Tolerability of inhaled N-chlorotaurine in humans: a double-blind randomized phase I clinical study.

BACKGROUND: N-chlorotaurine (NCT), a long-lived oxidant produced by human leukocytes, can be synthesized chemically and used topically as a well-tolerated antiseptic to different body regions including sensitive ones. The aim of this study was to test the tolerability of inhaled 1% NCT in aqueous solution upon repeated application. METHODS: The study was performed double-blind and randomized with a parallel test group (1% NCT) and control group (0.9% NaCl as placebo). There were two Austrian centres involved, the hospitals, Natters and Vöcklabruck. Healthy, full age volunteers were included, 12 in each centre. A total of 12 patients were treated with NCT, and 12 with placebo, exactly half of each group from each centre. The single dose was 1.2 ml inhaled over a period of 10 min using an AKITA JET nebulizer. One inhalation was done every day for five consecutive days. The primary criterion of evaluation was the forced expiratory volume in 1 second (FEV1). Secondary criteria were subjective sensations, further lung function parameters such as airway resistance, physical examination, and blood analyses (gases, electrolytes, organ function values, pharmacokinetic parameters taurine and methionine, immune parameters). RESULTS: All included 15 females and 9 males completed the treatment and the control examinations according to the study protocol. FEV1 (100.83% ± 8.04% for NCT and 92.92% ± 11.35% for controls) remained unchanged and constant during the treatment and in control examinations 1 week and 3 months after the treatment (98.75% ± 7.37% for NCT and 91.17% ± 9.46% for controls, p > 0.082 between time points within each group). The same was true for all other objective parameters. Subjective mild sensations with a higher frequency in the test group were chlorine taste ( p < 0.01) and occasional tickle in the throat ( p = 0.057). Taurine and methionine plasma concentrations did not change within 60 min after inhalation or later on. CONCLUSIONS: Inhaled NCT is well tolerated as in other applications of different body regions. Side effects are mild, topical and transitory. The study was registered prospectively in the European Clinical Trials Database of the European Medicines Agency. The EudraCT number is 2012-003700-12.

Multicenter Phase II Study Evaluating Two Cycles of Docetaxel, Cisplatin and Cetuximab as Induction Regimen Prior to Surgery in Chemotherapy-Naive Patients with NSCLC Stage IB-IIIA (INN06-Study).

BACKGROUND: Different strategies for neoadjuvant chemotherapy in patients with early stage NSCLC have already been evaluated. The aim of this study was to evaluate the tolerability and efficacy of a chemoimmunotherapy when limited to two cycles. METHODS: Between 01/2007 and 03/2010 41 patients with primarily resectable NSCLC stage IB to IIIA were included. Treatment consisted of two cycles cisplatin (40 mg/m2 d1+2) and docetaxel (75 mg/m2 d1) q3 weeks, accompanied by the administration of cetuximab (400 mg/m2 d1, then 250 mg weekly). The primary endpoint was radiological response according to RECIST. RESULTS: 40 patients were evaluable for toxicity, 39 for response. The main grade 3/4 toxicities were: neutropenia 25%, leucopenia 11%, febrile neutropenia 6%, nausea 8% and rash 8%. 20 patients achieved a partial response, 17 a stable disease, 2 were not evaluable. 37 patients (95%) underwent surgery and in three of them a complete pathological response was achieved. At a median follow-up of 44.2 months, 41% of the patients had died, median progression-free survival was 22.5 months. CONCLUSIONS: Two cycles of cisplatin/ docetaxel/ cetuximab showed promising efficacy in the neoadjuvant treatment of early-stage NSCLC and rapid operation was possible in 95% of patients. Toxicities were manageable and as expected. TRIAL REGISTRATION: EU Clinical Trials Register; Eudract-Nr: 2006-004639-31.

Longitudinal analysis of 2293 NSCLC patients: a comprehensive study from the TYROL registry.

INTRODUCTION: The aim of this study was to describe a large consecutive cohort of non-small cell lung cancer (NSCLC) patients treated in daily routine within the last 25 years. An extensive list of general baseline characteristics (comorbidities, laboratory values, symptoms, performance state), NSCLC related factors (stage, histology), treatment related parameters (approach, applied therapies) and outcome (PFS, RFS, OS, perspective of decades) were analyzed in detail. PATIENTS AND METHODS: Medical files of 2293 consecutive NSCLC patients diagnosed between 1989 and 2009 at the Medical University of Innsbruck and affiliated hospitals were retrospectively analyzed. Patients were documented within our institution's comprehensive lung cancer project "Twenty-Year Retrospective of Lung Cancer (TYROL study)". RESULTS: Mean age at diagnosis was 64.1 years and 1611 patients (70.3%) were male. Most patients were diagnosed in stage IV (37.9%). The most frequent comorbidities present at diagnosis were cardiovascular disease (62.1%) and COPD (62.0%). The most common symptoms at diagnosis were coughing (54.7%) and dyspnea (45.3%). Of all 2293 patients 1981 (86.4%) received adequate antineoplastic treatment. In total 874 patients were radically operated, 119 received radiotherapy/radio-chemotherapy and the majority of patients (n=1278) were treated in palliative intent. A 2nd, 3rd, 4th and 5th-line palliative therapy was administered to 612, 278, 102, and 36 patients. Median OS, RFS and PFS were 16.4 months, 86.4 months and 5.1 months, respectively. A multitude of factors was associated with all three outcome variables. Of note, outcome has improved stepwise in the recent decade based on increased response rates leading to prolonged OS. CONCLUSION: This work incorporates most clinical aspects relevant in the treatment of NSCLC and beyond. Therefore, this comprehensive analysis provides a definite benchmark for prognostication and epidemiology of NSCLC in a Western European society.

Comparative analyses of volatile organic compounds (VOCs) from patients, tumors and transformed cell lines for the validation of lung cancer-derived breath markers.

Breath analysis for the purpose of non-invasive diagnosis of lung cancer has yielded numerous candidate compounds with still questionable clinical relevance. To arrive at suitable volatile organic compounds our approach combined the analysis of different sources: isolated tumor samples compared to healthy lung tissues, and exhaled breath from lung cancer patients and healthy controls. Candidate compounds were further compared to substances previously identified in the comparison of transformed and normal lung epithelial cell lines. For human studies, a breath sampling device was developed enabling automated and CO2-controlled collection of the end-tidal air. All samples were first preconcentrated on multibed sorption tubes and analyzed with gas chromatography mass spectrometry (GC-MS). Significantly (p < 0.05) higher concentrations in all three types of cancer samples studied were observed for ethanol and n-octane. Additional metabolites (inter alia 2-methylpentane, n-hexane) significantly released by lung cancer cells were observed at higher levels in cancer lung tissues and breath samples (compared to respective healthy controls) with statistical significance (p < 0.05) only in breath samples. The results obtained confirmed the cancer-related origin of volatile metabolites, e.g. ethanol and octane that were both detected at significantly (p < 0.05) elevated concentrations in all three kinds of cancer samples studied. This work is an important step towards identification of volatile breath markers of lung cancer through the demonstration of cancer-related origin of certain volatile metabolites.

Neoadjuvant chemo-immunotherapy modifies CD4(+)CD25(+) regulatory T cells (Treg) in non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Regulatory T cells (Treg) are critical for cancer immune evasion; whereas natural killer (NK) cells are central for effective anti-tumor immunity including antibody-induced cellular cytotoxicity (ADCC). The predictive role of Treg levels for clinical response to chemo-immunotherapy in non-small cell lung cancer (NSCLC) as well as therapy-induced Treg changes remain to be defined. PATIENTS AND METHODS: The impact of Treg on NK-mediated cetuximab-dependent cellular cytoxicity was tested in vitro. Frequency and functional activity of Treg was analyzed in 31 NSCLC stage IB-IIIA patients treated by neoadjuvant Cetuximab/Docetaxel/Cisplatin prior to surgery. Data were correlated with clinical outcome variables and Treg tumor infiltration. RESULTS: Treg potently inhibit NK-mediated and cetuximab-induced ADCC in vitro. In addition, a significant correlation between Treg reduction and clinical response was seen. However, the grade of tumor infiltrating Treg in resected tumors did not correlate with peripheral Treg levels. Moreover, Treg levels at diagnosis did not predict clinical response to chemo-immunotherapy. CONCLUSIONS: The drop of Treg levels during neoadjuvant chemo-immunotherapy in NSCLC patients significantly correlates with clinical response. However, Treg at diagnosis are not linked to inferior clinical response to chemo-immunotherapy in NSCLC in vivo even though Treg efficiently inhibit ADCC in vitro.

High transforming growth factor ß expression represents an important prognostic parameter for surgically resected non-small cell lung cancer.

The tumor microenvironment comprises various cellular components and associated subcellular molecules with antitumor and protumor effects. Because respective targeted treatment strategies are arising, it is important to characterize the exact role of these parameters. This study provides a comprehensive analysis of key immunologic factors in the tumor microenvironment of 383 surgically resected non-small cell lung cancer specimens. CD4, CD8, forkhead box protein P3, transforming growth factor ß, Casitas B-cell lymphoma-b, programed death 1, T-cell-restricted intracellular antigen 1, granzyme B, mast cell tryptase, and stromal cell-derived factor 1 were analyzed by immunohistochemistry using a standardized tissue microarray platform. Extensive clinical data enabled detailed clinicopathologic correlations over a postoperative follow-up period of 15 years. Among the immunologic variables focused on, transforming growth factor ß expression was the only prognostically relevant factor. Transforming growth factor ß was more frequently expressed in adenocarcinoma as compared with other histologic subtypes. Expression of transforming growth factor ß in tumor-infiltrating lymphocytes or in tumor cells was associated with significantly reduced postoperative survival time especially in patients with squamous cell carcinoma (P = .035 and P = .046, respectively). In these patients, the amount of transforming growth factor ß-positive tumor-infiltrating lymphocytes represented the only independent immunologic parameter with prognostic significance by multivariat analysis (P = .021; hazard ratio, 2.602; 95% confidence interval, 1.159-5.844). These results should help to identify patients who are most suitable for therapeutic strategies aiming to block the transforming growth factor ß signaling pathway.

Basic clinical parameters predict gefitinib efficacy in non-small cell lung cancer.

BACKGROUND: In epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), the tyrosine-kinase inhibitor gefitinib is in broad use. We retrospectively analysed data for 82 patients with advanced NSCLC treated with gefitinib and correlated benefits with clinical baseline and therapy-related parameters. PATIENTS: Of all patients 48/82 were male; the median age at start of gefitinib was 67.2 years; 14/58 informative patients were never-smokers; 57/82 patients suffered from adenocarcinoma, including 7 with bronchoalveolar-carcinomas. RESULTS: As to be expected, partial remission was observed in 10% of patients, stable disease in 29%, progression-free survival was 3.1 months and overall survival 9.2 months. Gefitinib was more efficacious in women, never-smokers and patients with bronchoalveolar-carcinoma. Furthermore, anemia and elevated C-reactive protein levels were unfavourable for therapeutic efficacy. Patients developing skin reactions under gefitinib achieved response far more frequently, with longer progression-free survival and overall survival. CONCLUSION: Basic clinical parameters are good predictors for response to EGFR tyrosine-kinase inhibitor therapy, which may be of value if EGFR mutation status is not available.

Deregulation of p27 and cyclin D1/D3 control over mitosis is associated with unfavorable prognosis in non-small cell lung cancer, as determined in 405 operated patients.

INTRODUCTION: A large group of interacting molecular factors, involved in epithelial-mesenchymal transition, epidermal growth factor receptor (EGFR) signaling, and G1 mitotic phase, are shown to play an important role in cancerogenesis and progression of non-small cell lung cancer (NSCLC). Since success concerning potential correlations, structural and numeric gene aberrations, and biological risk assessment of these molecular factors are still lacking, combined analysis of a multitude of intertwined factors is currently a promising approach. METHODS: Cyclins (D1, D2, D3, and E), p21, p27, EGFR, Snail, E-cadherin, beta-catenin, phosphatidylinositol-3' kinase, phosphatase and tensin homologue, phosphorylated Akt, and phosphorylated signal transducer, and activator of transcription-3 were analyzed by immunohistochemistry in 405 surgically resected NSCLC, using a standardized tissue microarray platform. In addition, the gene status of EGFR and cyclin D1 was examined by fluorescence in situ hybridization. Extensive clinical data were acquired, enabling detailed clinicopathologic correlation during a postoperative follow-up period of up to 14 years. RESULTS: The protein overexpressions of nuclear p27, cyclin D1, cyclin D3, E-cadherin, and EGFR as assessed by immunohistochemistry were all associated with a significant reduction in overall survival time. In addition, cyclin D1 proved especially important, being the only independent molecular tumor-related factor with prognostic significance by multivariable analysis. In analogy to EGFR, recurrent numeric gene aberrations, particularly high-level amplifications, of cyclin D1 were obvious. CONCLUSIONS: The results emphasize that deregulation of controlling factors of the early G1 phase is of significant oncogenic relevance and may represent a potential treatment target in NSCLC.

Noninvasive detection of lung cancer by analysis of exhaled breath.

BACKGROUND: Lung cancer is one of the leading causes of death in Europe and the western world. At present, diagnosis of lung cancer very often happens late in the course of the disease since inexpensive, non-invasive and sufficiently sensitive and specific screening methods are not available. Even though the CT diagnostic methods are good, it must be assured that "screening benefit outweighs risk, across all individuals screened, not only those with lung cancer". An early non-invasive diagnosis of lung cancer would improve prognosis and enlarge treatment options. Analysis of exhaled breath would be an ideal diagnostic method, since it is non-invasive and totally painless. METHODS: Exhaled breath and inhaled room air samples were analyzed using proton transfer reaction mass spectrometry (PTR-MS) and solid phase microextraction with subsequent gas chromatography mass spectrometry (SPME-GCMS). For the PTR-MS measurements, 220 lung cancer patients and 441 healthy volunteers were recruited. For the GCMS measurements, we collected samples from 65 lung cancer patients and 31 healthy volunteers. Lung cancer patients were in different disease stages and under treatment with different regimes. Mixed expiratory and indoor air samples were collected in Tedlar bags, and either analyzed directly by PTR-MS or transferred to glass vials and analyzed by gas chromatography mass spectrometry (GCMS). Only those measurements of compounds were considered, which showed at least a 15% higher concentration in exhaled breath than in indoor air. Compounds related to smoking behavior such as acetonitrile and benzene were not used to differentiate between lung cancer patients and healthy volunteers. RESULTS: Isoprene, acetone and methanol are compounds appearing in everybody's exhaled breath. These three main compounds of exhaled breath show slightly lower concentrations in lung cancer patients as compared to healthy volunteers (p < 0.01 for isoprene and acetone, p = 0.011 for methanol; PTR-MS measurements). A comparison of the GCMS-results of 65 lung cancer patients with those of 31 healthy volunteers revealed differences in concentration for more than 50 compounds. Sensitivity for detection of lung cancer patients based on presence of (one of) 4 different compounds not arising in exhaled breath of healthy volunteers was 52% with a specificity of 100%. Using 15 (or 21) different compounds for distinction, sensitivity was 71% (80%) with a specificity of 100%. Potential marker compounds are alcohols, aldehydes, ketones and hydrocarbons. CONCLUSION: GCMS-SPME is a relatively insensitive method. Hence compounds not appearing in exhaled breath of healthy volunteers may be below the limit of detection (LOD). PTR-MS, on the other hand, does not need preconcentration and gives much more reliable quantitative results then GCMS-SPME. The shortcoming of PTR-MS is that it cannot identify compounds with certainty. Hence SPME-GCMS and PTR-MS complement each other, each method having its particular advantages and disadvantages. Exhaled breath analysis is promising to become a future non-invasive lung cancer screening method. In order to proceed towards this goal, precise identification of compounds observed in exhaled breath of lung cancer patients is necessary. Comparison with compounds released from lung cancer cell cultures, and additional information on exhaled breath composition in other cancer forms will be important.

Determination of volatile organic compounds in exhaled breath of patients with lung cancer using solid phase microextraction and gas chromatography mass spectrometry.

BACKGROUND: Analysis of exhaled breath is a promising diagnostic method. Sampling of exhaled breath is non-invasive and can be performed as often as considered desirable. There are indications that the concentration and presence of certain of volatile compounds in exhaled breath of lung cancer patients is different from concentrations in healthy volunteers. This might lead to a future diagnostic test for lung cancer. METHODS: Exhaled breath samples from 65 patients with different stages of lung cancer and undergoing different treatment regimes were analysed. Mixed expiratory and indoor air samples were collected. Solid phase microextraction (SPME) with carboxen/polydimethylsiloxane (CAR/PDMS) sorbent was applied. Compounds were analysed by means of gas chromatography (GC) and mass spectrometry (MS). RESULTS: The method we used allowed identification with the spectral library of 103 compounds showing at least 15% higher concentration in exhaled breath than in inhaled air. Among those 103 compounds, 84 were confirmed by determination of the retention time using standards based on the respective pure compound. Approximately, one third of the compounds detected were hydrocarbons. We found aromatic hydrocarbons, alcohols, aldehydes, ketones, esters, ethers, sulfur compounds, nitrogen-containing compounds and halogenated compounds. Acetonitrile and benzene were two of 10 compounds which correlated with smoking behaviour. A comparison of results from cancer patients with those of 31 healthy volunteers revealed differences in the concentration and presence of certain compounds. The sensitivity for detection of lung cancer patients based on eight different compounds not seen in exhaled breath of healthy volunteers was 51% and the specificity was 100%. These eight potential markers for detection of lung cancer are 1-propanol, 2-butanone, 3-butyn-2-ol, benzaldehyde, 2-methyl-pentane, 3-methyl-pentane, n-pentane and n-hexane. CONCLUSIONS: SPME is a relatively insensitive method and compounds not observed in exhaled breath may be present at a concentration lower than LOD. The main achievement of the present work is the validated identification of compounds observed in exhaled breath of lung cancer patients. This identification is indispensible for future work on the biochemical sources of these compounds and their metabolic pathways.

Idiopathic systemic amyloidosis primarily affecting the lungs with fatal pulmonary haemorrhage due to vascular involvement.

A patient who presented with dyspnea and suspected interstitial pulmonary fibrosis suffered a fatal pulmonary haemorrhage with no feasible cause for bleeding. Autopsy revealed abundant amyloid deposits in both lungs with a diffuse alveolar septal distribution pattern. Amyloid was also found in the cardiac interstitium and in many vessel walls. Considering the affected organs and the histological characteristics, the deposits were regarded as light chain-type. Amyloidosis, which is generally an uncommon disease, very rarely affects the lung predominantly. Haemorrhagic diathesis is a known complication in amyloidosis patients, although fatal haemorrhage is rare and has not yet been reported solely of pulmonary origin. This report describes an uncommon case of idiopathic systemic amyloidosis mainly manifesting in the lungs. The diagnosis was established after fatal pulmonary haemorrhage caused by vessel impairment due to additional vascular amyloid deposits.

[Updated strategies in Small Cell Lung Cancer post ASCO 2007]. / Das kleinzellige Bronchialkarzinom - neue Entwicklungen nach ASCO 2007.

Small Cell Lung Cancer (SCLC) is associated with intensive nicotine consumption and characterized by a very aggressive growth rate. Furthermore, metastases often appear very early. At the annual meeting of the "American Society of Clinical Oncology" (ASCO) 2007, recent issues which will influence the daily clinical practice were presented. New chemotherapy combinations such as carboplatin/irinotecan or pemetrexed as well as targeted therapies e.g. bevacizumab in combination with chemotherapy could extend our therapeutic options. A genetic polymorphism, which influences the pharmacokinetic of irinotecan, turned out to be one reason for the different outcome of an irinotecan/cisplatin therapy in a Japanese and Northern American population. In the field of radiotherapy, a phase III study showed for the first time a significant benefit in overall survival by prophylactic cranial radiation in the setting of extensive disease.

[Small cell lung cancer]. / Das kleinzellige Bronchialkarzinom.

With about 20% of all lung cancers small cell lung cancer (SCLC) represents a major subset of this entity. Although therapeutic improvements did not receive as much attention as in non small cell lung cancer (NSCLC), many small steps of clinical progress have been achieved within the last 20 years. An optimal treatment should be based on an interdisciplinary treatment plan. The standard treatment in localized stages represents combined radiation and chemotherapy. Cisplatin and etoposide are in this concern considered as a gold standard. 3D-planned conformal radiotherapy should start as early as possible and should be applied concomitantly to chemotherapy and in certain cases even in a hyperfractionated treatment protocol. In very early stages surgical resection could be an option in selected cases. In advanced stages a platinum-based doublet offers high response rates. As already established in limited disease prophylactic cranial irradiation is now also indicated in extensive disease in case of any tumor remission. In the second line treatment and in patients with reduced performance status topotecan is recommended. Similar as in NSCLC pemetrexed might become an alternative treatment option in the second line setting. In the field of new targeted therapies bevacizumab achieved the most promising results. The present review highlights historical milestones and up-to-date trends in radiotherapy, chemotherapy and surgery. Furthermore, the role of experimental strategies and the management of certain special clinical situations are discussed.