Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL, Transformed Follicular Lymphoma, Richter's Trans-Formed DLBCL and Germinal Center B-Cells.

Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1-CCR9, CXCR1-CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4-CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1-CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.

Intratympanic Triamcinolone Acetonide as a Salvage Treatment for Idiopathic Sudden Sensorineural Hearing Loss.

INTRODUCTION: Intratympanic steroid (ITS) injections represent an increasingly used salvage treatment option for patients with idiopathic sudden sensorineural hearing loss -(ISSHL) after systemic treatment. The most effective corticosteroid for this treatment modality still remains unclear. Triamcinolone acetonide has been used for ITS treatment in various clinical settings. However, there are limited clinical data of its usage in the therapeutic management of ISSHL. The aim of this study was to determine the efficacy of intratympanic triamcinolone acetonide injections as a salvage treatment for ISSHL. METHODS: We conducted a retrospective chart review on patients affected by ISSHL with insufficient hearing recovery after primary systemic corticosteroid therapy and who were treated with intratympanic triamcinolone acetonide as a salvage therapy between January 2014 and August 2019. The patients were divided into groups according to their degree of hearing recovery, and we evaluated potential predictors of hearing recovery. Audiometric results were then compared to historic studies using dexamethasone or methylprednisolone. RESULTS: One-hundred and fifty-two patients received up to 3 intratympanic injections with triamcinolone acetonide at 1-week intervals. The mean hearing improvement due to ITS salvage treatment was 15.9 ± 18.9 dB. Complete hearing recovery was noted in 15 patients (9.9%), while 73 patients (48%) obtained partial recovery, and 64 patients (42.1%) had no recovery. Primary systemic treatment delay, hearing improvement by primary systemic treatment, and severity of initial hearing loss were identified as significant predictors of hearing improvement. The first of the 3 injections resulted in the greatest hearing improvement. CONCLUSION: The use of triamcinolone acetonide in ITS salvage treatment resulted in similar hearing improvements as the use of the commonly used corticosteroids, namely, dexamethasone and methylprednisolone. Longer treatment delays, lower hearing improvement by primary systemic treatment, and higher initial hearing loss are associated with poorer prognoses of hearing recovery.

Complex Mandibular Reconstruction for Head and Neck Squamous Cell Carcinoma-The Ongoing Challenge in Reconstruction and Rehabilitation.

Large head and neck squamous cell carcinoma (HNSCC) tumors affecting the mandible require a versatile reconstruction to maintain form, function, and quality of life. Large defect reconstruction of soft and hard tissue in the head and neck necessitates, at best, one vascular system including various tissues by large dimensions. The subscapular flap system seems to meet these standards. A retrospective study was conducted focusing on clinical data, including an analysis of the quality of life with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires, (QLQ-C30 and QLQ-H&N43). A total of 154 patients (122 males, 32 females; age range: 31-71 years, mean: 54.5 years) treated at our department from 1983 through to 2019 were included. Of the subscapular system free flaps (SFFs), 147 were based on the angular artery branch of the thoracodorsal pedicle (95.45%), and the remaining seven cases (4.55%) were lateral scapular border flaps. Mean mandible defect length was 7.3 cm. The mean skin paddle dimension was 86.8 cm2. The most common recipient artery was the thyroid superior artery (79.22%). Major postoperative complications occurred in 13 patients (8.44%). This study confirms that SFFs offer excellent soft and hard tissue quality, component independence, a large arc of rotation length, and a large gauge of pedicle, making them the gold standard for the reconstruction of large composite defects of mandibular HNSCC tumors.

Correlation between work impairment, scores of rhinitis severity and asthma using the MASK-air® App.

BACKGROUND: In allergic rhinitis, a relevant outcome providing information on the effectiveness of interventions is needed. In MASK-air (Mobile Airways Sentinel Network), a visual analogue scale (VAS) for work is used as a relevant outcome. This study aimed to assess the performance of the work VAS work by comparing VAS work with other VAS measurements and symptom-medication scores obtained concurrently. METHODS: All consecutive MASK-air users in 23 countries from 1 June 2016 to 31 October 2018 were included (14 189 users; 205 904 days). Geolocalized users self-assessed daily symptom control using the touchscreen functionality on their smart phone to click on VAS scores (ranging from 0 to 100) for overall symptoms (global), nose, eyes, asthma and work. Two symptom-medication scores were used: the modified EAACI CSMS score and the MASK control score for rhinitis. To assess data quality, the intra-individual response variability (IRV) index was calculated. RESULTS: A strong correlation was observed between VAS work and other VAS. The highest levels for correlation with VAS work and variance explained in VAS work were found with VAS global, followed by VAS nose, eye and asthma. In comparison with VAS global, the mCSMS and MASK control score showed a lower correlation with VAS work. Results are unlikely to be explained by a low quality of data arising from repeated VAS measures. CONCLUSIONS: VAS work correlates with other outcomes (VAS global, nose, eye and asthma) but less well with a symptom-medication score. VAS work should be considered as a potentially useful AR outcome in intervention studies.

Apolipoprotein A-IV acts as an endogenous anti-inflammatory protein and is reduced in treatment-naïve allergic patients and allergen-challenged mice.

BACKGROUND: Recent studies pointed to a crucial role for apolipoproteins in the pathogenesis of inflammatory diseases. However, the role of apolipoprotein-IV (ApoA-IV) in allergic inflammation has not been addressed thoroughly thus far. OBJECTIVE: Here, we explored the anti-inflammatory effects and underlying signaling pathways of ApoA-IV on eosinophil effector function in vitro and in vivo. METHODS: Migratory responsiveness, Ca2+ -flux and apoptosis of human peripheral blood eosinophils were assessed in vitro. Allergen-driven airway inflammation was assessed in a mouse model of acute house dust mite-induced asthma. ApoA-IV serum levels were determined by ELISA. RESULTS: Recombinant ApoA-IV potently inhibited eosinophil responsiveness in vitro as measured by Ca2+ -flux, shape change, integrin (CD11b) expression, and chemotaxis. The underlying molecular mechanism involved the activation of Rev-ErbA-α and induced a PI3K/PDK1/PKA-dependent signaling cascade. Systemic application of ApoA-IV prevented airway hyperresponsiveness (AHR) and airway eosinophilia in mice following allergen challenge. ApoA-IV levels were decreased in serum from allergic patients compared to healthy controls. CONCLUSION: Our data suggest that ApoA-IV is an endogenous anti-inflammatory protein that potently suppresses effector cell functions in eosinophils. Thus, exogenously applied ApoA-IV may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophil-driven disorders.

Olfactory cleft proteome does not reflect olfactory performance in patients with idiopathic and postinfectious olfactory disorder: A pilot study.

Technical advances including liquid chromatography-tandem mass spectrometry and its data analysis enable detailed proteomic analysis of the nasal mucus. Alterations of the nasal mucus proteome may provoke substantial changes of the nasal physiology and have already been associated with rhinologic diseases such as allergic rhinitis. This study was conducted as a pilot study to map the olfactory cleft proteome using current techniques for proteomic analysis. Furthermore, we aimed to investigate proteomic changes as potential biomarkers in patients suffering from idiopathic and postinfectious olfactory disorders compared to healthy controls. Seven patients with idiopathic hyposmia and anosmia, seven patients with postinfectious hyposmia and anosmia and seven healthy controls were included in this study. In total, 1117 different proteins were detected in at least five patients in at least one group. Results of this study did not reveal significant differences regarding the proteomic composition of the olfactory cleft mucus between patients versus healthy controls. Among proteins involved in olfactory perception the G protein family was detected but also found unchanged between groups. Investigation of protein composition by liquid chromatography-tandem mass spectrometry enabled us to perform an in-depth analysis of the olfactory cleft mucus proteome regarding the diversity of different proteins in individual patients. However untargeted proteomics of the olfactory cleft mucus may not be an applicable approach to develop biomarkers for olfactory disorders. Targeted analyses of distinct proteins known to be involved in olfactory perception but not detected by our approach, e.g. odorant binding proteins, may provide more information regarding pathophysiology of olfactory diseases.

Limits of the endoscopic transnasal transtubercular approach.

INTRODUCTION: The endoscopic transnasal trans-sphenoidal transtubercular approach has become a standard alternative approach to neurosurgical transcranial routes for lesions of the anterior skull base in particular pathologies of the anterior tubercle, sphenoid plane, and midline lesions up to the interpeduncular cistern. For both the endoscopic and the transcranial approach indications must strictly be evaluated and tailored to the patients' morphology and condition. The purpose of this review was to evaluate the evidence in literature of the limitations of the endoscopic transtubercular approach. EVIDENCE ACQUISITION: A PubMed/Medline search was conducted in January 2018 entering following keywords. Upon initial screening 7 papers were included in this review. There are several other papers describing the endoscopic transtubercular approach (ETTA). We tried to list the limitation factors according to the actual existing literature as cited. EVIDENCE SYNTHESIS: The main limiting factors are laterally extending lesions in relation to the optic canal and vascular encasement and/or unfavorable tumor tissue consistency. CONCLUSIONS: The ETTA is considered as a high level transnasal endoscopic extended skull base approach and requires excellent training, skills and experience.

Gustatory Function in Patients With Chronic Rhinosinusitis.

OBJECTIVES: Recent research has shown that taste receptors in airway epithelial cells are involved in defending against upper respiratory tract infection. The aim of the present study was to investigate gustatory function in patients with chronic rhinosinusitis (CRS). METHODS: Taste function was assessed using the extended "taste strip" test in 37 patients with CRS (20 males, 17 females; mean age = 32.1 years; range, 20-82 years) and 135 healthy controls (70 males, 65 females; mean age = 29.5 years; range, 18-84 years). RESULTS: The mean (±SD) total extended taste score was 12.8 (±3.5) in patients and 14.5 (±3.2) in controls. Analysis of variance indicated an interaction of sinusitis and gender ( P < .05) with significantly lower total scores and significantly poorer results for the bitter taste among male patients compared to controls ( P < .01). In addition, CRS patients exhibited a trend toward decreased sweet taste perception compared to controls, but this did not reach significance ( P = .051). CONCLUSIONS: Patients with CRS exhibited decreased gustatory function compared to healthy controls. The effect was most pronounced for bitter taste. Thus, the assessment of gustatory function seems to be useful for detecting potential risk factors for recurrent upper respiratory tract infection.

The salivary microbiome as an indicator of carcinogenesis in patients with oropharyngeal squamous cell carcinoma: A pilot study.

This study aimed to undertake an initial, comparative analysis of the oral salivary microbiome of patients with oral and oropharyngeal squamous cell carcinoma versus healthy controls. This project, conceived as a pilot study, included 11 patients (1 female, 10 male, mean age 61.6 yrs., SD = 8.2 yrs.) and 11 healthy controls (1 female, 10 male, mean age 46.7 yrs., SD = 15.1 yrs.). Samples of saliva were analysed by high-throughput sequencing of the 16S rRNA gene using the MiSeq platform. Sequence data revealed microbial changes that may mirror disease progression and reflect clinical preconditions such as age, alcohol consumption, tumour size, lymph node status, smoking habit, and tumour HPV-positivity. Consequently, mapping microbial changes in patients with oral and oropharyngeal squamous cell carcinomas might improve our understanding of the pathobiology of the disease, and help in the design of novel diagnostic and treatment strategies.

Apolipoproteins have a potential role in nasal mucus of allergic rhinitis patients: a proteomic study.

OBJECTIVES/HYPOTHESIS: Nasal mucus is a defense barrier against aeroallergens. We recently found apolipoproteins to be elevated in the nasal mucus of allergic rhinitis patients. Apolipoproteins are involved in lipid metabolism, have immunomodulatory properties, and may represent interesting novel biomarkers. This study aims to validate our findings and analyze whether the increased abundance of apolipoproteins in nasal mucus is a local or systemic phenomenon in allergic rhinitis. STUDY DESIGN: Prospective controlled trial. METHODS: Nasal mucus of allergic rhinitis patients (n = 10) and healthy controls (n = 12) was collected, tryptically digested, and analyzed by LC-MS/MS. Areas under the curve (AUCs) of the total peptides identified and matched to apolipoproteins were used to compare relative protein abundances of the same protein between groups. RESULTS: In a total of 389 identified proteins in nasal mucus, apolipoproteins A-I, A-II, A-IV, and B 100 were detected. Apolipoprotein A-I (mean normalized AUC 1.49% [SEM = 0.5] vs. 0.42% [SEM = 0.2]) and A-II (mean normalized AUC 0.47% [SEM = 0.2] vs. 0.05% [SEM = 0.02]) were significantly more abundant in allergic rhinitis patients than controls (3.6-fold and 9.4-fold, respectively). Apolipoprotein A-IV (mean normalized AUC = 0.01%) and B-100 (mean normalized AUC = 0.02%) were each detected in only one allergic rhinitis patient out of 10. Myeloperoxidase was detected with a mean normalized AUC of 0.06% (SEM = 0.03) in allergic rhinitis patients and 0.18% (SEM = 0.08) in healthy controls without reaching significance. CONCLUSION: This study confirms the significantly higher abundance of apolipoproteins A-I and AII in allergic rhinitis mucus. Their release seems to be triggered by local mechanisms as an antiinflammatory response to allergens.

Altered inhibitory function of the E-type prostanoid receptor 4 in eosinophils and monocytes from aspirin-intolerant patients.

Prostaglandin (PG) E2 has been implicated in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). E-type prostanoid (EP) receptor 4 is known to confer inhibitory signals to eosinophils and monocytes, amongst others. In this study, we investigated whether the responsiveness of eosinophils and monocytes to PGE2 and EP4 receptor activation is altered in AERD patients. While the expression of the EP4 receptor in eosinophils was unaltered in AERD patients, inhibition of eosinophil chemotaxis by PGE2 or the EP4 agonist CAY10598 was less pronounced in AERD patients as compared to healthy control subjects. In monocytes, we found no changes in basal or lipopolysaccharide (LPS)-stimulated PGE2 synthesis, but the response to EP4 receptor activation with respect to inhibition of LPS-induced tumor necrosis factor-α release was reduced in AERD patients, especially in the presence of aspirin (acetylsalicylic acid). Our data point towards a decreased sensitivity of inhibitory EP4 receptor that may play a role in AERD.