Effect and Safety of Mycophenolate Mofetil in Idiopathic Pulmonary Fibrosis

Background. Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease with ineffective treatment. Mycophenolate mofetil (MMF) is an immunomodulatory agent which inhibits lymphocyte proliferation. Objective. We sought to determine the safety and efficacy profile of MMF in IPF patients. Methods. We retrospectively identified ten patients, who met the ATS/ERS 2000 criteria for IPF and received MMF 2 gr/day for 12 months. All of them had routine laboratory, pulmonary function and radiological (high resolution computed tomography-HRCT) data available and were enrolled in the study. Forced vital capacity (FVC), total lung capacity (TLC), diffusion capacity of the lung for carbon monoxide (DLCO), 6-minute walking distance (6MWD), HRCT scans and routine laboratory data at treatment onset were compared with respective values 12 months after treatment onset. Results. There were no significant alterations in FVC, TLC, DLCO and 6MWD pre- and 6 and 12 months post-treatment. HRCT evaluation showed deterioration of the total extent of disease (P = 0.002) and extent of ground-glass opacity (P = 0.02). No cases of clinically significant infection, leucopenia, or elevated liver enzymes were recorded. Conclusions. MMF is a safe therapeutic modality which failed to show a beneficial effect both in functional and radiological parameters in a small cohort of IPF patients

Effect and Safety of Mycophenolate Mofetil or Sodium in Systemic Sclerosis-Associated Interstitial Lung Disease: A Meta-Analysis

Background. Interstitial lung disease (ILD) is the most common complication of systemic sclerosis (SSc) with treatment ineffective. Objective: The aim of this meta-analysis was to provide an estimate of the safety and efficacy profile of Mycophenolate Mofetil (MMF) or sodium (MMS) in SSc-ILD patients. Materials and Methods. All studies were reviewed systematically. The main end-points were safety and efficacy profile as estimated by forced vital capacity (FVC)% and diffusion capacity of the lung for carbon monoxide (DLCO)% of the predicted normal value (%pred.) before and after treatment in patients with SSc-ILD. Quality assessment and data extraction were performed independently by two reviewers. Results. Seventeen studies were reviewed systematically. Six studies, one prospective, were eligible for analysis encompassing 69 patients, including 10 subjects from our, yet unpublished, retrospective study. There was no statistically significant difference in both efficacy outcomes of interest, including FVC% pred. (weighted mean difference 1.48, 95% confidence interval (CI): −2.77 to 5.72, P = 0.49) and DLCO % pred. (weighted mean difference −0.83, 95% CI: −4.75 to 3.09, P = 0.93). No cases of clinically significant side effects were documented. Conclusions. Meta-analysis data suggest that MMF is a safe therapeutic modality which was associated with functional stabilization in patients with SSc-ILD

Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal

<p>Abstract</p> <p>Background</p> <p>Idiopathic pulmonary fibrosis represents a lethal form of progressive fibrotic lung disorder with gradually increasing incidence worldwide. Despite intense research efforts its pathogenesis is still elusive and controversial reflecting in the current disappointing status regarding its treatment. Patients and Methods: We report the first protocol proposal of a prospective, unicentric, non-randomized, phase Ib clinical trial to study the safety and tolerability of the adipose-derived stem cells (ADSCs) stromal vascular fraction (SVF) as a therapeutic agent in IPF. After careful patient selection based on functional criteria (forced vital capacity-FVC > 50%, diffuse lung capacity for carbon monoxide-DL_CO> 35% of the predicted values) all eligible subjects will be subjected to lipoaspiration resulting in the isolation of approximately 100- 500 gr of adipose tissue. After preparation, isolation and labelling ADSCs-SVF will be endobronchially infused to both lower lobes of the fibrotic lungs. Procedure will be repeated thrice at monthly intervals. Primary end-point represent safety and tolerability data, while exploratory secondary end-points include assessment of clinical functional and radiological status. Results: Preliminary results recently presented in the form of an abstract seem promising and tantalizing since there were no cases of clinically significant allergic reactions, infections, disease acute exacerbations or ectopic tissue formation. In addition 6 months follow-up data revealed a marginal improvement at 6-minute walking distance and forced vital capacity.</p> <p>Conclusions</p> <p>Adipose tissue represents an abundant, safe, ethically uncontested and potentially beneficial source of stem cells for patients with IPF. Larger multicenter phase II and III placebo-controlled clinical trials are sorely needed in order to prove efficacy. However, pilot safety studies are of major importance and represent the first hamper that should be overcome to establish a rigid basis for larger clinical trials.</p

Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions.

The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer

Cell therapies for lung disease

Background: Idiopathic Pulmonary Fibrosis (IPF) is a lethal, destructive form of lung scarring disease of unknown pathogenesis. The use of cell therapies has recently emerged as an alternative option or even salvage treatment for end-stage lung disease. Mesenchymal Stem Cells represent a cell therapy option with many advantages. They can be easily harvested from many tissues and expanded in vitro with slight modifications. Their capacity for differentiation in different cell lines has been demonstrated. Numerous experimental studies support the concept of anti-inflammatory, immunomodulatory and potential anti-fibrotic properties of MSC. Importantly, MSCs are considered to be “immune privileged”.Aim: Our study group launched a phase Ib study aiming to explore the safety profile of the endobronchial infusion of autologous Adipose Derived Stem Cells – Stromal Vascular Fraction in a small cohort of patients with IPF (n=14) of mild-to-moderate disease severity. Our secondary endpoint was to assess efficacy based on pulmonary function tests, exercise capacity and indices of quality of life. Results: Results of this study demonstrated an acceptable safety and tolerability profile of endobronchial infusion of ADSCs-SVF during the entire study period (60 months), as indicated by absence of acute or chronic adverse events. Our patients experienced significant reductions in both %FVC and %DLCO at 24 and 18 months, respectively, following first endobronchial infusion; yet, declines in both were equal to 6% and thus did not exceed the clinically meaningful threshold of 10% and 15% respectively. Disease progression occurred 26 months following first administration of stem cells and median survival was 32 months. Importantly all our patients were alive 24 months and two patients are still alive 5 years after study initiation.Conclusions: To conclude, our study reports an acceptable longitudinal safety profile. Stem cell therapy failed to demonstrate improvement in lung function, however our study was underpowered for that endpoint and results have to be addressed with caution. Larger randomized placebo-controlled clinical trials are needed to assess the efficacy of stem cell treatment in patients with IPF.Εισαγωγή: Η ιδιοπαθής πνευμονική ίνωση αποτελεί μια καταστροφική μορφή χρόνιας προοδευτικής ινωτικής πνευμονοπάθειας αγνώστου αιτιολογίας. H πρόγνωση παραμένει δυσμενής και η προσπάθεια για την εξεύρεση αποτελεσματικότερων είναι επιβεβλημένη. Τα μεσεγχυματικά βλαστοκύτταρα αποτελούν έναν κυτταρικό πληθυσμό με πολλά πλεονεκτήματα: μπορούν να απομονωθούν εύκολα και να πολλαπλασιαστούν in vitro χωρίς ουσιώδη μεταβολή των ιδιοτήτων τους. Πολυάριθμες πειραματικές μελέτες υποστηρίζουν την αντι-φλεγμονώδη, ανοσοτροποποιητική και πιθανώς αντι-ινωτική δράση των βλαστοκυττάρων. Σκοπός της έρευνας είναι να διαπιστώσουμε εάν η ενδοβρογχική χορήγηση βλαστοκυττάρων προερχόμενων από το λιπώδη ιστό είναι ασφαλής για την αντιμετώπιση της Ιδιοπαθούς Πνευμονικής Ίνωσης. Η μελέτη σχεδιάστηκε ως μελέτη φάσης Ιβ, χωρίς ομάδα ελέγχου με εικονικό φάρμακο και χωρίς τυχαιοποίηση. Η ασφάλεια ελέγχθηκε με την καταγραφή όλων των ανεπιθύμητων ενεργειών και τον τακτικό κλινικοεργαστηριακό και ακτινολογικό έλεγχο. Ταυτόχρονα μελετήθηκε η αναπνευστική λειτουργία σε βάθος χρόνου, ως μέθοδος αποτελεσματικότητας.Αποτελέσματα: Κατά την διάρκεια της μελέτης, κανείς ασθενής δεν παρουσίασε σημαντικές παρενέργειες ή παρόξυνση της νόσου. Κανείς επίσης δεν παρουσίασε έκτοπο ιστό. Οι ασθενείς παρουσίασαν σημαντική ελάττωση της λειτουργίας του πνεύμονα καθώς και της ικανότητας για άσκηση 2 έτη μετά την 1η ενδοβρογχική έγχυση βλαστοκυττάρων. Ωστόσο, η μεταβολή ήταν μικρότερη από τα κλινικά σημαντικά όρια του 10% για την FVC και του 15% για την DLco. Η πρόοδος νόσου επήλθε στους 26 μήνες ενώ η μέση επιβίωση ήταν 32 μήνες. Κυρίως όμως, όλοι οι ασθενείς ζούσαν για τουλάχιστον 2 έτη μετά την 1η έγχυση ενώ δύο ασθενείς ζούσαν κατά τον τελευταίο έλεγχο στα 5 έτη. Συμπεράσματα: Συμπερασματικά, η μελέτη μας ικανοποιεί το πρωτεύον καταληκτικό σημείο της ασφάλειας. Δεν βρέθηκε να προσφέρει στην βελτίωση της αναπνευστικής λειτουργίας. Η διενέργεια καλύτερα σχεδιασμένων μελετών με μεγαλύτερο δείγμα ασθενών είναι αναγκαία

The Role of Microbiome and Virome in Idiopathic Pulmonary Fibrosis

The interest in the lung microbiome and virome and their contribution to the pathogenesis, perpetuation and progression of idiopathic pulmonary fibrosis (IPF) has been increasing during the last decade. The utilization of high-throughput sequencing to detect microbial and/or viral genetic material in bronchoalveolar lavage fluid or lung tissue samples has amplified the ability to identify and quantify specific microbial and viral populations. In stable IPF, higher microbial burden is associated with worse prognosis but no specific microbe has been identified to contribute to this. Additionally, no causative relation has been established. Regarding viral infections, although in the past they have been associated with IPF, causation has not been proved. Although in the past the diagnosis of acute exacerbation of IPF (AE-IPF) was not considered in patients with overt infection, this was amended in the last few years and infection is considered a cause for exacerbation. Besides this, a higher microbial burden has been found in the lungs of patients with AE-IPF and an association with higher morbidity and mortality has been confirmed. In contrast, an association of AE-IPF with viral infection has not been established. Despite the progress during the last decade, a comprehensive knowledge of the microbiome and virome in IPF and their role in disease pathogenesis are yet elusive. Although association with disease severity, risk for progression and mortality has been established, causation has not been proven and the potential use as a biomarker or the benefits of antimicrobial therapeutic strategies are yet to be determined

Burden of Comorbidities in Patients with OSAS and COPD-OSAS Overlap Syndrome

Background and Objectives: Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are usually associated with multi-morbidity. The aim of this study was to retrospectively investigate the prevalence of comorbidities in a cohort of patients with OSAS and COPD-OSAS overlap syndrome (OS) patients and to explore differences between these two groups. Materials and Methods: Included were consecutive OS patients and OSAS patients who had been referred to our sleep laboratory, and were matched in terms of sex, age, BMI, and smoking history. Presence of comorbidities was recorded based on their medical history and after clinical and laboratory examination. Results: The two groups, OS patients (n = 163, AHI > 5/h and FEV1/FVC n = 163, AHI > 5/h, and FEV1/FVC > 0.7), did not differ in terms of apnea hypopnea index (p = 0.346), and oxygen desaturation index (p = 0.668). Compared to OSAS patients, OS patients had lower average SpO2 (p = 0.008) and higher sleep time with oxygen saturation p = 0.002) during sleep, and lower PaO2 (p 2 (p = 0.04) in wakefulness. Arterial hypertension was the most prevalent comorbidity for both OS and OSAS, followed by dyslipidemia, cardiovascular disease (CVD) and diabetes. OS was characterized by a higher prevalence of total comorbidities (median (IQR):2 (1–3) vs. 2 (1–2), p = 0.033), which was due to the higher prevalence of CVD (p = 0.016) than OSAS. No differences were observed in other comorbidities. Conclusions: In OS patients, nocturnal hypoxia and impaired gas exchange in wakefulness are more overt, while a higher burden of CVD is observed among them in comparison to sex-, age- and BMI-matched OSAS patients