Darius Filsoof

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• Chrissian, A. A., Abbas, H., Chaddha, U., Debiane, L. G., DeBiasi, E., Filsoof, D., Hashmi, M. D., Morton, C., Naselsky, W. C., Pannu, J., Ronaghi, R., Salguero, B. D., Salmon, C., Stewart, S. J., & Channick, C. L. (2025). American Association of Bronchology and Interventional Pulmonology Essential Knowledge in Interventional Pulmonology Series: Selected Topics in Malignant Pleural Disease. Journal of bronchology & interventional pulmonology, 32(1).
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  The goal of the American Association of Bronchology and Interventional Pulmonology Essential Knowledge in Interventional Pulmonology Series is to provide clinicians with concise, up-to-date reviews of important topics in the field of interventional pulmonology. This 3-year alternating rotation of primary topics will start with a focus on selected topics in malignant pleural disease. In this article, we update the reader on malignant pleural effusion in 3 parts: part 1-diagnosis, focusing on imaging and fluid biomarkers; part 2-management, with review of multimodal approaches, cost considerations, and evolving targeted therapies; and part 3-pleural mesothelioma. These reviews complement the Essential Knowledge in Interventional Pulmonology Lecture Series presented at the 2023 AABIP Annual Conference, available for viewing on the AABIP website (https://aabip.memberclicks.net/essential-knowledge-in-interventional-pulmonology-series).
• Irfan, H., Filsuf, D., Mooney, K. L., Bedi, H., & Shaller, B. D. (2023). Endobronchial Ultrasound-guided Transbronchial Needle Aspiration of Primary Cardiac Synovial Sarcoma of the Left Ventricle. American journal of respiratory and critical care medicine, 207(9), e73-e74.
• Shaller, B. D., Filsoof, D., Pineda, J. M., & Gildea, T. R. (2022). Malignant Central Airway Obstruction: What's New?. Seminars in Respiratory and Critical Care Medicine. doi:10.1055/s-0042-1748187
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  Abstract Malignant central airway obstruction (MCAO) is a debilitating and life-limiting complication that occurs in an unfortunately large number of individuals with advanced intrathoracic cancer. Although the management of MCAO is multimodal and interdisciplinary, the task of providing patients with prompt palliation falls increasingly on the shoulders of interventional pulmonologists. While a variety of tools and techniques are available for the management of malignant obstructive lesions, advancements and evolution in this therapeutic venue have been somewhat sluggish and limited when compared with other branches of interventional pulmonary medicine (e.g., the early diagnosis of peripheral lung nodules). Indeed, one pragmatic, albeit somewhat uncharitable, reading of this article's title might suggest a wry smile and shug of the shoulders as to imply that relatively little has changed in recent years. That said, the spectrum of interventions for MCAO continues to expand, even if at a less impressive clip. Herein, we present on MCAO and its endoscopic and nonendoscopic management-that which is old, that which is new, and that which is still on the horizon.
• Shaller, B. D., Filsoof, D., Pineda, J. M., & Gildea, T. R. (2022). Malignant Central Airway Obstruction: What's New?. Seminars in respiratory and critical care medicine, 43(4), 512-529.
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  Malignant central airway obstruction (MCAO) is a debilitating and life-limiting complication that occurs in an unfortunately large number of individuals with advanced intrathoracic cancer. Although the management of MCAO is multimodal and interdisciplinary, the task of providing patients with prompt palliation falls increasingly on the shoulders of interventional pulmonologists. While a variety of tools and techniques are available for the management of malignant obstructive lesions, advancements and evolution in this therapeutic venue have been somewhat sluggish and limited when compared with other branches of interventional pulmonary medicine (e.g., the early diagnosis of peripheral lung nodules). Indeed, one pragmatic, albeit somewhat uncharitable, reading of this article's title might suggest a wry smile and shug of the shoulders as to imply that relatively little has changed in recent years. That said, the spectrum of interventions for MCAO continues to expand, even if at a less impressive clip. Herein, we present on MCAO and its endoscopic and nonendoscopic management-that which is old, that which is new, and that which is still on the horizon.
• Filsoof, D., Im, J. H., Garcia, P. A., Stedman, M., Anand, S., Neal, J. W., Wakelee, H. A., Ramchandran, K., Das, M., Padda, S. K., Sharifi, H., Mooney, J. J., Tsai, E. B., Lin, M., Guo, H. H., Leung, A. N., Katsumoto, T. R., Boer, K. d., & Raj, R. (2021). Pragmatic Application of Computed Tomography Lung Texture Analysis in Immune Checkpoint Inhibitor Pneumonitis: An Exploratory Study. American Thoracic Society International Conference 2021. doi:10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a1882
• Filsoof, D., Padda, S. K., Garcia, P. A., Stedman, M., Neal, J. W., Wakelee, H. A., Ramchandran, K., Das, M., Ramsey, M., Bedi, H., Sung, A., Raj, R., Anand, S., Boer, K. d., & Katsumoto, T. R. (2021). Immune Checkpoint Inhibitor Pneumonitis: Heterogeneity in Clinical Management. American Thoracic Society International Conference 2021. doi:10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a2116
• Murag, S., Murag, S., Melehani, J. H., Melehani, J. H., Filsoof, D., Filsoof, D., Nadeau, K., Nadeau, K., Chinthrajah, R. S., & Chinthrajah, R. S. (2021). DUPILUMAB UNMASKS EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS. Chest 2021 Annual Meeting. doi:10.1016/j.chest.2021.07.065
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  TOPIC: Allergy and Airway TYPE: Medical Student/Resident Case Reports INTRODUCTION: In 2018, dupilumab became the first fully human monoclonal antibody targeting both IL-4 and IL-13 cytokines which initiate type 2 helper T-cell inflammatory pathways behind eosinophilic and allergic diseases. The beneficial effects of dupilumab for treating atopic dermatitis and refractory asthma have been well recognized (1,2), but it has also been associated with adverse events such as transient eosinophilia in clinical trials (3,4) as well as in case studies (5,6,7). CASE PRESENTATION: We describe the case of a 41-year-old Caucasian male with a history of food allergies, atopic dermatitis and allergic rhinitis who developed eosinophilic granulomatosis with polyangiitis (EGPA) after the administration of dupilumab. Remote clinical history included nasal polyposis, treated with functional endoscopic sinus surgery. Given persistent symptoms of asthma and intolerance to treatment with high dose corticosteroids, he started add-on dupilumab every 2 weeks. His baseline absolute eosinophil count (AEC) was normal at 10 cells/mm3 at the start of therapy. However, within 3 months of treatment, he developed symptoms of chest pain with deep breathing, continued shortness of breath, and numbness in his hands and feet. Six months after starting dupilumab, the AEC rose to 1250 cells/mm3. An extensive workup including FISH sequencing for FIP1L1-PDGFRA, flow cytometry, vitamin B12, and antibodies to Strongyloides stercoralis was negative. CT chest demonstrated ground glass opacities in the left upper lobe that resolved with steroids. With the new onset eosinophilia, polyneuropathy and transient pulmonary opacities, he met the 1990 ACR criteria for and was diagnosed anti-neutrophil cytoplasmic antibody (ANCA) negative eosinophilic granulomatosis with polyangiitis (EGPA). Dupilumab was discontinued and he began treatment with an anti-IL-5 monoclonal antibody, mepolizumab, with improvement of his AEC to 0.3 cells/mm3. Respiratory and neurological symptoms improved. DISCUSSION: EGPA is a granulomatous eosinophilic vasculitis characterized by symptoms of systemic vasculitis, allergic rhinitis, and asthma in the setting of eosinophilia. Dupilumab has been shown to decrease the frequency of asthma exacerbations and improve lung function regardless of baseline eosinophil count.8 The rapid withdrawal of corticosteroid therapy, due to the efficacy of dupilumab, may result in the unmasking of underlying EGPA. A similar unmasking EGPA phenomenon has been described with the initiation of leukotriene receptor antagonists such as montelukast. In addition, dupilumab may directly perturb mechanisms of eosinophilic activation and homeostasis in some individuals9 leading to persistent eosinophilia. CONCLUSIONS: To our knowledge, this is the first case to highlight unmasking of EGPA as a consequence of dupilumab treatment. REFERENCE #1: Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. The Lancet. 2017;389(10086):2287-2303. doi:10.1016/S0140-6736(17)31191-1 REFERENCE #2: Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44. doi:10.1016/S0140-6736(16)30307-5 REFERENCE #3: Rabe KF, Nair P, Brusselle G, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. New England Journal of Medicine. 2018;378(26):2475-2485. doi:10.1056/NEJMoa1804093 DISCLOSURES: No relevant relationships by R. Sharon Chinthrajah, source=Web Response No relevant relationships by Darius Filsoof, source=Web Response No relevant relationships by Jason Melehani, source=Web Response No relevant relationships by Soumya Murag, source=Web Response Advisor relationship with Cour Pharma Please note: 2018-current Added 05/05/2021 by Kari Nadeau, source=Web Response, value=stock Removed 05/05/2021 by Kari Nadeau, source=Web Response Co-founder relationship with Before Brands Please note: 2018-present Added 05/05/2021 by Kari Nadeau, source=Web Response, value=stock Advisor relationship with Cour Pharma Please note: 2018-present Added 05/05/2021 by Kari Nadeau, source=Web Response, value=Stocks Co-founder relationship with AllAdapt Please note: 2018-present Added 05/05/2021 by Kari Nadeau, source=Web Response, value=stocks Co-founder relationship with Latitude Please note: 2018-present Added 05/05/2021 by Kari Nadeau, source=Web Response, value=Stocks Co-founder relationship with IgGenix Please note: 2018-present Added 05/05/2021 by Kari Nadeau, source=Web Response, value=Stocks
• Daniel, J. A., Pellegrini, M., Lee, B. S., Guo, Z., Filsuf, D., Belkina, N. V., You, Z., Paull, T. T., Sleckman, B. P., Feigenbaum, L., & Nussenzweig, A. (2012). Loss of ATM kinase activity leads to embryonic lethality in mice. The Journal of cell biology, 198(3), 295-304.
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  Ataxia telangiectasia (A-T) mutated (ATM) is a key deoxyribonucleic acid (DNA) damage signaling kinase that regulates DNA repair, cell cycle checkpoints, and apoptosis. The majority of patients with A-T, a cancer-prone neurodegenerative disease, present with null mutations in Atm. To determine whether the functions of ATM are mediated solely by its kinase activity, we generated two mouse models containing single, catalytically inactivating point mutations in Atm. In this paper, we show that, in contrast to Atm-null mice, both D2899A and Q2740P mutations cause early embryonic lethality in mice, without displaying dominant-negative interfering activity. Using conditional deletion, we find that the D2899A mutation in adult mice behaves largely similar to Atm-null cells but shows greater deficiency in homologous recombination (HR) as measured by hypersensitivity to poly (adenosine diphosphate-ribose) polymerase inhibition and increased genomic instability. These results may explain why missense mutations with no detectable kinase activity are rarely found in patients with classical A-T. We propose that ATM kinase-inactive missense mutations, unless otherwise compensated for, interfere with HR during embryogenesis.
• Daniel, J. A., Santos, M. A., Wang, Z., Zang, C., Schwab, K. R., Jankovic, M., Filsuf, D., Chen, H. T., Gazumyan, A., Yamane, A., Cho, Y. W., Sun, H. W., Ge, K., Peng, W., Nussenzweig, M. C., Casellas, R., Dressler, G. R., Zhao, K., & Nussenzweig, A. (2010). PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science (New York, N.Y.), 329(5994), 917-23.
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  Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here, we showed that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3)-MLL4 complex display impaired trimethylation of histone 3 at lysine 4 (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus, leading to defective immunoglobulin class switching. We also showed that PTIP accumulation at DSBs contributes to class switch recombination (CSR) and genome stability independently of Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR and suggest a nonredundant role for the MLL3-MLL4 complex in altering antibody effector function.