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Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune pathologies often associated with occult malignancies. Glucocorticoids (GCs) represent the initial therapy to control symptoms and avoid complications. Immune checkpoint inhibitors (ICIs) have shifted the paradigm of cancer treatment. Nivolumab has become the first-line therapy in combination with chemotherapy for untreated, unresectable, non-HER-2-positive advanced gastroesophageal adenocarcinoma. The use of ICIs increases the risk of immune-related adverse events (irAEs), especially in patients with autoimmune diseases, and patients receiving steroids or immunosuppressants might be associated with poorer immunotherapy efficacy. We describe the case of a 49-year-old male who was diagnosed with paraneoplastic dermatomyositis (PDM) and gastroesophageal adenocarcinoma. He was started on prednisone taper, and concomitantly, he was started on chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), with administration of pegfilgrastim and dexamethasone during each cycle. Additionally, he was started on nivolumab. His course was complicated by worsening episodes of myopathies due to the immunotherapy, requiring adjustments to the prednisone taper. A positron emission tomography (PET) scan and repeat endoscopic ultrasonography with biopsy eight months after therapy initiation showed no major evidence of disease compared to prior. In our case, we exemplified the importance of multidisciplinary management for dosing and tapering of GCs and timing of ICI initiation, and we described the successful response to nivolumab in a patient with autoimmune disease concurrently receiving GCs., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Poli De Frias et al.)

Balo's concentric sclerosis (BCS) is a rare demyelinating disorder of the central nervous system (CNS). Distinguishing BCS from other demyelinating disorders such as multiple sclerosis (MS) or from neoplasms can be difficult clinically; however, MRI aids in the identification of the disease. We describe the case of a 37-year-old female presenting with sudden onset of neurologic symptoms associated with a solitary rounded white-matter lesion suggestive of BCS. This rare disorder can present with heterogenous symptoms, imaging findings, and response to treatment. Furthermore, more in-depth analysis of the presentations and treatment outcomes of BCS are necessary in order to create a more robust plan of care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Vickaryous et al.)

Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-γ (IFN-γ) and T-box expressed in T cells (TBET) dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we found that pharmacological inhibition of phosphorylated SH2-containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFN-γ abundance, decreased large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8 + T cells. Mechanistically, we identified a posttranslational modification pathway in which the E3 F-box protein S-phase kinase-associated protein 2 (SKP2) targets TBET for ubiquitination in T cells under normal conditions. However, this pathway was disrupted by aberrant pSHP2 signaling in CD8 + T cells from patients with progressive pulmonary sarcoidosis and end-stage disease. Ex vivo inhibition of pSHP2 in CD8 + T cells from patients with end-stage sarcoidosis enhanced TBET ubiquitination and suppressed IFN-γ and collagen synthesis. Therefore, these studies provided new mechanistic insights into the SHP2-dependent posttranslational regulation of TBET and identified SHP2 inhibition as a potential therapeutic intervention against severe sarcoidosis. Furthermore, these studies also suggest that the small-molecule SHP2 inhibitor SHP099 might be used as a therapeutic measure against human diseases linked to TBET or ubiquitination.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initially infects and replicates in epithelial cells of the nasopharynx where there are relatively high levels of angiotensin-converting enzyme 2 receptor, which correlates with the highest sensitivity time point of the nasopharyngeal swab (NPS) real-time polymerase chain reaction (RT-PCR) during the first week, with subsequent decline thereafter. As viral shedding progresses throughout the respiratory tract, the virus can be detectable for up to 30 days in bronchoalveolar fluids. This report presents three cases of acute respiratory distress in the setting of multifocal pneumonia, with multiple false-negative NPS SARS-CoV-2/RT-PCR but positive SARS-CoV-2/RT-PCR in bronchoalveolar lavage (BAL) samples. Molecular RT-PCR testing remains the gold standard in the diagnosis of SARS-CoV-2 infection. However, the diagnostic accuracy of NPS RT-PCR may be affected by several factors. SARS-CoV-2/RT-PCR in BAL samples increases the diagnostic yield for coronavirus disease 2019 pneumonia; however, it is not widely available in many institutions and can be clinically challenging to perform. A multimodal approach is required for prompt diagnosis, especially in patients with a progressive disease, where a delay in therapy can be clinically detrimental., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Poli De Frias et al.)

Background: Coronavirus Disease 2019 (COVID-19) can lead to the development of acute respiratory distress syndrome (ARDS). In some patients with non-resolvable (NR) COVID-19, lung injury can progress rapidly to the point that lung transplantation is the only viable option for survival. This fatal progression of lung injury involves a rapid fibroproliferative response and takes on average 15 weeks from initial symptom presentation. Little is known about the mechanisms that lead to this fulminant lung fibrosis (FLF) in NR-COVID-19., Methods: Using a pre-designed unbiased PCR array for fibrotic markers, we analyzed the fibrotic signature in a subset of NR-COVID-19 lungs. We compared the expression profile against control lungs (donor lungs discarded for transplantation), and explanted tissue from patients with idiopathic pulmonary fibrosis (IPF). Subsequently, RT-qPCR, Western blots and immunohistochemistry were conducted to validate and localize selected pro-fibrotic targets. A total of 23 NR-COVID-19 lungs were used for RT-qPCR validation., Findings: We revealed a unique fibrotic gene signature in NR-COVID-19 that is dominated by a hyper-expression of pro-fibrotic genes, including collagens and periostin. Our results also show a significantly increased expression of Collagen Triple Helix Repeat Containing 1(CTHRC1) which co-localized in areas rich in alpha smooth muscle expression, denoting myofibroblasts. We also show a significant increase in cytokeratin (KRT) 5 and 8 expressing cells adjacent to fibroblastic areas and in areas of apparent epithelial bronchiolization., Interpretation: Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19., Funding: National Institute of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DoD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167-01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y., Competing Interests: Declaration of interests All authors declare no conflict of interest except for HJH who served as speaker and advisory panel member for Boehringer Ingelheim for Nintedanib., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)