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1.  Concurrent granulomatous hepatitis, pneumonitis and sepsis as a complication of intravesical BCG immunotherapy 
BMJ Case Reports  2013;2013:bcr2013200624.
Intravesical administration of BCG is a relatively simple procedure used successfully in the treatment of superficial transitional cell carcinoma of the urinary bladder. It is usually well tolerated with few major side effects. The authors report the case of an 80-year-old man who presented with sepsis, jaundice, hepatic and pulmonary failure 10 days after his last BCG instillation therapy, that was attributed to concurrent granulomatous hepatitis and pneumonitis due to Mycobacterium bovis dissemination. In rare instances severe life-threatening complications occur in relation with BCG instillation immunotherapy that may involve multiple organs and have different presentations and require a high index of suspicion and clinical awareness in a wide range of medical specialties.
doi:10.1136/bcr-2013-200624
PMCID: PMC3822071  PMID: 24114600
2.  Clinical asthma phenotypes in the real world: opportunities and challenges 
Breathe  2015;11(3):186-193.
Key Points
Asthma is a heterogeneous syndrome ranging from mild disease with barely noticeable symptoms to very severe disease with constant symptoms that may greatly hinder patients’ quality of life.
The aim of asthma treatment is control of asthma and the prevention of risk of exacerbations and fixed airflow limitation.
Asthma management must be individualised; tailored not only to the severity of the disease but importantly, to the phenotypic characteristics of the patient and modified according to response to treatment.
Educational Aims
To inform readers about the current understanding on the treatment of asthma.
To highlight the usefulness of phenotypes in treating asthmatic patients, especially those with severe disease.
To introduce the issues of severe asthma management and future planning.
Asthma is a common, chronic and heterogeneous syndrome, affecting people of all ages, all races and both sexes. It may range from mild disease with barely noticeable symptoms, to very severe disease with constant symptoms that greatly hinder the life of the patient. Guidelines issued by various medical societies provide guidance on how to diagnose and manage asthmatic patients. It is now increasingly recognised that asthma management must be individualised, tailored not only to the severity of the disease but to the phenotypic characteristics of each patient. The aim of asthma treatment is control of asthma and the prevention of risk of exacerbations and fixed airflow limitation. Asthma control can be easily assessed clinically through simple screening tools such as the use of validated questionnaires and spirometry. The use of inflammatory biomarkers can be an alternative approach that, however, requires more time and resources. Asthma treatment involves the use of controllers, mainly inhaled corticosteroids and long-acting β2-agonists, and relievers, mainly rapid-acting β2-agonists. Controller medications reduce airway inflammation, lead to better symptom control and reduce the risk of future exacerbations. Reliever (rescue) medications alleviate symptoms and prevent exercise-induced bronchoconstriction. Treatment must be based on a “stepwise approach” in order to achieve good control of symptoms and to minimise future risks of exacerbations. That is, less treatment for mild disease, more treatment for severe, uncontrolled disease. Once good asthma control has been achieved and maintained, treatment should be stepped down. In severe asthmatics, phenotypic characterisation becomes more clinically useful and add-on treatment such as anti-immunoglobulin E monoclonal antibodies may be required. Despite our better understanding of asthma, there are still patients who will not respond to treatment and remain symptomatic. Dissemination of guidelines and national plans allowing early diagnosis of asthma as well as access to specialised primary and secondary care for asthmatic patients, personalised treatment and continuity of care may lead to excellence in care and controlled asthma for the majority of patients. Education of the patient in asthma is also very important, as in every chronic disease, as the patients live with the disease every day while they visit a healthcare professional a few times a year. Future planning for new treatments should focus on the needs of such severe asthma patients.
An overview of treatment of asthma and introduction to issues of severe asthma management and future planning http://ow.ly/RbYc1
doi:10.1183/20734735.008115
PMCID: PMC4666449  PMID: 26632421
3.  Determination of EGFR and KRAS mutational status in Greek non-small-cell lung cancer patients 
Oncology Letters  2015;10(4):2176-2184.
It has been reported that certain patients with non-small-cell lung cancer (NSCLC) that harbor activating somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene may be effectively treated using targeted therapy. The use of EGFR inhibitors in patient therapy has been demonstrated to improve response and survival rates; therefore, it was suggested that clinical screening for EGFR mutations should be performed for all patients. Numerous clinicopathological factors have been associated with EGFR and Kirsten-rat sarcoma oncogene homolog (KRAS) mutational status including gender, smoking history and histology. In addition, it was reported that EGFR mutation frequency in NSCLC patients was ethnicity-dependent, with an incidence rate of ~30% in Asian populations and ~15% in Caucasian populations. However, limited data has been reported on intra-ethnic differences throughout Europe. The present study aimed to investigate the frequency and spectrum of EGFR mutations in 1,472 Greek NSCLC patients. In addition, KRAS mutation analysis was performed in patients with known smoking history in order to determine the correlation of type and mutation frequency with smoking. High-resolution melting curve (HRM) analysis followed by Sanger sequencing was used to identify mutations in exons 18–21 of the EGFR gene and in exon 2 of the KRAS gene. A sensitive next-generation sequencing (NGS) technology was also employed to classify samples with equivocal results. The use of sensitive mutation detection techniques in a large study population of Greek NSCLC patients in routine diagnostic practice revealed an overall EGFR mutation frequency of 15.83%. This mutation frequency was comparable to that previously reported in other European populations. Of note, there was a 99.8% concordance between the HRM method and Sanger sequencing. NGS was found to be the most sensitive method. In addition, female non-smokers demonstrated a high prevalence of EGFR mutations. Furthermore, KRAS mutation analysis in patients with a known smoking history revealed no difference in mutation frequency according to smoking status; however, a different mutation spectrum was observed.
doi:10.3892/ol.2015.3600
PMCID: PMC4579824  PMID: 26622815
non-small-cell lung cancer; epidermal growth factor receptor; Kirsten-rat sarcoma oncogene homolog; high-resolution melting curve analysis; Sanger sequencing; next generation sequencing
4.  ESR/ERS white paper on lung cancer screening 
Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and quality assurance plan. The establishment of a central registry, including biobank and image bank, and preferably on a European level, is strongly encouraged.
The ESR/ERS provide new recommendations for lung cancer screening in this white paper http://ow.ly/KbUck
doi:10.1183/09031936.00033015
PMCID: PMC4486375  PMID: 25929956
5.  ESR/ERS white paper on lung cancer screening 
European Radiology  2015;25(9):2519-2531.
Abstract
Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low-dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low-dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and a quality assurance plan. The establishment of a central registry, including a biobank and an image bank, and preferably on a European level, is strongly encouraged.
Key points
• Lung cancer screening using low dose computed tomography reduces mortality.
• Leading US medical societies recommend large scale screening for high-risk individuals.
• There are no lung cancer screening recommendations or reimbursed screening programmes in Europe as of yet.
• The European Society of Radiology and the European Respiratory Society recommend lung cancer screening within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres.
• High risk, eligible individuals should be enrolled in comprehensive, quality-controlled longitudinal programmes.
doi:10.1007/s00330-015-3697-0
PMCID: PMC4529446  PMID: 25929939
Lung cancer screening; Low-dose CT; Pulmonary nodule; Overdiagnosis
6.  Towards tuberculosis elimination: an action framework for low-incidence countries 
Lönnroth, Knut | Migliori, Giovanni Battista | Abubakar, Ibrahim | D'Ambrosio, Lia | de Vries, Gerard | Diel, Roland | Douglas, Paul | Falzon, Dennis | Gaudreau, Marc-Andre | Goletti, Delia | González Ochoa, Edilberto R. | LoBue, Philip | Matteelli, Alberto | Njoo, Howard | Solovic, Ivan | Story, Alistair | Tayeb, Tamara | van der Werf, Marieke J. | Weil, Diana | Zellweger, Jean-Pierre | Abdel Aziz, Mohamed | Al Lawati, Mohamed R.M. | Aliberti, Stefano | Arrazola de Oñate, Wouter | Barreira, Draurio | Bhatia, Vineet | Blasi, Francesco | Bloom, Amy | Bruchfeld, Judith | Castelli, Francesco | Centis, Rosella | Chemtob, Daniel | Cirillo, Daniela M. | Colorado, Alberto | Dadu, Andrei | Dahle, Ulf R. | De Paoli, Laura | Dias, Hannah M. | Duarte, Raquel | Fattorini, Lanfranco | Gaga, Mina | Getahun, Haileyesus | Glaziou, Philippe | Goguadze, Lasha | del Granado, Mirtha | Haas, Walter | Järvinen, Asko | Kwon, Geun-Yong | Mosca, Davide | Nahid, Payam | Nishikiori, Nobuyuki | Noguer, Isabel | O'Donnell, Joan | Pace-Asciak, Analita | Pompa, Maria G. | Popescu, Gilda G. | Robalo Cordeiro, Carlos | Rønning, Karin | Ruhwald, Morten | Sculier, Jean-Paul | Simunović, Aleksandar | Smith-Palmer, Alison | Sotgiu, Giovanni | Sulis, Giorgia | Torres-Duque, Carlos A. | Umeki, Kazunori | Uplekar, Mukund | van Weezenbeek, Catharina | Vasankari, Tuula | Vitillo, Robert J. | Voniatis, Constantia | Wanlin, Maryse | Raviglione, Mario C.
The European Respiratory Journal  2015;45(4):928-952.
This paper describes an action framework for countries with low tuberculosis (TB) incidence (<100 TB cases per million population) that are striving for TB elimination. The framework sets out priority interventions required for these countries to progress first towards “pre-elimination” (<10 cases per million) and eventually the elimination of TB as a public health problem (less than one case per million). TB epidemiology in most low-incidence countries is characterised by a low rate of transmission in the general population, occasional outbreaks, a majority of TB cases generated from progression of latent TB infection (LTBI) rather than local transmission, concentration to certain vulnerable and hard-to-reach risk groups, and challenges posed by cross-border migration. Common health system challenges are that political commitment, funding, clinical expertise and general awareness of TB diminishes as TB incidence falls. The framework presents a tailored response to these challenges, grouped into eight priority action areas: 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) undertake screening for active TB and LTBI in TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case-based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. The overall approach needs to be multisectorial, focusing on equitable access to high-quality diagnosis and care, and on addressing the social determinants of TB. Because of increasing globalisation and population mobility, the response needs to have both national and global dimensions.
Action framework for countries with low tuberculosis incidence: a coherent approach for eliminating tuberculosis http://ow.ly/H03ZZ
doi:10.1183/09031936.00214014
PMCID: PMC4391660  PMID: 25792630
7.  Circulating Conventional and Plasmacytoid Dendritic Cell Subsets Display Distinct Kinetics during In Vivo Repeated Allergen Skin Challenges in Atopic Subjects 
BioMed Research International  2014;2014:231036.
Upon allergen challenge, DC subsets are recruited to target sites under the influence of chemotactic agents; however, details pertinent to their trafficking remain largely unknown. We investigated the kinetic profiles of blood and skin-infiltrating DC subsets in twelve atopic subjects receiving six weekly intradermal allergen and diluent injections. The role of activin-A, a cytokine induced in allergic and tissue repair processes, on the chemotactic profiles of DC subsets was also examined. Plasmacytoid (pDCs) and conventional DCs (cDCs) were evaluated at various time-points in the blood and skin. In situ activin-A expression was assessed in the skin and its effects on chemokine receptor expression of isolated cDCs were investigated. Blood pDCs were reduced 1 h after challenge, while cDCs decreased gradually within 24 h. Skin cDCs increased significantly 24 h after the first challenge, inversely correlating with blood cDCs. Activin-A in the skin increased 24 h after the first allergen challenge and correlated with infiltrating cDCs. Activin-A increased the CCR10/CCR4 expression ratio in cultured human cDCs. DC subsets demonstrate distinct kinetic profiles in the blood and skin especially during acute allergic inflammation, pointing to disparate roles depending on each phase of the inflammatory response. The effects of activin-A on modulating the chemotactic profile of cDCs suggest it may be a plausible therapeutic target for allergic diseases.
doi:10.1155/2014/231036
PMCID: PMC4022198  PMID: 24877070
9.  Rhinovirus-induced basic fibroblast growth factor release mediates airway remodeling features 
Background
Human rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. The purpose of this study was to assess the possibility that rhinoviruses may also contribute to the fibrotic component of airway remodeling.
Methods
Levels of basic fibroblast growth factor (bFGF) mRNA and protein were measured following rhinovirus infection of bronchial epithelial cells. The profibrotic effect of epithelial products was assessed by DNA synthesis and matrix metalloproteinase activity assays. Moreover, epithelial cells were exposed to supernatants from cultured peripheral blood mononuclear cells, obtained from healthy donors or atopic asthmatic subjects and subsequently infected by rhinovirus and bFGF release was estimated. bFGF was also measured in respiratory secretions from atopic asthmatic patients before and during rhinovirus-induced asthma exacerbations.
Results
Rhinovirus epithelial infection stimulated mRNA expression and release of bFGF, the latter being positively correlated with cell death under conditions promoting rhinovirus-induced cytotoxicity. Supernatants from infected cultures induced lung fibroblast proliferation, which was inhibited by anti-bFGF antibody, and demonstrated increased matrix metalloproteinase activity. Rhinovirus-mediated bFGF release was significantly higher in an in vitro simulation of atopic asthmatic environment and, importantly, during rhinovirus-associated asthma exacerbations.
Conclusions
Rhinovirus infection induces bFGF release by airway epithelium, and stimulates stroma cell proliferation contributing to airway remodeling in asthma. Repeated rhinovirus infections may promote asthma persistence, particularly in the context of atopy; prevention of such infections may influence the natural history of asthma.
doi:10.1186/2045-7022-2-14
PMCID: PMC3492082  PMID: 22908984
Airway remodeling; Asthma; BFGF; Bronchial epithelium; Rhinovirus
10.  Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets 
Nature medicine  2007;13(5):570-578.
Osteopontin (Opn) is important for T helper type 1 (TH1) immunity and autoimmunity. However, the role of this cytokine in TH2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse TH2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of TH2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and TH2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established TH2 responses and protected mice from allergic disease. These effects on TH2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.
doi:10.1038/nm1580
PMCID: PMC3384679  PMID: 17435770

Results 1-10 (10)