Stratification of Breast Cancer Risk in Terms of the Influence of Age and Mammographic density. / Stratifizierung des Brustkrebsrisikos hinsichtlich der Einflüsse von Alter und mammografischer Dichte.

PURPOSE: Analysis of the influence of the singular risk factors age and breast density on the 2-year incidence of breast cancer among participants in the German mammography screening program. MATERIALS AND METHODS: The multicenter study includes 111 456 subsequent round digital mammographic screening examinations from four screening units with prospective visual categorization of breast density. Based on detection in screening and during the 2-year interval after negative screening participation (interval cancers), 2-year breast cancer incidences (2 YBCI) (‰) were calculated in the 5-year age groups (5 YAG) of the target group 50-69 years and in the BI-RADS density categories ACR 1-4. Multivariate statistical evaluations were carried out using logistic regression models. RESULTS: With an increase in the 5 YAG, the 2 YBCI increased by 5.0 ‰, 6.7 ‰, 8.5 ‰ to 9.7 ‰, and was significantly different among 55-59, 60-64 and 65-69-year-old women compared to the youngest reference group 50-54 years (odds ratio (OR): 1.34; 1.68; and 1.93; p-value < 0.0001). With an increase in density categories 1-4, the 2 YBCI increased from 2.6 ‰, to 5.8 ‰, 9.6 ‰, and 9.7 ‰. The 2 YBCI differed significantly in breast density categories 2, 3, 4 from reference group 1 (OR: 2.17; 3.65; and 3.76; p-value < 0.0001). Only within the two main breast density groups 2 (frequency 44.3 %) and 3 (44.7 %), a significant increase in the 2 YBCI was observed across the 5 YAG (category 2: 3.7-8.9 ‰; category 3: 5.8-11.7 ‰; p-value < 0.001 each). The 2 YBCI was above the median of 7.5 ‰ in women with breast density category 2 and aged 65-69 years, as well as in women with breast density categories 3 and 4 aged 55-69 years. A 2 YBCI below the median was seen in women between 50-54 years regardless of breast density, as well as women in category 1 in all age groups. CONCLUSION: Within the main breast density categories 2 and 3 (almost 90 % of participants), incidences increase with age to double. A consistently low incidence is found regardless of breast density at a young screening age and in women with the lowest breast density. KEY POINTS: · The risk of breast cancer is modified by age in density categories.. · Women aged 50-54 years have a low risk in all density categories.. · Women in category ACR 1 of any age group have a low risk.. CITATION FORMAT: · Weigel S, Heindel W, Dietz C et al. Stratifizierung des Brustkrebsrisikos hinsichtlich der Einflüsse von Alter und mammografischer Dichte. Fortschr Röntgenstr 2020; 192: 678 - 685.

Aspergillus fumigatus induction of IL-33 expression in chronic rhinosinusitis is PAR2-dependent.

OBJECTIVE: In the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP), Aspergillus fumigatus (A. fumigatus) can upregulate IL-33 from human sinonasal epithelial cells (SNECs), which then activates innate lymphoid cells causing release of IL-13, an important driver of allergic inflammation. However, the mechanism by which A. fumigatus mediates the induction of IL-33 expression remains to be elucidated. The objectives of this study were to determine the specific fungal component(s) and the receptor responsible for mediating the A. fumigatus induced increase in IL-33 expression in SNECs from patients with CRSwNP. METHODS: SNECs from CRSwNP patients were cultured and stimulated with various fungal components in the absence or presence of 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, an irreversible serine protease inhibitor, or GB83, a reversible protease activated receptor 2 (PAR2) inhibitor. IL-33 expression was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). PAR2 expression was examined in inflamed mucosa from nonatopic control and CRSwNP patients. RESULTS: Elevation of IL-33 expression in primary SNECs was found in response to fungal protease but not fungal cell wall components. PAR2 expression was elevated in inflamed mucosa from CRSwNP patients in comparison to controls. The A. fumigatus fungal protease-mediated elevation in IL-33 expression by human SNECs was serine protease- and PAR2-dependent. CONCLUSION: These data suggest that serine protease activity of A. fumigatus is capable of inducing IL-33 expression in CRSwNP SNECs via PAR2, a potential therapeutic target in the treatment of CRSwNP. LEVEL OF EVIDENCE: NA Laryngoscope, 129:2230-2235, 2019.

Distinguishing Molecular Features of Allergic Fungal Rhinosinusitis.

Objective Allergic fungal rhinosinusitis (AFRS) is a clinical subtype of chronic rhinosinusitis with nasal polyps (CRSwNP), characterized by eosinophilic mucin, evidence of fungal elements within the mucin, fungal-specific type I hypersensitivity, and characteristic computed tomography findings. It remains controversial whether AFRS represents a disease with a unique pathophysiology from chronic rhinosinusitis or is merely a severe form of CRSwNP. The goal of this study was to identify molecular features unique to AFRS. Study Design Cross-sectional case-control. Setting Single academic tertiary referral institution. Subjects and Methods Subjects included 86 patients undergoing endoscopic sinus surgery: CRSwNP (n = 34), AFRS (n = 37), and healthy controls (n = 15). Pathway and correlation analyses were performed with whole-genome microarray data for study patients undergoing surgery for recalcitrant chronic rhinosinusitis. Our findings were confirmed with quantitative polymerase chain reaction and immunohistochemical studies. Results AFRS was uniquely characterized by a pronounced association with adaptive T helper 2-associated immune gene expression. AFRS exhibited altered expression of proteins associated with secretory salivary peptides-namely, histatin, a peptide with known antifungal activity in the oral cavity. Furthermore, the expression of histatins correlated negatively with that of type 2 inflammatory mediators. We confirm the decreased expression of histatins in AFRS when compared with CRSwNP by quantitative polymerase chain reaction and localized its expression to a submucosal cell population. Conclusion There exist clear molecular profiles that distinguish AFRS from CRSwNP. This divergence translates into an altered ability to control fungal growth and may in part explain some of the phenotypical differences between CRSwNP and AFRS.

Innate Lymphoid Cells: The Innate Counterpart to T Helper Cells.

Innate lymphoid cells (ILCs) are a recently discovered subset of innate immune cells that are capable of secreting great amounts of cytokines that have been found to influence effector cell activity. Chronic rhinosinusitis (CRS) in the absence (CRSsNP) or presence (CRSwNP) of nasal polyps has been characterized as type 1- and type 2-skewed, respectively, based on the presence of cytokines characteristic of type 1 and 2 immune responses. Based on the ability of type 1 ILCs to secrete interferon-x03B3;, a type 1 cytokine found elevated in CRSsNP and type 2 ILCs to secrete IL-5 and IL-13, type 2 cytokines found elevated in CRSwNP, it is essential to examine the role that ILCs may play in the pathogenesis of CRS. This chapter introduces each subset of ILC (type 1-3) and the non-CRS pathologies they have been associated with in both mouse and human models. It will discuss the current research into ILCs in CRS, particularly ILC2s and NK cells in CRSwNP. Finally, the chapter will consider the therapeutic implications of ILC involvement in CRS and highlight the needs for future research into the role that ILCs play in CRS.