, the outbreak of coronavirus disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV) 2 (SARS-CoV-2), has led within a few months to a major global health and economic crisis. As of October 2020, more than 40 million confirmed cases have been reported worldwide, with nearly 1 million deaths, affecting 189 countries. 1 The respiratory tract is considered the main target of SARS-CoV-2 infection and a small subset of infected individuals becomes severely ill and may develop acute respiratory distress syndrome (ARDS) with potentially fatal outcome. 2 More recently, systemic features of the disease with the involvement of organs outside the respiratory tract, including the liver and gastrointestinal tract are receiving increasing attention, indicating that COVID-19 may be considered as a systemic infectious and inflammatory disease. 3-7 Although closely related to other Corona virus (CoV) family members SARS-CoV and MERS-CoV (Middle East Respiratory Syndrome CoV), infections with the new SARS-CoV-2 exhibit a different pathological pattern and the mechanistic link between CoVs-induced molecular pathophysiological changes and clinical manifestations remains incompletely understood.

Background and Aims Cholestasis is associated with disease severity and worse outcome in COVID‐19. Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection have been described. Approach and Results Hospitalized patients with COVID‐19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non‐advanced CLD (non‐ACLD), or (iii) advanced CLD (ACLD). Patients with CLD and non–COVID‐19 pneumonia were matched to patients with CLD and COVID‐19 as a control cohort. Liver chemistries before (Pre) and at first, second, and third blood withdrawal after SARS‐CoV‐2 infection (T1–T3) and at last available time point (last) were recorded. A total of 496 patients were included. In total, 13.1% ( n = 65) had CLD (non‐ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was NAFLD/NASH (60.0%). COVID‐19–related liver injury was more common among patients with CLD (24.6% vs. 10.6%; p = 0.001). After SARS‐CoV‐2 infection, patients with CLD exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (Pre: 91.0 vs. T1: 121.0 vs. last: 175.0 U/L; p < 0.001) and gamma‐glutamyl transferase (Pre: 95.0 vs. T1: 135.0 vs. last: 202.0 U/L; p = 0.001). A total of 23.1% of patients with CLD ( n = 15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6 mg/dl) during COVID‐19, and 15.4% of patients ( n = 10/65) developed SSC. SSC was significantly more frequent among patients with CLD and COVID‐19 than in patients with CLD and non–COVID‐19 pneumonia ( p = 0.040). COVID‐19–associated SSC occurred predominantly in patients with NAFLD/NASH and metabolic risk factors. A total of 26.3% ( n = 5/19) of patients with ACLD experienced hepatic decompensation after SARS‐CoV‐2 infection. Conclusions About 20% of patients with CLD develop progressive cholestasis after SARS‐CoV‐2 infection. Patients with NAFLD/NASH and metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID‐19.

Background Duration of invasive mechanical ventilation (IMV) prior to extracorporeal membrane oxygenation (ECMO) affects outcome in acute respiratory distress syndrome (ARDS). In coronavirus disease 2019 (COVID-19) related ARDS, the role of pre-ECMO IMV duration is unclear. This single-centre, retrospective study included critically ill adults treated with ECMO due to severe COVID-19-related ARDS between 01/2020 and 05/2021. The primary objective was to determine whether duration of IMV prior to ECMO cannulation influenced ICU mortality. Results During the study period, 101 patients (mean age 56 [SD ± 10] years; 70 [69%] men; median RESP score 2 [IQR 1–4]) were treated with ECMO for COVID-19. Sixty patients (59%) survived to ICU discharge. Median ICU length of stay was 31 [IQR 20.7–51] days, median ECMO duration was 16.4 [IQR 8.7–27.7] days, and median time from intubation to ECMO start was 7.7 [IQR 3.6–12.5] days. Fifty-three (52%) patients had a pre-ECMO IMV duration of > 7 days. Pre-ECMO IMV duration had no effect on survival (p = 0.95). No significant difference in survival was found when patients with a pre-ECMO IMV duration of < 7 days (< 10 days) were compared to ≥ 7 days (≥ 10 days) (p = 0.59 and p = 1.0). Conclusions The role of prolonged pre-ECMO IMV duration as a contraindication for ECMO in patients with COVID-19-related ARDS should be scrutinised. Evaluation for ECMO should be assessed on an individual and patient-centred basis.

Mast cell neoplasms are one of the most frequently diagnosed malignancies in dogs. The clinical picture, course, and prognosis vary substantially among patients, depending on the anatomic site, grade and stage of the disease. The most frequently involved organ is the skin, followed by hematopoietic organs (lymph nodes, spleen, liver, and bone marrow) and mucosal sites of the oral cavity and the gastrointestinal tract. In cutaneous mast cell tumors, several grading and staging systems have been introduced. However, no comprehensive classification and no widely accepted diagnostic criteria have been proposed to date. To address these open issues and points we organized a Working Conference on canine mast cell neoplasms in Vienna in 2019. The outcomes of this meeting are summarized in this article. The proposed classification includes cutaneous mast cell tumors and their sub-variants defined by grading- and staging results, mucosal mast cell tumors, extracutaneous/extramucosal mast cell tumors without skin involvement, and mast cell leukemia (MCL). For each of these entities, diagnostic criteria are proposed. Moreover, we have refined grading and staging criteria for mast cell neoplasms in dogs based on consensus discussion. The criteria and classification proposed in this article should greatly facilitate diagnostic evaluation and prognostication in dogs with mast cell neoplasms and should thereby support management of these patients in daily practice and the conduct of clinical trials.

Ponatinib is the only approved tyrosine kinase inhibitor (TKI) suppressing BCR-ABL1 T315I-mutated cells in chronic myeloid leukemia (CML). However, due to side effects and resistance, BCR-ABL1 T315I-mutated CML remains a clinical challenge. Hydroxyurea (HU) has been used for cytoreduction in CML for decades. We found that HU suppresses or even eliminates BCR-ABL1 T315I + sub-clones in heavily pretreated CML patients. Based on this observation, we investigated the effects of HU on TKI-resistant CML cells in vitro. Methods: Viability, apoptosis and proliferation of drug-exposed primary CML cells and BCR-ABL1+ cell lines were examined by flow cytometry and 3 H-thymidine-uptake. Expression of drug targets was analyzed by qPCR and Western blotting. Findings: HU was more effective in inhibiting the proliferation of leukemic cells harboring BCR-ABL1 T315I or T315I-including compound-mutations compared to cells expressing wildtype BCR-ABL1. Moreover, HU synergized with ponatinib and ABL001 in inducing growth inhibition in CML cells. Furthermore, HU blocked cell cycle progression in leukemic cells, which was accompanied by decreased expression of CDK4 and CDK6. Palbociclib, a more specific CDK4/CDK6-inhibitor, was also found to suppress proliferation in primary CML cells and to synergize with ponatinib in producing growth inhibition in BCR-ABL1 T315I + cells, suggesting that suppression of CDK4/CDK6 may be a promising concept to overcome BCR-ABL1 T315I-associated TKI resistance. Interpretation: HU and the CDK4/CDK6-blocker palbociclib inhibit growth of CML clones expressing BCR-ABL1 T315I or complex T315I-including compound-mutations. Clinical studies are required to confirm single drug effects and the efficacy of`ponatinib+HUandponatinib+palbociclibcombinations in advanced CML. Funding: This project was supported by the Austrian Science Funds (FWF) projects F4701-B20, F4704-B20 and P30625.