[Treatment of non small cell lung cancer]. / Lécebné postupy u nemalobunecného karcinomu plic.

According to the recent data lung cancer in Czech republic is the most common malignancy in men (incidence 93/100 000) and is the leading cause of cancer death in men (mortality 90/100 000). In women is the incidence of lung cancer 30/100 000. Non-small-cell lung cancer (NSCLC) accounts for 70% to 75% of all lung cancers, while small-cell lung cancer (SCLC) accounts for 25% to 30% of cases. These two types of lung cance have a different biological characteristics which leads to a different approach in the treatment of NSCLC and SCLC. The treatment of NSCLC is based on clinical stage of disease and different treatment modalities alone or in combination are used: surgery, radiotherapy, chemotherapy and recently a novel treatment strategy--targeted therapy with biologic agents.

Safety and tolerability of repeated administration of pyridoxal 2-chlorobenzoyl hydrazone in rabbits.

Recently, pyridoxal 2-chlorobenzoyl hydrazone (o-108) has been identified as an effective iron chelator [Link et al., Blood 2003; 101: 4172-79]. Since chronic treatment would be necessary in its potential indications, in the present study, the safety and tolerability of this agent after repeated administration was determined. Three doses of o-108 (25, 50, 100 mg/kg, in 10% Cremophor EL) were administered intraperitoneally, once weekly, for 10 weeks to three groups (n=5 each) of Chinchilla male rabbits. The effects on biochemical, haematological and cardiovascular parameters were examined during the experiment; histopathological examination was performed at the end of the experiment. Results were compared with control (saline 2 mL/kg, n=11) and vehicle groups (10% Cremophor EL, 2 mL/kg, n=12). No premature deaths occurred; the well-being of animals was evidenced by their body weight gain, although lower gain was observed with the highest dose (100 mg/kg). Significant elevations of cardiac troponin T plasma concentrations were observed with the highest dose of o-108, but no abnormalities were found in the cardiovascular function and only minor and inconsistent changes in haematological and biochemical parameters were observed. Histopathological examinations of selected organs revealed only weak and reversible changes through all studied groups. Thus, the data from this study suggest that o-108 remains a promising drug from the standpoint of the possibility of its repeated administration and warrants further investigation.

Milrinone and low cardiac output following cardiac surgery in infants: is there a direct myocardial effect?

We assessed the effect of milrinone on myocardial function in pediatric patients with postoperative low cardiac output syndrome by index of myocardial performance in a prospective, open-label, nonrandomized, consecutive study. Fifteen patients with low cardiac output syndrome following cardiac surgical treatment were studied in the tertiary cardiothoracic pediatric intensive care unit between April 2001 and November 2003 (age range, 0.2-16 months; median, 7; weight, 2.7-11.8 kg; median, 5). Echocardiographic, Doppler-derived, time interval-based index of myocardial performance (Tei index) was used to study cardiac function prior to and while on intravenous milrinone treatment for 18-24 hours. Treatment with milrinone led to improvement in biventricular myocardial function [mean right ventricular index from 0.521 (SD-0.213) to 0.385 (SD-0.215), p = 0.003; mean left ventricular index from 0.636 (SD-0.209) to 0.5 (SD-0.171), p = 0.012). No difference was found in the values of heart rate corrected right or left ventricular ejection time prior to and while on treatment with milrinone (right ventricle: mean, 1.23 (SD-0.42) and 1.14 (SD-0.48), p = 0.29; left ventricles: mean, 1.17 (SD-0.51) and 1.13 (SD-0.48), p = 0.66) Our data support the direct myocardial effect of milrinone as part of the mechanism behind its already proven benefit in children with low cardiac output syndrome following cardiac surgery.

Study of daunorubicin cardiotoxicity prevention with pyridoxal isonicotinoyl hydrazone in rabbits.

Risk of cardiotoxicity is the most serious drawback of the clinical usefulness of anthracycline antineoplastic antibiotics, which however, remain among the most powerful and widely employed anticancer drugs. In this study we have used daunorubicin-induced cardiomyopathy in rabbits as a model to investigate possible cardioprotective effects of pyridoxal isonicotinoyl hydrazone (PIH)-a principal representative of a novel group of aroylhydrazone iron chelators. Three groups of animals were used: a control group (n=11; i.v. saline), daunorubicin-treated animals (n=11; 3mg/kg, i.v.), and animals pretreated with PIH (n=9, 25 mg/kg, i.p.) 60 min before daunorubicin administration. All substances were administered once weekly for 10 weeks. Repeated administration of daunorubicin caused premature death in four animals and induced conspicuous histopathological changes in the myocardium, progressive and significant impairment of systolic heart function (a decrease in left ventricular dP/dt(max), ejection fraction, an increase in the pre-ejection period/left ventricular ejection time index), and a gradual increase in cardiac troponin T plasma concentrations. On the contrary, all the PIH-treated animals have survived all daunorubicin applications. Furthermore, in this group, the daunorubicin-induced cardiac changes were in most functional, biochemical as well as morphological parameters less pronounced than in the group receiving daunorubicin alone. Hence, PIH and other aroylhydrazones merit further investigation as potentially protective agents against anthracycline-induced cardiotoxicity.

Protein profiling in daunorubicin-induced cardiomyopathy.

The aim of this paper was to study the protein remodelling of the left ventricle following repeated administration of either daunorubicin (DNR) or DNR in combination with the cardioprotective agent dexrazoxane (DXZ). The experiment was carried out on three groups of Chinchilla male rabbits: 1. DNR (3 mg/kg i.v.), 2. DNR (3 mg/kg i.v.) + DXZ (60 mg/kg i.p.), and 3. the control group (saline 1 ml/kg i.v. in the same schedule). The drugs were given once weekly, max. 10 administrations. Protein fractions were isolated by stepwise extraction from the samples of the left ventricle. In the DNR-group, the concentrations of both, metabolic and contractile proteins were significantly reduced, while the amount of collagen was significantly higher in comparison with the control group. In the group treated with DNR and DXZ, the concentrations of individual protein fractions (except metabolic proteins) were comparable to those of the control group, which confirms a significant cardioprotective effect of DXZ. The changes of protein profiling corresponded to functional examination of both cardiac parameters (EF, dP/dt(max), PEP: LVET index) and histological examination. These data should be used in further studies dealing with evaluation of cardiotoxic and, possibly, cardioprotective effects of new drugs.

High dose rate intraluminal brachytherapy in the treatment of malignant airway obstructions.

Endobronchial brachytherapy has been increasingly used in an effort to improve local control and relieve symptoms of malignant airway obstructions. Results of the high dose rate (HDR) intraluminal brachytherapy in 67 patients with inoperable endobronchial tumor treated by combination of teletherapy and brachytherapy with curative (group A ) or palliative (group B) intent, patients with recurrent tumors after previous radiotherapy treated by endobronchial brachytherapy alone (group C), and patients treated by brachytherapy without teletherapy (group D) are presented. Symptomatic improvement was achieved in 66%, 74%, 64% and bronchoscopic response in 70%, 85%, 78% of patients in groups A, B and C, respectively. Median survival was 365, 242 and 884 days from diagnosis and 245, 151 and 153 days from the first brachytherapy application in groups A, B and C, respectively. In group D complete bronchoscopic response was achieved in 3 of 4 patients with early tumor and partial response in 6 of 7 patients with advanced disease. We observed 4 acute and 9 late complications. Brachytherapy is an effective palliative treatment of malignant airway stenosis, but the effect on survival is not apparent.

The limits of surgical treatment of non-small cell lung cancer.

Between January 1, 1991 until December 31, 1996, 286 patients with non-small cell lung cancer were diagnosed and treated in the Department of Tuberculosis and Respiratory Diseases and Palliative Care Unit in Babice nad Svitavou, Czech Republic. There were 251 (87.8%) males and 35 (12.2%) females. The mean age of the whole group was 63.8 years. According to TNM staging (regarding the locoregional extension of the disease) as the only criterion 112 patients (39.2%) were eligible for surgical resection of primary lung tumour. However lung surgery was performed in 57 patients (19.9%) with successful radical resection in 49 cases (17.1%) out of 286. Surgical procedure was contraindicated in 55 (49.1%) out of 112 potentially resectable patients mostly because of limited cardiopulmonary function. The strategy of neoadjuvant treatment before the resection of lung tumour was used for 12 (4.2%) patients. Chemotherapy, radiotherapy or the combination of both treatment modalities was used in 121 (42.3%) patients. Symptomatic therapy alone was chosen in 104 (36.4%) cases. The performance of radical resection of lung tumours resulted in a significant influence on the overall survival in the subgroup of all patients with potentially locoregionally operable disease according to the TNM staging. The median survival period reached 17 months if radical resection was done compared to 8.5 months if radical resection was not performed. This difference is statistically significant, p = 0.05.

[Some aspects of advances in the chemotherapy of bronchogenic carcinoma]. / Nekteré aspekty pokroku v chemoterapii bronchogenního karcinomu.

Bronchogenic carcinoma is in the Czech Republic the most frequent malignant tumour in males. For practice the classification into non-small cell bronchogenic carcinoma (NSCLC) and small cell bronchogenic carcinoma (SCLC) is most useful. Views on chemotherapy of NSCLC were before 1980 rather pessimistic. In untreated patients with advanced NSCLC the median survival is 6 months and one-year survival in 10 %. In the nineties, due to the introduction of cytostatics of the IIIrd generation into treatment of NSCLC, the median survival was prolonged to 10 - 12 months and one-year survival is reported in 40 - 50 % patients. The importance of chemotherapy in SCLC was never doubted. By concurrent chemotherapy and radiotherapy the total period of treatment of patients with SCLC was reduced and the percentage of objective responses increased. Introduction of cytostatics of the third generation is important in particular in treatment of line II SCLC. Basic prognostic factors of successful chemotherapy in patients with bronchogenic carcinoma are the stage of the disease, body weight loss, presence of paraneoplastic symptoms, immune state and clinical and sociodemographic characteristics.