European Respiratory Society guideline on various aspects of quality in lung cancer care.

This European Respiratory Society guideline is dedicated to the provision of good quality recommendations in lung cancer care. All the clinical recommendations contained were based on a comprehensive systematic review and evidence syntheses based on eight PICO (Patients, Intervention, Comparison, Outcomes) questions. The evidence was appraised in compliance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence profiles and the GRADE Evidence to Decision frameworks were used to summarise results and to make the decision-making process transparent. A multidisciplinary Task Force panel of lung cancer experts formulated and consented the clinical recommendations following thorough discussions of the systematic review results. In particular, we have made recommendations relating to the following quality improvement measures deemed applicable to routine lung cancer care: 1) avoidance of delay in the diagnostic and therapeutic period, 2) integration of multidisciplinary teams and multidisciplinary consultations, 3) implementation of and adherence to lung cancer guidelines, 4) benefit of higher institutional/individual volume and advanced specialisation in lung cancer surgery and other procedures, 5) need for pathological confirmation of lesions in patients with pulmonary lesions and suspected lung cancer, and histological subtyping and molecular characterisation for actionable targets or response to treatment of confirmed lung cancers, 6) added value of early integration of palliative care teams or specialists, 7) advantage of integrating specific quality improvement measures, and 8) benefit of using patient decision tools. These recommendations should be reconsidered and updated, as appropriate, as new evidence becomes available.

ERS statement on harmonised standards for lung cancer registration and lung cancer services in Europe.

The European Respiratory Society (ERS) task force for harmonised standards for lung cancer registration and lung cancer services in Europe recognised the need to create a single dataset for use in pan-European data collection and a manual of standards for European lung cancer services.The multidisciplinary task force considered evidence from two different sources, reviewing existing national and international datasets alongside the results of a survey of clinical data collection on lung cancer in 35 European countries. A similar process was followed for the manual of lung cancer services, with the task force using existing guidelines and national or international recommendations for lung cancer services to develop a manual of standards for services in Europe.The task force developed essential and minimum datasets for lung cancer registration to enable all countries to collect the same essential data and some to collect data with greater detail. The task force also developed a manual specifying standards for lung cancer services in Europe.Despite the wide variation in the sociopolitical landscape across Europe, the ERS is determined to encourage the delivery of high-quality lung cancer care. Both the manual of lung cancer services and the minimum dataset for lung cancer registration will support this aspiration.

Interleukin-22 is elevated in lavage from patients with lung cancer and other pulmonary diseases.

BACKGROUND: Interleukin-22 (IL-22) is involved in lung diseases such as pneumonia, asthma and lung cancer. Lavage mirrors the local environment, and may provide insights into the presence and role of IL-22 in patients. METHODS: Bronchoscopic lavage (BL) samples (n = 195, including bronchoalveolar lavage and bronchial washings) were analysed for IL-22 using an enzyme-linked immunosorbent assay. Clinical characteristics and parameters from lavage and serum were correlated with lavage IL-22 concentrations. RESULTS: IL-22 was higher in lavage from patients with lung disease than in controls (38.0 vs 15.3 pg/ml, p < 0.001). Patients with pneumonia and lung cancer had the highest concentrations (48.9 and 33.0 pg/ml, p = 0.009 and p < 0.001, respectively). IL-22 concentration did not correlate with systemic inflammation. IL-22 concentrations did not relate to any of the analysed cell types in BL indicating a potential mixed contribution of different cell populations to IL-22 production. CONCLUSIONS: Lavage IL-22 concentrations are high in patients with lung cancer but do not correlate with systemic inflammation, thus suggesting that lavage IL-22 may be related to the underlying malignancy. Our results suggest that lavage may represent a distinct compartment where the role of IL-22 in thoracic malignancies can be studied.

Thoracic oncology HERMES: European curriculum recommendations for training in thoracic oncology.

Thoracic oncology HERMES: European curriculum recommendations for training in thoracic oncology http://ow.ly/mdqT300NHqO.

Response to chemotherapy, reexposure to crizotinib and treatment with a novel ALK inhibitor in a patient with acquired crizotinib resistance.

The treatment of advanced non-small cell lung cancer (NSCLC) has dramatically changed over the last decade. It has developed from an unspecific approach based on platinum doublet chemotherapy to a personalized, molecularly targeted therapy. Crizotinib is a new tyrosine kinase inhibitor approved for the treatment of NSCLC with gene rearrangement of EML4 and ALK. Despite good initial responses, patients treated with crizotinib relapse after an average of 10 months. In this case report, we present a patient with acquired crizotinib resistance whose adenocarcinoma responded to a second course of crizotinib following a drug holiday and chemotherapy with pemetrexed. This is the second case report to suggest that retreatment with crizotinib is an option for patients with initial benefit from ALK inhibition.

The European initiative for quality management in lung cancer care.

Lung cancer is the commonest cause of cancer-related death worldwide and poses a significant respiratory disease burden. Little is known about the provision of lung cancer care across Europe. The overall aim of the Task Force was to investigate current practice in lung cancer care across Europe. The Task Force undertook four projects: 1) a narrative literature search on quality management of lung cancer; 2) a survey of national and local infrastructure for lung cancer care in Europe; 3) a benchmarking project on the quality of (inter)national lung cancer guidelines in Europe; and 4) a feasibility study of prospective data collection in a pan-European setting. There is little peer-reviewed literature on quality management in lung cancer care. The survey revealed important differences in the infrastructure of lung cancer care in Europe. The European guidelines that were assessed displayed wide variation in content and scope, as well as methodological quality but at the same time there was relevant duplication. The feasibility study demonstrated that it is, in principle, feasible to collect prospective demographic and clinical data on patients with lung cancer. Legal obligations vary among countries. The European Initiative for Quality Management in Lung Cancer Care has provided the first comprehensive snapshot of lung cancer care in Europe.

Preselection based on clinical characteristics in German non-small-cell lung cancer patients screened for EML4-ALK translocation.

BACKGROUND: The advent of multiple molecular targets in advanced non-small-cell lung cancer (NSCLC) has brought new treatments, but also new logistic and technical considerations, to the clinician. The small size of endoscopic biopsies and the increasing number of relevant but uncommon markers has increased the need for rational approaches to molecular testing. We present the results of clinical preselection before EML4-ALK testing in a German NSCLC cohort. METHODS: Patients with stage IV NSCLC were included. Clinicians were encouraged to consider screening epidermal growth factor receptor wild-type adenocarcinoma patients with a limited smoking history, relatively young age, or who had benefited from chemotherapy for a relatively long period. Break-apart fluorescence in situ hybridization using archived paraffin tissue was performed in a central facility. RESULTS: From April 2010 to September 2011 we included 61 patients: mean age 56.6 years, 41% women, 90% adenocarcinoma, 5% large-cell, and 5% squamous cell cancers. Only three patients had activating epidermal growth factor receptor mutations; 16.4% of patients were positive for EML4-ALK fusion. The anaplastic lymphoma kinase (ALK)-positive patients included 60% women, tended to be younger, had smoked less, and had received significantly more systemic therapy, on average 3.7 lines of treatment over 3 years, before ALK-testing compared with the ALK-negative patients. Long periods of progression-free survival were experienced by ALK-positive patients treated with pemetrexed, vinorelbine, or cetuximab. CONCLUSIONS: EML4-ALK fusion is uncommon, reported in about 5% of NSCLC patients; however, clinical preselection increased the yield of testing to 16.4%. EML4-ALK positive patients seem to have distinct clinical features and show long responses to a number of systemic therapies.

Sinonasal outcome under aspirin desensitization following functional endoscopic sinus surgery in patients with aspirin triad.

Recalcitrant forms of recurrent nasal polyposis are problematic for patients as for rhinosurgeons. In aspirin-sensitive patients, aspirin desensitization is supposed to prevent recurrence by targeting the metabolism of arachidonic acid. Aspirin-sensitive patients (n = 65) following aspirin desensitization after functional endoscopic sinus surgery (FESS) for recurrent nasal polyposis under daily intake of 500-mg aspirin were compared to a post-FESS group (n = 81) of aspirin-sensitive individuals using exclusively topical mometasone. Quality of life (QoL) scores including sinonasal, pulmonal and general QoL items as well as endoscopic endonasal examination findings were evaluated during the postoperative follow-up period. After a follow-up period of minimum 18 months, a significant improvement in nasal obstruction, rhinorrhea, post nasal drip, sense of smell, facial pain, sleep quality and further general QoL items in desensitized patients was found compared to aspirin-sensitive controls. Improvement in sinonasal symptoms was evident, whereas the severity of asthmatic symptoms showed no significant changes. Although the pathophysiology of aspirin sensitivity is still not fully understood and the therapy is not sufficiently investigated, aspirin desensitization seems to have a positive effect on QoL scores concerning sinonasal symptoms and should be regarded as a possible postoperative treatment modality for recurrent nasal polyposis in aspirin-sensitive individuals.

Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations.

The hedgehog (Hh) signaling pathway has been shown to be activated in the cancer stem cells of several tumor entities. The Hh inhibitor GDC-0449 has been proven to be effective in some cancers but not yet in lung cancer. We aimed at investigating whether GDC-0449 is effective in the lung cancer cell lines HCC (adenocarcinoma) and H1339 (small-cell-lung carcinoma), whether in these cell lines stem cell-like side populations (SPs) can be identified, and whether possible effects of GDC-0449 are mediated via SPs. SPs were identified by spectrum shift and decreased fluorescence after staining with 2.5 µg/ml Hoechst 33342. Expression of proteins was quantified by immunofluorescence. GDC-0449 (25 and 50 µM) inhibited concentration-dependent cell growth in HCC and H1339 cells. Further, the inhibitory effects of cisplatin on cell growth were augmented. In HCC and H1339 cell lines, SPs of 0.57 and 0.46% could be identified, respectively. SP, but not non-SP, cells were able to repopulate the original tumor population. The Hh receptor smoothened was detectable in SP but not in non-SP cells, showing the activation of the Hh pathway only in SPs. GDC-0449 considerably reduced SPs in HCC and H1339 cells. We demonstrate for the first time that GDC-0449 effectively reduces cell growth in lung cancer cell lines. This effect is mediated by the inhibition of stem cell-like SPs.

Nissen fundoplication and gastrointestinal-related complications: a guide for the primary care physician.

Gastroesophageal reflux disease is a common condition affecting many individuals in the Western world. Most patients are managed successfully with acid suppression, while others may require more invasive interventions. The majority of patients undergoing antireflux surgery will have favorable outcomes. A small percentage, however, will be considered surgical failures and will either present with new or recurrent symptoms, or develop postoperative complications. These include, but are not limited to, symptoms such as dysphagia, gas-bloat syndrome, and bowel dysfunctions that may significantly impair the patient's health and quality of life. As the number of antireflux procedures for this condition continue to increase, the number of complications is also likely to become more prevalent. The primary care physician will be challenged to recognize them and initiate appropriate management. In this review, we address the more common gastrointestinal complications of laparoscopic Nissen fundoplication and offer general guidelines in their diagnosis and management.

Cytochrome P4502A6 stability in a mini organ culture model of human nasal mucosa for genotoxicology studies as detected by flow cytometry.

Three dimensional mini organ cultures (MOCs) of human nasal turbinate epithelia have been shown to be a relevant tool in genotoxicology studies. MOCs allow repetitive or chronic exposure of cells in an organ specific mucosal architecture for an extended period of time and monitoring of possible adverse effects with, e.g., the comet assay. It is the aim to demonstrate whether the proteins of key enzymes of xenobiotic metabolism, represented by cytochrome P450 2A6 (CYP2A6), remain on a stable level for a culture period that allows repetitive or chronic exposure to xenobiotics. Culture of mini organs was performed by cutting pieces of 1 mm(3) from fresh specimens of human nasal turbinates. MOCs of five tissue donors were incubated on multi-well plates with BEBM, on days 0, 4, 7, 9, and 11 aliquots were transmitted to flow cytometric quantification of the CYP2A6 protein. The CYP2A6 protein could be demonstrated on all days of culture investigated. Interindividual differences were more pronounced on day 0 than at later stages of culture. Although there appeared to be a slight decrease over the culture period, flow cytometric analysis did not reveal a significant loss of the signals up to day 11. The present data could show a pre-requisite of metabolic competence of MOCs that is in contrast to single cell cultures. Thus, this type of organ culture provides an in vitro model suitable for the assessment of genotoxic effects of environmental pollutants mimicking the in vivo situation with target cells of carcinogens in their functional organ specific architecture.

In-vivo kinetics of inhaled 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in bronchial tissue.

BACKGROUND: In the diagnosis of early-stage lung cancer photosensitizer-enhanced fluorescence bronchoscopy with inhaled 5-aminolevolinic acid (5-ALA) increases sensitivity when compared to white-light bronchoscopy. This investigation was to evaluate the in vivo tissue pharmacokinetics of inhaled 5-ALA within the bronchial mucosa in order to define the time optimum for its application prior to bronchoscopy. METHODS: Patients with known or suspected bronchial carcinoma were randomized to receive 200 mg 5-ALA via inhalation 1, 2, 3, 4 or 6 hours before flexible fluorescence bronchoscopy was performed. Macroscopically suspicious areas as well as areas with visually detected porphyrin fluorescence and normal control sites were measured spectroscopically. Biopsies for histopathology were obtained from suspicious areas as well as from adjacent normal areas. RESULTS: Fluorescence bronchoscopy performed in 19 patients reveals a sensitivity for malignant and premalignant changes (moderate dysplasia) which is almost twice as high as that of white-light bronchoscopy, whereas specificity is reduced. This is due to false-positive inflammatory lesions which also frequently show increased porphyrin fluorescence. Malignant and premalignant alterations produced fluorescence values that are up to 5 times higher than those of normal tissue. According to the pharmacokinetics of porphyrin fluorescence measured by spectroscopy, the optimum time range for 5-ALA application is 80-270 min prior to fluorescence bronchoscopy, with an optimum at 160 min. CONCLUSION: According to our results we propose inhalation of 5-ALA 160 min prior to fluorescence bronchoscopy, suggesting that this time difference provides the best tumor/normal tissue fluorescence ratio.

Cumulative genotoxic and apoptotic effects of xenobiotics in a mini organ culture model of human nasal mucosa as detected by the alkaline single cell microgel electrophoresis assay and the annexin V-affinity assay.

Three-dimensional mini organ cultures of human inferior nasal turbinate epithelia have proved to be a useful tool in genotoxicology studies. They allow repetitive or chronic exposure of cells to xenobiotics in a well-preserved organ-specific mucosal architecture for an extended period of time. It is the aim of the present study to concurrently monitor cumulative genotoxic and apoptotic effects of sodium dichromate, N-nitrosodiethylamine (NDEA) and N-methyl-N-nitro-N-nitroso-guanidine (MNNG). Mini organs were raised by separating fresh specimens of human inferior nasal turbinates (n=11) into 1 mm3 sized pieces and culturing them on multiwell plates with bronchial epithelial basal medium for 6 days. Aliquots of the mini organs were subsequently exposed to sodium dichromate (1.0 mM, 1h), NDEA (50 mM, 1h) or MNNG (0.07 mM, 1h) on days 7, 9 and 11 versus a single exposure on day 11 only. DNA fragmentation and apoptotic events were assessed on day 11 using the alkaline single cell microgel electrophoresis assay (comet assay) and the annexin V-affinity assay. Significant DNA fragmentation could be demonstrated after a single exposure of the mini organs to sodium dichromate. Following three subsequent incubations, there was a further increase in the genetic damage observed, accompanied by an increase in the rate of apoptotic cells. In contrast, after single and triple incubation with NDEA there was neither an increase in genetic damage nor in the fraction of apoptotic cells detectable. Repetitive exposure to MNNG resulted in an accumulation of DNA damage without an observable increase in apoptosis. The results verify the need to assess apoptosis in genotoxicology research and to investigate cumulative effects of xenobiotics. Three-dimensional mini organ cultures of human upper aerodigestive tract epithelia have shown to be well-suited for improving the ability to distinguish between cumulative genotoxic and apoptotic effects.

IL-13Ralpha2 reverses the effects of IL-13 and IL-4 on bronchial reactivity and acetylcholine-induced Ca+ signaling.

BACKGROUND: The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13Ralpha2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13Ralpha2 remains vague. METHODS: Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca(2+) signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy. RESULTS: IL-4 or IL-13 up to 50 ng/ml induced bronchial hyperreactivity. But after incubation with 100 ng/ml this effect was lost and bronchial responsiveness was again comparable to the control level. The effects of IL-4 and IL-13 on bronchial reactivity were paralleled by the effects on ASMC proliferation. Fifty nanograms per milliliter of IL-4 and IL-13 increased the Ca(2+) response of human ASMC to ACH. At 100 ng/ml, however, the effects of the cytokines on the Ca(2+) response were no longer evident. The expression of IL-13Ralpha2 increased with increasing concentrations of IL-4 or IL-13, reaching its maximum at 100 ng/ml. Blocking IL-13Ralpha2, the loss of the effect of IL-4 and IL-13 at 100 ng/ml on human ASMC proliferation and the ACH-induced Ca(2+) response were no longer present. CONCLUSIONS: IL-4 and IL-13 induce bronchial hyperreactivity by changing the Ca(2+) homeostasis of ASMC. These effects are counteracted by IL-13Ralpha2. The biological significance of IL-13Ralpha2 might be a protective function by regulating IL-13- and IL-4-mediated signal transduction and thereby limiting pathological alterations in Th2-mediated inflammatory diseases.

Rotation frequency of human bronchial and nasal epithelial spheroids as an indicator of mucociliary function.

BACKGROUND: We evaluated a new in vitro model for mucociliary transport function. Spheroids of human respiratory epithelium show beating cilia at their surface. When cultured in their own mucus, spheroids can rotate along their axis due to coordinated ciliary beating. OBJECTIVE AND METHODS: To assess whether this setup yields meaningful results we measured rotation frequency (RF) of human bronchial or nasal epithelial spheroids under different temperatures and concentrations of isoproterenol. Isoproterenol was administered either as caged compound releasing active isoproterenol after illumination with UV light, or through a permeable membrane in a two-chamber system. RESULTS: Under stable conditions, RF remained constant over 200 min. Between 27 and 35 degrees C, there was a temperature-dependent increase: RF(27)( degrees )(C) = 0.27 +/- 0.08 s(-1), and RF(37)( degrees )(C) = 0.43 +/- 0.10 s(-1) (means +/- SEM). Isoproterenol (10(-5), 10(-4) and 10(-3) mmol/l) induced concentration-dependent increases in RF (9, 20 and 25%, respectively; medians) if applied in the two-chamber system. The experiments with caged isoproterenol did not yield conclusive results, probably because the byproducts from photolysis negatively affected ciliary function. The transport velocity at the surface of bronchial and nasal spheroids was estimated to be 2.96 and 3.62 mm/min (medians), respectively, which is in the same range as mucus transport velocity measured in vivo in humans. CONCLUSIONS: This setup can be used to study mucociliary transport function under controlled conditions in vitro, in particular as RF is likely to reflect not only ciliary beat frequency, but also the coordination of ciliary beating and the properties of the mucus.

Ca2+-signaling in airway smooth muscle cells is altered in T-bet knock-out mice.

BACKGROUND: Airway smooth muscle cells (ASMC) play a key role in bronchial hyperresponsiveness (BHR). A major component of the signaling cascade leading to ASMC contraction is calcium. So far, agonist-induced Ca2+-signaling in asthma has been studied by comparing innate properties of inbred rat or mouse strains, or by using selected mediators known to be involved in asthma. T-bet knock-out (KO) mice show key features of allergic asthma such as a shift towards TH2-lymphocytes and display a broad spectrum of asthma-like histological and functional characteristics. In this study, we aimed at investigating whether Ca2+-homeostasis of ASMC is altered in T-bet KO-mice as an experimental model of asthma. METHODS: Lung slices of 100 to 200 microm thickness were obtained from T-bet KO- and wild-type mice. Airway contraction in response to acetylcholine (ACH) was measured by video-microscopy and Ca2+-signaling in single ASMC of lung slices was assessed using two-photon-microscopy. RESULTS: Airways from T-bet KO-mice showed increased baseline airway tone (BAT) and BHR compared to wild-type mice. This could be mimicked by incubation of lung slices from wild-type mice with IL-13. The increased BAT was correlated with an increased incidence of spontaneous changes in intracellular Ca2+-concentrations, whereas BHR correlated with higher ACH-induced Ca2+-transients and an increased proportion of ASMC showing Ca2+-oscillations. Emptying intracellular Ca2+-stores using caffeine or cyclopiazonic acid induced higher Ca2+-elevations in ASMC from T-bet KO- compared to wild-type mice. CONCLUSION: Altered Ca2+-homeostasis of ASMC contributes to increased BAT and BHR in lung slices from T-bet KO-mice as a murine asthma model. We propose that a higher Ca2+-content of the intracellular Ca2+-stores is involved in the pathophysiology of these changes.