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OBJECTIVE Type 2 diabetes may affect the humoral immune response after vaccination, but data concerning coronavirus disease 19 (COVID-19) vaccines are scarce. We evaluated the impact of diabetes on antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in older residents of long-term care facilities (LTCFs) and tested for differences according to antidiabetic treatment. RESEARCH DESIGN AND METHODS For this analysis, 555 older residents of LTCFs participating in the GeroCovid Vax study were included. SARS-CoV-2 trimeric S immunoglobulin G (anti-S IgG) concentrations using chemiluminescent assays were tested before the first dose and after 2 and 6 months. The impact of diabetes on anti-S IgG levels was evaluated using linear mixed models, which included the interaction between time and presence of diabetes. A second model also considered diabetes treatment: no insulin therapy (including dietary only or use of oral antidiabetic agents) and insulin therapy (alone or in combination with oral antidiabetic agents). RESULTS The mean age of the sample was 82.1 years, 68.1% were women, and 25.2% had diabetes. In linear mixed models, presence of diabetes was associated with lower anti-S IgG levels at 2 (β = −0.20; 95% CI −0.34, −0.06) and 6 months (β = −0.22; 95% CI −0.37, −0.07) after the first vaccine dose. Compared with those without diabetes, residents with diabetes not using insulin had lower IgG levels at 2- and 6-month assessments (β = −0.24; 95% CI −0.43, −0.05 and β = −0.30; 95% CI −0.50, −0.10, respectively), whereas no differences were observed for those using insulin. CONCLUSIONS Older residents of LTCFs with diabetes tended to have weaker antibody response to COVID-19 vaccination. Insulin treatment might buffer this effect and establish humoral immunity similar to that in individuals without diabetes.

Background Congenital intranasal encephaloceles (ECs) are rare malformations of the pediatric age, complex to diagnose and treat, above all if associated with genetic syndromes or concomitant dysmorphisms. The aims of the study were to report our experience in managing nasal ECS in children, to evaluate the efficacy and safety of the transnasal endoscopic repair, and to analyze in an overall way the surgical long-term outcomes. Moreover, we sought to contribute to the debate on pathogenesis of ECs, investigating possible related risk factors described in the literature. Methods A retrospective analysis was performed of pediatric nasal ECs managed with a transnasal endoscopic approach at a tertiary referral center through clinical follow-up and telephone survey. Results Twenty-three patients with nasal ECs fitted the criteria of the study. Mean age at surgery was 5 years (69 months) and the mean follow-up was 59 months. The clinical presentation is described in detail, with particular emphasis on syndromic cases. Of 23 patients, 17 had an isolated EC, and in 4 patients, a malformation syndrome was associated. EC recurred in 2/23 patients (8.7%) after surgical correction, necessitating a revision procedure. No perioperative complications or long-term sequelae were noted in the entire population. Conclusions Endonasal endoscopic management of congenital ECs is feasible in children, although regular long-term follow-up is essential. Furthermore, the surgical approach does not seem to affect patients' development and quality of life, although more studies and validated questionnaires are needed. No recurrent risk factors were observed able to justify a certain etiologic relation.

Valore prognostico del Sinonasal Outcome Test 22 (SNOT-22) nella rinosinusite cronica.Studi in letteratura hanno evidenziato che il punteggio basale del Sinonasal Outcome Test 22 (SNOT-22) influenza l’outcome chirurgico nella rinosinusite cronica (CRS) ed hanno suggerito che un approccio SNOT-22-mediato potrebbe migliorare la comprensione delle aspettative dei pazienti dopo il trattamento. Il presente studio mirava a verificare questa ipotesi in una popolazione italiana di CRS. In 457 pazienti con CRS, trattati con chirurgia endoscopica endonasale dopo fallimento della terapia medica massimale, sono stati calcolati la percentuale di raggiungimento della differenza minima clinicamente rilevabile (MCID) e la percentuale di miglioramento relativo dopo l’intervento chirurgico. Inoltre, è stato studiato l’impatto di diversi fattori sul punteggio dello SNOT-22 preoperatorio e postoperatorio. Il miglioramento dei sintomi si è verificato nella maggior parte dei pazienti ed era direttamente proporzionale alla SNOT-22 basale. Il 79,7% dei pazienti ha raggiunto l’MCID e la percentuale di miglioramento relativo è stata del 50,1%. Le implicazioni psicologiche e sociali hanno influenzato significativamente i punteggi dello SNOT-22. Un’analisi di regressione multipla ha mostrato che la storia di precedenti interventi chirurgici, asma, score endoscopico preoperatorio e SNOT-22 basale hanno statisticamente predetto il punteggio dello SNOT-22 postoperatorio (R2 = 0,229). Sottoporre i pazienti con CRS a SNOT-22 prima dei trattamenti chirurgici potrebbe quindi aiutare ad informarli sui probabili esiti, sebbene sia fortemente influenzato dalla percezione individuale. Sono necessari ulteriori studi per identificare un set efficace di parametri soggettivi e oggettivi per la valutazione dei risultati.Previous studies have highlighted that baseline Sinonasal Outcome Test 22 (SNOT-22) score affects surgical outcomes in chronic rhinosinusitis (CRS) and suggested that a SNOT-22-based approach might ameliorate patients’ understanding of expectations after treatment. Our study aimed at verifying this hypothesis in an Italian CRS population. In 457 CRS patients treated with endoscopic sinus surgery after failure of maximal medical therapy, the percentage of achieving a minimal clinically important difference (MCID) and the percentage of relative improvement after surgery were calculated. Moreover, the impact of several factors on preoperative and postoperative SNOT-22 score was investigated. Symptom improvement occurred in the majority of patients and was directly proportional to baseline SNOT-22. 79,7% of patients achieved the MCID and the percentage of relative improvement was 50,1%. Psychological and social-functioning implications significantly affected SNOT-22 scores. Multiple regression analysis showed that history of previous surgery, asthma, preoperative endoscopic and SNOT-22 scores predicted the postoperative SNOT-22 score (R2 = 0,298). Submitting CRS patients to SNOT-22 prior to surgical treatments might help to inform about probable outcomes, although it is strongly influenced by individual perception. Further studies are needed to identify an effective set of subjective and objective parameters for evaluation of outcomes.

Previous studies have demonstrated that both subcutaneous (SCIT) and sublingual specific immunotherapy (SLIT) are effective in treating allergic rhinitis (AR). Further studies have evaluated the efficacy of allergen-specific immunotherapy (AIT) on different ear, nose, and throat (ENT) manifestations, in which allergy might have an etiopathogenetic role, such as local allergic rhinitis (LAR), rhinosinusitis (RS), otitis media (OM), and adenotonsillar (AT) disease. Nevertheless, the management of allergy in ENT diseases is still debated. To the best of our knowledge, this is the first systematic review assessing the efficacy of AIT in ENT diseases aside from AR. Literature data confirmed that AIT might be an effective therapeutic option in LAR, although its effect is restricted to studies with short-term follow-up. Furthermore, previous research demonstrated that AIT may improve symptoms and surgical outcomes of chronic rhinosinusitis when used as an adjunctive treatment. Few studies supported the hypothesis that AIT may exert positive therapeutic effects on recurrent upper airway infections as adenotonsillar disease. Finally, some clinical observations suggested that AIT may add some benefits in the management of otitis media with effusion (OME). The results of this systematic review allow us to conclude that the efficacy of AIT in ENT disorders has been only slightly investigated and additional studies are needed.

Background: Local and systemic corticosteroids have long been the workhorse in management of chronic rhinosinusitis with nasal polyps (CRSwNP), although there is no universally accepted modality of prescription. We carried out a survey in Italy to capture current trends in the use of topical and systemic corticosteroids in patients with CRSwNP. Methods: A survey was set up on Survey Monkey®. Each author distributed the link to the survey in an ad hoc manner and a total of 437 participants filled out the survey. Results: Mometasone furoate (79.3%) was the most frequently prescribed, administered daily by 61.9% of participants; the remaining preferred to discontinue treatment for brief periods to reduce side effects or to modulate the therapy in mild cases. The majority believe that a short cycle of systemic steroids should be prescribed for re-exacerbation of symptoms and that the number of cycles in the previous year should be evaluated to define control of the disease even if international guidelines do not provide clear indications on this topic. A certain degree of divergence emerged from responses regarding how long and the maximal dose of systemic steroids which place patients at high risk for adverse events. Finally, systemic corticosteroids seem to offer only temporary benefit on recovery of smell without guaranteeing long-term control even if the patient is adherent to topical corticosteroids. Conclusions: Our results highlight the need for clear guidelines on oral steroids, which could help supporting the use of a precision medicine approach, including indications for new biological agents.

Objective: The upcoming introduction of mepolizumab represents a promising treatment for chronic rhinosinusitis with nasal polyps (CRSwNP). The present study aimed to evaluate the effectiveness of mepolizumab on sinonasal outcomes of comorbid CRSwNP and severe asthma in a real-life setting. The primary endpoint was to evaluate changes in the SinoNasal Outcome Test (SNOT)-22 score, Nasal Polyp (NP) score, and blood eosinophil count during a 12-month treatment with mepolizumab. Secondary endpoints were to quantify mepolizumab’s effects on the mentioned parameters, identify clinical variables influencing the degree of response to treatment, and portray responder and nonresponder patients. Methods: A multicentric retrospective no-profit observational study on severe asthmatic patients, treated with mepolizumab, and comorbid CRSwNP was conducted. All patients were followed for at least 12 months. SNOT-22 score, NP score, and blood eosinophil count (and other CRS-specific variables) were collected at baseline and after 12 months. Results: Forty-three patients were included. A statistically significant reduction was observed for SNOT-22 score (mean t0 SNOT-22 54.8 ± 25.9; mean t12 SNOT-22 31.5 ± 21.3, p < 0.0001), NP score (median t0 NPS 3 (IQR 3); median t12 NPS 2 (IQR 4), p < 0.0001), and blood eosinophil count (mean t0 blood eosinophils 804.7 ± 461.5 cell/µL; mean t12 blood eosinophils 107.5 ± 104.6 cell/µL, p < 0.0001) after 12 months of treatment. Twenty patients (47%) gained improvement both in clinical and endoscopic outcome. Mepolizumab responder patients presented a t0 SNOT-22 significantly higher than nonresponders (p = 0.0011). Conclusions: Mepolizumab improved CRSwNP outcomes in a population of severe asthmatic patients. No clinical feature emerged to outline the profile of a “typical” responder patient, except for baseline SNOT-22 score, which seemed to affect the response to treatment. Further studies would be necessary to supplement these preliminary evaluations.

Background TMPRSS2, ACE2 and TMPRSS11D are genes coding for proteins necessary for SARS-CoV-2 activation, infection and transmission. Once SARS-CoV-2 enters the host cell, it leads to an exaggerated inflammatory state of the lungs mediated by overexpressed TNF-, IL-6, and IL-1β. We assessed azithromycin's effect on the aforementioned genes and their associated pathways to evaluate its potential use as a possible treatment. Objective Confirm the role azithromycin may play in the regulation of pathways and genes involved in inflammation and SARS-CoV-2 activation and cell-to-cell transmission. Methods Primary airway nasal epithelial cells collected from nasal biopsies of three patients with chronic rhinosinusitis (CRS) were primary cultured and treated or not with 10µg of azithromycin. RNA was extracted from these samples and analyzed using a microarray chip. Differential gene expression profiles and gene set enrichment analysis (GSEA) were obtained between both groups. Results Cell cultures treated with 10µg of azithromycin significantly downregulated receptor-mediated endocytosis canonical pathways involving TMPRSS2 and TMPRSS11D genes. Downregulated inflammation-associated genes included IL-1β and NDST1. Interestingly, numerous genes in the cholesterol biosynthesis pathway were significantly upregulated as part of a potential process named drug-induced phospholipidosis (DLP). Conclusions This proof of concept demonstrates azithromycin downregulates pathways involving serine proteases TMPRSS2 and TMPRSS11D required for SARS-CoV-2 activation and its cell-to-cell transmission while downregulating pro-inflammatory cytokine IL-1β, NDST-1 and their associated pathways. This may help reduce the characteristic excessive respiratory epithelial inflammation, key feature of SARS-CoV-2 infection. Finally, azithromycin may also decrease available cholesterol in lipid rafts which may hinder SARS-CoV-2 infection.

ObjectiveThe extent of surgery, the type of device used and head position may influence nasal irrigation. The aim of this study was to determine the effectiveness of topical irrigant delivery to the paranasal sinuses according to these factors.MethodFour cadaveric heads underwent four stepwise endoscopic dissections. Irrigations were evaluated after every stage using different delivery devices (squeeze-bottle, gravity-dependent device and syringe) in two head positions (nose-to-sink and vertex down). Irrigant penetration into each sinus was estimated using a four-point scale.ResultsA significant positive effect of surgery was demonstrated for each sinus as well as for the delivery device. High-volume irrigant devices are more effective, and the head position plays a significant role in irrigant distribution to the frontal sinus.ConclusionThis study further confirms the efficacy of high-volume irrigant devices. A vertex down position during the irrigation could improve delivery to the frontal sinus, and the widening of the ostia increases irrigant access to the sinuses.

Objectives Spontaneous cerebrospinal fluid (CSF) leaks are a rare but insidious clinical entity. In the recent literature, their pathogenesis has been linked with idiopathic intracranial hypertension (IIH). Considering a worse surgical outcome compared to traumatic leaks, a medical treatment of the underlying IIH has been suggested in order to prevent relapses. Nevertheless, some aspects of this rare pathology remain unclear. We report our long experience in the management of spontaneous CSF leaks. Methods A retrospective evaluation of all patients with spontaneous CSF leaks treated from 1998 to 2018 in a tertiary referral center was carried out. All patients received surgery without any adjuvant routine medical treatment. Epidemiological and clinical data were reviewed. A telephone survey was conducted to investigate IIH-related symptoms in this population. Results One hundred sixty-seven patients and 195 procedures were included in the study. The total rate of failure after surgical treatment was 9%. Eight patients suffered a relapse in the same site (4%, 8 of 195), whereas seven patients experienced a relapse in a different site (4%, 7 of 167). Twenty-nine percent of the population interviewed referred at least one IIH-related symptom. Conclusion Spontaneous CSF leaks represent a complex pathology that need a multidisciplinary evaluation. Surgical treatment seems to guarantee favorable results in most of the patients. Despite this, a not negligible percentage of patients experienced a relapse during a long-term follow-up. Further studies are needed to reach a deeper understanding of the presentation and course of this particular condition. Level of evidence 4 Laryngoscope, 131:E401-E407, 2021.

The introduction of monoclonal antibody (mAb) therapies represents a promising treatment for refractory chronic rhinosinusitis (CRS). We assessed the effects of selected mAbs (omalizumab, mepolizumab, benralizumab) on CRS in severe asthmatic patients in a real-life setting.A prospective observational study on severe asthmatic patients, treated with 3 different mAb (omalizumab, mepolizumab, benralizumab), and comorbid CRS was conducted. All patients were followed for 52 weeks. The degree of nasal control, SinoNasal Outcome Test (SNOT) 22, Nasal Polyp Score (NPS), Lund Kennedy Score (LKS) were collected at baseline and at 52-week.40 patients (33 with nasal polyps) were studied. 33 patients (82.5%) had uncontrolled nasal disease at baseline, and 15 (37.5%) were uncontrolled after 52 weeks. Significant improvement was observed for SNOT 22 (P0.001), SNOT 1-12 (P0.001) and degree of nasal control (P0.001). Differences in NPS (P = 0.130) and LKS (P = 0.124) were not significant. Net change in the above-mentioned parameters among the three treatment groups was not significantly different.The study shows an improvement of nasal symptoms after 52 weeks of mAb treatment, which was not associated with significant improvement of endoscopic findings. Larger studies are needed to assess the real-life efficacy of mAbs in CRS.L’efficacia delle terapie biologiche sulla rinosinusite cronica nel paziente asmatico severo.L’introduzione degli anticorpi monoclonali (mAb) rappresenta una promettente risorsa per il trattamento delle rinosinusiti croniche (RSC) refrattarie. Obiettivo dello studio è valutare l’efficacia del trattamento biologico sulla RSC nel paziente asmatico severo in un contesto real-life.È stato condotto uno studio osservazionale di 52 settimane su pazienti asmatici severi, trattati con 3 diversi mAb (omalizumab, mepolizumab, benralizumab), e con RSC come comorbidità. Sono stati raccolti raccolti dati riguardanti il grado di controllo nasale, il SinoNasal Outcome Test (SNOT) 22, il Nasal Polyp Score (NPS), il Lund Kennedy Score (LKS) al baseline e a 52 settimane.Sono stati analizzati 40 pazienti (33 con polipi nasali). 33 pazienti (82.5%) presentavano una RSC non controllata al baseline, 15 (37.5%) soffrivano ancora di RSC non controllata dopo 52 settimane. Un miglioramento significativo è descritto per lo SNOT 22 (P0.001), lo SNOT 1-12 (P0.001) e il grado di controllo nasale (P0.001); differenze nel NPS (P = 0.130) e LKS (P = 0.124) sono risultate non significative. Il cambiamento netto dei sopracitati parametri tra i tre gruppi di trattamento non era significativamente differente.Lo studio evidenzia a 52 settimane di trattamento con mAb un miglioramento dei sintomi, non associato a cambiamenti significativi dei riscontri endoscopici. Sono necessari studi più ampi per determinare l’efficacia nella real-life dei mAb nella RSC.

Characterising the eosinophilic profile represents the main step in chronic rhinosinusitis (CRS) endotyping. The aim of the study is to verify the correlation between different methods for tissue eosinophilia quantification.33 CRS patients undergoing endoscopic sinus surgery and 30 controls undergoing non-CRS surgeries were enrolled. Blood venous sampling, nasal biopsy on uncinate process (UP), nasal cytology on inferior turbinate (IT) and middle meatus (MM) were performed.Differences in eosinophil count in blood (P=0.0001), UP (P#x003C;0.0001), IT (P = 0.01) and MM (P = 0.0006) were significant between CRS cases and controls. A weak correlation was found between UP and blood eosinophil count (r = 0.34, P = 0.006) and between UP and IT eosinophil count (r = 0.30, P = 0.017). Moderate correlation between UP and MM (r = 0.51, P #x003C; 0.0001) was shown. ROC analysis predicted eosinophilic CRS with an overall low sensitivity. Once allergic patients were excluded from the analysis, the sensitivity decreased for sampling on IT and increased for MM sampling.This study suggests that MM cytology gives more accurate information on the degree of tissue eosinophilia. Replication in wide and unbiased cohorts is necessary to verify these results and define accurate thresholds.Il ruolo della citologia nasale nella rinosinusite cronica.L’identificazione del profilo eosinofilico è uno step fondamentale nell’endotipizzazione della rinosinusite cronica (RSC). Lo scopo dello studio è verificare il grado di correlazione tra le diverse metodiche di quantificazione dell’eosinofilia.Sono analizzati, per 33 pazienti RSC candidati a chirurgia endoscopica nasosinusale e 30 controlli sottoposti a chirurgia non RSC-correlata, un campione di sangue venoso periferico, una biopsia del processo uncinato (PU), un citologico sul turbinato inferiore (TI) e un citologico nel meato medio (MM).Differenze tra RSC e controlli negli eosinofili su sangue periferico (P = 0,0001), PU (P #x003C; 0,0001), TI (P = 0,01) e MM (P = 0,0006) sono risultate statisticamente significative. È stata dimostrata una correlazione debole tra sangue periferico e PU (r = 0.34, P = 0,006) e tra PU e IT (r = 0,30, P = 0,017), e una correlazione moderata tra PU e MM (r = 0,51, P #x003C; 0,0001). Le curve ROC hanno predetto forme di RSC eosinofila con una sensibilità globalmente bassa. Escludendo i pazienti allergici la sensibilità si riduce ulteriormente per TI mentre aumenta per MM.Il presente studio suggerisce di eseguire il prelievo citologico nel MM al fine di identificare le RSC eosinofile. Sono necessari studi più ampi per verificare i risultati e definire valori limite adeguati.

Cerebrospinal fluid (CSF) leaks associated with endoscopic sinus surgery (ESS) are a rare complication related to anatomical and technical factors. The anatomical variations at skull base level are imperative to be detected preoperatively by CT scan to avoid this complication. Identifying the factors playing a role in the incidence of the CSF leaks during and after ESS and the common leak sites. A retrospective review of 24 patients presented with incidental CSF leaks, gathered from 1999 to 2016 was performed. Images interpretation of the skull base area was done using four parameters includes Keros classification, skull base slope, fovea plane and maxillary ethmoid height ratio (MER). Each parameter is classified into three types according to the anatomical configuration, then these parameters scores categorized according to the level of the safety into a level I, II and III, all levels were correlated with each other and with the site of leakage. It was found that the major group presented with the level I and the least group with level III safety, with an evidence of the most unsafe anatomical variation was the least relevant. Parameters measurements revealed that the larger group of the anatomical variation type III was in the MER and the commonest leak site was in the posterior ethmoidal roof. CT scan study of the skull base is crucial in delineating the variations and be a roadmap to proceed safely through the dissection remembering that incidental CSF leaks are multifactorial in etiology.

Background Lesions affecting sphenoid sinus lateral recess (SSLR) are difficult to visualize and manipulate through the transnasal routes, especially when the sinus is highly pneumatized. External approaches to this area involve extensive surgery and are associated with significant morbidity. The aims of this study are to present our experience with the endoscopic transpterygoid approach as a method for approaching lesions of the SSLR and to evaluate the outcomes of this procedure.Methods Clinical charts of patients who had lesions in the SSLR and who were treated at our institution from September 1998 to June 2018 were retrospectively reviewed. All these patients were managed by the endoscopic endonasal transpterygoid approach.Results Thirty-nine patients were identified. No cerebrospinal fluid leak recurrences were observed during follow-up (range: 1–19.7 years; median: 2.3 years). Hypoesthesia (temporary, 1; persistent, 4) in the region innervated by the maxillary branch of the trigeminal nerve was detected in five (12.8%) patients, while symptoms due to the Vidian nerve damage (dry eye, 3; dry nasal mucosa, 1) were present in four (10%) patients.Conclusions Although the endoscopic endonasal transpterygoid approach is an excellent corridor for dealing with lesions of the SSLR, limited rate of neurologic and lacrimal complications was observed. Potential morbidity of the intervention should be discussed during preoperative counselling.

Background The aim of this article is to describe the Riedel-Mosher’s surgical technique and identify its current role in the endoscopic endonasal era based on the experience of a tertiary care medical centre. It also provides a brief excursus on materials available for frontal reconstruction. Methods A retrospective review of patients submitted to Riedel-Mosher’s procedure from 2005 to 2018 at a single tertiary care centre was carried out. Details of the surgical technique along with data on frontal reconstruction timing and materials used were collected. Results A total of 21 patients (16 males and 5 females) underwent the Riedel-Mosher’s procedure. The age of the patients ranged from 15 to 84 years. The underlying pathology was represented mainly by chronic osteitis of the frontal bone (17 cases), followed by benign tumours (3 cases) and malignancy (1 case). Perioperative complications occurred in 3 patients. Cranioplasty was carried out only on 16 cases and delayed by an average time of 10 months. Materials for reconstruction included titanium, ceramic, plastic and free flap . Conclusions Nowadays, Riedel-Mosher’s procedure is still indicated in selected cases of benign and malignant pathologies of the frontal sinus and/or frontal bone. Surgical expertise is key to approach the frontal sinus safely. Its reconstruction requires proper planning and a wide variety of materials to perform it is now available.

Il profilo di espressione genica multipla rivela una disfunzione epiteliale nella rinosinusite cronica polipoide.La rinosinusite cronica (CRS) è un disturbo infiammatorio eterogeneo risultante da una complessa interazione genetico-ambientale. Sebbene l’eziologia rimanga tuttora sfuggente, numerosi studi riportano alterazioni nell’espressione genica di diversi fattori implicati nell’ambito della risposta infiammatoria. Tuttavia, la gran parte di queste sono analisi isolate, non replicate, che prendono in considerazione un singolo gene alla volta. Inoltre, gli studi riguardanti analisi di espressione genica multipla, solitamente su mediatori infiammatori (es. citochine), spesso presentano risultati contrastanti, che in parte possono essere dovuti all’eterogeneità dei campioni o a metodologie analitiche di potenza limitata. In quest’ottica, il nostro obiettivo è stato di verificare simultaneamente l’espressione genica di un pannello di geni (AQP5, MUC5AC, CAV1, LTF, COX2, PGDS, TNFα, TGFβ1, MGB1) potenzialmente coinvolti nei meccanismi infiammatori della CRS. Nonostante la gran parte dei campioni sia stata esclusa dall’analisi a causa del deterioramento dell’RNA tissutale, siamo stati in grado di dimostrare una riduzione statisticamente significativa dell’espressione dei geni AQP5, CAV1, LTF e MGB1, in uno specifico sottogruppo di pazienti affetti da CRS nella variante con polipi nasali senza le tipiche comorbidità frequentemente associate (asma, allergia, intolleranza all’acido acetil-salicilico). Questi dati sembrano suggerire una disfunzione della barriera epitaliale nella CRS polipoide. Ulteriori studi saranno necessari per incrementare ulteriormente la nostra conoscenza sulla patogenesi della CRS. A tal proposito l’applicazione delle nuove e più potenti tecniche di sequenziamento, come la next-generation RNA sequencing, e la disponibilità di analisi bioinformatiche più complete potranno migliorare la caratterizzazione del transcriptoma negli endotipi della CRS.Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disorder resulting from a complex gene-environment interaction. Although its aetiology remains elusive, numerous studies reported gene expression alterations of factors apparently implicated in all aspects of the inflammatory response. However, most investigations are limited, unconfirmed analyses of a single gene. Moreover, studies concerning multiple gene expression analyses, usually on inflammatory mediators (e.g. cytokines), show contrasting outcomes in part due to use of heterogeneous samples or methodologies with limited power. In this scenario, our goal was to simultaneously evaluate the expression of a panel of selected genes (AQP5, MUC5AC, CAV1, LTF, COX2, PGDS, TNFα, TGFβ1, MGB1) potentially involved in CRS inflammatory mechanisms. While most of the samples collected were excluded from the analysis because of poor quality RNA, we were able to demonstrate statistically significant downregulation of the AQP5, CAV1, LTF, MGB1 genes in a specific subset of polypoid CRS (patients without typical comorbidities), which might suggest relevant underlying epithelial dysfunction. Further studies are needed to enrich our knowledge on the pathogenesis of CRS. Forthcoming approaches might utilise next-generation RNA sequencing and comprehensive bioinformatics analyses to better characterise the transcriptome profiles of CRS endotypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Several authors highlighted the limitations of the Keros classification system in predicting intracranial entry risk. Recently, our group proposed a new classification system based on the angle formed between the lateral lamella of the cribriform plate (LLCP) and the continuation of an horizontal plane passing through the cribriform plate (Gera classification). The aim of this study was to analyze whether the risk of iatrogenic cerebrospinal fluid leak (CSF-L) was better predicted by Keros or Gera classification. Methodology: The pre-operative CT scans of 24 patients (CSF-L group) who suffered from iatrogenic CSF-L during endoscopic sinus surgery (ESS) were compared to those obtained from a group of 100 patients who underwent uneventful ESS (control group). The skull base measurements as well as the distribution of Keros and Gera classes in the 2 groups were analyzed. Results: No difference in the distribution of Keros classes or in the depth of the cribriform plate between CSF-L and control group were demonstrated. On the contrary, significant differences in the distribution of Gera classes and in the degree of the angle formed by the LLCP and the continuation of the horizontal plane passing through the cribriform plate were found. In particular, according to Gera classification system, 19 out of 24 patients in the CSF-L group were considered at risk for iatrogenic CSF-L. Conclusions: Gera classification system might be more sensitive to anatomical variations associated with CSF-L than the Keros one, further suggesting the application of the former during the preoperative CT scan evaluation.

Snail mucus is a mixture of active substances commonly thought to have healthy properties for the treatment of skin disorders. Although snail mucus is an ingredient of several cosmetic and para-pharmaceutic products, a comprehensive characterization of chemical composition and biological effects is still missing. Crude purified extracts from Helix aspersa muller mucus (HelixComplex) were prepared and, after chemical characterization, tested on in vitro experimental models. Differently from what expected, HelixComplex was characterized by the presence of small amounts of glycolic acid and allantoin. By using different in vitro assays on fibroblast cultures, we found that HelixComplex lacked of cytotoxicity, protected cells from apoptosis (p

Stefania Gallo,1,* Maria Vittoria Arcidiacono,2,* Veronica Tisato,1 Roberta Piva,3 Letizia Penolazzi,3 Cristina Bosi,1 Carlo V Feo,1 Roberta Gafà,1 Paola Secchiero1 1Department of Morphology, Surgery, Experimental Medicine and LTTA Center, University of Ferrara, Ferrara, Italy; 2Institute for Maternal and Child Health, IRCCS “Burlo Garofolo,” Trieste, Italy; 3Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy *These authors contributed equally to this work Background: Tumor-specific isoforms generated by alternative splicing (AS) are demonstrated to contribute to tumor progression and can represent potential biomarkers. NOVA2 is an AS factor that in physiological conditions regulates endothelial cells’ (ECs) polarity and vessel lumen maturation, likely by mediating AS of apical–basal polarity regulators. However, NOVA2 expression in tumor ECs and its regulation have never been investigated. Methods: To elucidate this, 40 colorectal cancer patients were enrolled and NOVA2 expression was investigated by immunohistochemistry in samples bearing both the normal mucosa and the tumor tissue. Results: NOVA2 was found expressed in ECs of tumor vasculature and, importantly, it was upregulated in tumor ECs with respect to normal mucosa ECs in all cases (P

Chronic rhinosinusitis (CRS) is a debated topic in the international rhinologic literature because of its high prevalence, heterogeneity of clinical manifestations and unpredictability of disease course. Recently, the focus in CRS research has moved to identify biological subtypes that might explain its aetiology and clinical variability. However, these analyses are still expensive and limited to scientific purposes, so that they cannot be used on a large scale in daily practice. For this reason, we wondered if it was possible to define a risk stratification for CRS patients based only on first level investigations. The heterogeneity of the disease has given us a large amount of data compelling to find an additional storage system. Herein, we present the results of our work, the RhinoBank, as we believe that it is an easy-to-use tool for those professionals dealing with CRS and an effective system to exploit in clinical research.Strategie integrative nella raccolta dati del paziente affetto da rinosinusite cronica.La rinosinusite cronica (CRS) rappresenta un argomento dibattuto nella letteratura rinologica internazionale a causa della sua alta prevalenza, dell’eterogeneità delle manifestazioni cliniche e della difficoltà a predire l’andamento della malattia. Recentemente l’attenzione della ricerca nella CRS si è spostata verso l’identificazione di sottotipi biologici che possano giustificare l’eziologia e la variabilità clinica. Tuttavia, queste analisi risultano ancora costose e limitate nell’impiego per scopi di ricerca, per cui non applicabili su larga scala e nella pratica clinica quotidiana. Per questo motivo ci siamo domandati se fosse possibile ottenere una stratificazione del paziente rinosinusitico solo sulla base di indagini di primo livello. L’eterogeneità intrinseca della malattia ci ha messo di fronte ad una vasta quantità di dati obbligandoci a trovare strategie di archiviazione addizionali. Presentiamo quindi il frutto del nostro lavoro, il RhinoBank, principalmente per due motivi. Crediamo che sia uno strumento di facile impiego a disposizione di chiunque tratti questa patologia ed un sistema efficace da sfruttare nella ricerca clinica.

Background: Chronic kidney disease (CKD) patients experience a high risk of cardiovascular disease (CV); however, the factors involved in CV-related morbidity and mortality in these patients have not been fully defined. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine, which exhibits pleiotropic activities on endothelial, vascular smooth muscle and inflammatory cells, with relevant effects on atheromatous plaque formation. On this basis, the present study aims to investigate the role of TRAIL in atheromatosis progression in CKD patients. Methods: Circulating TRAIL levels were measured in 378 CKD patients belonging to the Spanish National Observatory of Atherosclerosis in Nephrology (NEFRONA) study. All patients were free of previous CV events. Carotid and femoral B-mode ultrasound was performed to detect the presence of plaque at baseline and after 24 months of follow-up. Results: The lowest levels of TRAIL at baseline were significantly (p

Background The aim of this study is to propose a classification of the angle formed by the lateral lamella of the cribriform plate (LLCP) and the horizontal plane passing through the cribriform plate. In particular, the angle was classified into class I (over 80 degrees), class II (45 to 80 degrees, and class III (under 45 degrees) METHODOLOGY: A total of 190 computed tomography scans were retrospectively reviewed in order to obtain four sets of measurements. 1) depth of the cribriform, 2) angle, 3) length of the LLCP, 4) width of the fovea ethmoidalis. The relationship among these measurements were analyzed. Results The angle was significantly correlated with the depth of the cribriform and the length of the fovea, while it was negatively correlated with the length of the LLCP. Significant negative correlation was also found between the length of the LLCP and the width of the fovea. Conclusions This angle classification is based on the theoretical risk of iatrogenic injuries, but it could be helpful also in clinical practice by providing indirect information on the thickness of the anterior skull base. As the angle decreases, in fact, the portion of the anterior skull base composed by the LLCP, increases.

Background The purpose of this study was to evaluate the clinical behavior of oncocytic Schneiderian papillomas in relation to the rate of malignant transformation and recurrences and to report the long-term results of the endoscopic endonasal treatment. Methods A retrospective analysis was carried out on patients with oncocytic papilloma, endoscopically managed over the past 20 years, at 2 university centers following a uniform policy. Results Thirty-three patients were treated between November 1991 and December 2010. The mean follow-up period was 62 months. We observed 2 cases of persistence (6%) at the maxillary sinus level. Both of these patients underwent endoscopic surgical revision. Squamous cell carcinoma (SCC) was observed in 1 patient (3%). Conclusion The endonasal endoscopic technique proved to be a safe and effective approach for the treatment of oncocytic papillomas. An oncocytic papilloma is not to be considered a negative prognostic factor in terms of malignant transformation or recurrence. © 2013 Wiley Periodicals, Inc. Head Neck 36: 624–630, 2014

// Paola Secchiero 1, * , Rebecca Voltan 1, * , Erika Rimondi 1 , Elisabetta Melloni 1 , Emmanouil Athanasakis 2 , Veronica Tisato 1 , Stefania Gallo 1 , Gian Matteo Rigolin 3 and Giorgio Zauli 1 1 Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy 2 Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy 3 Department of Medical Sciences, Section of Hematology, University of Ferrara, Ferrara, Italy * These authors have contributed equally to this work Correspondence to: Giorgio Zauli, email: giorgio.zauli@unife.it Paola Secchiero, email: paola.secchiero@unife.it Keywords: B-leukemic cells, Ibrutinib, γ-secretase inhibitors, NOTCH1, combination therapy Received: May 05, 2017 Accepted: June 20, 2017 Published: July 22, 2017 ABSTRACT Ibrutinib blocks B-cell receptor signaling and interferes with leukemic cell-to-microenvironment interactions. Ibrutinib plays a key role in the management of B-CLL and is recommended for first line treatment of high-risk CLL patients with 17p deletion. Therefore, elucidating the factors governing sensitivity/resistance to Ibrutinib represents a relevant issue. For this purpose, in 3 B-CLL patient samples harboring functional TP53 mutations, the frequency of the mutated clones was monitored during in vivo Ibrutinib therapy, revealing a progressive decline of the frequency of TP53 mut clones during 12 months of treatment. In parallel, the anti-leukemic activity of Ibrutinib was assessed in vitro on B-CLL patient cell cultures in combination with γ-secretase inhibitors (GSI). In the in vitro assays, the combination of Ibrutinib+GSI exhibited enhanced cytotoxicity on B-CLL cells also in the presence of stroma and it was coupled to the down-regulation of the stroma-activated NOTCH1 and c-MYC pathways. Moreover, the combined treatment was effective in reducing CXCR4 expression and functions. Therefore, the ability of GSI to enhance the Ibrutinib anti-leukemic activity in B-CLL cells, by down-regulating the NOTCH1 and c-MYC pathways, warrants further experimentation for its potential therapeutic applications.

Objective The purposes of this study were to report our experience with endoscopic treatment of choanal atresia (CA), to illustrate our surgical technique and analyse the different factors that may affect outcomes. Material and methods A retrospective review was performed of patients affected by congenital CA and treated between June 1996 and November 2013 at three referral centres which follow a uniform policy. Results Eighty-four patients with CA (55 unilateral and 29 bilateral), aged between one day and 76 years (mean, 13 years) were included. Associated malformations were present in 28 patients. The overall success rate was 93%, with 96.3% and 86.2% success rates for unilateral and bilateral CA respectively. Six patients (7%) required revision surgery for early symptomatic restenosis. Statistical analysis revealed that outcomes were not influenced by sex, previous surgeries, unilateral versus bilateral atresia or associated anomalies. However, age seemed to be a prognostic risk factor for patients under one year-old. Conclusion The endoscopic endonasal approach is safe and effective, with a very high success rate and low morbidity. The removal of the vomer and the use of mucoperiosteal flaps are the main keys to avoiding postoperative stenosis. The use of stents or Mitomycin C is therefore not mandatory.

The aim of this study is to evaluate the reliability and validity of the Italian SNOT-22 (I-SNOT-22). The study consisted of five phases: item generation, reliability analysis, normative data generation, validity analysis and responsiveness analysis. The item generation phase followed the five-step, cross-cultural, adaptation process of translation and back-translation. A group of 222 patients with chronic rhinosinusitis (CRS) were enrolled for the internal consistency analysis. Sixty patients completed the I-SNOT-22 twice, 2 weeks apart, for test–retest reliability analysis. A group of 119 asymptomatic subjects completed the I-SNOT-22 for normative data generation. I-SNOT-22 scores obtained by CRS patients and asymptomatic subjects were compared for validity analysis. I-SNOT-22 scores were correlated with Lund-Mackay and visual analogue scale (VAS) scores in 50 CRS patients for criterion validity analysis. Finally, I-SNOT-22 scores obtained in a group of 59 CRS patients before and after surgical treatment for CRS were compared for responsiveness analysis. All the enrolled subjects managed to complete the I-SNOT-22 without needing any assistance. Internal consistency was satisfactory (α = 0.86). Test–retest reliability was also satisfactory (ICC = 0.85). A significant difference in the I-SNOT-22 scores between the CRS patients and the asymptomatic subjects was found (p

Background Chronic rhinosinusitis (CRS) is a frequent disease with high social impact and multifactorial pathogenesis. Recently, single nucleotide polymorphisms within the TAS2R38 gene have been implicated as possible contributors to the complex gene-environment interactions in CRS. The purpose of this study was to confirm the proposed correlation between TAS2R38 genotype, CRS and related comorbidities. Methods Fifty-three CRS patients and 39 healthy individuals were genotyped at the TAS2R38 locus. CRS patients were treated by endoscopic sinus surgery and medical therapies and subdivided in CRS with nasal polyps (CRSwNPs) and CRS without nasal polyps (CRSsNPs). The effect of genotype on CRS and CRS-related comorbidities was assessed. Results The distribution of the different genotypes at the TAS2R38 locus was not significantly different between CRS patients, either with or without nasal polyps, and controls. Besides, no association was found between the different genotypes at the TAS2R38 locus and CRS-related comorbidities. Conclusions No association was found between TAS2R38 alleles or genotypes and CRS, thus questioning its role in the pathogenesis of CRS. Electronic supplementary material The online version of this article (doi:10.1186/s12881-016-0321-3) contains supplementary material, which is available to authorized users.

Riassunto Obiettivi La fistola oro-antrale e una comunicazione osteomucosa fra cavo orale e seno mascellare che non tende alla riparazione spontanea. Il trattamento piu frequente e la chiusura chirurgica per via transorale mediante lembi locali, con risultati spesso poco soddisfacenti. L’obiettivo del lavoro e valutare il ruolo del ripristino di un’adeguata funzionalita del complesso ostiomeatale nella gestione di questa patologia. Materiali e metodi Presentiamo il caso di una paziente con fistola oro-antrale in esiti di plurimi tentativi falliti di chiusura chirurgica con lembi locali. Alla luce del quadro endoscopico-radiologico di blocco del complesso ostiomeatale, la paziente e stata sottoposta a chirurgia endoscopica endonasale funzionale. Risultati La procedura chirurgica e risultata efficace, con riabilitazione del complesso ostiomeatale e chiusura spontanea della fistola oro-antrale a tre mesi dall’intervento naso-sinusale. Conclusioni In base all’esperienza degli autori, la corretta gestione della fistola oro-antrale non puo prescindere da un inquadramento collegiale radiologico, otorinolaringoiatrico e odontoiatrico prima di procedere al tentativo di chiusura chirurgica per via transorale.

Chronic rhinosinusitis (CRS) in children is difficult to treat, with resultant frequent recurrences and failures. There are controversies in the treatment, mirroring the debate over the exact etiology of this disorder. The available medical treatments are antibiotics, topical nasal corticosteroids, and nasal lavage with saline solutions; though, there is no general agreement on the efficacy of the latter. The new technique of balloon sinuplasty allows ventilation to the sinuses to be restored with minimal risk and trauma to the tissues, and initial outcome seems promising, being successful in most treated children. Concerning the surgical approach, adenoidectomy is among the most frequent surgical procedures performed on children, but its therapeutic effect is controversial, because randomized studies have failed to prove that adenoidectomy alone is sufficient in curing CRS. Instead, functional endoscopic sinus surgery is a minimally invasive technique which restores the sinus ostia patency and can re-establish ventilation and drainage through the natural pathways. It is important that the effectiveness of any treatment is also evaluated by patient-reported outcomes (PROs) that refer to all health-related reports coming from the patients, without any involvement or interpretations by physician or others. Among PROs, health-related quality of life (HRQL) is the one most widely known and used. HRQL can be measured by means of validated questionnaires, which provide scores proportional to the degree of well-being perceived by patients. Concerning diseases of the upper airway including RS, there are numerous instruments specifically designed for children and caregivers, which allow to assess the effects of treatments in a more extensive and complete manner.

Alternative splicing generates multiple mRNAs from a single transcript and is a major contributor to proteomic diversity and to the control of gene expression in complex organisms. Not surprisingly, this post-transcriptional event is tightly regulated in different tissues and developmental stages. An increasing body of evidences supports a causative role of aberrant alternative splicing in cancer. However, very little is known about its impact on cellular processes crucially involved in tumor progression. The aim of this review is to discuss the link between alternative splicing and the epithelial-to-mesenchymal transition (EMT), one of the major routes by which cancer cells acquire invasive capabilities and become metastatic. We begin with a brief overview of alternative splicing. Next, we discuss alternative splicing factors that regulate EMT. Finally, we provide examples of target genes presenting alternative splicing changes that contribute to the morphological conversions in the EMT process.

Mucociliary clearance is a key defence mechanism in human upper and lower airways and its impairment predisposes to chronic infections of the nose, paranasal sinuses and respiratory tract. Nasal mucociliary clearance is a first-line physiological function of nasal cavity, that helps protecting the lower respiratory tract from undesirable organic and inorganic matter, including microorganisms. On one hand, multiple investigations have demonstrated a marked decrease in nasal mucociliary clearance in patients with rhinitis or chronic rhinosinusitis. Ciliary motility analysis allows us to have an index of our defense mechanisms functionality and of our ability to react to microorganisms. The ciliary motility can be evaluated with a light microscope using phase contrast. Sampling should be performed through a brushing at the level of the middle third of the inferior turbinate and the sample must be analyzed immediately after collection. Through the analysis of the sample, it is possible to evaluate the presence of ciliated cells with a functional edge, to calculate the length of the ciliary motilia, to assess the direction of movement and to evaluate the coordination of the lashes. The time needed for this examination is short, it only takes 5 to 10 minutes, and it appears to be not invasive, repeatable and not painful. The ciliary function may also be influenced by the use of certain medications, such as anti-histamines, whereas it may be stimulated and improved by the use of topical hyaluronic acid. HA may be an important regulator of the inflammatory process. During nasal inflammation, high-molecular weight HA breaks down under the influence of free radicals and enzymes. Low-molecular weight fragments deliver signals regarding tissue damage and mobilize immune cells, while the high molecular weight form suppresses immune cells function and prevents excessive exacerbation of inflammation. Based on the known background of the effects of HA in the regulation of vasomotor tone, mucous gland secretion and in the modulation of the inflammatory process, it is suggested that HA may improve ciliary motility, nasal mucosa cellularity and inflammatory status.

Background Chronic rhinosinusitis (CRS) is a frequent disease with a high social impact and multifactorial pathogenesis. Recently, single nucleotide polymorphisms (SNPs) within the TAS2R38 gene were pointed at as possible contributors to the complex gene-environment interactions in CRS. This hypothesis was supported by in vitro evidence of the protective effect exerted by the functional bitter taste receptor T2R38 on sinonasal mucosa, due to its role in innate immunity. The purpose of this study was to confirm the proposed correlation between TAS2R38 genotype and CRS comorbidities and to assess whether the presence of a particular allele can be considered a prognostic marker.