The "real life" efficacy of dupilumab is independent of initial polyp size and concomitant steroids in CRSwNP.

BACKGROUND: Dupilumab significantly improves symptom control in chronic rhinosinusitis with nasal polyps (CRSwNP). Patients with large polyps at the initiation of treatment (total polyp score (TPS) ≥ 5) have been the focus in published studies. Patients with significant burden of disease but small polyps (TPS ≤ 4) have not yet been evaluated for clinical response. This study set out to evaluate the benefit of dupilumab treatment on cohorts of small (TPS ≤ 4) compared to large polyps (TPS ≥ 5). Furthermore, benefit of concomitant oral and/or nasal steroid therapy has been evaluated. METHODS: 97 patients with CRSwNP, who were begun on dupilumab between January 2020 and October 2021, were included. All patients were followed-up for 6 months. At each visit they underwent nasal endoscopy, smell identification tests and filled out validated patient questionnaires. RESULTS: Significant drops in TPS were seen in both patient groups after 6 months of therapy, dropping from a median score of 3 to 0 and from 6 to 2 in patients with small and large polyps respectively. Furthermore, a linear mixed model calculated a drop of 22% and 24% in TPS per month in patients with small and large polyps respectively with no significant difference in rate of decline. Finally the model showed that neither oral nor nasal steroids influenced the rate of response to dupilumab therapy. CONCLUSIONS: Polyp size at the initiation of dupilumab therapy and whether patients continue to take steroid therapy does not appear to influence effectiveness of dupilumab treatment.

Low free triiodothyronine and immune-related hyperthyroidism are associated with overall and progression-free survival in head and neck squamous cell carcinoma treated with pembrolizumab.

INTRODUCTION: Thyroid function is frequently impaired in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In patients treated with pembrolizumab, immune-related adverse events (irAEs) of the thyroid are common. However, the prognostic significance of baseline and on-treatment thyroid dysfunction is currently unclear. METHODS: This study included 95 patients who received pembrolizumab for R/M HNSCC between 2016 and 2022. Baseline thyroid status, according to serum hormone levels, and irAEs were assessed. Univariable and multivariable Cox regression analyses were performed for overall survival (OS) and progression-free survival (PFS). Furthermore, the best overall response according to the prognostic groups was examined. RESULTS: Low fT3 (HR: 2.52, p = 0.006), immune-related hyperthyroidism (HR: 0.11, p = 0.038), ECOG performance status ≥2 (HR: 3.72, p = 0.002), and platinum-refractory disease (HR: 3.29, p = 0.020) were independently associated with OS. Furthermore, immune-related hyperthyroidism was associated with longer PFS (HR: 0.13, p = 0.007), a higher objective response rate (83% vs. 31%, p = 0.018), and a higher disease control rate (100% vs. 43%, p = 0.008). Thyroid-related autoantibodies were elevated in 40% of thyroid irAEs cases with available measurements. Out of 16 thyroid irAEs, 15 occurred in patients with fT3 above the lower limit of normal. CONCLUSION: Low fT3 was associated with worse OS. Immune-related hyperthyroidism was correlated with both improved OS and PFS. Baseline fT3 assessment and close on-treatment monitoring of serum thyroid levels may be valuable for risk stratification in R/M HNSCC patients receiving pembrolizumab.

Nasal IL-13 production identifies patients with late-phase allergic responses.

BACKGROUND: There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regard to the "late allergic response," which occurs in approximately 40% to 50% of patients with allergy. OBJECTIVE: We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response. METHODS: In this randomized, double-blind, placebo-controlled trial, birch pollen-allergic participants were challenged with birch pollen extract (n = 20) or placebo (n = 10) on 3 consecutive days. On days 1 and 3, nasal secretions were collected at selected time points over a 24-hour time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. RESULTS: Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and the soluble IL-33 receptor serum stimulation 2 (sST2) in nasal secretions within minutes compared with the placebo group. Eight of 20 provoked participants displayed high IL-13 levels 2 to 8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction, which significantly differed from IL-13 nonresponders after 6 hours. CONCLUSIONS: IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

The nasal microbiome in patients suffering from non-steroidal anti-inflammatory drugs-exacerbated respiratory disease in absence of corticosteroids.

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease phenotypically classified by the absence (CRSsNP) or presence of nasal polyps (CRSwNP). The latter may also be associated with asthma and hypersensitivity towards non-steroidal anti-inflammatory drugs (NSAID) as a triad termed NSAID-exacerbated respiratory disease (N-ERD). The role of the microbiome in these different disease entities with regard to the underlying inflammatory process and disease burden is yet not fully understood. To address this question, we measured clinical parameters and collected nasal samples (nasal mucosal fluids, microbiome swabs from middle meatus and anterior naris) of patients suffering from CRSsNP (n=20), CRSwNP (n=20) or N-ERD (n=20) as well as from patients without CRS (=disease controls, n=20). Importantly, all subjects refrained from taking local or systemic corticosteroids or immunosuppressants for at least two weeks prior to sampling. The nasal microbiome was analyzed using 16S rRNA gene amplicon sequencing, and levels of 33 inflammatory cytokines were determined in nasal mucosal fluids using the MSD platform. Patients suffering from N-ERD and CRSwNP showed significantly worse smell perception and significantly higher levels of type 2 associated cytokines IL-5, IL-9, Eotaxin and CCL17. Across all 4 patient groups, Corynebacteria and Staphylococci showed the highest relative abundances. Although no significant difference in alpha and beta diversity was observed between the control and the CRS groups, pairwise testing revealed a higher relative abundance of Staphylococci in the middle meatus in N-ERD patients as compared to CRSwNP (p<0.001), CRSsNP (p<0.01) and disease controls (p<0.05) and of Lawsonella in patients suffering from CRSwNP in middle meatus and anterior naris in comparison to CRSsNP (p<0.0001 for both locations) and disease controls (p<0.01 and p<0.0001). Furthermore, we observed a positive correlation of Staphylococci with IL-5 (Pearson r=0.548) and a negative correlation for Corynebacteria and Eotaxin-3 (r=-0.540). Thus, in patients refraining from oral and nasal corticosteroid therapy for at least two weeks known to alter microbiome composition, we did not observe differences in microbiome alpha or beta diversity between various CRS entities and disease controls. However, our data suggest a close association between increased bacterial colonization with Staphylococci and decreased colonization by Corynebacteria as well as increased type 2 inflammation.

Chronic rhinosinusitis symptoms differentially impact the likelihood of major depressive disorders.

OBJECTIVES: The extent to which sinonasal symptoms impact the likelihood of major depressive disorders in chronic rhinosinusitis patients with nasal polyposis (CRSwNP) remains incompletely characterized. In this study, we sought to determine whether individual symptom clusters differentially impact the likelihood of depression in a cohort of CRSwNP patients. METHODS: We retrospectively included 77 patients with CRSwNP. The severity of sinonasal symptoms was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22) and grouped according to a previously validated four-subdomain structure: nasal, otologic/facial pain, sleep, and emotional subdomains. The likelihood of major depressive disorders was assessed using the Patient Health Questionnaire-2 (PHQ-2). The clinical characteristic of symptom severity (nasal polyp size) and disease-specific information, such as the number of previous sinonasal surgeries, were also collected. RESULTS: The sleep subdomain was most strongly associated with the likelihood of major depressive disorders, followed by the otologic/facial pain subdomain, after controlling for demographics and clinical indicators of symptom severity (nasal polyp size). We found a SNOT-22 score ≥ 30.5 to be an accurate indicator of scoring higher than or equal to 2 on the PHQ-2 in CRSwNP patients. This had a sensitivity of 83.33% and a specificity of 75.47%. CONCLUSION: Distinct sinonasal symptom clusters differentially impact the likelihood of depression in CRSwNP patients. Raising awareness for those with severe sinonasal symptomatology might help identify more patients with a higher probability of comorbid depression.Level of Evidence: 4.

Radiosensitizing effect of galunisertib, a TGF-ß receptor I inhibitor, on head and neck squamous cell carcinoma in vitro.

BACKGROUND: Resistance to radiation therapy poses a major clinical problem for patients suffering from head and neck squamous cell carcinoma (HNSCC). Transforming growth factor ß (TGF-ß) has emerged as a potential target. This study aimed to investigate the radiosensitizing effect of galunisertib, a small molecule TGF-ß receptor kinase I inhibitor, on HNSCC cells in vitro. METHODS: Three HNSCC cell lines were treated with galunisertib alone, or in combination with radiation. Of those three cell lines, one has a known inactivating mutation of the TGF-ß pathway (Cal27), one has a TGF-ß pathway deficiency (FaDu) and one has no known alteration (SCC-25). The effect on metabolic activity was evaluated by a resazurin-based reduction assay. Cell migration was evaluated by wound-healing assay, clonogenic survival by colony formation assay and cell cycle by FACS analysis. RESULTS: Galunisertib reduced metabolic activity in FaDu, increased in SCC-25 and had no effect on CAL27. Migration was significantly reduced by galunisertib in all three cell lines and showed additive effects in combination with radiation in CAL27 and SCC-25. Colony-forming capabilities were reduced in SCC-25 by galunisertib and also showed an additive effect with adjuvant radiation treatment. Cell cycle analysis showed a reduction of cells in G1 phase in response to galunisertib treatment. CONCLUSION: Our results indicate a potential antineoplastic effect of galunisertib in HNSCC with intact TGF-ß signaling in combination with radiation.

Preventive Administration of Non-Allergenic Bet v 1 Peptides Reduces Allergic Sensitization to Major Birch Pollen Allergen, Bet v 1.

IgE-mediated allergy to birch pollen affects more than 100 million patients world-wide. Bet v 1, a 17 kDa protein is the major allergen in birch pollen responsible for allergic rhinoconjunctivitis and asthma in birch pollen allergic patients. Allergen-specific immunotherapy (AIT) based on therapeutic administration of Bet v 1-containing vaccines is an effective treatment for birch pollen allergy but no allergen-specific forms of prevention are available. We developed a mouse model for IgE sensitization to Bet v 1 based on subcutaneous injection of aluminum-hydroxide adsorbed recombinant Bet v 1 and performed a detailed characterization of the specificities of the IgE, IgG and CD4+ T cell responses in sensitized mice using seven synthetic peptides of 31-42 amino acids length which comprised the Bet v 1 sequence and the epitopes recognized by human CD4+ T cells. We then demonstrate that preventive systemic administration of a mix of synthetic non-allergenic Bet v 1 peptides to 3-4 week old mice significantly reduced allergic immune responses, including IgE, IgG, IgE-mediated basophil activation, CD4+ T cell and IL-4 responses to the complete Bet v 1 allergen but not to the unrelated major grass pollen allergen Phl p 5, without inducing Bet v 1-specific allergic sensitization or adaptive immunity. Our results thus demonstrate that early preventive administration of non-allergenic synthetic T cell epitope-containing allergen peptides could be a safe strategy for the prevention of allergen-specific IgE sensitization.

The molecular march of primary and recurrent nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) results from the aberrant and uncontrolled growth of the nasopharyngeal epithelium. It is highly associated with the Epstein-Barr virus, especially in regions where it is endemic. In the last decade, significant advances in genetic sequencing techniques have allowed the discovery of many new abnormal molecular processes that undoubtedly contribute to the establishment, growth and spread of this deadly disease. In this review, we consider NPC as EBV induced. We summarise the recent discoveries and how they add to our understanding of the pathophysiology of NPC in the context of genomics first in primary and then in recurrent disease. Overall, we find key early events lead to p16 inactivation and cyclin D1 expression, allowing latent viral infection. Host and viral factors work together to affect a variety of molecular pathways, the most fundamental being activation of NF-κB. Nonetheless, much still yearns to be discovered, especially in recurrent NPC.

Tracing Human IgE B Cell Antigen Receptor-Bearing Cells With a Monoclonal Anti-Human IgE Antibody That Specifically Recognizes Non-Receptor-Bound IgE.

Up to 30% of the population suffers from immunoglobulin E (IgE)-mediated allergies. Despite current stepwise gating approaches, the unambiguous identification of human IgE-producing cells by flow cytometry and immunohistology remains challenging. This is mainly due to the scarcity of these cells and the fact that IgE is not only expressed in a membrane-bound form on the surface of IgE-producing cells in form of the B cell antigen receptor (BCR), but is more frequently found on various cell types bound to the low and high affinity receptors, CD23 and FcϵRI, respectively. Here we sought to develop a sequential gating strategy for unambiguous detection of cells bearing the IgE BCR on their surface. To that aim we first tested the monoclonal anti-IgE antibody omalizumab for its ability to discriminate between IgE BCR and receptor-bound IgE using cells producing IgE or bearing IgE bound to CD23 as well as basophils exhibiting FcϵRI receptor-bound IgE. Using flow cytometry, we demonstrated that omalizumab recognized IgE producing cells with a high sensitivity of up to 1 IgE+ cell in 1000 human peripheral blood mononuclear cells (PBMCs). These results were confirmed by confocal microscopy both in cell suspensions as well as in nasal polyp tissue sections. Finally, we established a consecutive gating strategy allowing the clear identification of class-switched, allergen-specific IgE+ memory B cells and plasmablasts/plasma cells in human PBMCs. Birch pollen specific IgE+ memory B cells represented on average 0.734% of total CD19+ B cells in allergic patients after allergen exposure. Thus, we developed a new protocol for exclusive staining of non-receptor bound allergen-specific IgE+ B cell subsets in human samples.

Differences in men and women suffering from CRSwNP and AERD in quality of life.

PURPOSE: While the overall impact of chronic rhinosinusitis (CRS) on patients' health is diverse, many affected individuals have a substantially impaired quality of life (QoL). The aim of this study was to evaluate the impact of sex-associated differences specifically in the subgroups of CRS with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) by assessing QoL parameters in women and men separately. METHODS: In a retrospective single-center study, 59 patients with CRSwNP (39 males and 20 females) and 46 patients with AERD (18 males and 28 females) were included. Patient-reported outcome measures (PROM) evaluating QoL via the Sino-Nasal Outcome Test-20 German Adapted Version (SNOT-20 GAV) as well as the total polyp score (TPS) were analysed. RESULTS: There was no significant difference in TPS (p = 0.5550) and total SNOT-20 GAV scores (p = 0.0726) between male or female patients with CRSwNP or AERD. Furthermore, no significant sex differences were found within disease groups regarding the subcategories of the SNOT-20 GAV items. CONCLUSION: Thus, quality of life is severely impaired in patients suffering from various forms of CRS regardless of their sex.

Associations between the Quality of Life and Nasal Polyp Size in Patients Suffering from Chronic Rhinosinusitis without Nasal Polyps, with Nasal Polyps or Aspirin-Exacerbated Respiratory Disease.

Chronic rhinosinusitis (CRS) is a common disease that substantially impairs the quality of life (QoL). Here, we aimed to assess patients' QoL in different subtypes of CRS and correlated this with nasal polyp size to improve the clinical understanding of the burden of disease. In this retrospective single-center study, 107 patients with the following diagnoses were analyzed: CRS without nasal polyps (CRSsNP), CRS with nasal polyps (CRSwNP), or aspirin-exacerbated respiratory disease (AERD). Sino-Nasal Outcome Test-20 German Adapted Version (SNOT-20 GAV) scores and their correlation with endoscopic Total Polyp Scores (TPS) were evaluated. The mean SNOT-20 GAV scores were highest in patients with AERD (AERD = 43.4, CRSwNP = 36.3, CRSsNP = 30.9). A statistically significant correlation of total SNOT-20 GAV score with TPS was observed in CRSwNP patients (r = 0.3398, p = 0.0195), but not in AERD patients (r = 0.2341, p = 0.1407). When analyzing single SNOT-20 parameters, a strong correlation with TPS was observed for blockage/congestion of the nose, particularly in AERD patients (r = 0.65, p < 0.0001). The impact of nasal polyp size on the QoL differs amongst the subgroups of CRS. Nasal symptoms have the greatest impact on QoL in patients suffering from AERD. CRSwNP and AERD patients should be separately analyzed in clinical investigations and interpretations due to significant differences in QoL.

Allergen-specific IgE levels and the ability of IgE-allergen complexes to cross-link determine the extent of CD23-mediated T-cell activation.

BACKGROUND: CD23 mediates IgE-facilitated allergen presentation and subsequent allergen-specific T-cell activation in allergic patients. OBJECTIVE: We sought to investigate key factors regulating IgE-facilitated allergen presentation through CD23 and subsequent T-cell activation. METHODS: To study T-cell activation by free allergens and different types of IgE-Bet v 1 complexes, we used a molecular model based on monoclonal human Bet v 1-specific IgE, monomeric and oligomeric Bet v 1 allergen, an MHC-matched CD23-expressing B-cell line, and a T-cell line expressing a human Bet v 1-specific T-cell receptor. The ability to cross-link Fcε receptors of complexes consisting of either IgE and monomeric Bet v 1 or IgE and oligomeric Bet v 1 was studied in human FcεRI-expressing basophils. T-cell proliferation by monomeric or oligomeric Bet v 1, which cross-links Fcε receptors to a different extent, was studied in allergic patients' PBMCs with and without CD23-expressing B cells. RESULTS: In our model non-cross-linking IgE-Bet v 1 monomer complexes, as well as cross-linking IgE-Bet v 1 oligomer complexes, induced T-cell activation, which was dependent on the concentration of specific IgE. However, T-cell activation by cross-linking IgE-Bet v 1 oligomer complexes was approximately 125-fold more efficient. Relevant T-cell proliferation occurred in allergic patients' PBMCs only in the presence of B cells, and its magnitude depended on the ability of IgE-Bet v 1 complexes to cross-link CD23. CONCLUSION: The extent of CD23-mediated T-cell activation depends on the concentration of allergen-specific IgE and the cross-linking ability of IgE-allergen complexes.

Analysis of Perioperative Platelet Indices and Their Prognostic Value in Head and Neck Cancer Patients Treated with Surgery and Postoperative Radiotherapy: A Retrospective Cohort Study.

OBJECTIVES: Activated platelets might play an important role in tumor progression. Mean platelet volume (MPV) has been used as a surrogate marker for platelet activation, and therefore its value as a marker of tumor prognosis has attracted recent attention. In this study, we aimed to critically evaluate the prognostic significance of the perioperative platelet count (COP), MPV and the MPV/COP ratio in head and neck cancer patients. Additionally, we explored the individual postoperative trajectory of these indices and their association with overall survival (OS) and disease-free survival (DFS). METHODS: We retrospectively evaluated 122 head and neck squamous cell carcinoma patients receiving surgery with curative intent followed by postoperative radiotherapy. Platelet indices were measured preoperatively and on days 1 and 7 postoperatively. OS and DFS were analyzed using Kaplan-Meier estimators, the log-rank test and uni and multivariable Cox models. Cutoffs to dichotomize patients for Kaplan-Meier curves and log-rank tests were empirically chosen at the respective median. The median follow-up was 8.8 years. RESULTS: The adjusted preoperative COP, MPV and MPV/COP ratio were not associated with disease outcome. A low postoperative COP and a high MPV/COP ratio on the first postoperative day were independently associated with worse OS and DFS. In comparison to the preoperative measurements, patients whose COP increased by day 1 post-op showed a better OS (hazard ratio (HR) per 50 G/L increase: 0.73, 95% confidence interval (CI): 0.58-0.93, p = 0.013) and DFS (HR per 50 G/L increase: 0.74, 95% CI: 0.58-0.94, p = 0.018) in multivariable analysis. CONCLUSIONS: Our results suggest that a low postoperative COP and a high MPV/COP ratio represent a negative prognostic factor for OS and DFS. Notably, patients with an increase in COP by day 1 post-op when compared to their preoperative value showed a significantly better OS and DFS.

Analysis of cosmetic results of metopic synostosis: concordance and interobserver variability.

Trigonocephaly is caused by premature fusion of the metopic suture of the calvarium. The resultant facial and skull deformities place a newborn at a higher risk of cerebral impairment. Frontal orbital advancement and remodeling is the accepted surgical management. An analysis was undertaken to assess the cosmetic results for nonsyndromic metopic synostosis following frontal orbital advancement and remodeling and to determine whether the observer technique used had validity.The photographs of 20 consecutive patients with metopic synostosis were assessed preoperatively, postoperatively, and at 3 and 5 years of age. Each photograph was analyzed by 2 pairs of trained rotating observers. The findings were compared and reviewed by the fifth member, who acted as a "referee." Where there were disagreements between the findings, the referee came to a final decision. The presence and severity of trigonocephaly, temporal hollowing, hypotelorism, orbital asymmetry, epicanthic folds, and scarring were assessed. κ Analysis was used to determine the validity of observer concordance when using photographic material.There was a significant overall trend in craniofacial aesthetic improvement with time. However, 12% had some persistence of trigonocephaly. Temporal hollowing was usually persistent. κ Statistics varied among attributes and time period assessed. The greatest concordance was for improvement of epicanthic folds and trigonocephaly, with observers agreeing 84.1% and 82.6% of the time, respectively. There was least concordance for severity of hypotelorism and scarring.This study suggests that observer analysis of photographic records is a valid outcome measure for cosmesis, although it yields variable interobserver concordance according to the feature assessed. Surgery corrected most but not all the features of trigonocephaly. The prognostic indicators for good cosmetic outcome are presented.