Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Characterization of Individuals Taking Part in Low Dose Computed Tomography (LDCT) Screening Program.

UNLABELLED: In the past years the participation rate in conventional voluntary x-ray lung screening has been around 22 % in Somogy County in Hungary. Due to the high morbidity and mortality rates of lung cancer, low participation rate of the high risk individuals on the screening is a primary question in Hungary. To obtain an effectively high level of participation in our ongoing low dose CT screening program, we had to emphasize the benefits of participation for the targeted individuals. As a first step, our aim was to gather information on the aspects affecting the individuals' will for participation. We used the most accessible source of information: individuals over the age of 50, who attended the conventional voluntary lung screening, were approached to fill a questionnaire on their habits relating to smoking, health issues and their prior participation of lung screening. 1080 adults anonymously completed the questionnaire. Analyzing the results, beside other findings, we found a unique variable factor, which altered negatively the compliance for the screening: older individuals, who started participating in the screening in obligation to the health regulations, took part in the voluntary screening programs at a significantly lower rate. Our findings led us to better understanding the complexity of decision making affecting the individual's participation and attitudes toward health issues. TRIAL REGISTRATION: IG/03833/2012.

[Preliminary experiences with low-dose computed tomography for lung cancer screening in Hungary]. / Alacsony dózisú CT-vel történo tüdorákszurés magyarországi bevezetésének elso tapasztalatai.

INTRODUCTION: Lung cancer has the highest mortality rate of all types of cancers both in developed countries and Hungary. AIM: To obtain experience and facilitate the application of low-dose computed tomography-based lung cancer screening as a targeted public health screening procedure. METHOD: Volunteers without thoracic complaints above the age of 40 years (n = 963) were screened for lung cancer using digital chest radiography and low-dose computed tomography. RESULTS: Two lung cancers were found among the participants screened with digital chest radiography (0.2%). After informed consent, 173 individuals with normal chest radiography findings (n = 943) took the opportunity to voluntarily participate in low-dose computed tomography screening for lung cancer. After 3 or 12 months, 65 individuals had follow up control examinations based on the size and characteristics of the detected lesions. Among them, one participant was found to have lung cancer using low-dose computed tomography. CONCLUSIONS: These results indicate that low-dose computed tomography-based lung cancer screening as a public health screening procedure can enhance the success of screening with 50% (from 0.2% to 0.3%). The cost-benefit ratio can be raised if chest radiography is performed prior to the low-dose computed tomography examination.

First result of differentiated communication--to smokers and non-smokers--in order to increase the voluntary participation rate in lung screening.

BACKGROUND: Lung cancer is the most common fatal malignancy and also the primary cause of cancer mortality. Participation in lung screening is an important step in diagnosing patient in early stage and it can promise better outcomes. The aim of this preliminary study was to determinate the differences in the participation rate of smokers and non-smokers in lung cancer screening and to determine the communication strategies to increase the participation rate. METHODS: In the given period of time (from May to August 2012) out of 1426 people who participated in the lung screening program 1,060 adult volunteers (331 males and 729 females, average age 54.0 ± 9.3 years), completed fully and anonymously author's questionnaire that contained 28 questions. 25.7% of the respondents were smokers (n=272), 64.6% have never smoked, while 9.7% were former smokers. RESULTS: Mostly former smokers considered lung screening as an effective method for early detection of pulmonary diseases (86.4%). The most important source (41.0%) of information was the general practitioner. The participation rate of non-smokers is higher in lung screening than the ratio of non-smokers in the population. The unclear data suggest that smokers need distinct, concise messages to know why they should regularly undergo lung screening and doctors have a major role in this. CONCLUSIONS: We found that smokers significantly more frequently took part in lung screening annually. It is positive that the participation rate of former smokers is higher than non-smokers, it is just a bit lower than the participation rate of smokers--both in annual and biannual participation. The participation rate of non-smokers is higher in lung screening than the rate of non-smokers in the population.

Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial.

PURPOSE: Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non-small-cell lung cancer (NSCLC), based on the importance of the signaling pathways involved in tumor growth, angiogenesis, and metastasis. This phase III trial investigated overall survival (OS) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC. PATIENTS AND METHODS: Patients previously treated with one to two chemotherapy regimens (including one platinum-based regimen) for recurrent NSCLC, and for whom erlotinib was indicated, were randomly assigned (1:1) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d, stratified by prior bevacizumab use, smoking history, and epidermal growth factor receptor expression. The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: In all, 960 patients were randomly assigned, and baseline characteristics were balanced. Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone (hazard ratio [HR], 0.922; 95% CI, 0.797 to 1.067; one-sided stratified log-rank P = .1388). Median PFS was 3.6 months versus 2.0 months (HR, 0.807; 95% CI, 0.695 to 0.937; one-sided stratified log-rank P = .0023), and ORR was 10.6% versus 6.9% (two-sided stratified log-rank P = .0471), respectively. Treatment-related toxicities of grade 3 or higher, including rash/dermatitis, diarrhea, and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm. CONCLUSION: In patients with refractory NSCLC, sunitinib plus erlotinib did not improve OS compared with erlotinib alone, but the combination was associated with a statistically significantly longer PFS and greater ORR. The incidence of grade 3 or higher toxicities was greater with combination therapy.

The EvA study: aims and strategy.

The EvA study is a European Union-funded project under the Seventh Framework Programme (FP7), which aims at defining new markers for chronic obstructive pulmonary disease (COPD) and its subtypes. The acronym is derived from emphysema versus airway disease, indicating that the project targets these two main phenotypes of the disease. The EvA study is based on the concept that emphysema and airway disease are governed by different pathophysiological processes, are driven by different genes and have differential gene expression in the lung. To define these genes, patients and non-COPD controls are recruited for clinical examination, lung function analysis and computed tomography (CT) of the lung. CT scans are used to define the phenotypes based on lung density and airway wall thickness. This is followed by bronchoscopy in order to obtain samples from the airways and the alveoli. These tissue samples, along with blood samples, are then subjected to genome-wide expression and association analysis and markers linked to the phenotypes are identified. The population of the EvA study is different from other COPD study populations, since patients with current oral glucocorticoids, antibiotics and exacerbations or current smokers are excluded, such that the signals detected in the molecular analysis are due to the distinct inflammatory process of emphysema and airway disease in COPD.

[Non-surgical biopsy in lung cancer: a paradigm shift]. / Paradigmaváltás a tüdorákok nem sebészi mintavételében.

Histological subgroups of non-small cell lung cancer have different prognosis and they require different therapeutic approaches. Accordingly, there is a clinical need in this field to supplement conventional pathological diagnostics with protein and genetic biomarkers that can help to recognize patients responsive to these therapies. Methods for subgroup classification and target identification were developed using surgical samples (surgical lung tumor specimens are available only in 20% of all lung cancer cases). The majority of lung cancer patients, however, have tumors that are irresectable at the time of diagnosis. Therefore, their diagnosis is usually based on bronchoscopically removed tissue or needle biopsy samples analyzed mainly by cytology. Because of the growing need for immunohistochemistry and molecular pathology in lung cancer diagnosis, emphasis should be given to diagnostic bronchoscopic procedures providing tissue samples. Combination of the different biopsy techniques (histology, cytology, bronchial brush, BAL, TBNA etc.), embedding the cells (preparing cell blocks) and, moreover, the availability of immunohistochemical and molecular pathological facilities are all required to set up the proper diagnosis and therapeutic strategy in human lung cancer. Strausz J, Tímár J. Non-surgical biopsy in lung cancer: a paradigm shift.

[Changes in the diagnostic and therapeutic strategies of non-small cell lung cancer]. / Változások a nem-kissejtes tüdorák diagnosztikus és terápiás stratégiájában.

Major advancements have been made in the clinical management of non-small cell lung cancer (NSCLC) in the past decade. This development involved the introduction of pemetrexed and several targeted therapies (bevacizumab, erlotinib, gefitinib) in the first and second line treatments of NSCLC. Novel maintenance therapeutic strategies for NSCLC (erlotinib) and for non-squamous-NSCLC (pemetrexed, bevacizumab+erlotinib) have also been developed resulting in a significant improvement in patient's survival. These changes have modified registrations of various drugs and require continuous update of guidelines and reimbursement schemes as well. These advantages are based on refinement of differential diagnosis of NSCLC and on the development of molecular predictive markers. Our aim is to summarize the changes in the diagnosis and therapy of NSCLC and to present the altered therapeutic scheme.

Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) remains a clinical management problem after treatment with highly emetogenic chemotherapy (HEC). We therefore designed and carried out a multicentre, randomised, double-blind, placebo-controlled trial to assess whether a three-drug antiemetic regimen of ondansetron, dexamethasone, and the neurokinin-1-receptor antagonist casopitant mesylate was able to prevent acute and delayed CINV events in patients naive to chemotherapy with a malignant solid tumour who were scheduled to receive cisplatin-based HEC regimens. METHODS: The study was done between Nov 6, 2006, and Oct 9, 2007, in 77 participating centres in 22 countries. All 810 patients enrolled in the trial received dexamethasone and ondansetron. Patients were randomly assigned to also receive placebo (n=269), single oral dose of casopitant mesylate (150 mg oral, n=271), or 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3, n=270). Randomisation was done using a central telephone system at the study level, because some centres were expected to recruit only a few patients during the study period. The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h after receiving HEC. Efficacy analysis was done on the modified intention-to-treat population (n=800), which included all patients who received placebo or study drug and HEC (n=265 control, n=266 single-dose oral casopitant mesylate, n=269 3-day intravenous and oral casopitant mesylate). Safety was reported in 802 patients who received either placebo or study medication. This study is registered with ClinicalTrials.gov, NCT00431236. FINDINGS: Significantly more patients in each casopitant group achieved complete response in cycle 1 of HEC treatment than did those in the control group (175 [66%] patients in the control group, 228 [86%] in the single-dose oral casopitant mesylate group [p<0.0001 vs control], and 214 [80%] in the 3-day intravenous plus oral casopitant mesylate group (p=0.0004 vs control]). This improvement was sustained over multiple cycles of HEC. Adverse events occurred in 205 (77%) patients in the single-dose oral casopitant mesylate group and 203 (75%) patients in the 3-day intravenous and oral casopitant mesylate group compared with 194 (73%) of patients in the control group. The most common serious adverse events were neutropenia (n=5 [3%] in the control group, n=3 [1%] in the single-dose oral casopitant mesylate group, and n=11 [4%] in the 3-day intravenous plus oral casopitant mesylate group), febrile neutropenia (n=1 [<1%] in the control group, n=4 [1%] in the single-dose oral casopitant mesylate group, and n=6 [2%] in the 3-day intravenous plus oral casopitant mesylate group), and dehydration (n=4 [2%] in the control group, n=2 [<1%] in the single-dose oral casopitant mesylate group, and n=1 [<1%] in the 3-day intravenous plus oral casopitant mesylate group). INTERPRETATION: A three-drug regimen including a single oral dose or 3-day intravenous plus oral regimen of casopitant mesylate plus dexamethasone and ondansetron significantly reduced CINV events in patients receiving HEC compared with a two-drug regimen of dexamethasone and ondansetron. FUNDING: GlaxoSmithKline.

High VEGFR-3-positive circulating lymphatic/vascular endothelial progenitor cell level is associated with poor prognosis in human small cell lung cancer.

PURPOSE: The newly identified bone marrow-derived cell population, called lymphatic/vascular endothelial progenitor cells (LVEPC), has been shown to contribute to lymph capillary growth in experimental tumor systems. The clinical significance of these cells has not yet been investigated in a human malignancy. Our aim was to study whether peripheral blood circulating LVEPCs participate in the progression of human small cell lung cancer (SCLC). EXPERIMENTAL DESIGN: A total of 88 patients with limited-stage SCLC and 32 tumor-free control subjects were included. Peripheral blood circulating LVEPC labeled with CD34 and vascular endothelial growth factor receptor-3 (VEGFR3) antibodies and the serum levels of the key lymphangiogenic molecule VEGF-C were measured by flow cytometry and ELISA, respectively. RESULTS: CD34-positive/VEGFR3-positive LVEPC levels were significantly increased in patients (versus controls; P<0.01), and there was also a significant relationship between LVEPC counts and lymph node metastasis (P<0.01). High pretreatment circulating LVEPC numbers correlated with poor overall survival (P<0.01). Although we observed significantly elevated VEGF-C concentrations in patients (versus controls; P<0.01), there was no significant correlation between VEGF-C and LVEPC levels. Moreover, no significant differences in peripheral blood VEGF-C levels were seen between patients subgrouped by clinicopathologic variables including tumor and lymph node stages and survival. CONCLUSIONS: Peripheral blood levels of bone marrow-derived LVEPCs are significantly increased in patients with SCLC and correlate with lymphatic involvement and prognosis. This is the first study that shows evidence of increased numbers of circulating LVEPC in patients with a malignant tumor.

Comparison of virtual and fiberoptic bronchoscopy in the management of airway stenosis.

Noninvasive imaging methods can be valuable tools for diagnosing thoracic diseases, especially malignancies. The aim of this study was to compare the effectiveness of conventional and virtual bronchoscopy in the follow-up of patients with large airway stenosis. Twenty-three consecutive patients with stenoses of the trachea and/or the main bronchi were enrolled in this prospective observer study. The causes of stenosis included malignant or benign tumours, goiter, and postintubation stenoses. Patients were evaluated before and after treatment (which included mechanical dilation, laser photocoagulation, stent implantation, radiotherapy, chemotherapy, and surgical resection). The mean time between baseline and follow-up endoscopy was 140 days. No significant differences were observed between the estimated and measured data from bronchofibroscopy and virtual bronchoscopy. Exact measurement of stenoses was performed with virtual bronchoscopy.

Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.

PURPOSE: Erlotinib is a potent inhibitor of the epidermal growth factor receptor tyrosine kinase, with single-agent antitumor activity. Preclinically, erlotinib enhanced the cytotoxicity of chemotherapy. This phase III, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of erlotinib in combination with cisplatin and gemcitabine as first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received erlotinib (150 mg/d) or placebo, combined with up to six 21-day cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1). The primary end point was overall survival (OS). Secondary end points included time to disease progression (TTP), response rate (RR), duration of response, and quality of life (QoL). RESULTS: A total of 1,172 patients were enrolled. Baseline demographic and disease characteristics were well balanced. There were no differences in OS (hazard ratio, 1.06; median, 43 v 44.1 weeks for erlotinib and placebo groups, respectively), TTP, RR, or QoL between treatment arms. In a small group of patients who had never smoked, OS and progression-free survival were increased in the erlotinib group; no other subgroups were found more likely to benefit. Erlotinib with chemotherapy was generally well tolerated; incidence of adverse events was similar between arms, except for an increase in rash and diarrhea with erlotinib (generally mild). CONCLUSION: Erlotinib with concurrent cisplatin and gemcitabine showed no survival benefit compared with chemotherapy alone in patients with chemotherapy-naïve advanced NSCLC.

[Imaging technics in bronchology]. / A bronchológia és a képalkotó eljárások.

Bronchoscopic imaging and diagnostics are tightly connected with radiological and pathological techniques. While computer tomography (virtual bronchoscopy) makes possible to mimic a realistic endobronchial situation, autofluorescent bronchoscopy holds significant potential to discover precancerous lesions not identifiable by standard bronchoscopy. Endoscopic ultrasound and fluoroscopy can be applied in order to obtain images and tissue samples from the extrabronchial areas. Electromagnetic navigation during flexible bronchoscopy, a novel technology that facilitates approaching peripheral lung lesions, involves creating an electromagnetic field around the thorax and localizing an endoscopic tool using a microsensor overlaid upon previously acquired CT images. In conclusion, parallel use of invasive and non-invasive imaging has the potential for considerable improvements in the diagnostic possibilities of routine bronchoscopic procedures.

[Bronchoscopic lung volume reduction surgery in emphysema]. / A tüdotérfogat csökkentésének bronchoszkóos lehetoségei emphysemában.

Despite of the clinical studies proving the benefits of lung volume reduction surgery and determining the indications and candidates, the surgical intervention has not penetrated into the standard treatment of emphysema. Perioperative mortality is relatively high at patients with end-stage emphysema, therefore a less invasive procedure might be most useful in medical practice. Bronchoscopic lung volume reduction is a technically simple procedure including insertion of a bronchial blocker (plug) or an endobronchial valve, either totally blocking the air flow, or blocking it only during the inspiration. However, there are only few clinical data available concerning of surgical and bronchial interventions. A multinational clinical study is in progress in three Hungarian pulmonological centers implanting endobronchial plugs into the subsegmental bronchi of patients with severe emphysema.

Pathology of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease is one of the leading causes of death and morbidity worldwide. Despite intensive investigation, its pathology and pathophysiology are not well understood. The hallmarks of the disease are irreversible airflow limitation and chronic inflammation. Small airway obstruction due to progressive inflammation and fibrosis, and the loss of elastic recoil mediated by elastolysis and apoptosis equally contribute to pathologic changes. However, it is debated to what extent the obstruction of large airways leads to altered lung function. Three morphologic entities are described in the literature under one disease; chronic bronchitis, obstructive bronchiolitis and emphysema may appear in the same patient at the same time. The authors review pathologic changes observed in chronic obstructive pulmonary disease, including acute exacerbations and secondary pulmonary hypertension as severe but common complications of the disease. Furthermore, we detail recent scientific evidences for major cellular and molecular inflammatory pathway activation. These mechanisms result in accelerated apoptosis, remodeling and increased proinflammatory cytokine release. Targeting intracellular pathological changes may lead to the discovery of a new generation of drugs that could reduce chronic obstruction before airway irreversibility is established.

[Management of malignant and benign airway stenosis by stent implantation]. / Malignus és benignus légúti szukületek megoldása légúti protézis (stent) beültetésével.

INTRODUCTION: In the last few decades the different bronchoscopic procedures have gained an important role in the treatment of airway stenosis, and the number of implanted airway stents has also greatly increased. PATIENTS: Between 1998 and 2004 the authors implanted altogether 108 airway prosthesis in 90 patients at the Institute of Pulmonology of Pest County. 58% of the patients were males, 42% females, the average age was 57.5 years, the average follow-up time was 7 months. RESULTS: On the basis of different etiology the patients were separated into two main groups. In 57% the airway stenosis was caused by malignant illnesses, in these cases stents can be used only with palliative purpose. However, in case of benign lesions they can offer a long-term solution and require an adequate follow-up of the patients. The authors' main aim was to get an overall picture of the interventions they had done by processing the data, with the help of the measurable characteristics that make possible to follow the airways' permeability and its changes. Analysing the results of the respiratory function and blood gas examinations they didn't find a significant difference inspite of the subjective improvement.

Efficacy of gemcitabine--cisplatin treatment in stage IIIA ("bulky"N2), IIIB and IV non-small cell lung cancer.

UNLABELLED: The objective of the study was to assess the efficacy of a gemcitabine and cisplatin combination for patients with stage IIIA"bulky"N2, IIIB or IV non-small cell lung cancer(NSCLC). PATIENTS AND METHODS: Patients with histological and/or cytological diagnosis of NSCLC were administered gemcitabine 1250 mg/m2 on days 1 and 8, and cisplatin 70 mg/m2 on day 1, every 3 weeks. RESULTS: One hundred and twenty patients with NSCLC, with median age of 53 years, and a WHO performance status of 0 (26%) or 1 (74%), were evaluated. The overall response rate was 40.0% with 37.5% partial response (PR) and 2.5% complete response (CR). Also, 38% of the patients had either minimal response (MR) or stable disease (SD). The median survival was 54.9 weeks. The time to progression was 28.1 weeks. There was no treatment-related death in this series. CTC grade 3/4 neutropenia occurred in 4.4% of the patients, while febrile neutropenia developed in 0,9% of the patients. CTC grade 4 thrombocytopenia occurred in 2.2%, and CTC grade 3/4 anemia developed in 3.3%. CONCLUSION: Our results support that gemcitabine and cisplatin administered as a 3-week cycle is an effective and safe regimen for the treatment of locally advanced or metastatic NSCLC.

[The role of bronchoscopy in examination and treatment of esophageal tumours]. / A bronchoszkópia szerepe a nyelocsodaganatok kivizsgálásában és kezelésében.

The role of bronchoscopy in examination and treatment of esophageal tumours. The esophageal tumours are diagnosed in many cases in inoperable stage, and if a surgical resolution is possible, it's a heroic, great operation with high mortality rates and poor results. The involvement of great airways should be explored preoperatively by imaging methods, but bronchoscopy is also mandatory. The authors report their one year's experience of 121 bronchoscopic examinations in esophageal cancer patients. The finding was negative in 40.5% of all examinations, and 29.7% was concerned the cancer propagation to bronchial system. 29.8% of all examinations resulted a suspicion of propagation. The opinion of bronchologist can be decisive postoperatively if a fistula is suspected, or after an esophageal stent implantation airway symptoms occur. Bronchoscopy is a standard method for removal of airway excretion. The author's overview is comparing their fifteen years experience with international literature.

[Our experience using autofluorescence bronchoscopy]. / Autofluoreszcens bronchoszkópiával szerzett tapasztalataink.

INTRODUCTION: Lung cancer is responsible for most cancer deaths in the world. The main reason for the poor prognosis is late diagnosis. Many patients could be successfully treated in early stage. AIMS: The authors performed 369 bronchological examination on 336 patients using autofluorescence bronchoscopy between 1998 and 2003 to detect preinvasive lesions and early forms of lung cancer. METHODS: Storz D-Light autofluorescence system has been used to perform the examinations. RESULTS: In one third of these patients invasive lung cancer developed during follow-up. Combining traditional white light and autofluorescence technique 50% more intraepithelial lesions have been observed and sensitivity has been increased by 69% compared to the lone use of white light bronchoscopy. CONCLUSIONS: Supported by most international studies these results emphasise that autofluorescence bronchoscopy has a major role in the early diagnosis of preinvasive bronchial lesions and may help in the prevention and early therapy of lung cancer.