Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial.

BACKGROUND: Afatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy. PATIENTS AND METHODS: Patients with relapsed/refractory disease following ≥1 line of chemotherapy, and whose tumors had progressed following initial disease control (≥12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m(2)/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes. RESULTS: Two hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n = 134) or single-agent chemotherapy (n = 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P = 0.003) and ORR (32.1% versus 13.2%, P = 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent. CONCLUSION: Afatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy. TRIAL REGISTRATION NUMBER: NCT01085136 (clinicaltrials.gov).

Therapeutic bronchoscopy with immediate effect: laser, electrocautery, argon plasma coagulation and stents.

Minimally invasive diagnostic and therapeutic approaches in medicine have been applied for a more selective and tailored approach to reduce patients' morbidity and mortality. The efficacy of interventional pulmonology for palliation of patients with central airways obstruction has been established and its curative potential for intralesional treatment of early cancer has raised great interest in current screening programmes. This is due to the fact that surgical resection and systemic nodal dissection as the gold standard is relatively morbid and risky, especially when dealing with individuals with limited functional reserves due to smoking-related comorbidities, such as chronic obstructive pulmonary disease. Furthermore, such comorbidities have been proven to harbour early stage lesions of several millimetres in size without involvement of nodal disease that may be amenable to local bronchoscopic treatment. Therefore, the success of minimally invasive strategies for palliation and treatment with curative intent strongly depends on the diligent identification of the various factors in lung cancer management, including full comprehension of the limits and potential of each particular technique. Maximal preservation of quality of life is a prerequisite in successfully dealing with individuals at risk of harbouring asymptomatic early lung cancer, to prevent aggressive surgical diagnostic and therapeutic strategies since overdiagnosis remains an issue that is heavily debated. In the palliative setting of alleviating central airway obstruction, laser resection, electrocautery, argon plasma coagulation and stenting are techniques that can provide immediate relief, in contrast to cryotherapy, brachytherapy and photodynamic therapy with delayed effects. With curative intent, intraluminal techniques that easily coagulate early stage cancer lesions will increase the implementation of interventional pulmonology for benign and relatively benign diseases, as well as early cancer lesions and its precursors at their earliest stage of disease.

Autofluorescence bronchoscopy with white light bronchoscopy compared with white light bronchoscopy alone for the detection of precancerous lesions: a European randomised controlled multicentre trial.

BACKGROUND: The potential of autofluorescence bronchoscopy (AFB) to detect precancerous lesions in the central airways and its role in lung cancer screening is uncertain. A study was undertaken to evaluate the prevalence of moderate/severe dysplasia (dysplasia II-III) and carcinoma in situ (CIS) using a newly developed AFB system in comparison with conventional white light bronchoscopy (WLB) alone. METHODS: In a prospective randomised multicentre trial, smokers > or = 40 years of age (> or = 20 pack-years) were stratified into four different risk groups and investigated with either WLB+AFB (arm A) or WLB alone (arm B). RESULTS: 1173 patients (916 men) of mean age 58.7 years were included. Overall (arms A and B), preinvasive lesions (dysplasia II-III and CIS) were detected in 3.9% of the patients. The prevalence of patients with preinvasive lesions in the WLB arm was 2.7% compared with 5.1% in the WLB+AFB arm (p = 0.037). For patients with dysplasia II-III, WLB+AFB increased the detection rate by a factor of 2.1 (p = 0.03), while for CIS the factor was only 1.24 (p = 0.75). The biopsy based sensitivity of WLB alone and WLB+AFB for detecting dysplasia II-III and CIS was 57.9% compared with 82.3% (1.42-fold increase). The corresponding specificity was 62.1% compared with 58.4% (0.94-fold decrease). CONCLUSIONS: This first randomised study of AFB showed that the combination of WLB+AFB was significantly superior to WLB alone in detecting preneoplastic lesions. Our findings do not support the general use of AFB as a screening tool for lung cancer, but suggest that it may be of use in certain groups. The precise indications await further study.

[Rare association of rare diseases: Langerhans-cell histiocytosis and lymphangioleiomyomatosis in the lung]. / Ritka betegségek ritka társulása: Langerhans-sejtes histiocytosis és lymphangioleiomyomatosis együttes elöfordulása a tüdöben.

This is a case history of a 24-year-old female patient in whom two rare pulmonary diseases occurred: Langerhans cell histiocytosis and four years later lymphangioleiomyomatosis were diagnosed. Both diseases were verified by the examination of the lung tissue removed by the surgery for pneumothorax. The patient's symptoms were characterised by coughing, dyspnoe, repeated pneumothorax. The authors summarised the characteristics and treatment of these diseases. This case history is worth of reporting for its unique rareness.

[Virtual bronchoscopy: a new non-invasive diagnostic method in pulmonology]. / Virtuális bronchoszkópia: új noninvazív vizsgálati lehetóség a pulmonológiában.

Virtual reality (3 dimensional modelling of the human body) has developed as a convergence of advancing digital imaging modalities and computer graphics technologies. With this method endoscopic simulations of cavitary organs are feasible. Virtual bronchoscopy was initially described in 1993. The authors selected patient with previously detected stenosis of the trachea or the main bronchi with bronchofiberscope. They performed targeted, thin-slice helical computer tomography of the lesions. These data were transferred to a workstation and the virtual endoscopic models of the airways were generated using dedicated software. Based on cases the authors describe their preliminary experience with the method. The findings were compared with those of bronchofiberscopy. Analyzing these results and the literature the potential clinical applications of virtual bronchoscopy are discussed.

Bronchial capillary hemangioma in adults.

Two cases with capillary hemangioma of the trachea and the left upper lobe bronchus are presented. The adult patients were referred to the hospital because of hemoptysis and cough. The chest radiographs were normal in both cases. The bronchoscopic examination revealed circumscribed lesions with a capillarized surface protruding into the lumen of the trachea and the left upper lobe bronchus, respectively. The lesions were excised in toto with flexible bronchoscopic forceps. The specimens contained typical capillary hemangiomas without any signs of malignancy. Capillary hemangioma in the bronchial tree is an extremely rare benign lesion in adults. Nevertheless, it should be considered as a possible cause of hemoptysis and cough.

Pathomorphology of the airways in asthma.

Asthma is a chronic inflammatory disorder of the airways with a characteristic infiltrate of eosinophils, lymphocytes, mast cells, and monocytes in the bronchial epithelium and peribronchial tissue. Bronchial-, bronchoalveolar lavage and bronchoscopic biopsies have proved to be safe and useful techniques for studying the inflammatory processes in the airways, they have contributed to our basic knowledge concerning the pathomechanism of asthma. The data derived from the clinical and experimental studies have made possible to perform an international consensus on the diagnosis and treatment of asthma.

P53 expression in stage I squamous cell lung cancer.

P53 expression was studied using immunohistochemistry in patients (n=94) with pathologic stage I squamous cell lung cancer treated surgically between 1991-1992. The overall p53 positivity ratio was 48/94. 83 of the cases proved to be suitable for follow-up analysis carried out in November, 1995. 46/83 were p53 positive, and 25/46 patients were alive at the time of analysis. The patients who died (21/46) had a mean survival time of 17.5 months. In p53 negative cases (37/83), however, 29/37 patients were still alive at the time of follow-up, and 8/37 had died with a mean survival time of 23.1 months. A significant correlation could be found between p53 immunopositivity and reduced survival time (p=0.0125). Interestingly, out of 83 cases analyzed histologic evidence of tuberculous scar tissue was present in 9 tumors with a p53 positivity ratio of only 1/9. When flow cytometry was used to examine tumor samples from all subgroups mentioned above (n=32), no correlation was found between the p53 immunopositivity or the prognosis and the DNA content of tumor tissues. Our results suggest that in the early stage of squamous cell lung cancer the p53 positivity may be an indicator of a more aggressive tumor behavior and a shortened survival time.

[Expression of macrophage markers in childhood and adult Langerhans histiocytosis (LCH)]. / Lymphoid és macrophag markerek expressziója gyermekkori és felnöttkori Langerhans-sejtes histiocytosisban (LCH).

In the diagnosis of the Langerhans cell histiocytosis several monocyte and macrophag markers have been tested in the recent years. We compared the expression of macrophage and lymphoid markers in childhood and adult type Langerhans cell histiocytosis. Ten childhood and 11 adult cases were tested using paraffin sections of biopsy samples. We have examined 6 markers: the S-100, Lysozyme, CD68 macrophag and the CD1a, CD4, HLA-DR lymphoid markers. We have found that the CD68 marker was more frequently positive than the other examined macrophag markers, and proved to be almost as reliable as the recently discovered CD1a. The most interesting result was that the expression of the markers was different in the childhood and adult type of the disease. On the basis of our experience the possibility arise that the phenotype of the childhood and adult type of the Langerhans cell histiocytosis is different.

[Bronchoscopic evaluation of pulmonary complications following kidney transplantation]. / Vesetranszplantáción átesett betegek késöi tüdöszövödményeinek bronchoscopos vizsgálata.

The authors evaluated the efficiency of bronchoscopy in kidney transplanted patients with late pulmonary complications (mean 370 days after transplantation). The bronchoscopy was made meanly 9.5 days after recognizing pulmonary diseases, in that time 7 patients were mechanically ventilated. In 15 cases therapy guided by the cytological, histological and microbiological results has been hoped to improve outcome. This study suggest that bronchoscopy might be important in the diagnosis of the late pulmonary complications of kidney transplanted patients.

[Fiberoptic bronchoscopy in intensive care units]. / Bronchofiberoscopia az intenzív osztályokon.

The authors have retrospectively analysed 161 bedside fiberoptic bronchoscopies performed at intensive care units and demonstrate its' main indications, results and influences on the patients' condition. In 35.4% of cases immediate improvement was observed, in 31.6% the examination contributed to choose the proper treatment. Due to the safe method only one serious complication occurred because of bronchoscopy. The results justify-according to the literature-that fiberoptic bronchoscopy is an indispensable method to check airways and for diagnostical and therapeutic interventions of critically ill patients.

[Postintubation stenosis of the trachea treated by silicone stent implantation]. / Postintubatiós tracheastenosis kezelése stentbeültetéssel.

22 patients with postintubation trachea stenosis were treated by silicone stent insertion. The stenosis were discovered 107 days after an average 14 days of mechanical ventilation. Mechanical and/or laser photocoagulation were followed by silicone stent implantation. In 13/22 case this combined therapy resulted a significant improvement in the ventilation. After unsuccessful intervention in 2 cases surgical resection, in 5 cases Montgomery T-tube implantation were performed. A tracheotomy was performed in one case, an other patient died due to the unresolved main airway stenosis. These results suggest that in the treatment of postintubation stenosis the silicone stent implantation is indicated as a first line therapy. 12 months after the insertion could attempt to remove the prosthesis. In the case of restenosis surgical resection or Montgomery T-tube implantation are the choice of therapy.

[Surgical excision of tracheal and bronchial tumors after endobronchial Nd-YAG laser photocoagulation]. / Trachea és hörgödaganatok sebészi eltávolítása endobronchialis Nd-YAG laser photocoagulatio után.

Sixteen patients with tracheal and bronchial (13 malignant and 3 benign) tumours were operated 4-6 weeks after Nd-YAG laser photocoagulation. The indication of the laser photocoagulation was predicted to maintain the airway patency, to aspirate the accumulated secretion due to tumour obstruction and to examine the bronchial system beyond the tumour. The endobronchial laser photocoagulation is applied in most of the cases as a palliative treatment, since its application may contribute to decrease the perioperative complications of bronchial tumours.

Beryllium-induced disturbances of the murine immune system reflect some phenomena observed in sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder of unknown origin. In respect to clinical and immunological characteristics, it is indistinguishable from berylliosis. As an approach to develop a murine model reflecting some aspects of sarcoidosis, we attempted to induce berylliosis in mice by treating inbred F1 mice (C57B16 x DBA/2) with 3 mg beryllium sulfate (BeSO4) per kg body weight intraperitoneally. Either pure BeSO4 or BeSO4 in combination with incomplete Freund's adjuvant was administered. Alternatively, pure BeSO4 was injected 2 days after a single application of cyclophosphamide (150 mg/kg). The spleen index, the spontaneous and phorbolmyristate acetate (PMA)-induced radical oxygen intermediates (ROI) released by peritoneal macrophages, and the proliferative activity of spleen mononuclear cells in response to BeSO4 and concanavalin A (ConA) were evaluated and compared to the corresponding changes observed in sarcoidosis. In all three modes of BeSO4 treatment, the spontaneous ROI release by peritoneal macrophages was significantly elevated. These elevations were very similar to those observed with alveolar macrophages in active sarcoid alveolitis. After BeSO4 treatment, a small proliferative activity of spleen mononuclear cells in response to BeSO4 could be observed. Further, BeSO4-treated spleen mononuclear cells exhibited a markedly reduced response to ConA stimulation (approximately 20% of control) which parallels the reduced proliferative capacity of sarcoid peripheral blood mononuclear cells (approximately 45% of control). This reduction could be abolished by pretreating the mice with cyclophosphamide. BeSO4 treatment in combination with incomplete Freund's adjuvant resulted in a significant increase of spleen mononuclear cell proliferation (1.9-fold) after in vitro stimulation with BeSO4, and prevented the low responsiveness to ConA.(ABSTRACT TRUNCATED AT 250 WORDS)

[Experience with transbronchial lung biopsy]. / Transbronchialis tüdöbiopsiával szerzett tapasztalataink.

The histological results of transbronchial lung biopsies have been analysed in 109 patients with diffuse or localised lung diseases. This diagnostic procedure is relatively safe, well tolerable and can be carried out in outpatients. In diffuse lung diseases its use can replace the open lung biopsy. The efficacy of this method depends on the availability of biplanar fluoroscopy, the quality of the excisors, the quantity and size of the biopsy material and the technique of the histological handling.

[The role of Nd-YAG in the management of tracheobronchial stenosis]. / Neodymium-YAG laser szerepe a tracheobronchialis szükületek kezelésében.

122 patients with the main airway stenosis were treated with Nd-YAG laser phototherapy. The endobronchial laser treatment was performed either with flexible bronchoscope (64%), or with rigid instrument (36%). This method can result a final recovery of the patients with benign tumors, or inflammatory processes, at the patients with malignant tumors can be achieved an effective palliation. Taking account the generally accepted indications and contraindications of the endobronchial laser phototherapy the number of the complications can be reduced.

[Combination of high dose after-loading radiation therapy and percutaneous irradiation in the management of tumors of the major airways]. / Endobronchialis magas dózisú afterloading sugárkezelés és percutan besugárzás kombinációja nagylégúti daganatok kezelésében.

17 patients with malignant main airway tumours were treated with combined high dose rate afterloading and external beam irradiation. The improvement of the general conditions of the patients and that of the leading symptoms (dyspnoe, cough) were observed in all cases. First experiences corresponding with those of others suggest that this method should be integrated routinely in the management of main airway malignancies with endoluminal exophytic involvement.

[The importance of CT-guided needle biopsy in the diagnosis of thoracic diseases]. / A CT-vezérelt tübiopsziák jelentösége a mellkasi elváltozások diagnosztikájában.

In the report on 35 CT-guided fine needle transthoracic biopsies the authors show the relevance of invasive radiological methods in tumor diagnostics. The results are compared with those published in the literature. CT-guided transthoracic biopsy is of crucial importance in final diagnosis of certain thoracic diseases.