[The position of neoadjuvant chemotherapy in the treatment of non-small-cell lung carcinoma]. / Postavení neoadjuvantní chemoterapie v lébe nemalobunecného plicního karcinomu.

Surgical treatment of patients with non-small-cell lung carcinoma (NSCLC) offers greatest chances for long-term survival. However, the treatment is applicable only to patients diagnosed at an early stage of the disease, i.e. at stage I or II. The five year survival rate of patients operated at stage IIIA is as low as 23%. Hence there is a great need for improving survival results, especially in the sphere of systemic chemotherapy, as most tumour relapses involve the formation of metastases. Even though neoadjuvant chemotherapy in the operable stages of NSCLC still appeared very promising as a method of treatment a couple of years ago, recently published results have shown that its role has not yet been fully clarified and is still a subject of research. Additional results from randomised studies are necessary before neoadjuvant therapy may become a treatment standard. The dilemma as to whether or not to apply adjuvant, neoadjuvant or both types of chemotherapy in patients operated on for NSCLC therefore remains unsolved. On the whole, the positive role of neoadjuvant chemotherapy does not appear to be proven in the treatment of operable stage I and II NSCLS. In contrast, results of randomised studies first published in 2004 were in favour of post-surgical adjuvant chemotherapy as opposed to surgical treatment alone in NSCLC stage IB, II and IIIA. The question of whether it is better to apply chemotherapy prior to or after surgery can only be answered by the extensive randomised studies underway. The role of neoadjuvant chemotherapy in patients with NSCLC at clinical stage IIIA remains uncertain. The most rational approach to such patients appears to be neoadjuvant chemotherapy or chemotherapy with subsequent surgery.

[Adjuvant chemotherapy in the treatment of non-small cell lung cancer]. / Adjuvantní chemoterapie v lécbe nemalobunecného plicního karcinomu.

For its high incidence and lethality lung cancer represents one of the most serious medical and social problems. Even the early stages of non-small cell lung carcinomas (NSCLC) in comparison with tumours of other location have comparatively unfavourable prognosis, even if the patient undergoes radical surgical treatment. Most of patients die from remote metastases. Most probably it is due to the presence of clinically undetectable micro-metastases developing already in the time of surgery, which progress when the primary tumor was removed. Endeavour to improve results of surgical treatment in early stages of NSCLC disease is aimed at neoadjuvant preoperative and adjuvant postoperative chemotherapy. Present recommendations concerning the adjuvant NSCLC chemotherapy result from recent studies. Prognosis of patients in NSCLC stage IA is comparatively favourable and no evidence has been presented that adjuvant chemotherapy improves survival. Adjuvant chemotherapy is therefore indicated after the radical surgery of NSCLC stage IB-II. Adjuvant chemotherapy should include combination of paclitaxel, docetaxel, vinorelbine or gemcitabin with platin derivates. Patients in good clinical conditions should receive four cycles of chemotherapy in three weeks intervals. Treatment should start at latest 6 weeks after the surgery. Maximal effort to administer the planned dose of chemotherapy in the planned schedule should be given. The role of adjuvant chemotherapy in NSCLC patients of stage IIIA remains indeterminate. The most rational approach to those patients is the neoadjuvant chemotherapy or chemoradiotherapy with subsequent surgical treatment.

[Treatment of the unresectable non small cell lung carcinoma]. / Lécba neresekabilní nemalobunecné plicní rakoviny.

In recent years, treatment of the locally advanced unresectable Non Small Cell Lung Cancer (NSCLC) has evolved from the radiotherapy alone to sequential therapy settings with induction chemotherapy followed by radiotherapy. During recent years, concomitant chemoradiotherapy has become the standard treatment for these patients. The addition of chemotherapy during the course of radiotherapy provides better locoregional control of the disease by killing the radioresistant cells, inhibition of the reparation processes in the sublethally damaged cells and accumulation of the cells in the G2/M phase, when the cells are sensitive to radiation. It also reduces the spread of the micrometastases. Administration of cisplatin-based regimens appears to be the most effective. Acute pneumonias can be effectively suppressed by amifostine administration. Locally advanced inoperable NSCLC can be cured by chemoradiotherapy in more than 10% of patients. Fractionation radiotherapy does not yield prolonged survival. Currently the other clinical studies investigating the effects of hyperfractionation, 3D conformal radiotherapy and IMRT (intense modified radiotherapy) are being conducted. Also the role of various radiosensitizing agents is currently under clinical evaluation. The results of a study, comparing various doublet combinations of taxanes and gemcitabine with cisplatin or carboplatin demonstrate, that as for the efficacy, the standard doublet regimens reached a certain plateau and that they prolong the survival in comparison with the standard regimens used before 1990. The only statistically significant difference in the efficacy among the individual treatment arms is the significantly longer time to the progressive disease in the arm treated by gemcitabine and cisplatin. Studies with triplet regimens show that the addition of the third cytotoxic agent might increase the overall response rate with the increase of toxicity and only a very small survival benefit. The replacement of the platinum derivate by some of the new cytotoxic agents does not appear to yield lower efficacy and also shows a more favorable toxicity profile; it is, however, significantly more expensive. Overall differences among the cytostatic combinations based on cisplatin in comparison with combinations based on carboplatin are not very distinct. Nevertheless, the combination of cisplatin with third generation cytotoxic agents is recommendable as it is more effective for patients with advanced NSCLC without renal impairment and with adequate bone marrow reserve. A high percentage of patients with NSCLC are older that 70 and this percentage will increase further. Earlier, chemotherapy was not used for these patients with the explanation that elderly people are usually polymorbid and the function of their organs which metabolize the cytostatics is reduced. However, a survival benefit in elderly patients treated by cytotoxic monotherapy was proven in comparison with the best supportive care. Other studies, however, found significant differences neither in toxicity nor in survival in comparison with younger patients, when using the same treatment regimens. Platinum doublets, based namely on carboplatin, are useful for patients older than 70, who are in good clinical condition. In the second-line therapy of NSCLC pemetrexed demonstrates identical efficacy as docetaxel, which is considered as a standard monotherapy in the second-line treatment of NSCLC. Moreover, pemetrexed is associated with less toxicity. These data show that in future, pemetrexed may become the standard treatment for second-line therapy of NSCLC. In patients with stage IIIB/IV of NSCLC, the addition of biological treatment to standard doublet cytostatic combination does not bring any survival benefit. In future, more detailed attention should be paid to selection of the patients for this treatment modality. When comparing survival time by meta-analysis, significantly longer survival time of the patients treated with gemcitabine combination was found in comparison with other treatment. Similarly, the progression-free survival is significantly longer in the patients treated with gemcitabine containing regimen. This data has proven good clinical efficacy of gemcitabine in the first-line therapy of advanced NSCLC.

Adsorption of NO on alumina-supported oxides and oxide-hydroxides of manganese.

The adsorption capacity for NO of alumina-supported oxides and oxide-hydroxides of manganese have been studied. Two series of samples have been prepared by precipitation on gamma-alumina and appropriate thermal treatment. The samples have been characterized by adsorption methods, magnetic methods, electronic paramagnetic resonance (EPR), transient response technique, and temperature-programmed desorption (TPD). The influence of the concentration of the initial manganese-containing solution has been investigated. The sample, prepared with a solution with Mn concentration of 4 g/100 ml, has been shown to be the best adsorbent for NO under the conditions of the experiment. It has been found that the presence mainly of Mn3+ ions on the surface of the support is probably responsible for the enhanced adsorption capacity.

Low mutational rate of K-ras codon 12 in singular bronchoscopy specimens in suspected lung cancer.

Mutations of the K-ras gene are found in a subset of non-small- cell lung carcinomas (NSCLC). The aim of our study was to determine the K-ras codon 12 mutation in the first, singular bronchoscopy specimen in parallel with the cytological examination for the diagnosis of lung cancer. Samples were obtained by diagnostic bronchoscopy in 140 patients with suspected lung tumors. The analysis of K-ras mutations was carried out by a sensitive two-step mutation- enriched polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. This method has been confirmed earlier to be positive for mutated tumor cells and negative for normal lung parenchyma and bronchus. Of the 140 patients with suspected cancer, 93 were diagnosed as NSCLC by cytology or histology in either the same specimen used for the detection of K-ras mutation or in later biopsies. However, only four K-ras codon 12 mutations were detected in the first bronchoscopic material: one in adenocarcinoma, two in squamous cell tumors, and one mutation was found in a patient with dysplasia which was diagnosed later as a squamous cell carcinoma. Our findings indicate that although the K-ras (codon 12) mutation is a gene lesion infrequently detectable in a singular specimen taken at the first bronchoscopy examination in cases of clinically suspected lung cancer, the detection of this mutation can help to confirm the cytological diagnosis of NSCLC or may be even diagnostic in cytologically negative cases.

[Treatment of benign stenoses of the large airways at the Faculty Hospital Praha-Motol during 1998-2003]. / Lécba benigních stenóz velkých dýchacích cest ve Fakultní nemocnici Praha-Motol v letech 1998-2003.

The authors present diagnostic and therapeutical results in the group of 80 patients with benign stenoses of large airways, who were hospitalized at the TRN ward (Department of TB and respiratory disorders) of the Faculty hospital Motol in Prague between the years 1998-2003. 62 patients sufferred from stenoses in cosequence of their tracheal intubation or tracheostomy. In 18 cases the stenoses resulted from other disorders or pathological condidtions (Wegener's granulomatosis, status post lung transplantation, etc.) 38 patients were sent for surgery. Up until the date of the assessment (September 2003), 8 of them had had a relaps of the condiditon. 6 operated subjects had their restenosis corected using bronchological methods, 2 subjects had to undergo reoperation, which is 5.2% of the total number of the operated subjects. The remaining 42 patients were treated using the interventional bronchological methods (electrocauther, laser, stents) which proved curative in 35 patients, i.e 44% of the whole group. In 7 inoperable patients the above methods failed, 6 of them having a permanent tracheostomy and one female-patient exited 2 days after an incomplete recanalization. In the subgroup of 18 patients with other than postintubation stenoses, stent operations were the most frequent (12 times), 4 patients were cured using other methods of interventional bronchology, and resection of the stenosis was indicated in two cases. Up until the date of the assessment, 65 subjects had survived and 15 exited. 5 of them died 3-14 months (median of 4 months) following the surgical procedure of other disorders than of the respiratory airways stenoses. 10 unoperated patients, with a single exception, also died due to other causes than the tracheobroncheal lesions (the survival rate median was 9 months). Following the initial freeing of the airways, the authors call for considering a surgical therapeutical option in each case. Provided the surgical approach was contraindicated, the interventional bronchological methods would replace it appropriately.

[Results of treatment of malignant stenoses of the respiratory tract in a long term study]. / Výsledky lécby maligních stenóz dýchacích cest v dlouhodobém sledování.

BACKGROUND: :The malignant stenoses complicate the course of the disease in about 50% of patients with lung tumors. Management of them can influence the quality of life of the afflicted. There is no general agreement about optimal methods of their therapy, of selection of the best methods and also there is only few data about survival of these patients. METHODS AND RESULTS: 130 patients with tumors stenoses of the airways were prospectively followed in the 1998-2003 period, 93 of them suffered from lung cancer. Besides other treatment of the tumor they underwent also interventional bronchoscopy (Nd YAG laser, electrocautery i.e.). The airways were opened completely in 62% of the set of patients. The interventional bronchoscopy was complicated in 9% of patients, 32 patients lived at the 31st December of 2003, 98 of them had died. One year survival was 23.1%, median survival of the whole set of patients was 7 months. The patients with lung cancer had significantly worse survival than patients with other types of lung tumors, 6 months versus 10 months. There were no significant survival differences of the whole set according to the achieved grade of recanalisation, or according the inclusion of the brachytherapy to the set of interventional methods. The patients with inserted stent had significantly worse prognosis than the those without stenting. To homogenize the study group, the subset of patients with epidermoid lung cancer in the stage IIIB were selected (n = 51). Significantly longer survival of patients with complete recanalisation, insignificant longer survival in patients who underwent also brachytherapy and significantly shorter survival in patients with stenting were proved in this subgroup of patients. CONCLUSIONS: The interventional bronchoscopy has a low rate of complications and in most cases it has a palliative effect. The survival of patients is more influenced by the extension and the type of the tumor, their general status, polymorbidity, age etc. than by effect or selection of interventional bronchoscopical methods.

[Benign stenoses of the large respiratory airways]. / Benigní stenózy velkých dechových cest.

BACKGROUND: Benign stenoses of main respiratory pathways develop usually in patients after intubation or tracheostomy. Incidence of such states is not known, they are frequently diagnosed too late, and there are different views of their treatment. In order to contribute to the improvement of our knowledge of this serious impairment we followed prospectively all patients with this diagnose at our department since March 1998. METHODS AND RESULTS: The group of 31 patients with benign stenoses of non-tumorous origin diagnosed and treated at the TRN of the Teaching Hospital Motol in years 1998 to 2000 consisted of 24 males and 7 females, age median was 52 years. Stenosis was caused in 27 patients by intubation, in 4 patients by some other causes. At admission we performed in 30 patients electrocauterization and dilatation of stenosis, one patient was immediately indicated for surgery. Beside two cases we always achieved sufficient patency of stenosis and weighted indication to surgery. We sent for surgery 15 patients, 10 patients were permanently healed using methods of interventional bronchoscopy, including introduction of stent in 6 cases. From the remaining 6 patients, two of them are planned for resection of stenosis, four are inoperable from various reasons, and two died of causes not related to stenosis. CONCLUSIONS: Based on our experience we recommend as an optimal management of such patients is the dilatation or removal of stenosis and then always to consider resection of trachea. In inoperable cases methods of interventional bronchoscopy should be used. Authors recommend sending all patients intubated longer than 2 days for bronchoscopic examination in interval of 2 months.

The role of neoadjuvant chemotherapy in marginally resectable or unresectable stage III non-small cell lung cancer.

The study was undertaken to test whether marginally resectable or unresectable stage IIIa-IIIb non-small cell lung cancer (NSCLC) patients could reach complete resectability after induction chemotherapy. Fifty six patients were included into the study and treated either by vinorelbine 35 mg/m2 day 1 and cisplatin 75 mg/m2 day 1 (n=28) or by vinorelbine 30 mg/m2 day 1 and 8 and cisplatin 80 mg/m2 day 1 (n=28). Cycles were repeated every 21 days. At the completion of induction therapy patients assessed to be resectable underwent thoracotomy. Radiation therapy was applicated in nonresected cases. The minimal follow up was 24 months. 32% of patients with marginally resectable or unresectable stage IIIa-IIIb NSCLC could reach a complete resectability after induction chemotherapy. Survival of patients stage IIIa was comparable to stage IIIb. Responders and resected patients survived significantly longer comparing to the patients with stable disease and progression, respectively to the incompletely resected plus nonresected patients. Perioperative complications were rare and there were no treatment-related deaths in our study. The main surgery-related complication was late bronchopleural fistula.

Long-term clinical benefits of the low dose rate endobronchial irradiation of malignant airway obstructions.

Brachytherapy allows the delivery of higher radiation doses, possibly leading to improved locoregional tumor control and subsequent prolonged survival. The purpose of our study was to evaluate the long-term clinical survival in patients with malignant airway compromise treated with endobronchial brachytherapy and to estimate possible influence of other factors on survival and to review complications of the therapy. In a retrospective study 55 patients with malignant inoperable tracheobronchial lesions underwent 71 brachytherapy treatments with 137Cesium. Either MicroSelectron (N=56) or Selectron (N=15) were used. All except 4 patients received external radiation, 20 patients received chemotherapy, 37 patients received laser excision. Major symptomatic improvement was noted in 75% of patients. Substantial or complete relief of hemoptysis was achieved in 85%, of dyspnea in 65% and of cough in 68%. Response evaluation showed no complete response, partial response was achieved in 70.9% and the endoscopic finding was not changed, or recurrence of the tumor was found in 29.1%. A relatively small number of complications of the endobronchial brachytherapy occured. Significant bleeding was observed in 1 procedure and an inability to tolerate in 3 cases. In 2 cases, it was not possible to place an applicator due to extreme hypoxia. Bronchomediastinal fistula developed in 1 patient and tracheal stenosis in 1 patient. The overall incidence of complications was 15%. The median survival from establishing the diagnosis was 510 days. The median survival after the first brachytherapy treatment was 200 days. We compared the survival in the subgroups of patients in relation to TNM status, chemotherapy, laser debulking brachytherapy device used. The stage IIIA patients survived longer from diagnosis than IIIB patients but the difference was on the border of significance (p = 0.090). In the evaluation of chemotherapy, more patients survived 12 months from the diagnosis (p = 0.045) when treated by chemotherapy comparing to the patients treated without chemotherapy. However, this difference disappeared during the further development of the disease. In the Nd-YAG laser treatment, the patients treated by brachytherapy with the previous laser debulking survived significantly longer from the time of the first brachytherapy session (p = 0.005). No statistical difference was found in the survival of patients treated by either the Selectron or MicroSelectron device. The LDR endobronchial brachytherapy is a well tolerated, safe and effective technique for palliation of malignant airway occlusions. In our group of patients, the long-term survival was longer in IIIA stage comparing to the IIIB, in the group treated by the previous chemotherapy compared to the patients without chemotherapy and in the group with the Nd-YAG laser therapy, comparing to the group treated by the brachytherapy only. No difference of the brachytherapy device used was found.

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.

[Adaptation of attenuated strain of P. parainfluenzae-3 in cultured swine kidney cells and analysis of its immunogenicity]. / Adaptirane na atenuiran shcham na P. parainfluenza-3 vurkhu kletuchni kulturi ot svinski bubrek i prouchvane na imunogennostta mu.

Strain Mihailovgrad of P. parainfluenza-3 was successfully adapted to cell cultures of pig kidney at its 15th passage. Its testing for innocuity was carried out through the inoculation of test calves with high amounts of the pathogen. No pathologic, temperature, and anaphylactic reactions were established. This confirmed the harmless character of the attenuated strain. Comparative testing for immunogenicity was performed with 8-month-old calves. Full coincidence with the antibody response was obtained with strain Mihailovgrad as a vaccinal strain. The use of the adapted strain for the production of a vaccine is to be preferred as there is no possibility of contamination with other bovine viruses.

[Interferon induction in calves after experimental infection with bovine herpesvirus 1]. / Induktsiia na interferon u teleta sled eksperimentalno zaraziavane s bovidniia kherpesvirus 1.

A total of 9 calves were used to test the interferon-inducing activity of strain Vulchedrum of the bovid Herpes virus 1. The virus of stomatitis vesiculosa adapted to cell cultures of calf kidney was used as an indicator of interferon. The antiviral action of interferon was demonstrated in the serum and the nose discharge of calves. The dynamics of interferon production in calves varied, depending on the venous, muscular, and tracheal route of application of the virus. Highest interferon titer in the serum was established at the venous application. In the nose discharge highest titers were found following tracheal application. Additional criteria demonstrating the presence of interferon in the positive serum and discharge samples were the unchanged activity at pH 2 and 4 degrees C for 24 hours; the unchanged activity following heating at 56 degrees C for 30 min; the unchanged activity following treatment with ether; the lack of activity following heating at 25 degrees C for 30 min; and the lack of activity at incubation with trypsin. The positive samples showed also antiviral unspecificity--inhibited was not only the virus of stomatitis vesiculosa, but also M. parainfluenza-3.