Susceptibility of healthcare personnel with severe acute respiratory coronavirus virus 2 (SARS-CoV-2) hybrid immunity to XBB lineage reinfection.

Among 8,678 vaccinated healthcare personnel (HCP) with previous coronavirus disease 2019 (COVID-19), by August 28, 2023, 909 (10%) had an infection of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) omicron XBB variant. Reinfection risk was comparable irrespective of previous infection type except for the omicron BQ.1 variant. Bivalent vaccination had a protective effect. COVID-19 vaccines remain vital to protect HCP, including those with hybrid immunity.

PDGFRß Signaling Cooperates with ß-Catenin to Modulate c-Abl and Biologic Behavior of Desmoid-Type Fibromatosis.

PURPOSE: This study sought to identify ß-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRß), affect these targets to alter natural history or treatment response in patients. EXPERIMENTAL DESIGN: In vitro experiments utilized primary desmoid cell lines to examine regulation of ß-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies. RESULTS: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a ß-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRß signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRß and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRß/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment. CONCLUSIONS: The ß-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.

A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma.

PURPOSE: Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes. PATIENTS AND METHODS: This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1. RESULTS: Thirty patients were enrolled [60% male; median age 54 years (range, 24-78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%-17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9-26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway-related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline. CONCLUSIONS: Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.

Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 3 (FGFR3) occur in ∼15% of muscle-invasive bladder cancers (MIBCs) and metastatic urothelial carcinomas (mUCs). OBJECTIVE: To determine the association between FGFR3 status and response to platinum-based chemotherapy in patients with MIBC or mUC. DESIGN, SETTING, AND PARTICIPANTS: The authors conducted a retrospective review and comparison of patients having (1) MIBC treated with neoadjuvant chemotherapy (NAC), (2) mUC treated with first-line platinum-based chemotherapy (M1 cohort), and (3) MIBC who were from The Cancer Genome Atlas (TCGA). INTERVENTION: Platinum-based chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pathologic response, recurrence-free (RFS) or progression-free (PFS) survival, and overall survival (OS) were compared between patients with FGFR3 alteration (FGFR3alt) and those without it (FGFR3wild type [FGFR3wt]) in the three cohorts. RESULTS AND LIMITATIONS: Nine of 72 NAC patients (13%) had FGFR3alt, of whom none had pathologic complete response and three had residual non-MIBC (carcinoma in situ, n = 1; pT1, n = 2). FGFR3alt was associated with shorter RFS (hazard ratio, 2.74; p = 0.044) but not OS. Among TCGA patients who underwent adjuvant chemotherapy (n = 74), FGFR3alt patients had shorter RFS as well. Conversely, among chemotherapy-naive TCGA patients, FGFR3alt was associated with longer RFS and OS. In the M1 cohort (FGFR3alt, n = 27; FGFR3wt, n = 81), FGFR3alt was associated with higher rates of pulmonary metastases and nonregional lymphadenopathy. Despite lower response rates among FGFR3alt patients (37% vs 49%; p = 0.056), PFS and OS were not significantly different from FGFR3wt patients. CONCLUSIONS: FGFR3 status is associated with lower responses to platinum-based chemotherapy, which may prompt exploration of nonchemotherapeutic approaches for perioperative management of FGFR3alt urothelial cancers. PATIENT SUMMARY: Approximately 15% of bladder cancers harbor mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Our findings suggest that FGFR3 mutations might be associated with lower responses and shorter time to recurrence among patients with muscle-invasive bladder cancer who received perioperative platinum-based chemotherapy. FGFR3 status does not significantly impact response to chemotherapy among those with metastatic urothelial cancers.