Citations

3134 Background: Mucinous breast cancer (MuBC) is a rare subtype of invasive ductal carcinoma (IDC) that accounts for less than 2% of all breast cancers and is associated with a favorable prognosis. Since MuBCs are rare in clinical trials, current treatment guidelines are extrapolated from IDC-no special type (IDC-NST). To provide better understanding of MuBCs and factors contributing to their clinical behavior, we examined the transcriptomic profiles of MuBCs in our FLEX study. Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III breast cancer patients who receive MammaPrint (MP)/BluePrint (BP) testing and consent to full transcriptome and clinical data collection. For this study, histologically confirmed MuBCs (n = 102) in the FLEX database were included. All patients examined were ER+/HER2- by immunohistochemistry and Luminal by BP. MuBC was compared with IDC matched for Age, MP, and BP index (n = 97). Differential gene expression analyses (DGEA) were performed with R package ‘limma’ and differentially expressed genes (DEGs) were considered significant if they had an adjusted p < 0.05 and fold change ≥ 2. Results: DGEA comparing MuBC (n = 102) with IDC (n = 97) revealed 60 DEGs, regardless of the genomic risk, of which 42 genes were upregulated and 18 were downregulated in MuBC relative to IDC. Genes associated with MuBC, such as MUC2, TFF1, CARTPT were among the upregulated genes. Of the 102 MuBC patients, 56 were Luminal A (MP Low Risk-LR) and 46 were Luminal B (MP High Risk-HR) by MammaPrint and BluePrint. Comparison of LR MuBC with LR IDC revealed 111 DEGs. Functional enrichment showed upregulation of pathways involved in estrogen response (early & late) and androgen response and a downregulation of the epithelial to mesenchymal transition (EMT) and E2F pathways in LR MuBC compared to LR IDC. DGEA between HR MuBC and HR IDC revealed only 22 DEGs with immune pathways being downregulated in HR MuBC. DGEA comparing LR MuBC with HR MuBC resulted in 63 DEGs, indicating LR and HR MuBC are biologically distinct types. Interestingly in LR MuBC, the tumor suppressor marker SCUBE2 is upregulated. Over expression of SCUBE2 is associated with better prognosis. Conclusions: Although MuBCs are often expected to have low clinical risk, MP revealed that half of the MuBCs examined in this study were MP High Risk (Luminal B). MP low risk MuBC is biologically different from MP low risk IDC, and downregulation of E2F and EMT pathways might lead to favorable prognoses in MP low risk MuBC. MP high risk MuBC showed limited DEGs compared to high-risk IDCs indicating these tumor types are highly genomically similar and likely to benefit from chemotherapy. The downregulation of immune pathways in MP high risk MuBC may lead to immune surveillance escape resulting in metastasis and further investigation is needed. Clinical trial information: NCT03053193.

Abstract Aims CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. Method and Results Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe−/− background were generated (CD40wt and CD40mac−/−, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac−/− compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac−/− atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b− macrophages in the atherosclerotic aorta of CD40mac−/− compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac−/− mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1). Conclusions We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.

Purpose: To evaluate the safety and therapeutic effects of orally administered AKST4290 (formerly BI 144807 and ALK4290) in treatment-naive patients with neovascular age-related macular degeneration. Methods: In this prospective, multicenter, open-label Phase 2a pilot clinical study, 30 patients with newly diagnosed neovascular age-related macular degeneration self-administered AKST4290 (400 mg) orally twice daily for 6 weeks. Patients were examined weekly for safety, to measure best-corrected visual acuity (BCVA), and to perform exploratory morphologic assessments. The primary endpoint was the mean change in BCVA from baseline to end of treatment, and the secondary endpoint was safety. Exploratory endpoints investigated potential changes in macular morphology. Results: Mean BCVA improved by +7.0 letters (95% CI, 2.2–11.7); 24 patients (82.8%) had stable or improved BCVA, with 6 (20.7%) gaining ≥15 letters. No patients experienced severe or serious adverse events. Conclusion: In this 6-week study, AKST4290 treatment was associated with improved BCVA scores in patients with treatment-naive neovascular age-related macular degeneration. All adverse events were mild or moderate in severity and no safety issues were identified. Treatment of neovascular age-related macular degeneration with AKST4290 warrants further investigation in randomized, placebo-controlled trials.

Abstract ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis‐associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8 + tumour‐infiltrating lymphocytes (CD8 + TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8 + TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients ( p = 0.012) and was associated with MMRd ( p < 0.001) and the presence of CD8 + TILs ( p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss‐of‐function mutation as a result of small indels ( p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8 + TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8 + TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss‐of‐function mutations in endometriosis‐associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT. Methods: From 2 international registries of patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31–3.17]; and HR, 1.99 [95% CI, 1.20–3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]). Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.