Nissim Arish

Characteristics of Sarcoidosis in Patients with Previous Malignancy: Causality or Coincidence?

Background: The association between sarcoidosis and malignancy is poorly defined. Sarcoidosis can precede, be diagnosed concurrently with, or follow malignancy. Objectives: We describe the clinical and radiological features of patients with sarcoidosis following malignancy to determine whether this association is causal or coincidental. Methods: We performed a search for all patients with confirmed sarcoidosis following malignancy in our institution during 2001-2015. Clinical and radiological features, bronchoscopic findings, bronchoalveolar lavage cell counts, and pulmonary function tests (PFTs) were reviewed to evaluate patterns of disease involvement. Details of the histological type of cancer, staging, treatment, and follow-up were reviewed. Results: Twenty-nine patients were identified. The most prevalent malignancies were breast cancer and lymphoma (24% each). Based on the incidence of these malignancies, we estimated the incidence of sarcoidosis was 175 times higher after lymphoma and 38 times higher after breast cancer as compared to the general population. Most patients had early stage cancer (stage I, II) (75%), and only 2 patients (7%) had recurrence of their malignancy after diagnosis of sarcoidosis. Sarcoidosis was diagnosed within 5 years of malignancy in over half the patients, 76% were asymptomatic and 69% had normal PFTs. Mediastinal lymphadenopathy was present in 81% of cases, hilar lymphadenopathy in 67%, and pulmonary parenchymal involvement in 41%. Fifty percent of patients had received Adriamycin, 38% cyclophosphamide, and 33% vincristine. Conclusions: Sarcoidosis following malignancy is indistinguishable from “idiopathic” sarcoidosis, although it is frequently asymptomatic. The high frequency of sarcoidosis after specific cancers but not others, suggests a causative association between malignancy and development of sarcoidosis.

Overexpression of Telomerase Protects Human and Murine Lung Epithelial Cells from Fas- and Bleomycin-Induced Apoptosis via FLIP Upregulation

High doses of bleomycin administered to patients with lymphomas and other tumors lead to significant lung toxicity in general, and to apoptosis of epithelial cells, in particular. Apoptosis of alveolar epithelium is an important step in the pathogenesis of bleomycin-induced pulmonary fibrosis. The Fas-FasL pathway is one of the main apoptotic pathways involved. Telomerase is a ribonucleoprotein RNA-dependent DNA polymerase complex consisting of an RNA template and a catalytic protein, telomerase reverse transcriptase (TERT). Telomerase also possess extra-telomeric roles, including modulation of transcription of anti-apoptotic genes, differentiation signals, and more. We hypothesized that telomerase overexpression affects Fas-induced epithelial cell apoptosis by an extra-telomeric role such as regulation of anti-apoptotic genes, specifically FLICE-like inhibitory protein (FLIP). Telomerase in mouse (MLE) and human (A549) lung epithelial cell lines was upregulated by transient transfection using cDNA hTERT expression vector. Telomerase activity was detected using a real-time PCR-based system. Bleomycin, and bleomycin-induced Fas-mediated apoptosis following treatment with anti-Fas activating mAb or control IgG, were assessed by Annexin V staining, FACS analysis, and confocal microscopy; caspase cleavage by Western blot; FLIP or Fas molecule detection by Western blot and flow cytometry. hTERT transfection of lung epithelial cells resulted in a 100% increase in their telomerase activity. Fas-induced lung epithelial cell apoptosis was significantly reduced in hTERT-transfected cells compared to controls in all experiments. Lung epithelial cells with increased telomerase activity had higher levels of FLIP expression but membrane Fas expression was unchanged. Upregulation of hTERT+ in human lung epithelial cells and subsequent downregulation of FLIP by shFLIP-RNA annulled hTERT-mediated resistance to apoptosis. Telomerase-mediated FLIP overexpression may be a novel mechanism to confer protection from apoptosis in bleomycin-exposed human lung epithelial cells.

Avoiding Routine Chest Radiography after Transbronchial Biopsy Is Safe

Background: Fiberoptic bronchoscopy (FOB) with transbronchial biopsy (TBB) is complicated by a pneumothorax in 1-4% of cases. Performance of routine post-TBB chest radiography (CXR) results in an extremely low diagnostic yield but nevertheless is the common clinical practice prevailing today. It has previously been suggested that routine post-TBB CXR could be avoided in asymptomatic patients. Objective: The objective of this study was to prospectively assess the feasibility and safety of this approach. Methods: The study group included 201 consecutive patients who underwent FOB with TBB at our institution between January 2009 and September 2014. All subjects completed a preprocedural, a 2-hour postprocedural, and a 24- to 48-hour postprocedural symptom questionnaire (chest pain, dyspnea, and cough). Post-TBB CXR was ordered by the treating physician only if indicated. All cases of pneumothorax were documented. Additionally, the following information was recorded: sex, age, immune status, indication for FOB, total number of biopsies done, lobe sampled, and pulse oxygen saturation. Results: Sixteen CXRs were ordered by the treating physician due to suspected pneumothorax (8%). Early-onset pneumothorax (i.e. within 2 h of TBB) was diagnosed radiologically in 6 patients (3%). Two late-onset pneumothoraxes (1%) were diagnosed more than 24 h after TBB. No pneumothoraxes of clinical significance were diagnosed among asymptomatic patients without significant oxygen desaturation events. Conclusions: Among asymptomatic patients without significant desaturation events, pneumothorax is rare and usually of negligible clinical significance. Therefore, performance of routine CXR after TBB is not necessary and can be safely avoided in this category of patients.

The association between osteopontin gene polymorphisms, osteopontin expression and sarcoidosis

Background Sarcoidosis is a systemic inflammatory disease of unknown etiology. Osteopontin (SPP1, OPN) is an extra cellular matrix glycoprotein and cytokine with a known role in granuloma formation and in autoimmune and inflammatory diseases. Objective To determine whether plasma OPN levels are elevated in patients with sarcoidosis and compare the frequency of four single nucleotide polymorphism (SNPs) variants in the OPN gene in sarcoidosis patients compared to healthy controls. Methods Demographic and clinical information, radiological studies and pulmonary function tests were evaluated in 113 patients with sarcoidosis and in 79 healthy controls. Blood samples were analyzed for SNPs of the OPN gene and for plasma OPN and CRP levels. Association between clinical features of disease and OPN levels as well as SNP frequencies was determined. Results Plasma OPN levels were higher in sarcoidosis patients than in healthy subjects, (median: 217 vs 122ng/ml, p<0.001). Area under the curve for receiver operator curves (ROC) was 0.798 (0.686–0.909 95% CI.) No differences were observed between sarcoidosis patients and controls in the frequency of any of the SNPs evaluated. Presence of lung parenchymal involvement was associated with SNP distribution at rs1126772 (p = 0.02). We found no correlation between SNPs distribution and plasma OPN levels. Conclusions Osteopontin protein levels are elevated in sarcoidosis. We found no evidence for an association between SNPs on the osteopontin gene and plasma OPN levels or the presence of sarcoidosis, however, an association between genotype and several phenotypic clinical parameters of disease was observed.

Asthma Education Delivered in theEmergency Department: Does it EncourageAsthma Self-management?

Background: The rates of optimal asthma control and compliance to treatment in Israel are reportedly low. We postulated that adults attending our emergency department (ED) with asthma exacerbation were not using self-management strategies optimally. Objectives: This pilot study aims to: (a) verify the above hypothesis and, if applicable, (b) determine whether an asthma education intervention (AEI) administered in the ED would encourage post-discharge use of a written asthma action plan (AAP). Methods: Thirty-eight adults (>18 yr.) visiting the ED with asthma exacerbation received a 30-min AEI including a written AAP. Prior asthma education was assessed by questionnaire. Follow-up, carried out by phone ≥ 12 months after discharge, assessed AAP use, asthma control (GINA), and exacerbations in the past year. Results: At baseline, participants denied previous education on asthma selfmanagement and AAP use. Of 27 patients available for follow-up, only 5 (18.5%) were using the AAP, assisted by their care-provider. Eighteen subjects (66.7%) presented uncontrolled asthma while, as a whole, the group reported significantly more exacerbation episodes than at enrolment (mean (SD)=5.1 (6.5) vs. 2.7 (3.0) (p=0.0498)). Finally, compared with AAP non-users (n=22) AAP users (n=5) tended to have better asthma control (60% vs. 18%) and fewer episodes of exacerbations (mean (SD)=2.8 (2.2) vs 5.9 (6.9)) but the differences did not reach significance. Conclusion: Delivery to adults of a short AEI in the ED was of limited efficiency in post-discharge boosting of patient/doctor partnership, resulting in sub-optimal AAP use. Feasibility of the AEI in a crowded ED, however, justifies further research on AEI delivery coupled with alternative follow-up strategies targeting patient and doctor perception of AAPs.

Randomized Controlled Crossover Trial of a New Oscillatory Device as Add-On Therapy for COPD

Abstract A new oscillatory device administers predetermined pressure oscillation sequences into the chest cavity over inhaled/exhaled air streams at low positive pressure. We assessed device safety and effect on 6MW performance, pulmonary function, and health-related quality-of-life (HRQOL) in moderate-to-very severe COPD in a randomized, double-blind, controlled, crossover study. Outcomes with an oscillatory device (PulsehalerTM, Respinova Ltd, Herzliya, Israel) and a “muted” sham device (control) of identical appearance that delivered continuous positive air pressure were compared in two groups receiving opposite treatment sequences: 2-week oscillatory device/control, 2-week washout, 2-week control/oscillatory device, 2-week washout. The clinical trial was registered (www.clinicaltrials.gov, NCT00821418) and approved by the Hadassah—Hebrew University Medical Center Institutional Review Board (08–608). All participants signed informed consent; 22 patients completed the study with no marked differences in COPD exacerbations or side effects. A total of 91% of patients treated with the oscillatory device had a clinically significant improvement (increase >40 m) in 6MW performance. The 6MW distance with the oscillatory device increased significantly after 1 week of treatment (51.6 ± 7.6 m, +13.5 ± 2.3%, p < 0.001), and more after 2 weeks (61.8 ± 9.0 m, 16.3 ± 2.7%, p < 0.001). This increase with the oscillatory device was significantly greater (p < 0.001) than the 15.4 ± 10.4 m increase (4.2 ± 2.6%, NS) with control. FVC and inspiratory capacity (IC) improved significantly (p = 0.03 for each) with the oscillatory device but not with control. HRQL improved markedly (≥1 point) for dyspnea and mastery with the oscillatory device (p = 0.02) but not control. Treatment with a new oscillatory device appears to be safe, and to improve 6MW performance, pulmonary function, and HRQL in COPD. Further evaluation is warranted.