Anastasia Oikonomou

A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis

IntroductionRegenerative medicine and particular adult stem cells represent an alternative option with several fruitful therapeutic applications in patients suffering from chronic lung diseases including idiopathic pulmonary fibrosis (IPF). Nevertheless, lack of knowledge regarding the origin and the potential of mesenchymal stem cells (MSCs) to differentiate into fibroblasts has limited their use for the treatment of this dismal disease.Patients and methodsTo this end, we conducted a phase Ib, non-randomized, clinical trial to study the safety of three endobronchial infusions of autologous adipose derived stromal cells (ADSCs)-stromal vascular fraction (SVF) (0.5 million cells per kgr of body weight per infusion) in patients with IPF (n=14) of mild to moderate disease severity (forced vital capacity –FVC>50% predicted value and diffusion lung capacity for carbon monoxide-DLCO>35% of predicted value). Our primary end-point was incidence of treatment emergent adverse events within 12 months. Alterations of functional, exercise capacity and quality of life parameters at serial time points (baseline, 6 and 12 months after first infusion) were exploratory secondary end-points.ResultsNo cases of serious or clinically meaningful adverse events including short-term infusional toxicities as well as long-term ectopic tissue formation were recorded in all patients. Detailed safety monitoring through several time-points indicated that cell-treated patients did not deteriorate in both functional parameters and indicators of quality of life.ConclusionsThe clinical trial met its primary objective demonstrating an acceptable safety profile of endobronchially administered autologous ADSCs-SVF. Our findings accelerate the rapidly expanded scientific knowledge and indicate a way towards future efficacy trials.

Organizing pneumonia: the many morphological faces

Abstract. Organizing pneumonia is a non-specific response to various forms of lung injury and is the pathological hallmark of the distinct clinical entity termed cryptogenic organizing pneumonia. The typical imaging features of this syndrome have been widely documented and consist of patchy air-space consolidation, often subpleural, with or without ground-glass opacities. The purpose of this article is to highlight the less familiar imaging patterns of organizing pneumonia which include focal organizing pneumonia, a variety of nodular patterns, a bronchocentric distribution, band-like opacities, a perilobular pattern and a progressive fibrotic form of organizing pneumonia.

CT imaging of blunt chest trauma

BackgroundThoracic injury overall is the third most common cause of trauma following injury to the head and extremities. Thoracic trauma has a high morbidity and mortality, accounting for approximately 25% of trauma-related deaths, second only to head trauma. More than 70% of cases of blunt thoracic trauma are due to motor vehicle collisions, with the remainder caused by falls or blows from blunt objects.MethodsThe mechanisms of injury, spectrum of abnormalities and radiological findings encountered in blunt thoracic trauma are categorised into injuries of the pleural space (pneumothorax, hemothorax), the lungs (pulmonary contusion, laceration and herniation), the airways (tracheobronchial lacerations, Macklin effect), the oesophagus, the heart, the aorta, the diaphragm and the chest wall (rib, scapular, sternal fractures and sternoclavicular dislocations). The possible coexistence of multiple types of injury in a single patient is stressed, and therefore systematic exclusion after thorough investigation of all types of injury is warranted.ResultsThe superiority of CT over chest radiography in diagnosing chest trauma is well documented. Moreover, with the advent of MDCT the imaging time for trauma patients has been significantly reduced to several seconds, allowing more time for appropriate post-diagnosis care.ConclusionHigh-quality multiplanar and volumetric reformatted CT images greatly improve the detection of injuries and enhance the understanding of mechanisms of trauma-related abnormalities.

Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal

BackgroundIdiopathic 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-DLCO > 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.ConclusionsAdipose 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.

The efficacy of canakinumab in the treatment of a patient with familial Mediterranean fever and longstanding destructive arthritis

Self-limited, non-destructive arthritis is a common clinical presentation of familial Mediterranean fever (FMF), while protracted, refractory to standard treatment arthritis is a rare manifestation of the disease, potentially resulting in severe damage and disability.1,–,3 We report on a 25-year-old woman with FMF, homozygous for the MEFV gene M694V mutation, and with longstanding articular involvement affecting her hips and her left knee, effectively treated with canakinumab. She had been under treatment with colchicine since the age of 5. In 2005, she experienced long-lasting arthritis of her right hip and treatment with anakinra (100 mg/day) was added. Anakinra was discontinued shortly afterwards due to severe injection site reactions, precluding the evaluation of its efficacy. She was switched to treatment with etanercept (25 mg twice weekly) and low dose prednisone (5–7.5 mg/day). In 2008, she developed destructive arthritis of the right hip, which lead to total hip replacement, and chronic arthritis of her left knee. Methotrexate (10 mg/week) was added to the existent treatment. Long-term remission was not achieved, as indicated by the clinical findings and the elevated inflammatory …

Loss of FEV1 in cystic fibrosis: correlation with HRCT features

Abstract. The purpose of this study was to determine which high-resolution computed tomography (HRCT) features in patients with cystic fibrosis are most strongly associated with functional impairment as expressed by forced expiratory volume in one second (FEV1). Forty-seven patients with cystic fibrosis underwent chest HRCT and had pulmonary function tests. The HRCT examinations were evaluated for 11 features scored using a modification of Bhalla system and FEV1 was recorded as percentage of the predicted value. Univariate and multivariate correlations between HRCT scores and FEV1 were performed. The most common HRCT feature was bronchiectasis (98%) followed by atelectasis–consolidation (81%), bronchial wall thickening (77%), tree-in-bud sign (74%), mucous plugging (72%) and mosaic perfusion pattern (47%). On univariate analysis the following features correlated strongly with FEV1: bronchial wall thickening (p<0.0000001), tree-in-bud sign (p<0.0000001), mucous plugging (p<0.0000001), atelectasis–consolidation (p<0.0000001), thickening of interlobular septa (p<0.0002), severity (p<0.0002) and extent of bronchiectasis (p<0.0002). On multivariate analysis bronchial wall thickening and atelectasis–consolidation were the strongest independent determinants of the FEV1. We found a regression equation between FEV1 and the two HRCT features: FEV1=constant variable+a multiplied by bronchial wall thickening+b multiplied by atelectasis–consolidation (a and b=regression coefficients, R2=0.48). The major morphological determinants of functional abnormality in cystic fibrosis, as expressed by the loss of FEV1, are bronchial wall thickening and atelectasis–consolidation.

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.

Increased incidence of autoimmune markers in patients with combined pulmonary fibrosis and emphysema

BackgroundCombined pulmonary fibrosis and emphysema (CPFE) is an umbrella term encompassing upper lobe emphysema and lower lobe pulmonary fibrosis with pathogenesis elusive. The aim of our study was to investigate the incidence of autoimmune markers in patients with CPFE.MethodsIn this multicenter study we retrospectively evaluated records from patients with CPFE (n=40) and IPF (n=60) without emphysema. Baseline demographic characteristics, high-resolution computed tomography (HRCT), spirometry, histopathological, treatment, serum immunologic and survival data were investigated. B cell presence was estimated with CD20 immunostaining in representative lung biopsy samples from CPFE patients and control subjects.ResultsA statistically significant increased number of CPFE patients with elevated serum ANA with or without positive p-ANCA titers compared to patients with IPF without emphysema was observed. Patients with CPFE and positive autoimmune markers exhibited improved survival compared to patients with a negative autoimmune profile. A massive infiltration of clusters of CD20+ B cells forming lymphoid follicles within the fibrotic lung in CPFE patients with positive serum immunologic profile compared to patients with negative profile, was noted and positively correlated with improved survival.ConclusionsA significant proportion of patients with CPFE may present with underlying auto-immune disorders that may reside insidiously and be associated with favorable prognosis. Early identification of these patients using a panel of auto-antibodies may lead to more targeted and effective therapeutic applications.

Acute fibrinous and organising pneumonia: a case report and review of the literature

IntroductionOrganising pneumonia is a distinct histopathological entity characterized by intra-alveolar buds of granulation tissue, called Masson bodies, which mainly comprise of activated fibroblasts and loose connective tissue. This histopathologic pattern has been described in idiopathic cases, characterizing cryptogenic organising pneumonia as well as in the context of pulmonary infection, drug-induced pneumonitis and following lung transplantation. Although distinct as a clinical and pathological entity, community organising pneumonia may present with atypical clinical and pathological features, such as intra-alveolar fillings of fibrin balls and organising tissue that resembles acute respiratory distress syndrome or diffuse alveolar damage. The latter characteristics constitute a recently described anatomoclinical entity called acute fibrinous and organising pneumonia.Case presentationHere, we describe a rare case of acute fibrinous and organising pneumonia, in an otherwise healthy 65-year-old Greek woman who complained of dry cough, fever, weight loss and progressive dyspnoea. She had never been a smoker. Her clinical symptoms showed a rapid deterioration in the two weeks before admission, despite a course of oral antibiotics. After excluding infection and malignancy with routine laboratory tests and flexible bronchoscopy, high resolution computed tomography and video assisted thoracoscopic lung biopsy were performed. Diagnosis was based on radiological features typical of community organising pneumonia coupled with pathologic features characteristic of acute fibrinous and organising pneumonia. The patient was treated with corticosteroids and showed excellent clinical and radiological response three months after treatment initiation.ConclusionAcute fibrinous and organising pneumonia is an extremely rare pathologic entity, often misdiagnosed as typical community organising pneumonia. To our knowledge, this is the seventh case of acute fibrinous and organising pneumonia in the literature, with no identifiable cause or association in a female patient, with no underlying lung disease or known exposures and with an unremarkable previous medical history. We highlight the need for careful review of lung biopsies from patients with clinical and radiologic characteristics typical of community organising pneumonia. Although it remains uncertain whether fibrin alters the favourable prognosis and treatment response of community organising pneumonia, it becomes obvious that a thorough pathologic review, apart from establishing the diagnosis of acute fibrinous and organising pneumonia, may predict a more unfavorable outcome therefore alerting the clinician to administer more aggressive and prolonged therapeutic regimens.

Endoscopic treatment of a gastrocutaneous fistula using the over-the-scope-clip system: a case report.

The over-the-scope-clip (OTSC; Ovesco Endoscopy GmbH, Tuebingen, Germany) system is a newly designed method for the mechanical compression of large areas in the gastrointestinal tract. So far, indications for OTSC application are hemostasis of primary or postinterventional bleeding, closure of iatrogenic full-thickness or covered perforations. Recently closure of gastrointestinal tract fistulas using this device has been described. A 44-year-old man developed a gastrocutaneous fistula after surgical treatment for a perforated gastric ulcer. We describe the successful endoscopic closure of the fistula using the OTSC system. The patients clinical followup was uneventful. Fistula closure was successfully implemented as it was documented by imaging and endoscopic examinations performed on the 2nd day and 6th week after the application of the clip. Endoscopic application of the OTSC device was safe and effective for the treatment of a gastrocutaneous fistula.