Biomarkers for predicting response to long-term high dose aspirin therapy in aspirin-exacerbated respiratory disease.

INTRODUCTION: Aspirin-exacerbated respiratory disease (AERD) is a phenotype of asthma characterized by eosinophilic inflammation in the airways, mast cell activation, cysteinyl leukotriene overproduction, and acute respiratory reactions on exposure to cyclooxygenase-1 inhibitors. Aspirin desensitization followed by daily high-dose aspirin therapy is a safe and effective treatment option for the majority of patients with AERD. However, there is still some percentage of the population who do not derive benefits from daily aspirin use. METHODS: Based on the current literature, the biomarkers, which might predict aspirin treatment outcomes in AERD patients, were evaluated. RESULTS AND CONCLUSIONS: Patients with severe symptoms of chronic rhinosinusitis, type 2 asthma based on blood eosinophilia, non-neutrophilic inflammatory phenotype based on sputum cells, as well as high plasma level of 15-hydroxyeicosatetraenoic acid (15-HETE) are potentially good responders to long term high-dose aspirin therapy. Additionally, high expression of the hydroxyprostaglandin dehydrogenase gene, HPGD encoding prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and low expression of the proteoglycan 2 gene, PRG2 encoding constituent of the eosinophil granule in sputum cells might serve as a predictor of good response to aspirin therapy. Variations in the expression of cysteinyl leukotriene receptor 1 in the airways could additionally influence the response to long-term aspirin therapy. Arachidonic acid metabolites levels via the 5-lipoxygenase as well as via the cyclooxygenase pathways in induced sputum supernatant do not change during high dose long-term aspirin therapy and do not influence outcomes of aspirin treatment.

Dendritic Cells Are Associated with Prognosis and Survival in Breast Cancer.

Dendritic cells (DCs) constitute a part of the tumour microenvironment, but we are still far from understanding their complex role in immune response to the tumour. This study aimed to investigate the density of DCs expressing CD1a, CD83, CD123, DC-LAMP3 (CD208) and DC-SIGN (CD209) in breast cancer. The correlations between DC density and molecular subtype of breast cancer, its hormone receptor status, spatial location and their associations with clinical and pathological prognostic factors were evaluated. We have shown that intratumoural CD1a+ cells were significantly associated with progression-free survival. For LAMP3+ and CD123+ DCs, higher cell densities were associated with non-luminal as compared to luminal cancer phenotype. In contrast, dense CD83+ DC infiltrate was observed in luminal tumours. The number of CD1a+ DCs in both locations was the highest in luminal B/HER2+ cancers. The highest positive cell count of LAMP3+ cells was observed in the triple-negative subtype in both locations. We found higher numbers of LAMP3+ DCs both intratumourally and at the invasive margin, as well as CD123+ DCs intratumourally in tumours with negative expression of oestrogen or progesterone receptors. Our study demonstrates associations between DC subpopulations and histological and clinical characteristics, as well as molecular subtypes in breast carcinoma.

Biomarkers for predicting response to aspirin therapy in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin desensitization followed by daily aspirin use is an effective treatment for aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To assess clinical features as well as genetic, immune, cytological and biochemical biomarkers that might predict a positive response to high-dose aspirin therapy in AERD. METHODS: We enrolled 34 AERD patients with severe asthma who underwent aspirin desensitization followed by 52-week aspirin treatment (650 mg/d). At baseline and at 52 weeks, clinical assessment was performed; phenotypes based on induced sputum cells were identified; eicosanoid, cytokine and chemokine levels in induced sputum supernatant were determined; and induced sputum expression of 94 genes was assessed. Responders to high-dose aspirin were defined as patients with improvement in 5-item Asthma Control Questionnaire score, 22-item Sino-Nasal Outcome Test (SNOT-22) score and forced expiratory volume in 1 second at 52 weeks. RESULTS: There were 28 responders (82%). Positive baseline predictors of response included female sex (p = .002), higher SNOT-22 score (p = .03), higher blood eosinophil count (p = .01), lower neutrophil percentage in induced sputum (p = .003), higher expression of the hydroxyprostaglandin dehydrogenase gene, HPGD (p = .004) and lower expression of the proteoglycan 2 gene, PRG2 (p = .01). The best prediction model included Asthma Control Test and SNOT-22 scores, blood eosinophils and total serum immunoglobulin E. Responders showed a marked decrease in sputum eosinophils but no changes in eicosanoid levels. CONCLUSIONS AND CLINICAL RELEVANCE: Female sex, high blood eosinophil count, low sputum neutrophil percentage, severe nasal symptoms, high HPGD expression and low PRG2 expression may predict a positive response to long-term high-dose aspirin therapy in patients with AERD.

Prostaglandin E2 decrease in induced sputum of hypersensitive asthmatics during oral challenge with aspirin.

BACKGROUND: A special regulatory role for prostaglandin E2 (PGE2 ) has been postulated in nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD). OBJECTIVE: To investigate the effect of systemic aspirin (acetylsalicylic acid) administration on airway PGE2 biosynthesis in induced sputum supernatant (ISS) among subjects with NERD or aspirin-tolerant asthma with chronic rhinosinusitis with nasal polyposis (ATA-CRSwNP), as well as healthy controls (HC). METHODS: Induced sputum (IS) was collected from patients with NERD (n = 26), ATA-CRSwNP (n = 17), and HC (n = 21) at baseline and after aspirin challenge. Sputum differential cell count and IS supernatant (ISS) levels of prostanoids, PGE2 , 8-iso-PGE2 , tetranor-PGE-M, 8-iso-PGF2 α, and leukotriene C4 , D4 , and E4 , were determined using mass spectrometry. Urinary excretion of LTE4 was measured by ELISA. RESULTS: NERD subjects had elevated sputum eosinophilic count as compared to ATA-CRSwNP and HC (median NERD 9.1%, ATA-CRSwNP 2.1%, and HC 0.4%; P < 0.01). Baseline ISS levels of PGE2 were higher in asthmatics as compared to HC at baseline (NERD vs HC P = 0.04, ATA-CRSwNP vs HC P < 0.05). Post-challenge ISS levels of PGE2 compared to baseline significantly decreased in NERD and HC (P < 0.01 and P = 0.01), but not in ATA-CRSwNP. In NERD, a similar decrease in PGE2 as in HC resulted from 2.8 times lower dose of aspirin. CONCLUSION: Aspirin-precipitated bronchoconstriction is associated with a decrease in airway PGE2 biosynthesis. These results support the mechanism of PGE2 biosynthesis inhibition as a trigger for bronchoconstriction in NERD.

CD207+/langerin positive dendritic cells in invasive and in situ cutaneous malignant melanoma.

INTRODUCTION: Dendritic cells are crucial for cutaneous immune response. Their role in melanoma progression is however a matter of controversy. MATERIAL AND METHODS: The number of dendritic cells within epidermis and in peri- and intratumoral location was analyzed using CD207 immunostain in 17 cases of in situ and 25 case of invasive melanoma. RESULTS: Average peritumoral CD207+ cells count was 22.88 for all cases, 17.94 for in situ lesions and 26.24 for invasive cases. Average epidermal CD207+ cells count was 164.47 for all cases, 183.00 for in situ lesions and 150.78 - for invasive cases. In case of invasive melanomas, peritumoral CD207+ cells count was positively correlated with Breslow stage (R = 0.59) mitotic activity within the tumor (R = 0.62). Invasive cases with regression showed higher intratumoral and epidermal CD207+ cells count than the ones without (275.00 vs. 95.32 and 173.20 vs. 148.35) but lower peritumoral CD207+ cells count (17.60 vs. 27.26). Invasive cases with ulceration showed higher intratumoral and peritumoral CD207+ cells count than the ones without ulceration (220.08 vs. 55.67 and 44.17 vs. 9.69). CONCLUSIONS: CD207+ cells play a role in both progression and regression of melanoma but their exact role needs further studies.