CT evaluation of lung infiltrates in the two months preceding the Coronavirus disease 19 pandemic in Canton Ticino (Switzerland): were there suspicious cases before the official first case?

PURPOSE: The main objective of this study was to assess the presence of pulmonary infiltrates with computed tomography (CT) appearance compatible with infection by coronavirus disease 2019 (COVID-19), in Canton Ticino in the 2 months preceding the first official case. Secondary aims were to compare the classification of infiltrates in the same time frame in 2020 and 2019; to compare the number of chest CT scans in the same period; to search for pathological confirmation of the virus. MATERIALS AND METHODS: Chest CT scans performed between January 1 and February 24 in 2019 and 2020 were collected and classified by COVID-19 Reporting and Data System (CO-RADS). Pathological presence of the virus was searched for when appropriate material was available. RESULTS: The final cohort included 881 patients. Among the CO-RADS 3 and 4 categories, 30 patients had pneumonitis of unknown etiology. Pathological specimens were available in six patients but they were negative for COVID-19. CONCLUSION: Before the first official case of COVID-19 infection, in Canton Ticino there were about 30 cases of pneumonitis of uncertain origin, with CT appearance compatible with infection by COVID-19, but with no confirmation of the disease. The number of chest CT scans in the first two months of 2020 was > 12% compared to 2019.

Correlation of KRAS G12C Mutation and High PD-L1 Expression with Clinical Outcome in NSCLC Patients Treated with Anti-PD1 Immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 improved the survival of non-small cell lung cancer (NSCLC) patients with PD-L1 expression ≥50% and without alterations in EGFR, ALK, ROS1, RET. However, markers able to predict the efficacy of ICIs, in combination with PD-L1 expression are still lacking. Our aim in this hypothesis-generating pilot study was to evaluate whether the KRAS G12C variant may predict the efficacy of ICIs in advanced NSCLC patients with PD-L1 ≥ 50%. METHODS: Genomic DNA or tissue sections of 44 advanced ICI-treated NSCLC cases with PD-L1 ≥ 50% without EGFR, ALK, ROS1, RET alterations were tested using Next Generation Sequencing, Fluorescence in Situ Hybridization and immunohistochemistry. Statistical analyses were carried out fitting univariate and multivariate time to event models. RESULTS: KRAS G12C mutant patients (N = 11/44) showed a significantly longer progression-free survival (PFS) at univariate and multivariate analyses (p = 0.03). The Kaplan-Meier plot of the PFS time-to-event supports that G12C positive patients have a longer time to progress. PFS improvement was not observed when any KRAS mutations were compared to wild-type cases. CONCLUSIONS: Given the limitations due to the small sample size and exploratory nature of this study, we tentatively conclude the KRAS G12C mutation should be considered in future trials as a predictive marker of prolonged response to first-line ICIs in NSCLC patients overexpressing PD-L1. This finding could be relevant as anti-KRAS G12C therapies enter the therapeutic landscape of NSCLC.

P1245 Polymorphic Variants of HSD3B1 Gene Confer Different Outcome in Specific Subgroups of Patients Infected With SARS-CoV-2.

Introduction: Severe respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the androgen receptor (AR), through ACE2 receptor and TMPRSS2, to enter nasal and upper airways epithelial cells. Genetic analyses revealed that HSD3B1 P1245C polymorphic variant increases dihydrotestosterone production and upregulation of TMPRSS2 with respect to P1245A variant, thus possibly influencing SARS-CoV-2 infection. Our aim was to characterize the HSD3B1 polymorphism status and its potential association with clinical outcomes in hospitalized patients with COVID-19 in Southern Switzerland. Materials and Methods: The cohort included 400 patients hospitalized for COVID-19 during the first wave between February and May 2020 in two different hospitals of Canton Ticino. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue blocks, and HSD3B1 gene polymorphism was evaluated by Sanger sequencing. Statistical associations were verified using different test. Results: HSD3B1 polymorphic variants were not associated with a single classical factor related to worse clinical prognosis in hospitalized patients with SARS-CoV-2. However, in specific subgroups, HSD3B1 variants played a clinical role: intensive care unit admission was more probable in patients with P1245C diabetes compared with P1245A individuals without this comorbidity and death was more associated with hypertensive P1245A>C cases than patients with P1245A diabetes without hypertension. Discussion: This is the first study showing that HSD3B1 gene status may influence the severity of SARS-CoV-2 infection. If confirmed, our results could lead to the introduction of HSD3B1 gene status analysis in patients infected with SARS-CoV-2 to predict clinical outcome.

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation.

Although reactivation and accumulation of autoreactive CD4+ T cells within the CNS are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the mechanisms of how these cells recognize their target organ and induce sustained inflammation are incompletely understood. Here, we report that mice with conditional deletion of the essential autophagy protein ATG5 in classical dendritic cells (DCs), which are present at low frequencies in the nondiseased CNS, are completely resistant to EAE development following adoptive transfer of myelin-specific T cells and show substantially reduced in situ CD4+ T cell accumulation during the effector phase of the disease. Endogenous myelin peptide presentation to CD4+ T cells following phagocytosis of injured, phosphatidylserine-exposing oligodendroglial cells is abrogated in the absence of ATG5. Pharmacological inhibition of ATG-dependent phagocytosis by the cardiac glycoside neriifolin, an inhibitor of the Na+, K+-ATPase, delays the onset and reduces the clinical severity of EAE induced by myelin-specific CD4+ T cells. These findings link phagocytosis of injured oligodendrocytes, a pathological hallmark of MS lesions and during EAE, with myelin antigen processing and T cell pathogenicity, and identify ATG-dependent phagocytosis in DCs as a key regulator in driving autoimmune CD4+ T cell-mediated CNS damage.