Demosthenes Bouros

Lung cancer in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease of unknown etiology. With a gradually increasing worldwide prevalence and a mortality rate exceeding that of many cancers, IPF diagnosis and management are critically important and require a comprehensive multidisciplinary approach. This approach also involves assessment of comorbid conditions, such as lung cancer, that exerts a dramatic impact on disease survival. Emerging evidence suggests that progressive lung scarring in the context of IPF represents a risk factor for lung carcinogenesis. Both disease entities present with major similarities in terms of pathogenetic pathways, as well as potential causative factors, such as smoking and viral infections. Besides disease pathogenesis, anti-cancer agents, including nintedanib, have been successfully applied in the treatment of patients with IPF while an oncologic approach with a cocktail of several pleiotropic anti-fibrotic agents is currently in the therapeutic pipeline of IPF. Nevertheless, epidemiologic association between IPF and lung cancer does not prove causality. Currently there is significant lack of knowledge supporting a direct association between lung fibrosis and cancer reflecting to disappointing therapeutic algorithms. An optimal therapeutic strategy for patients with both IPF and lung cancer represents an amenable need. This review article synthesizes the current state of knowledge regarding pathogenetic commonalities between IPF and lung cancer and focuses on clinical and therapeutic data that involve both disease entities.

Diagnostic and prognostic challenges in Idiopathic Pulmonary Fibrosis: A patient's “Q and A” approach

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, debilitating disease of unknown etiology that leads to death nearly half of the patients within 3-3.5 years. The past 15 years, the scientific community has made tremendous progress towards standardized diagnostic and prognostic algorithms that led to the generation of the 2011 ATS/ERS/JRS/ALAT guidelines. The latest guidelines provided us with fundamental diagnostic algorithms that set the diagnosis in the majority of cases; however, they leave a significant minority of patients without diagnostic and most importantly, therapeutic umbrella. To this end current guidelines should be revisited in light of research advances, including the tools of fibromics and at the same time provide practical guidance to the real-world of IPF in order to address patients needs. The scope of this review article is to summarize challenges in the everyday IPF clinical practice and make an effort to provide realistic answers to patients questions.

Toll-like receptors in the pathogenesis of pulmonary fibrosis.

Pulmonary fibrosis (PF) constitutes the end stage of a broad range of heterogeneous interstitial lung diseases, characterized by the destruction of the pulmonary parenchyma, deposition of extracellular matrix and dramatic changes in the phenotype of both fibroblasts and alveolar epithelial cells. More than 200 causes of pulmonary fibrosis have been identified so far, yet the most common form is idiopathic pulmonary fibrosis (IPF). IPF is a lethal lung disorder of unknown etiology with a gradually increasing worldwide incidence and a median survival of 3-5 years from the time of diagnosis. Despite intense research efforts, the pathogenesis remains elusive and no effective treatment is available. Accumulating body of evidence suggests an abnormal wound healing response followed by extracellular matrix deposition, destruction of lung architecture, ultimately leading to respiratory failure. The contribution of immune system in lung fibrogenesis had been largely underscored due to the absence of response to immunosuppressive agents; however, the premise that lung fibrosis has an immunologic background has been recently revived. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs), which link innate and adaptive immune response and regulate wound healing. TLRs promote tissue repair or fibrosis in many disease settings including lung fibrosis, albeit with profound differences depending on the cellular microenvironment. This review summarizes the current state of knowledge regarding the mechanistic implications between TLRs and lung fibrosis and highlights the therapeutic potential of targeting TLR signaling at the ligand or receptor level.

Safety and efficacy of pirfenidone in severe Idiopathic Pulmonary Fibrosis: A real-world observational study

BACKGROUNDnPirfenidone is a novel anti-fibrotic drug that has shown efficacy in five randomized multicenter clinical trials enrolling patients with Idiopathic Pulmonary Fibrosis of mild-to-moderate disease severity. Scarce data supports the use of pirfenidone in IPF patients with more advanced disease.nnnOBJECTIVEnTo investigate the safety and efficacy profile of pirfenidone in IPF patients with severe lung function impairment.nnnPATIENTS AND METHODSnThis was a retrospective study enrolling patients with advanced IPF (FVC%predictedxa0<xa050% and/or (DLco%predicted <35%) receiving pirfenidone for at least 6 months.nnnRESULTSnBetween September 2011 and March 2013, we identified 43 patients with severe IPF (baseline meanFVC%predicted±SD: 63.8xa0±xa020.3, meanDLCO%predicted: 27.3xa0±xa08.2), of mean age±SD: 66.3xa0+xa09.7, 34 males (81%) that received pirfenidone (2.403 mg/daily) for one year. Pirfenidone treatment was associated with a trend towards decrease in functional decline compared to 6-months before treatment initiation but failed to show any benefit after one year of treatment (ΔFVC:xa0-3.3xa0±xa04.6 vs 0.49xa0±xa011.4 and vs.xa0-5.8xa0±xa011.8, pxa0=xa00.06 and pxa0=xa00.04, respectively and ΔDLCO:xa0-13.3xa0±xa015.2 vs.xa0-10.1xa0±xa016.6 and vs. 28.3xa0±xa019.2, pxa0=xa00.39 and pxa0=xa00.002, respectively). Gastrointestinal disorders (34.9%), fatigue (23.2%) and photosensitivity (18.6%) were the most common adverse events. Adverse events led to treatment discontinuation in 9 patients (20.9%) and dose reduction in 14 (32.5%).nnnCONCLUSIONnPirfenidone appears to be safe when administered in patients with advanced IPF. Pirfenidone efficacy in IPF patients with severe lung function impairment may diminish after 6 months of treatment.

Safety and efficacy of nintedanib in idiopathic pulmonary fibrosis: A real-life observational study in Greece

BACKGROUNDnNintedanib represents an antifibrotic compound able to slow down disease progression of patients with idiopathic pulmonary fibrosis (IPF).nnnOBJECTIVEnTo investigate the safety and efficacy of nintedanib in patients with IPF in a real-life setting.nnnMETHODSnThis was a multicentre, retrospective, observational, real-life study for patients with IPF receiving nintedanib between October 2014 and October 2016.nnnRESULTSnWe identified 94 patients with IPF receiving nintedanib (72 males, mean age±SD: 73.8u202f±u202f7.5, mean%FVC±SDu202f=u202f68.1u202f±u202f18.3, mean%DLCo±SDu202f=u202f44.4u202f±u202f14.5). Diarrhea (nu202f=u202f52, 55.3%) was the most commonly reported adverse event. Twenty patients (21.2%) had to permanently discontinue nintedanib due to severe adverse events. In the 6-months follow-up, median decline in %FVC predicted and %DLCO predicted were 1.36 (95%Cl: 0 to 2.97) and 4.00 (95%Cl: 2.01 to 6.20), respectively, when deaths were censored and excluded from the analysis. At 12 months, mean%FVC±SD and mean%DLCo±SD were 64.5u202f±u202f19.1 and 43.7u202f±u202f15.4, respectively. With regards to mortality, 17 patients (18.1%) died over a study period of 730 days.nnnCONCLUSIONnNintedanib demonstrated an acceptable safety and efficacy profile in our real-world observational study. Prospective observational studies in the context of registries that collect well-defined supporting data over time are sorely needed to answer residual questions on drugs performance.

Longitudinal “Real-World” Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece

Background Pirfenidone is an antifibrotic compound able to slow down disease progression in patients with idiopathic pulmonary fibrosis (IPF). Objective To investigate the safety and efficacy of pirfenidone in patients with IPF in a real-life setting. Methods This was a multicenter, retrospective, real-life, observational study for patients with IPF receiving pirfenidone. Results We identified 92 patients with IPF receiving pirfenidone. Eighty patients (70 males and 10 females, mean ageu2009±u2009SD: 68.1u2009+u20097.5, mean %FVCu2009±u2009SDu2009=u200974.9u2009±u200917.2, mean %DLCOu2009±u2009SDu2009=u200948.1u2009±u200916.9) were included in the analysis. Skin-related (25%) and gastrointestinal (17.5%) adverse events were the most common and led to drug discontinuation in 22.5% of cases. The majority (87%) of patients experienced side effects during the first 6u2009months of treatment. At 36u2009months, changes in %FVC and %DLCO were −9.25u2009±u200916.34 and −9.26u2009±u200915.26, respectively. At 6, 12, and 24u2009months after treatment initiation (nu2009=u200980, 60, and 26), 18, 15, and 5 patients (22.5, 25, and 19.2%) experienced significant (>10%) and 11, 3, and 3 patients (13.8, 5, and 11.5%) experienced marginal (5–10%) %FVC improvement; and 13, 6, and 1 patient (16.2, 10, and 3.9%) experienced marginal (−5 to −10%) and 20, 21, and 8 patients (25, 35, and 30.8%) experienced significant decline (<−10%) in %FVCpred. Median survival was 851u2009days, and 41 patients died during the study period. Conclusion Pirfenidone demonstrated an acceptable safety and therapeutic profile in patients with IPF on a longitudinal basis. Prospective observational registries are urgently needed to provide a real-world view of outcomes of pirfenidone in clinical practice.

Extracellular matrix remodeling in idiopathic pulmonary fibrosis. It is the ‘bed’ that counts and not ‘the sleepers’

ABSTRACT Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by irreversible fibrosis. Current disease pathogenesis assumes an aberrant wound healing process in response to repetitive injurious stimuli leading to apoptosis of epithelial cells, activation of fibroblasts and accumulation of extracellular matrix (ECM). Particularly, lung ECM is a highly dynamic structure that lies at the core of several physiological and developmental pathways. The scope of this review article is to summarize current knowledge on the role of ECM in the pathogenesis of IPF, unravel novel mechanistic data and identify future more effective therapeutic targets. Areas covered: The exact mechanisms through which lung microenvironment activates fibroblasts and inflammatory cells, regulates profibrotic signaling cascades through growth factors, integrins and degradation enzymes ultimately leading to excessive matrix deposition are discussed. Furthermore, the potential therapeutic usefulness of specific inhibitors of matrix deposition or activators of matrix degradation pathways are also presented. Expert commentary: With a gradually increasing worldwide incidence IPF still present a major challenge in clinical research due to its unknown etiopathogenesis and current ineffective treatment approaches. Today, there is an amenable need for more effective therapeutic targets and ECM components may represent one.

Association Study for 26 Candidate Loci in Idiopathic Pulmonary Fibrosis Patients from Four European Populations.

Idiopathic pulmonary fibrosis (IPF) affects lung parenchyma with progressing fibrosis. In this study, we aimed to replicate MUC5B rs35705950 variants and determine new plausible candidate variants for IPF among four different European populations. We genotyped 26 IPF candidate loci in 165 IPF patients from four European countries, such as Czech Republic (nu2009=u200941), Germany (nu2009=u200933), Greece (nu2009=u200940), France (nu2009=u200951), and performed association study comparing observed variant distribution with that obtained in a genetically similar Czech healthy control population (nu2009=u200996) described in our earlier data report. A highly significant association for a promoter variant (rs35705950) of mucin encoding MUC5B gene was observed in all IPF populations, individually and combined [odds ratio (95% confidence interval); p-value as 5.23 (8.94–3.06); 1.80u2009×u200910−11]. Another non-coding variant, rs7934606 in MUC2 was significant among German patients [2.85 (5.05–1.60); 4.03u2009×u200910−4] and combined European IPF cases [2.18 (3.16–1.50); 3.73u2009×u200910−5]. The network analysis for these variants indicated gene–gene and gene–phenotype interactions in IPF and lung biology. With replication of MUC5B rs35705950 previously reported in U.S. populations of European descent and indicating other plausible polymorphic variants relevant for IPF, we provide additional reference information for future extended functional and population studies aimed, ideally with inclusion of clinical parameters, at identification of IPF genetic markers.

Patients with IPF and lung cancer: diagnosis and management

Idiopathic pulmonary fibrosis (IPF) is a debilitating fibrotic lung disease of unknown origin and pathogenesis with a steady increase in both incidence and mortality in recent years. Despite encouraging efficacy data for pirfenidone and nintedanib, neither of these compounds has been tested prospectively in the context of IPF coexisting with lung cancer, a frequent comorbid condition of IPF. Indeed, epidemiological evidence suggests that up to 22% of patients with IPF develop lung cancer, with a risk nearly five times as high as that of the general population. Despite abundant epidemiological and mechanistic links between IPF and lung cancer, little is known about the diagnostic and therapeutic management of these patients. The most recent ATS/ERS/JRS/ALAT guidelines, updated in 2015, do not address this crucial issue. Identifying a solitary nodule on chest high-resolution CT (HRCT) in patients with IPF represents a major diagnostic pitfall for physicians owing to problematic diagnostic approaches. The Fleischner Society’s updated guidelines suggest a PET scan for nodules greater than 8 mm in diameter with low or moderate pre-test probability. When PET uptake is negative, CT surveillance or nonsurgical lung biopsy is recommended. For moderate or high uptake, the guidelines recommend surgical lung biopsy and resection; however, this approach could be detrimental for patients with IPF, especially those with advanced disease, owing to the potential induction of acute exacerbation. Additionally, it is unknown whether patients undergoing pulmonary resection have a better prognosis than do those who do not undergo surgery and are simply monitored with low-dose HRCT. A large , retrospective analysis has shown that in patients with IPF with surgically treated non-small-cell lung cancer, surgeryrelated mortality was higher (7·1% vs 1·9%; p=0·03) and 5-year survival was lower (61·6% vs 83·0%; p=0·019) than in patients without IPF. CT-guided transthoracic needle biopsy (TTNB) might offer a fruitful diagnostic alternative, avoiding the complications of general anaesthesia, surgery, and mechanical ventilation; however, extra care should be taken in cases with concomitant emphysema owing to the increased risk of iatrogenic pneumothorax. We suggest that patients with IPF should be considered at high risk for lung cancer. Close surveillance with yearly HRCT should be mandatory not only to monitor disease progression but also for early detection of malignancy. Considering the relatively advanced age of most of these patients, the estimated radiological risk is low. The diagnostic approach of assessing the solitary nodule in patients with IPF should be applied on an individual basis, based on each patient’s performance status and preferences. We suggest the following algorithm: HRCT once a year in all patients with IPF. For nodules of less than 8 mm diameter, we suggest close monitoring of patients with HRCT every 3–6 months. If HRCT shows progression of the nodule, we recommend a PET-CT scan. For nodules with diameter of at least 8 mm, PET-CT scan is highly recommended. If PET uptake indicates tumour lesion, we suggest minimally invasive diagnostic procedures, including TTNB for peripheral lesions or endobronchial ultrasound-guided transbronchial needle biopsy if pathological lymph nodes (≥8 mm) are also present. If the patient is not suitable for biopsy, we suggest multidisciplinary discussion for a personalised approach. For advanced tumour lesions, we recommend discussion on an individual basis regarding prognosis and management, which might include no further diagnostic procedures and mild therapeutic regimens (ie, antifibrotic agents and palliative care). Data are scarce on the optimal chemotherapeutic regimen in patients with IPF and lung cancer. Studies have shown increased pulmonary toxicity in patients with interstitial lung disease who were treated with conventional chemotherapeutic regimens, except for with carboplatin. Case series have shown deleterious effects of radiotherapy on patients with established lung fibrosis, which should therefore be avoided unless life-threatening situations arise. Proton beam therapy, which can deliver a more concentrated dose of radiation than conventional approaches, has shown promising results. Studies investigating the effects of new immunomodulatory agents including PD-L1 inhibitors would be of substantial interest for a selective number of cases, yet are associated with a high risk of drug-induced pneumonitis. Standard molecular lung cancer testing could also be used for targeted treatments. We suggest that implementation of aggressive chemotherapeutic regimens should generally be avoided in patients with IPF and lung cancer because the risk for complications including acute exacerbations outweighs the benefits. The same applies to irradiation treatment, which is more detrimental than beneficial. Al ice S ./B SI P/

Longitudinal outcomes of patients enrolled in a phase Ib clinical trial of the adipose-derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis

Cell‐based therapies have been used for the management of several diseases, holding promising results. Few studies have evaluated their use in chronic lung diseases. Idiopathic pulmonary fibrosis (IPF) remains a lethal disease although new therapies have emerged the recent years. We have recently published a phase I study of 14 patients receiving endobronchially adipose‐derived stem cells (ADSCs). The aim of this report is to assess the outcome for our patients population.