Clinical Post-SARS-CoV-2 Infection Scenarios in Vaccinated and Non-Vaccinated Cancer Patients in Three German Cancer Centers: A Retrospective Analysis.

COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients

Characterizing the NF-κB signaling pathway in Arid1a-deficient PDAC subtypes

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, fast proliferating disease with an overall 5-year survival rate of less than 8%. Although therapeutic options have increased within the last years, the extreme molecular heterogeneity remains a major problem. In order to target the genetic background of the different tumor subtypes, patient individualized and subtype-specific therapies are an important opportunity.  The tumor suppressor gene ARID1A, a member of the SWI/SNF chromatin remodeling complex, is often mutated in different tumor entities. Its loss of function correlates with inflammatory phenotypes. In 20% of PDAC specimen a mutation along with a loss of function of ARID1A could be shown. Therefore, targeting inflammatory pathways such as the NFκB-signaling or the JAK-STAT pathway may be a potential therapeutic strategy in ARID1A-deficient tumor subtypes. To investigate the role of ARID1A loss in controlling the inflammatory environment, IHC staining was performed comparing PDACs in mice with or without conditional ARID1A mutation. Different TFs in ARID1A wildtype and knockout (CRISPR/CAS9) cells were analyzed using Western blot and immunofluorescence. QRT-PCR and cytokine ELISA demonstrated the upregulated expression of inflammatory cytokines. Luciferase assays were used to analyze the transactivation of a NFκB-responsive Promoter. The functional effects of blocking inflammatory signaling pathways were investigated by Annexin/PI- and BrdU-based flow cytometry. Cytokine expression and secretion were upregulated in the context of ARID1A loss. The analysis of the JAK-STAT and the NFκB-signaling pathways showed an increased activation in different signaling specific subunits and an enhanced transcription of target genes. Additionally, Annexin/PI staining revealed an ARID1A-dependent induction of apoptosis. Loss of ARID1A expression leads to an upregulation of inflammation, a trigger of carcinogenesis. A change in the transcription of cytokines resulted in increased secretion of inflammatory cytokines in the context of ARID1A-deficiency. Therefore, targeting inflammatory signaling pathways such as the NFκB or the JAK-STAT pathway could be a promising therapeutic option in ARID1A-deficient PDAC.2021-08-2