Aspirin use is safe in patients undergoing transbronchial lung cryobiopsy.

Background: Aspirin has been shown to be safe for patients undergoing certain diagnostic bronchoscopy procedures, such as transbronchial biopsies and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration. However, there are no studies documenting the safety of aspirin in patients undergoing trans-bronchial lung cryobiopsy (TBLC). Objective: To determine whether aspirin increases the risk of bleeding during or following TBLC. Methods: 172 consecutive patients undergoing TBLC were included in this retrospective cohort study. Data on demographic characteristics, comorbidities etc. were collected. Bleeding severity was defined by the intervention needed to stop the bleeding: mild-cold saline injection, moderate-adrenalin/hexakarpon injection, or severe - Intensive Care Unit admission after bronchoscopy. Results: Fifty-one patients (29.6 %) were under aspirin treatment at the time of TBLC. Overall, there was no significant difference between the aspirin and the control groups regarding the incidence of moderate-severe bleeding (41.2 % vs. 33.1 %, respectively, p.0.31). the Clopidogrel was found as a risk factor for increased bleeding when taken together with aspirin (Odds ratio = 9.8 (1.1-86), p = 0.013). When taken alone, clopidogrel was also found as a risk factor to increased bleeding, yet these results didn't reach significance due to low number of patients (fig. 1, N = 5, Odds ratio = 2.8 (0.46-17.35), p = 0.245). No difference was observed between the groups regarding additional post-procedural complications, including pneumothorax, hospitalizations, and mortality. Conclusion: To the best of our knowledge, this is the first study examining bleeding risk of cryobiopsy under aspirin treatment. Based on our results, it seems safe to perform TBLC under aspirin treatment, except for patients who are concurrently treated with clopidogrel. Further research should be conducted to substantiate this conclusion.

Chylothorax associated with sarcoidosis: a review of the literature.

OBJECTIVE: To review the medical literature regarding chylothorax associated with sarcoidosis. METHODS: A literature review of all reported cases of sarcoidosis-associated chylothorax, we included a novel case report to the analysis. RESULTS: Of sixteen cases included in the study, 10 were women (62.5%), mean age 47±17years. In 6 subjects (37.5%) chylothorax was part of the initial presentation of sarcoidosis. Four subjects (25%) additionally suffered from lymphedema and chylous ascites, and one from chylous ascites only. Thoracic lymphadenopathy was reported for 13/16 subjects (81.3%) and lung parenchymal disease in 8/16 (50%). Compression of the thoracic duct was considered as a causative factor in 10 cases (62.5%). One case was attributed to granulomatous pleural inflammation, one to generalized lymphangiectasia, and no specific causative factors were identified in 4 remaining cases (25%). Overall mortality rate was 18.8% (3/16 subjects). Of note, all the subjects treated with corticosteroids survived. CONCLUSIONS: Since the association of sarcoidosis with chylothorax is exceedingly rare, alternative etiologies should be pursued even when chylothorax develops in a subject with preexisting sarcoidosis. However, the possibility of sarcoidosis should be entertained when other etiologies for a newly diagnosed chylothorax are ruled out. A multidisciplinary approach is required for optimal management, both for elucidating the diagnosis and for employing therapy, which could be multimodal. A trial of immunosuppressive therapy with corticosteroids should be considered.

MiR-608 overexpression in idiopathic pulmonary fibrosis (IPF).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease that causes scarring of the lungs. The disease is associated with the usual interstitial pneumonia pattern, which was not yet fully recapitulated by an animal model. Therefore, the disease is considered 'human specific'. miRNA-608 is a primate specific miRNA with many potential targets, such CdC42 and Interlukin-6 (IL-6) that were previously implicated in IPF pathology. OBJECTIVE: To test miR-608 expression and its targets in IPF patient samples. METHODS: RNA was extracted from Formalin fixed paraffin embedded tissue sections (N = 18). miRNA-608 and Cdc42 and IL-6 levels were analyzed by qPCR. Acetylcholinesterase (AChE) is another target of miRNA-608. Its' rs17228616 allele has a single-nucleotide polymorphism causing weakened miR-608 interaction (C2098A). Thus, DNA was extracted from whole blood samples from 56 subjects with fibrosing interstitial lung disease and this region was sequenced for assessment of rs17228616 allele polymorphism. RESULTS: miR-608 is significantly overexpressed in IPF samples in comparison with controls (p < 0.05). Cdc42 and IL-6 levels were lower in the IPF patient samples compared with control samples (p < 0.001 and p < 0.05, respectively). The frequency of the rs17228616 minor A-allele was 17/56 (30.4%) with all patients being heterozygous. This result is significant vs. the published Israeli cohort of healthy individuals, which reported 17% prevalence of this allele in healthy control volunteers (p = 0.01, OR = 2.1, CI 95% [1.19-3.9]). CONCLUSION: miR-608 is overexpressed in IPF patients. While the exact mechanism remains to be discovered, it could potentially promote fibrotic disease.

Clinical and Radiological Characteristics of Patients Diagnosed with Spontaneous Pneumothorax: Treatment Options and Clinical Outcomes. A Retrospective Analysis 2004 to 2017.

BACKGROUND: Primary spontaneous pneumothorax (PSP) tends to occur in young adults without underlying lung diseases and is usually followed by limited symptoms, while secondary spontaneous pneumothorax (SSP) is a complication of a pre-existing lung disease. Surprisingly, for such common conditions, there is a considerable inconsistency regarding management guidelines. OBJECTIVES: To evaluate the risk factors for spontaneous pneumothoraxes and to summarize outcomes and complications based on our clinical experience. METHODS: This retrospective study group was comprised of 250 consecutive patients older than 18 years of age who were diagnosed with spontaneous pneumothorax and hospitalized at the Meir Medical Center (2004-2017). Data on demographic characteristics, indicating symptoms, chest X-rays, and chest computed tomography (CT) results were collected. Our experience and outcomes were then compared to a large multicenter study. RESULTS: Most of the patients were male (85%) and past or current smokers; 69% presented with PSP, while the rest were SSP. No occupational relation was noted. About 55% of the cases presented with a moderate or large pneumothorax (over 1/3 hemithorax). Most patients (56%) required chest tube drainage and 20% undergone surgery. Nearly 10% presented with a recurrent pneumothorax with the mean time to recurrence being 11 ± 20 days. Although the length of hospital stay of patients that underwent surgery was the longest (P < 0.001) for both PSP and SSP, the recurrence rate was actually reduced, suggesting some benefit for the surgical treatment option. CONCLUSIONS: Our experience showed that the traditional approach to the PSP treatment should be further considered, as previously suggested.

The Profile of COPD Patients with Prolonged Hospitalizations: A Retrospective Analysis of 200 Hospital Admissions.

BACKGROUND: Patients with severe chronic obstructive pulmonary disease (COPD) experience frequent exacerbations and need to be hospitalized, resulting in an economic and social burden. Although data exist regarding reasons of frequent hospitalizations, there is no data available about the impact on the length of stay (LOS). OBJECTIVES: To characterize the causes of prolonged hospitalizations in COPD patients. METHODS: A retrospective study was conducted of patients who were diagnosed and treated in the pulmonary department for severe COPD exacerbations. All patient demographic data and medical history were collected. Data regarding the disease severity were also collected (including Global Initiative for Obstructive Lung Disease [GOLD] criteria, pulmonologist follow-up, prior hospitalizations, and LOS). RESULTS: The study comprised 200 patients, average age 69.5 ± 10.8 years, 61% males. Of these patients, 89 (45%) were hospitalized for up to 4 days, 111 (55%) for 5 days or more, and 34 (17%) for more than 7 days. Single patients had longer LOS compared with married patients (48% vs. 34%, P = 0.044). Multivariate analysis showed that the number of prior hospital admissions in the last year was a predictor of LOS (P = 0.038, odds ratio [OR] = 0.807, 95% confidence interval [95%CI] = 0.659-0.988), as well as the use of non-invasive respiratory support by bilevel positive airway pressure (BiPAP) during the hospitalization (P = 0.024, OR = 4.662, 95%CI = 1.229-17.681). CONCLUSIONS: Fewer previous hospitalizations due to COPD exacerbations and the need for non-invasive respiratory support by BiPAP were found as predictors of longer LOS.

Integrin alpha-5 silencing leads to myofibroblastic differentiation in IPF-derived human lung fibroblasts.

BACKGROUND AND OBJECTIVE: The term 'fibroblast' covers a heterogeneous cell population in idiopathic pulmonary fibrosis (IPF). The fibroblasts are considered as main effector cells, because they promote disease progression by releasing exaggerated amounts of extracellular matrix proteins and modifying cell microenvironment. As IPF-derived human lung fibroblasts (IPF-HLFs) were shown to express higher levels of integrin alpha-5 (ITGA5) than normal derived HLFs (N-HLFs), we explored the importance of ITGA5 to IPF progression. METHODS: IPF-HLF and N-HLF primary cultures were established. ITGA5 was silenced by specific small interfering RNA (siRNA)s and its effects on cell phenotype (e.g. cell number, size, cell death, migration) and gene expression (e.g. RNA sequencing, quantitative polymerase chain reaction [qPCR], western blot and immunofluorescence) were tested. Specific integrin expression was evaluated in IPF patient formalin-fixed paraffin embedded sections by immunohistochemistry (IHC). RESULTS: ITGA5-silencing resulted in reduced IPF-HLF proliferation rates and cell migration (p < 0.05), as well as elevated cell death. transforming growth factor beta (TGF-ß) targets (e.g. Fibronectin (FN1), Matrix metalloproteinase 2 (MMP2), TGFB1) were surprisingly elevated following ITGA5 silencing (p < 0.05). N-HLFs, however, were only slightly affected. Interestingly, ITGA5-silenced cells differentiated into myofibroblasts (e.g. elevated alpha-smooth muscle actin [αSMA], collagen1a, large cell size). RNA-sequencing revealed that following differentiation on 3D-Matrigel for 24 h, ITGA5 levels are reduced while integrin alpha-8 (ITGA8) are elevated in IPF-HLFs. This was confirmed in IPF patients, in which ITGA5 was mainly found in fibroblastic foci, while ITGA8 was mostly observed in old fibrous tissue in the same patient. CONCLUSIONS: ITGA5 expression facilitates a more aggressive proliferative phenotype. Downregulation of this integrin results in myofibroblastic differentiation, which is accompanied by elevated ITGA8. Specific targeting could present a therapeutic benefit.

Peripheral blood telomere alterations in ground glass opacity (GGO) lesions may suggest malignancy.

A ground glass opacity (GGO) lung lesion may represent early stage adenocarcinoma, which has an excellent prognosis upon prompt surgical resection. However, GGO lesions have broad differential diagnoses, including both benign and malignant lesions. Our objective was to study telomere length and telomerase activity in patients with suspected lung cancer in which GGO was the predominant radiographic feature. Knowledge of telomere biology may help distinguish malignant from benign radiographic lesions and guide risk assessment of these lesions. Peripheral blood samples were taken from 22 patients with suspected adenocarcinoma with the GGO radiographic presentation. Multidisciplinary discussion confirmed the need for surgery in all cases. We used an age and gender-matched group without known lung disease as a control. Telomere length and aggregates were assessed by quantitative fluorescence in situ hybridization (QFISH) and quantitative PCR. Cell senescence was evaluated by senescence-associated heterochromatin foci. Subjects with GGO lesions had a higher percentage of lymphocytes with shorter telomeres (Q-FISH, P = 0.003). Furthermore, relative telomere length was also reduced among the GGO cases (qPCR, P < 0.05). Increased senescence was observed in the GGO group compared to controls (P < 0.001), with significant correlation between the senescence-associated heterochromatin foci and aggregate formation (r = -0.7 and r = -0.44 for cases and controls, respectively). In conclusion, patients with resectable early adenocarcinoma demonstrate abnormal telomere length and cell senescence in peripheral blood leukocytes compared to control subjects. Abnormal telomere biology in the peripheral blood may increase suspicion of early adenocarcinoma among patients with GGO lesions.

Computed Tomography Angiography Findings in Pulmonary Embolism Patients Vary Following Thrombolytic Treatment.

BACKGROUND: Pulmonary embolism (PE) is the third most frequently occurring cardiovascular disease. However, the clinical presentation in patients with PE is variable. OBJECTIVES: To evaluate the prevalence of radiological findings detected in contrast-enhanced computed tomography angiography (CTA) and their significance in patients with PE; and to assess whether the CTA findings differed in patients receiving tissue plasminogen activator (tPA) therapy from those who did not. METHODS: We retrospectively reviewed CTA scans of 186 patients diagnosed with acute PE. Incidental findings on CTA scan were assessed, including mediastinal and parenchymal lymph nodes, pleural effusion, space-occupying lesions, consolidations, emphysema, and pericardial effusion. RESULTS: Patients receiving tPA (19.9%) were less likely to have pleural effusion (29.7% vs. 50.3%, P = 0.024). Other CTA findings did not differ between the tPA and non-tPA groups, including lung infiltrates (40.5% vs. 38.9, P = 0.857), space-occupying lesions (5.4% vs. 6.7%, P = 1), pericardial effusion (8.1% vs. 8.7%, P = 1), emphysema (21.6% vs. 17.4%, P = 0.557), lung (18.9% vs. 24.2%, P = 0.498), and mediastinal ( 24.3% vs. 25.5%, P = 0.883) lymph nodes, respectively. CONCLUSIONS: The prevalence of pleural effusion (unilateral or bilateral) was higher in patients not treated with tPA. Therefore, in patients with a borderline condition, the presence of pleural effusion could support the decision not to give tPA treatment.

Inhaled Tranexamic Acid for Hemoptysis Treatment: A Randomized Controlled Trial.

BACKGROUND: Tranexamic acid (TA) is an antifibrinolytic drug currently used systemically to control bleeding. To date, there have been no prospective studies of the effectiveness of inhaled TA for the treatment of hemoptysis. OBJECTIVES: The goal of this study was to prospectively assess the effectiveness of TA inhalations (ie, nebulized TA) for hemoptysis treatment. METHODS: This analysis was a double-blind, randomized controlled trial of treatment with nebulized TA (500 mg tid) vs placebo (normal saline) in patients admitted with hemoptysis of various etiologies. Patients with massive hemoptysis (expectorated blood > 200 mL/24 h) and hemodynamic or respiratory instability were excluded. Mortality and hemoptysis recurrence rate were assessed at 30 days and following 1 year. RESULTS: Forty-seven patients were randomized to receive TA inhalations (n = 25) or normal saline (n = 22). TA was associated with a significantly reduced expectorated blood volume starting from day 2 of admission. Resolution of hemoptysis within 5 days of admission was observed in more TA-treated patients than in those receiving placebo (96% vs 50%; P < .0005). Mean hospital length of stay was shorter for the TA group (5.7 ± 2.5 days vs 7.8 ± 4.6 days; P = .046), with fewer patients requiring invasive procedures such as interventional bronchoscopy or angiographic embolization to control the bleeding (0% vs 18.2%; P = .041). No side effects were noted in either group throughout the follow-up period. In addition, a reduced recurrence rate was noted at the 1-year follow-up (P = .009). CONCLUSIONS: TA inhalations can be used safely and effectively to control bleeding in patients with nonmassive hemoptysis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01496196; URL: www.clinicaltrials.gov.

Rheumatological Assessment Is Important for Interstitial Lung Disease Diagnosis.

OBJECTIVE: Interstitial lung diseases (ILD) form a diverse group of parenchymal lung disorders. Currently, a multidisciplinary team (MDT) including pulmonologists, radiologists, and pathologists is the gold standard for ILD diagnosis. Recently, additional subtypes of connective tissue disease (CTD)-ILD with autoimmune features were defined, making the rheumatological assessment increasingly important. We aimed to assess the effect of adding a rheumatologist to the MDT for routine rheumatology assessment. METHODS: A prospective study that assessed newly diagnosed ILD patients by 2 parallel blinded arms; all patients were evaluated by both MDT (e.g., history, physical examination, blood tests, pulmonary function tests, and biopsies, if needed) and a rheumatologist (e.g., history, physical examination, blood and serological tests). RESULTS: Sixty patients were assessed with the mean age of 67.3 ± 12 years, 55% male, and 28% smokers. The rheumatological assessment reclassified 21% of the idiopathic pulmonary fibrosis as CTD. Moreover, the number of CTD-ILD with autoimmune features was increased by 77%. These included antineutrophil cytoplasmic antibody-associated vasculitis, antisynthetase syndrome, and IgG4-related ILD. Retrospectively, rheumatological evaluation could have saved 7 bronchoscopies and 1 surgical biopsy. CONCLUSION: Adding routine rheumatology assessments could significantly increase diagnostic accuracy and reduce invasive procedures.

Fibroblast paracrine TNF-α signaling elevates integrin A5 expression in idiopathic pulmonary fibrosis (IPF).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis. Inflammatory cytokines play a significant role in IPF pathology. However, the fibroblast itself is also believed to be the primary effector in IPF. We hypothesized that the fibroblasts themselves secrete pro-inflammatory cytokines that could propagate IPF by affecting normal neighboring cells. Thus, we explored the effects of IPF fibroblast derived media on normal fibroblast characteristics. METHODS: Primary IPF/normal tissue derived fibroblast cultures were established and their supernatants were collected (IPF/N-SN, respectively). These supernatants were added to normal fibroblasts. Cell death (caspase-3, western blot), proliferation, viability (WST-1), migration (scratch test) and cell detachment (crystal violet and fibronectin adhesion assays) were tested. 10 inflammatory cytokines were measured by ELISA-based quantitative array. Integrin α5 (ITGA5), pIκBα, p/total STAT3 levels were measured by western blot/IHC. TNF-α involvement was confirmed using Infliximab ®, anti-TNF-α mAb. RESULTS: The IPF-SN facilitated fibroblast cell detachment and reduced cell migration (p < 0.05). Nevertheless, these effects were reversed when cells were seeded on fibronectin. The exposure to the IPF-SN also elevated ITGA5 levels, the fibronectin receptor, in addition to NFκB pathway activation (pIκBα↑ 150%, p < 0.05). In accordance, IPF derived fibroblasts were found to express higher ITGA5 than the normal cells (44%↑, p < 0.05). ITGA5 was also expressed in the fibroblastic foci. The IPF-SN contained high TNF-α levels (3-fold, p < 0.05), and Infliximab pretreatment successfully reversed all the above observations. CONCLUSION: We suggest a possible mechanism in which IPF fibroblast secreted TNF-α modifies neighboring fibroblast cell behavior.

Sarcoidosis in Israel: Clinical Outcome Status, Organ Involvement, and Long-Term Follow-Up.

PURPOSE: Sarcoidosis is a chronic granulomatous inflammatory disease of unknown etiology with heterogeneous outcomes. This study reviewed the clinical outcome status (COS) and organ involvement of Israeli sarcoidosis patients during a five-year period. Further, we compared our results to the 'World Association of Sarcoidosis and Other Granulomatous Disease' (WASOG) COS and the 'A Case Control Etiologic Study of Sarcoidosis' (ACCESS) instruments in order to evaluate their relevance to the Israeli population. METHODS: The retrospective study group consisted of 166 sarcoidosis patients for the period of 2010-2015. Data on demographic characteristics, presenting symptoms, co-morbidities, disease duration, lung function tests, treatment program, chest X-ray, and chest high-resolution computed tomography were collected. RESULTS: The median patient age was 62 ± 14, which was significantly higher than the WASOG and ACCESS cohorts (p < 0.0001), and the average disease duration was 9.8 ± 7.5 years. Resembling the ACCESS cohort, most patients were women (67.5%). The majority of patients suffered from constitutional symptoms (86%), as well as from respiratory symptoms (38.5%). Similarly to the ACCESS cohort, 91% of patients presented with lung involvement. However, significant differences in the involvement of other organs were noted, including lymph nodes (3 vs. 15.2%), liver (3.6 vs. 11.5%), CNS (7.2 vs. 4.6%), and joints (3.6 vs. 0.5%). In addition, significant differences were observed in the COS of the Israeli population in comparison to the WASOG data (p < 0.01). CONCLUSIONS: Sarcoidosis in Israel is a unique and challenging disease with its clinical presentations that differ from previously reported studies.

The role of bacterial culture by bronchoscopy in patients with lung cancer: a prospective study.

BACKGROUND: Patients with lung cancer undergoing surgical and medical treatment are at increased risk for pulmonary complications. The importance of routine bronchoscopy procedure in populations with lung cancer has rarely been defined. We aimed to determine the growth of potentially pathogenic microorganisms (PPM) among patients evaluated by bronchoscopy for lung cancer. METHODS: This prospective study included 155 consecutive patients with lung mass or radiologic findings suspicious for malignancy. Baseline demographic, clinical and radiologic features were collected. Clinical features of infection were compared to microbiologic and histologic results. RESULTS: The bacterial spectrum of lung cancer patients was similar to those without malignancy. The most frequently isolated organisms were Pseudomonas sp. and Staphylococcus aureus. Among all patients, bronchial bacterial positive PPM growth was noted in 30% (46/155). The significant PPM growth rate was three-fold higher among those with clinical signs of infection (P<0.001). Interestingly, 30 of these 46 patients (66%) did not show signs of clinical infection. CONCLUSIONS: Bronchoscopic evaluations should include bacterial cultures for direct targeted antibiotic therapy only in the symptomatic patients.

Nintedanib (BIBF 1120) blocks the tumor promoting signals of lung fibroblast soluble microenvironment.

RATIONALE: Nintedanib is a potent, triple angiokinase inhibitor of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, and has been recently approved for the treatment of non-small cell lung cancer (NSCLC), following first-line chemotherapy. It is well established that microenvironment plays an important role in tumor progression. Therefore, targeting tumor microenvironment-cancer cell interaction may provide a significant therapeutic target. In this study we tested the effect of Nintedanib on NSCLC cells directly and in the presence of normal and tumor soluble microenvironment. METHODS: Primary fibroblast cultures derived from NSCLC tumors and normal lung tissues were established and their supernatants were collected. These supernatants were added to NSCLC cell lines (H1299, H460 and A549) cultured with/without Nintedanib (0.1-10µM) for 24 and 48h. Cell death (AnnexinV-PI, flow-cytometry), cell number, proliferation (PCNA), protein expression (immunoblotting) and cell migration (scratch test), were tested. Expression of 10 pro-angiogenic cytokines was measured by ELISA-based quantitative array. RESULTS: Tumor and normal supernatants demonstrated similar pro-metastatic effects on the NSCLC phenotype: both elevated cancer cell number, PCNA levels, reduced total and apoptotic cell death and facilitated cell migration. Nintedanib had limited but significant effects on the NSCLC cell number, cell death and migration, but required high doses. However, at lower doses Nintedanib caused cell detachment and elevated integrin-alpha 5 and EGFR levels, both markers of anoikis resistance. This suggests them as possible targets in combination with Nintedanib. Moreover, Nintedanib completely blocked the supernatants ability to facilitate the aggressive cancer cell characteristics. While cytokine array analysis showed no significant changes in FGF, PDGF or VEGF, we found that both supernatants contained high HGF levels, suggesting it as the facilitator of cell migration and proliferation. CONCLUSION: Our results demonstrate that tumor microenvironment-cancer cell interaction is a therapeutic target and should be considered when new drugs are tested.

McCune-Albright syndrome in a discordant monozygotic twin.

BACKGROUND: McCune-Albright syndrome is a sporadic disorder characterized by polystotic fibrous dysplasia, pigmented patches of skin, and endocrinological abnormalities. OBJECTIVES: To compare the genetic characteristics of the GNAS1 gene in a monozygotic pair of twins, one of whom was diagnosed with MAS while the other had no indication of the syndrome. METHODS: We performed a molecular analysis of the GNAS1 gene in DNA extracted from peripheral blood cells and quantification of mRNA extracted from lymphoblastoid cells from both twins by quantitative real-time polymerase chain reaction. RESULTS: Monozygosity of the twins was confirmed by typing them to four highly polymorphic microsatellites. Molecular analysis of the GNAS1 gene extracted from both twins did not reveal the cause of this discordance. CONCLUSIONS: It is possible that the exact molecular mechanism for the MAS discordance can only be determined by sampling affected tissues.