detection in formalin-fixed paraffin-embedded tumour tissue at the time of diagnosis. Thyroid transcription factor 1 expression was detected in the tumour tissue from 76.0% of patients, and tumours from 24.0% of patients were thyroid transcription factor 1 negative. The median progression-free survival and overall survival for patients with thyroid transcription factor 1 positive tumours were 4.8 and 11.8 months compared to 2.8 and 8.3 months for those with thyroid transcription factor 1 negative tumours (p = 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that thyroid transcription factor 1 expression was significantly associated with progression-free survival (hazard ratio = 1.57, p < 0.001) and also with overall survival (hazard ratio = 1.73, p < 0.001). In conclusion, the results of the conducted retrospective study suggest that the thyroid transcription factor 1 expression was independently associated with progression-free survival and overall survival in patients with advanced-stage non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

Radiotherapy of Lung Tumours in Idiopathic Pulmonary Fibrosis

BACKGROUND This article is a joint statement of the Czech Pneumological and Physiological Society and the Czech Society for Radiation Oncology, Biology and Physics, and reviews current opinions on radiotherapy in patients with idiopathic pulmonary fibrosis (IPF). In general, radiotherapy of lung tumours is associated with risk of radiation pneumonitis (RP); moreover, IPF may be complicated by acute exacerbations (AE-IPF). Both complications may immediately threaten patients lives. MATERIAL AND METHODS Assessment of individual radiotherapy modalities has shown that conventional radiotherapy is not appropriate, especially in large tumours. Up to 30% of patients are at risk of developing AE-IPF. As a result, as many as 83% of patients die within 3 months of initiation of lung cancer treatment. Fatal RP is most commonly observed within 2 months of radiotherapy. In IPF accompanied by early-stage non-small cell lung cancer (NSCLC), stereotactic body radiation therapy (SBRT) may be considered. NSCLC should be treated with chemotherapy. Several cases report severe exacerbations of subclinical IPF after SBRT even with minimal signs of previous interstitial involvement. Grade 2 RP has been reported in up to 50% of cases with any level of interstitial change detected by lung CT prior to radiotherapy. In palliative radiotherapy, external radiation may be considered as an exception if the main bronchi are involved. Similarly, brachytherapy may be indicated for certain cases of bronchial stenosis. RESULTS The presence of any level of interstitial change suggests a risk for fatal RP and AE-IPF. This is also supported by the fact that, at the present time, there are no dose limitations for radiation therapy of lung cancer in IPF, irrespective of whether conventional fractionated radiotherapy or SBRT is used. Moreover, there are no reliable predictive factors for lung involvement. In some studies, RP was more frequently associated with high CRP and LDH levels, PS 2 and interstitial changes of 10% or more. Treatment depends on the severity of the involvement. In more severe forms, corticosteroids, antibiotics and oxygen therapy should be administered. Ventilation support is often needed. CONCLUSION Radiotherapy for patients with IPF and lung cancer or other chest tumours requires an individual approach depending on the local findings, the patients lung function and general condition, and the prognosis of the primary disease. Decision-making should take into consideration potential benefits and risks, and be carried out by a multidisciplinary team comprising a pulmonologist and clinical and radiation oncologists. Treatment should always be thoroughly discussed with the patient signing an informed consent form.Key words: idiopathic pulmonary fibrosis - chest radiotherapy - indications - radiation pneumonitis - acute exacerbation of idiopathic pulmonary fibrosis - treatment This work was supported by grant AZV 16-32-318 A. 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: 4. 5. 2017Accepted: 18. 5. 2017.

Association of the postoperative white blood cells (WBC) count in peripheral blood after radical surgical treatment of left upper lobe non-small cell lung cancer (NSCLC) with overall survival - single center results

INTRODUCTION The individual patient prognosis after radical surgery for Non-small cell lung cancer (NSCLC) of left upper lobe remains still unclear. The purpose of this study is to evaluate the predictive value of elevated white blood cell count in peripheral blood as early indicator of postoperative NSCLC prognosis. METHODS A retrospective statistical analysis was performed studying patients subject to radical treatment of left upper lobe NSCLC in period of five years with subsequent one to three-year monitoring of morbidity and mortality of the patient population. The statistical ROC (Receiver Operating Characteristic) analysis of the WBC count in peripheral blood third day after the operation was used to evaluate the relationship with overall survival, with respect to patients surviving for at least 24 months. RESULTS Based on the results of the ROC analysis with a total area under the curve (AUC) of 0.67, it is possible to confirm that the WBC count established third day after the operation allows us to classify patients into groups according to the 24-month overall survival. CONCLUSION Our findings confirm the potential of using WBC count to improve current protocols to establish postoperative prognosis for NSCLC of the upper left lobe (Tab. 2, Fig. 1, Ref. 11).

Efficient Procedure for N-Glycan Analyses and Detection of Endo H-Like Activity in Human Tumor Specimens

Although the importance of glycosylation has been thoroughly recognized in association with a number of biological processes, efficient assessments of glycans have been hampered by both the limited size of specimens and lengthy sample preparations, particularly in clinical settings. Here we report a simple preparative method for N-glycan analyses. It involves only short one-step chloroform-methanol extraction in presence or absence of water prior to PNGase F deglycosylation. The procedure was successfully applied to the investigation of N-glycans obtained from small numbers of in vitro cultured cancer cells (≤1 × 10(5)) and to tumor tissues, including patient biopsies of small size. MALDI-MS analysis confirmed the efficient release of all N-glycan types including complex forms with poly-N-acetyllactosamine chains. In addition, nonaqueous extraction of specimens from several established cancer cell lines, as well as patient tumor tissues, yielded high-mannose glycans with one GlcNAc moiety (Man3-9GlcNAc), strongly suggesting preservation of enzymatic activity analogous to Endo H enzyme. In summary, the method is both a step toward the practical use of glycan profiling and a way to detect Endo H-like activity in cancer specimens.

Effects of Treatment with Crizotinib on Non-small Cell Lung Carcinoma with ALK Translocation in the Czech Republic

BACKGROUND Patients with advanced anaplastic lymphoma kinase (ALK) -positive non-small cell lung cancer (NSCLC) may gain significant benefit from treatment with the first-generation ALK inhibitor crizotinib. This study investigated the effects of crizotinib in advanced ALK-positive NSCLC patients via analyzing data submitted to the TULUNG registry by pneumo-oncology centers in the Czech Republic. PATIENTS AND METHODS We analyzed the data of 60 NSCLC patients submitted to the TULUNG registry by pneumo-oncology centers who had ALK translocation confirmed by fluorescence in situ hybridization and complete data records from 2011 to 2017. RESULTS The median age of patients was 58 years. A total of 53% of patients were men, 90% had adenocarcinomas, 61.7% were smokers or ex-smokers, and 65% had a performance status of 0. Upon initiation of crizotinib therapy, most patients were at stage IV (88.3%) and the remainder were at stage IIIA or IIIB. Crizotinib was the second-line therapy in 71.7% of patients. A total of 20% of patients suffered side effects, while 11.7% suffered grade 3 and 4 adverse effects. A total of, 6.7, 25, 21.7, and 25% of patients displayed a complete response, a partial response, stable disease, and progressive disease, resp. Progression-free survival (PFS) was 5.8 months. Overall survival (OS) was 27.9 months from the initiation of the first-line therapy and 12.6 from the initiation of crizotinib therapy. PFS and OS were longer among nonsmokers and ex-smokers than among smokers (PFS, 9.7 vs. 5.8 vs. 3.8 months, p = 0.029; OS, 26.8 vs. 15.3 vs. 7.0 months, p = 0.015). CONCLUSION Targeted crizotinib therapy is well tolerated and has significant benefit in patients with advanced ALK-positive NSCLC. Although international guidelines recommend that crizotinib is only used as a first-line therapy, it is used as a second-line and higher-line therapy in the Czech Republic. Clinical studies provide evidence that targeted therapy elicits better effects and less toxicity than routine chemotherapy. Key words: ALK translocation - crizotinib - targeted biological therapy - tyrosine kinase inhibitors This work was supported by AZV grant No. 17- 30748A. 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: 17. 1. 2018 Accepted: 20. 2. 2018.

Capillary Electrophoretic Analysis of Exhaled Breath Condensate in the Diagnosis of Gastroesophageal Reflux Disease

Abstract In this work, capillary electrophoresis with contactless conductometric detection (CCD) was used for the analysis of the ionic content of exhaled breath condensate (EBC) to differentiate between healthy individuals and patients with gastroesophageal reflux disease (GERD). The exhaled breath condensate was collected using a miniature sample collection device and the content analyzed using a separation electrolyte composed of 20 mM 2-(N-morpholino)ethanesulfonic acid, 20 mM L-histidine, 2 mM 18-Crown-6 and 30 M cetyltrimethylammonium bromide. The separation of anions took less than 2.5 minutes, while the cations were separated in less than 1.5 minutes. The most significantly elevated ions in the group of patients suffering from gastroesophageal reflux disease were chloride, nitrate, propionate and butyrate. Although the number of subjects was too small to draw definite conclusions with regard to the discriminatory power of these ions, the pilot data are promising for EBC as a useful non-invasive alternative for other methods used in the diagnosis of gastroesophageal reflux disease