Citations

PurposeTo investigate the use of magnetic resonance elastography (MRE) in the quantitative assessment of pulmonary fibrosis by comparing quantitative shear stiffness measurements of lung parenchyma in patients diagnosed with fibrotic interstitial lung disease (ILD) and healthy controls.Materials and MethodsA 1.5T spin‐echo, echo planar imaging MRE (SE‐EPI MRE) pulse sequence was utilized to assess absolute lung shear stiffness in 15 patients with diagnosed ILD and in 11 healthy controls. Data were collected at residual volume (RV) and total lung capacity (TLC). Spirometry data were obtained immediately prior to scanning. To test for statistical significance between RV and TLC shear stiffness estimates a two‐sample t‐test was performed. To assess variability within individual subject shear stiffness estimates, the intraclass correlation coefficient (ICC) and Krippendorff's alpha were calculated.ResultsPatients with ILD exhibited an average (±1 standard deviation) shear stiffness of 2.74 (±0.896) kPa at TLC and 1.32 (±0.300) kPa at RV. The corresponding values for healthy individuals were 1.33 (±0.195) kPa and 0.849 (±0.250) kPa, respectively. The difference in shear stiffness between RV and TLC was statistically significant (P < 0.001). At TLC, the ICC and alpha values were 0.909 and 0.887, respectively. At RV, the ICC and alpha values were 0.852 and 0.862, respectively.ConclusionIn subjects with known fibrotic interstitial lung disease, parenchymal shear stiffness is increased when compared to normal controls at both RV and TLC, with TLC demonstrating the most significant difference. MRE‐derived parenchymal shear stiffness is a promising new noninvasive imaging‐based biomarker of interstitial lung disease.Level of Evidence:1J. MAGN. RESON. IMAGING 2017;46:1–1

PurposeTo investigate the use of magnetic resonance elastography (MRE) in the quantitative assessment of pulmonary fibrosis by comparing quantitative shear stiffness measurements of lung parenchyma in patients diagnosed with fibrotic interstitial lung disease (ILD) and healthy controls.Materials and MethodsA 1.5T spin‐echo, echo planar imaging MRE (SE‐EPI MRE) pulse sequence was utilized to assess absolute lung shear stiffness in 15 patients with diagnosed ILD and in 11 healthy controls. Data were collected at residual volume (RV) and total lung capacity (TLC). Spirometry data were obtained immediately prior to scanning. To test for statistical significance between RV and TLC shear stiffness estimates a two‐sample t‐test was performed. To assess variability within individual subject shear stiffness estimates, the intraclass correlation coefficient (ICC) and Krippendorff's alpha were calculated.ResultsPatients with ILD exhibited an average (±1 standard deviation) shear stiffness of 2.74 (±0.896) kPa at TLC and 1.32 (±0.300) kPa at RV. The corresponding values for healthy individuals were 1.33 (±0.195) kPa and 0.849 (±0.250) kPa, respectively. The difference in shear stiffness between RV and TLC was statistically significant (P < 0.001). At TLC, the ICC and alpha values were 0.909 and 0.887, respectively. At RV, the ICC and alpha values were 0.852 and 0.862, respectively.ConclusionIn subjects with known fibrotic interstitial lung disease, parenchymal shear stiffness is increased when compared to normal controls at both RV and TLC, with TLC demonstrating the most significant difference. MRE‐derived parenchymal shear stiffness is a promising new noninvasive imaging‐based biomarker of interstitial lung disease.Level of Evidence: 1Technical Efficacy: Stage 2J. MAGN. RESON. IMAGING 2017;46:365–374

AbstractBackgroundLangerhans cell histiocytosis (LCH) is a clonal neoplasm characterized by widely varied clinical presentations, including multisystem involvement and systemic inflammatory symptoms. The AKT pathway is relevant to survival and proliferation of dendritic cells, and is also often upregulated in hematopoietic malignancies. A clinical response in an adult patient with LCH participating in the first‐in‐human trial of afuresertib prompted this prospective trial.ProcedureThe population in the current study included treatment‐naïve (n = 7) and recurrent/refractory patients with LCH (n = 10), who received oral afuresertib (125 mg). The majority of patients were treated for > 24 weeks, with four patients receiving treatment for > 48 weeks.ResultsPharmacokinetic analysis showed similar exposures in previously reported patients with other hematologic malignancies. Primary drug‐related toxicities included Grade 1/2 nausea, diarrhea, dyspepsia, and vomiting. Grade 3 toxicities included fatigue, diarrhea, and pain (one of each). Another severe adverse event involved soft tissue necrosis. The overall response rate in evaluable subjects was 33% in treatment‐naïve patients and 28% in patients with recurrent/refractory disease, which did not meet the predefined Bayesian criteria for efficacy.ConclusionAfuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.

Long‐term exposure to cigarette smoke (CS) triggers airway hyperreactivity and remodeling, effects that involve airway smooth muscle (ASM). We previously showed that CS destabilizes the networked morphology of mitochondria in human ASM by regulating the expression of mitochondrial fission and fusion proteins via multiple signaling mechanisms. Emerging data link regulation of mitochondrial morphology to cellular structure and function. We hypothesized that CS‐induced changes in ASM mitochondrial morphology detrimentally affect mitochondrial function, leading to CS effects on contractility and remodeling. Here, ASM cells were exposed to 1% cigarette smoke extract (CSE) for 48 h to alter mitochondrial fission/fusion, or by inhibiting the fission protein Drp1 or the fusion protein Mfn2. Mitochondrial function was assessed via changes in bioenergetics or altered rates of proliferation and apoptosis. Our results indicate that both exposure to CS and inhibition of mitochondrial fission/fusion proteins affect mitochondrial function (i.e., energy metabolism, proliferation, and apoptosis) in ASM cells. In vivo, the airways in mice chronically exposed to CS are thickened and fibrotic, and the expression of proteins involved in mitochondrial function is dramatically altered in the ASM of these mice. We conclude that CS‐induced changes in mitochondrial morphology (fission/fusion balance) correlate with mitochondrial function, and thus may control ASM proliferation, which plays a central role in airway health. J. Cell. Physiol. 232: 1053–1068, 2017. © 2016 Wiley Periodicals, Inc.

Abstract The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Abstract The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophysiological processes spanning the spectrum from airway obstruction to lung remodeling can lead to multifocal cyst development in the lung. Although lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis are perhaps more frequently seen in the clinic, disorders such as Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, follicular bronchiolitis, and light-chain deposition disease are increasingly being recognized. Obtaining an accurate diagnosis can be challenging, and management approaches are highly disease dependent. Unique imaging features, genetic tests, serum studies, and clinical features provide invaluable clues that help clinicians distinguish among the various etiologies, but biopsy is often required for definitive diagnosis. In part II of this review, we present an overview of the diffuse cystic lung diseases caused by lymphoproliferative disorders, genetic mutations, or aberrant lung development and provide an approach to aid in their diagnosis and management.

Abstract The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous processes that are characterized by the presence of multiple spherical or irregularly shaped, thin-walled, air-filled spaces within the pulmonary parenchyma. Although the mechanisms of cyst formation remain incompletely defined for all DCLDs, in most cases lung remodeling associated with inflammatory or infiltrative processes results in displacement, destruction, or replacement of alveolar septa, distal airways, and small vessels within the secondary lobules of the lung. The DCLDs can be broadly classified according to underlying etiology as those caused by low-grade or high-grade metastasizing neoplasms, polyclonal or monoclonal lymphoproliferative disorders, infections, interstitial lung diseases, smoking, and congenital or developmental defects. In the first of a two-part series, we present an overview of the cystic lung diseases caused by neoplasms, infections, smoking-related diseases, and interstitial lung diseases, with a focus on lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis.

Usual interstitial pneumonia (UIP) is the most common idiopathic interstitial pneumonia (IIP) and is associated with a poor prognosis and poor responsiveness to immunosuppressive therapy. We present a case of a woman with steroid-responsive biopsy-proven UIP with significant and sustained improvement in pulmonary function. A female in her 40s presented following a one-year history of progressive dyspnea, a 20 lb weight loss, and fatigue. Imaging of the chest with computed tomography (CT) showed bibasilar subpleural reticular opacities and minimal peripheral honeycombing. Comprehensive connective tissue disease (CTD) antibody testing was negative. Pulmonary function testing showed moderate impairment with reduction in forced vital capacity (FVC, 69% predicted), forced expiratory volume in one second (FEV 1 73% predicted), and diffusing capacity for carbon monoxide (DLCO, 52% predicted). Surgical lung biopsy showed UIP with prominent inflammatory infiltrates. Following treatment with prednisone and azathioprine, the patient's symptoms resolved, while objective pulmonary function testing showed normalization of lung function, which is sustained at >4 years of follow-up. Improvement in lung function following immunosuppressive therapy is distinctly uncommon in either idiopathic or secondary UIP. This report suggests that occasionally, patients with secondary UIP occurring in the context of otherwise undefinable autoimmune clinical syndromes may be responsive to immunosuppressive therapy.

Cigarette smoke is a common environmental insult associated with increased risk of developing airway diseases such as wheezing and asthma in neonates and children. In adults, asthma involves airway remodeling characterized by increased airway smooth muscle (ASM) cell proliferation and increased extracellular matrix (ECM) deposition, as well as airway hyperreactivity. The effects of cigarette smoke on remodeling and contractility in the developing airway are not well-elucidated. In this study, we used canalicular-stage (18–20 wk gestational age) human fetal airway smooth muscle (fASM) cells as an in vitro model of the immature airway. fASM cells were exposed to cigarette smoke extract (CSE; 0.5–1.5% for 24–72 h), and cell proliferation, ECM deposition, and intracellular calcium ([Ca 2+ ] i ) responses to agonist (histamine 10 μM) were used to evaluate effects on remodeling and hyperreactivity. CSE significantly increased cell proliferation and deposition of ECM molecules collagen I, collagen III, and fibronectin. In contrast, [Ca 2+ ] i responses were not significantly affected by CSE. Analysis of key signaling pathways demonstrated significant increase in extracellular signal-related kinase (ERK) and p38 activation with CSE. Inhibition of ERK or p38 signaling prevented CSE-mediated changes in proliferation, whereas only ERK inhibition attenuated the CSE-mediated increase in ECM deposition. Overall, these results demonstrate that cigarette smoke may enhance remodeling in developing human ASM through hyperplasia and ECM production, thus contributing to development of neonatal and pediatric airway disease.