Anaplastic thyroid carcinoma (ATC) is a deadly disease with very limited therapeutic options. There is an urgent need for new and efficacious drugs. Unfortunately accrual in clinical trials is problematic because of the rarity of the disease and often poor performance status at diagnosis. Recently some data have emerged suggesting a role for immunotherapy in the treatment of ATC. We describe the case of a 75-year-old patient with poor performance status and compromised airway and oesophagus at diagnosis, showing a rapid and dramatic response to first line single agent pembrolizumab. Disease progression in the brain occurred 16 months after initial diagnosis. At that time there was ongoing extracranial disease control.

Aims Viral myocarditis (VM) is an inflammatory pathology of the myocardium triggered by a viral infection that may cause sudden death or heart failure, especially in the younger population. Current treatments only stabilise and improve cardiac function without resolving the underlying inflammatory cause. The factors that induce VM to progress to heart failure are still uncertain, but neutrophils have been increasingly associated with the negative evolution of cardiac pathologies. The present study investigates the contribution of neutrophils to VM disease progression in different ways. Methods and Results In a Coxsackievirus B3- (CVB3) induced mouse model of VM, neutrophils and neutrophil extracellular traps (NETs) were prominent in the acute phase of VM as revealed by ELISA analysis and immunostaining. Anti-Ly6G-mediated neutrophil blockade starting at model induction decreased cardiac necrosis and leukocyte infiltration, preventing monocyte and Ly6CHigh pro-inflammatory macrophage recruitment. Furthermore, genetic peptidylarginine deiminase 4 (PAD4)-dependent NET blockade significantly reduced cardiac damage and leukocyte recruitment, significantly decreasing cardiac monocyte and macrophage presence. Depleting neutrophils with anti-Ly6G antibodies at 7 days post-infection, after the acute phase, did not decrease cardiac inflammation. Conclusions Collectively, these results indicate that the repression of neutrophils and the related NET response in the acute phase of VM improves the pathological phenotype by reducing cardiac inflammation. Translational perspective Viral myocarditis (VM) is a form of acute heart failure prompted by viral infection that still lacks a specific therapy addressing the cardiac inflammation causing the disease. Increasing evidence suggests that neutrophils actively contribute to the severity of inflammatory and cardiovascular pathologies. Our study demonstrates that inhibition of neutrophil functions in the early phases of VM decreases cardiac damage and inflammation and, therefore, may be considered a very early therapeutic strategy in preventing disease progression.

Background Venous thromboembolism (VTE) frequently occurs in hospitalized patients with coronavirus disease 2019 (COVID‐19). The optimal dose of anticoagulation for thromboprophylaxis in COVID‐19 is unknown. Aims To report VTE incidence and bleeding before and after implementing a hospital‐wide intensified thromboprophylactic protocol in patients with COVID‐19. Methods On March 31, 2020, we implemented an intensified thromboprophylactic protocol consisting of 50 IU anti‐Xa low molecular weight heparin (LMWH)/kg once daily at the ward, twice daily at the intensive care unit (ICU). We included all patients hospitalized in a tertiary care hospital with symptomatic COVID‐19 between March 7 and July 1, 2020. The primary outcome was the incidence of symptomatic or subclinical VTE and major bleeding during admission. Routine ultrasound screening for VTE was performed whenever logistically possible. Results We included 412 patients, of which 116 were admitted to the ICU. Of 219 patients with standard a prophylactic dose of LMWH, 16 (7.3%) had VTE, 10 of which were symptomatic (4.6%). Of 193 patients with intensified thromboprophylaxis, there were no symptomatic VTE cases, three incidental deep venous thrombosis cases (1.6%), and one incidental pulmonary embolism (0.5%). The major bleeding rate was 1.2% in patients with intensified thromboprophylaxis and 7.7% when therapeutic anticoagulation was needed. Conclusion In hospitalized patients with COVID‐19, there were no additional symptomatic VTEs and a reduction in incidental deep vein thrombosis after implementing systematic thromboprophylaxis with weight‐adjusted prophylactic (ward) to intermediate (ICU), but not therapeutic dosed anticoagulation. This intensified thromboprophylaxis was associated with a lower risk of major bleeding compared with therapeutic dosed anticoagulation.

IMPORTANCE: Myeloperoxidase (MPO)-DNA complexes, biomarkers of neutrophil extracellular traps (NETs), have been associated with arterial and venous thrombosis. Their role in aneurysmal subarachnoid hemorrhage (aSAH) is unknown. OBJECTIVES: To assess whether serum MPO-DNA complexes are present in patients with aSAH and whether they are associated with delayed cerebral ischemia (DCI). DESIGN, SETTING, AND PARTICIPANTS: Post-hoc analysis of a prospective, observational single-center study, with de novo serum biomarker measurements in consecutive patients with aSAH between July 2018 and September 2020, admitted to a tertiary care neuroscience ICU. MAIN OUTCOMES AND MEASURES: We analyzed serum obtained at admission and hospital day 4 for concentrations of MPO-DNA complexes. The primary outcome was DCI, defined as new infarction on brain CT. The secondary outcome was clinical vasospasm, a composite of clinical and transcranial Doppler parameters. We used Wilcoxon signed-rank-test to assess for differences between paired measures. RESULTS: Among 100 patients with spontaneous subarachnoid hemorrhage, mean age 59 years (sd ± 13 yr), 55% women, 78 had confirmed aSAH. Among these, 29 (37%) developed DCI. MPO-DNA complexes were detected in all samples. The median MPO-DNA level was 33 ng/mL (interquartile range [IQR], 18–43 ng/mL) at admission, and 22 ng/mL (IQR, 11–31 ng/mL) on day 4 (unpaired test; p = 0.015). We found a significant reduction in MPO-DNA levels from admission to day 4 in patients with DCI (paired test; p = 0.036) but not in those without DCI (p = 0.17). There was a similar reduction in MPO-DNA levels between admission and day 4 in patients with (p = 0.006) but not in those without clinical vasospasm (p = 0.47). CONCLUSIONS AND RELEVANCE: This is the first study to detect the NET biomarkers MPO-DNA complexes in peripheral serum of patients with aSAH and to associate them with DCI. A pronounced reduction in MPO-DNA levels might serve as an early marker of DCI. This diagnostic potential of MPO-DNA complexes and their role as potential therapeutic targets in aSAH should be explored further.

Background Thromboinflammation plays a central role in severe COVID‐19. The kallikrein pathway activates both inflammatory pathways and contact‐mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID‐19 patients. Methods In this multicenter open‐label randomized clinical trial (EudraCT 2020‐001739‐28), patients hospitalized with COVID‐19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin‐1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2‐point improvement on the 7‐point World Health Organization ordinal scale for clinical status, or discharge. Findings Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N = 67 vs. SOC N = 35). Twenty‐five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50‐1.19], p = 0.24) or mortality (intervention n = 3 [4.6%] vs. SOC n = 2 [5.7%], HR 0.82 [CI 0.14‐4.94], p = 0.83). There was one treatment‐related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding. Conclusions In hospitalized COVID‐19 patients, modulation of thromboinflammation with high‐dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID‐19.