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Background: Chronic rhinosinusitis with nasal polyps affects approximately 2–4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. Methods: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49–52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. Findings: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians −0·73, 95% CI −1·11 to −0·34; p

The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed Spatial Transcriptomics of VDJ sequences (Spatial VDJ), which maps immunoglobulin and TR antigen receptors in human tissue sections. Spatial VDJ captures lymphocyte clones matching canonical T, B, and plasma cell distributions in tissues and amplifies clonal sequences confirmed by orthogonal methods. We confirm spatial congruency between paired receptor chains, develop a computational framework to predict receptor pairs, and link the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity, class switch recombination, and lineage trajectories within their spatial context. Taken together, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, which could have important therapeutic implications.One-Sentence SummarySpatial transcriptomics-based technology co-captures T and B cell receptors within their anatomical niche in human tissue.

Severe nasal polyposis and mucosal inflammation, in patients with chronic rhinosinusitis (CRS) may include a dysregulated eicosanoid profile, but a clinical role for eicosanoids in CRS with nasal polyps (NP; CRSwNP) remains to be elucidated. This study focused on assessing levels and clinical implications of inflammatory mediators in nasal secretions and urine from patients with different NP severity or Aspirin Exacerbated Respiratory Disease (AERD). Levels of leukotrienes E

Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA

Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA+ILCs. CD45RA+CD62L+ILCs (CD62L+ILCs) resembled circulating naïve ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA+CD62L−ILCs (CD62L−ILCs) were epigenetically similar to CD62L+ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L+and CD62L−ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L+and CD62L−ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L−ILCs with preferential differentiation capacity toward IL-22–producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L+and CD62L−ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.

Chronic tonsillitis (CT) and tonsillar hypertrophy (TH) are common tonsillar diseases that are related to infection and inflammation. Little is known about tonsillar microbiota and its role in CT and TH. This study aims to identify palatine tonsillar microbiota both on the surface and in the core tissues of CT and TH patients. In total, 22 palatine tonsils were removed and collected from CT and TH patients who underwent surgery. The surface and core microbiota in the tonsils of CT and TH patients were compared using 16S rRNA gene sequencing of V3-V4 regions. Differential tonsillar microbiotas were found in the CT versus TH patients and surface versus core tissues. Further, a higher relative abundance of bacterial genera, including Haemophilus, Streptococcus, Neisseria, Capnocytophaga, Kingella, Moraxella, and Lachnospiraceae [G-2] in patients with TH and Dialister, Parvimonas, Bacteroidales [G-2], Aggregatibacter, and Atopobium in patients with CT, was observed. Of these, the differential genera of Dialister, Parvimonas, and Neisseria served as key factors in the tonsillar microbiota network. Notably, four representable tonsillar microbial types were identified, with one, consisting of a higher abundance of Haemophilus and Neisseria, exclusively detected in the TH patients. This study analyzed the different tonsillar microbiota from the surface and core tissues of CT and TH patients. Several bacteria and various microbial types related to CT and TH were identified, along with potential bacterial networks and related immune pathways. IMPORTANCE The human microbiota has been shown to be functionally connected to infectious and inflammation-related diseases. So far, only limited studies had been performed on tonsillar microbiota, although tonsils play an essential role in the human immune defense system and encountered numerous microorganisms. Our work presented different tonsillar microbiota from surface and core tissues of chronic tonsillitis (CT) and tonsillar hypertrophy (TH) patients. Notably, one tonsillar microbiota type, which contains a higher abundance of Haemophilus and Neisseria, was only detected in the TH patients. Furthermore, certain bacteria, such as Haemophilus, Neisseria, Dialister, and Parvimonas, may serve as microbial biomarkers to discriminate CT patients from TH patients. These data provide important microbiota data in the tonsillar research area and are highly useful for researchers both in the oral microbiome field and clinical field.

Introduction: Sinonasal malignancies (SNM) are rare and the prognosis is generally poor. Recently, a change in incidence for SNM has been reported. In this study, we investigated population-based trends for SNM in Sweden. Methods: We identified 3,221 patients from the Swedish National Cancer Registry diagnosed with primary malignancies arising from the nasal cavity, paranasal sinuses, or both, during the period 1960 through 2010. Incidence, gender and age, anatomical sites and relative survival were investigated. Results: The incidence for SNM decreased except for sinonasal malignant melanoma (SNMM) and adenoid cystic cancer (even though a very small group) during the study period. More than 50 % of the malignancies involved the nasal cavity. The five-year relative survival was highest for adenoid cystic cancer followed by adenocarcinoma. SNMM and undifferentiated carcinoma had the poorest prognosis. Conclusion: We found that the incidence for SNM has decreased during the study period 1960 through 2010, except for SNMM that has increased.

The role of human papillomavirus (HPV) in tonsillar squamous cell carcinomas (TSCC) is of interest, since a considerable proportion of TSCC in Sweden and other Western countries is HPV positive. Nevertheless, the natural history of HPV in normal tonsils, and the progression from localized infection to pre-malignant lesion to cancer are poorly understood. The aim of this study was to investigate whether HPV types found in mouthwash samples correlated to those in tonsillar tissue from the same individuals undergoing tonsillectomy.Mouthwash samples from 232 patients, aged 3-56 years, undergoing tonsillectomy, the majority with chronic tonsillitis, were collected at the time of surgery and analysed for the presence of 27 HPV types by a bead based multiplex assay.An HPV prevalence of 10.3% (24/232) was observed in mouthwash samples, with HPV 69 being the dominant type (10/24). Ten patients were positive for high risk HPV (HPV 16, 33, 35, 45, 56, 59). None of the tonsils resected from patients with HPV-positive mouthwash samples were positive for HPV.Despite an oral HPV prevalence of 10.3% in mouthwash samples from tonsillectomized patients, with dominance of HPV 69, none of the corresponding tonsillar samples exhibited the presence of HPV.

Sinonasal malignant melanoma (SNMM) comprises less than 1% of all melanomas and is located in the nasal cavity and the paranasal sinuses. The majority of SNMMs have unknown underlying oncogenic driver mutations. The recent identification of a high frequency of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in cutaneous melanoma led us to investigate whether these mutations also occur in SNMM. Our aim was to determine the TERT promoter mutation frequencies in primary SNMMs. Laser capture microdissection and manual dissection were used to isolate tumour cells from 49 formalin-fixed paraffin-embedded tissues. The tumours were screened for TERT promoter mutations by direct Sanger sequencing. Information on NRAS, BRAF and KIT mutation was available from an earlier study. Overall, 8% (4/49) of SNMMs harboured TERT promoter mutations. One of these mutated tumours had a coexistent NRAS mutation and one had a BRAF mutation. Our findings show that TERT promoter mutations are present in a moderate proportion of SNMM. No conclusion can be drawn on their potential influence on the clinical outcome or tumour progression.