Real-life evidence of low-dose mepolizumab efficacy in EGPA: a case series.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, small vessel, necrotizing vasculitis. The disease is mainly characterized by hypereosinophilia and asthma with frequent sinonasal involvement, although multiple organs can be affected, including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system. IL-5 production is pathogenetically central for the development of the disease by promoting proliferation, transvascular migration and functional activation of eosinophils. The degree of blood and tissue eosinophilia appears to be associated with disease pathogenesis and eosinophil depletion represents a promising treatment approach for EGPA. We prospectively evaluated the efficacy and safety of a low dose (100 mg q4w), 12-month course of mepolizumab, an anti-IL-5 monoclonal antibody, in eight patients with severe asthma and active EGPA. Patients were recruited by the tertiary care center of Clinical Immunology and Allergy, University of Naples Federico II. The following outcomes were assessed before (T0), and after 6 (T6) and 12 months (T12) of mepolizumab treatment: Birmingham Vasculitis Activity Score (BVAS), prednisone intake, Sino-Nasal Outcome Test (SNOT-22), Total Endoscopic Polyp Score (TENPS), Asthma Control Test (ACT), Forced Expiratory Volume one second (FEV1)%, blood eosinophilia. BVAS score significantly decreased showing a sharp reduction in disease activity score. Clinical improvements in terms of sinonasal scores and asthma symptoms were observed, in parallel with a drastic drop in eosinophil blood count. Prednisone intake was significantly reduced. In two patients, asthma exacerbations led to discontinuation in mepolizumab therapy after 6 and 12 months despite BVAS reduction. Mepolizumab treatment was well tolerated, and no severe adverse drug effects were registered. In conclusion, our 12-month real-life study suggests that mepolizumab may be beneficial and safe in active EGPA patients by improving disease activity score, sinonasal and asthma outcomes while reducing the burden of prednisone intake.

Otolaryngological features in a cohort of patients affected with 22q11.2 deletion syndrome: A monocentric survey.

Otorhinolaryngologic manifestations are common in 22q11.2 deletion syndrome (22q11.2DS), but poorly described. This study aimed to better define the ear-nose-throat (ENT) phenotype of 22q11.2DS patients, in the attempt to best detect subjects requiring subspecialist intervention. We enrolled 25 patients affected with 22q11.2DS. Anatomic and functional ENT findings were investigated using clinical, laboratory, and instrumental data. Immunophenotype and frequency of infections were evaluated. Univariate and multivariate analyses were performed. ENT anomalies were found in 88% of patients, and in 20% congenital palate defects required surgery. Adenoid or palatine tonsil hypertrophy was noted in 80% and 48%. Forty-eight percent of subjects had rhinolalia/phonia, severe in half of these. We also found nasal regurgitation or laryngeal penetration/aspiration in 20% and 16%, respectively. Instrumental exams revealed a mild conductive hearing loss in 32% (bilateral in most cases), tympanometric anomalies in 28%, and swallowing abnormalities in 16%. Statistical univariate analysis showed a direct association between rhinolalia/phonia and episodes of laryngeal aspiration (p = .016) and between tympanometric anomalies and increased adenoid volume (p = .044). No association between episodes of food aspiration and palatal anomalies was found. Moreover, no statistically significant association was observed between the number of airway infections and the ENT findings. This study contributes to better define the ENT phenotype in patients with 22q11.2DS, helpful to prevent potential complications. Furthermore, the identification of a subcategory of patients may allow the early adoption of specific speech therapy programs to improve the clinical outcome of 22q11.2DS patients.

Delay in diagnosis affects the clinical outcome in a cohort of cvid patients with marked reduction of iga serum levels.

Common variable immunodeficiency disorders (CVID) represent a collection of diseases leading to an absent or strongly impaired antibody production. CVID presents a wide range of immunological abnormalities and clinical manifestations, including infections, inflammatory and autoimmune diseases, and malignancies. The aim of this observational study was to analyze the epidemiological and clinical features of a cohort of 75 Italian CVID patients, and evaluate the correlation with comorbidity and mortality. Clinical data were retrospectively collected: the cohort was followed-up for a maximum of 30years (mean time of 10.24years, median of 9years). An higher age at the diagnosis of CVID and an higher age at onset of symptoms were significantly associated with a reduction of patients survival if stratified per median of IgA (less than or >8.00mg/dl). Thus IgA levels at diagnosis are correlated with patients survival contributing to identify a subset with a worse prognostic outcome.

Aerodynamic Study of Velopharyngeal Insufficiency in 22q11.2 Deletion Syndrome.

OBJECTIVES: We aim to verify velopharyngeal sphincter function in 22q11.2 deletion syndrome patients (22q11.2DS) to establish correlations between aerodynamic and perceptual measures of nasality, and to identify aerodynamic measures differentiating typical from atypical velopharyngeal behavior. METHODS: Eleven subjects with 22q11.2DS and twenty similar-age control subjects were recruited. The aerodynamic measures were mean Sound Pressure Level, air pressure peak, pressure wave duration, airflow pattern and nasal airflow during the sequence /pi/. The nasality perceptual measures were rhinolalia, rhinophony and nasal air escape. RESULTS: Airflow patterns and perceptual measures were statistically different in the two groups. Pressure wave duration and air pressure peak were lower in study subjects than in controls. Air pressure peak and nasal airflow were negatively correlated with rhinolalia; pressure wave duration was negatively correlated with nasal air escape and rhinolalia in 22q11.2DS patients. CONCLUSIONS: This aerodynamic study identified velopharyngeal qualitative and quantitative dysfunctions, suggesting heterogeneous models of velopharyngeal function in syndromic subjects as compared to controls.

Quality of Life and Respiratory Performance in the Laryngectomized Patient: Role of the HME Filters during Physical Activity.

Background: Permanent tracheostomy because of total laryngectomy surgery entails significant consequences for patients regarding respiratory physiopathology, such as the loss of the filtering, humidifying, and heating of air by the nose. The use of special stomal filters can provide adequate protection of the tracheal-bronchopulmonary system with a reduction in respiratory pathologies. In fact, in most cases, laryngectomy patients are first cigarette smokers who for this reason also already have respiratory diseases such as chronic obstructive pulmonary disease (COPD). Despite the availability of tracheal filters, as reported in the literature, patients often tend to limit their use due to reported breathing difficulties, especially in conditions of intense breathing. Methods: The objective of this clinical study was to evaluate the most suitable stomal filter for laryngectomy patients during physical activity. The filters studied were an INHEALTH device (Blom-Singer SpeakFree HME); two ATOS devices (Provox® Life™ Energy HME and Provox® Life™ Home HME); and an FAHL device (Laryvox HME Sport). Results: For this purpose, the performances of 31 laryngectomy patients, subjected to medium-high physical effort, were analyzed through a standardized pneumological test, the Six Minute Walking Test (6MWT), which involves a sustained walk lasting six minutes, with an evaluation of heart rate, oxygen saturation, and meters traveled every 60 s; furthermore, we examined two subjective indices, namely, the basal and final dyspnea index and the initial and final muscular fatigue index. Conclusions: The multidisciplinary approach of the laryngectomee patient must also take pulmonary rehabilitation into consideration. It is the task of the medical team and speech therapy support to help the patient in the correct choice of HME filters taking into account daily needs.

Effects of guidelines on adeno-tonsillar surgery on the clinical behaviour of otorhinolaryngologists in Italy.

BACKGROUND: Several guidelines on adeno-tonsillar disease have been proposed in recent years and some discrepancies in relation both to clinical manifestations and indications for surgical treatment have emerged. The aim of the study was to verify what influence (adeno)-tonsillectomy guidelines have had on the clinical behaviour of ENT specialists in Italy. Our study is a retrospective and multi-centre case series with chart review. METHODS: The survey involved 14,770 children, aged between the ages of 2 and 11, who had undergone adeno-tonsillar surgery between 2002 and 2008 in fourteen Italian tertiary and secondary referral centres. Anova test was used for the statistical analysis, assuming p < 0.05 as the minimum statistical significance value. RESULTS: The frequency of adeno-tonsillar surgeries did not change significantly (p>0.05) during the study period and following the Italian policy document publication. Overall, adeno-tonsillectomy was the most frequent intervention (64.1%), followed by adenoidectomy (31.1%) and tonsillectomy (4.8%). The indications for surgery did not change significantly for each of the operations (p>0.05), with the exception of adeno-tonsillectomy in case of feverish episodes due to acute recurrent tonsillitis ≥ 5 without nasal obstruction (decreased p= 0.010) , even when the feverish episodes due to acute recurrent tonsillitis were < 5 over the last year. Nasal obstruction was associated with feverish episodes due to acute recurrent tonsillitis in 65.2% of operated cases, while otitis media had been diagnosed in 43.3% of the patients studied. CONCLUSIONS: The recommendations first developed in Italy in a 2003 policy document and then resumed in guidelines in 2008, were not implemented by ENT units involved in the survey. The study highlights the fact that the indications for adeno-tonsillar operations are based on the overall clinical presentation (comorbidity) rather than on a single symptom. Guidelines are necessary to give coherent recommendations based on both the findings obtained through randomized controlled trials and the data collected from observational studies.

Subjective Perception and Psychoacoustic Aspects of the Laryngectomee Voice: The Impact on Quality of Life.

PURPOSE: A retrospective study is presented to correlate the inter-judge consistency for the different psycho-perceptual parameters of the recently proposed Impression Noise Fluency Voicing (INFVo) perceptual rating scale for substitution voices, and the vocal function as perceived by the patient. METHODS: The scale Voice-Related Quality of Life (V-RQoL) and the Self Evaluation of Communication Experiences After Laryngectomy scale (SECEL)-a self-evaluation questionnaire of communicative experience after laryngectomy surgery-were administered to 89 total laryngectomees, subdivided in four groups depending on their type of alaryngeal voice (i.e., tracheoesophageal and esophageal speakers, electro larynx users, voiceless patients), in order to evaluate the impact of the impairment of the phonatory function on the quality of life. RESULTS: No significant differences exist among the various groups on their perception of QoL using subjective questionnaires, whereas the INFVo scale has proven to be a useful tool for the description and analysis of the psychoacoustic characteristics of the vocal signal and a reliable instrument to correctly classify the patients. It is also notable that the judgement of the patients on their own voice and those of the referees are highly significant. CONCLUSION: Although speech rehabilitation for the acquisition of a substitution voice offers a new way of communication for the laryngectomized patients, nonetheless, their QoL is not significantly related to the type of substitution voice. Therefore, improving the patient's adaptation to the new phonatory condition is mandatory.

Effect of Implant Surface Roughness and Macro- and Micro-Structural Composition on Wear and Metal Particles Released.

BACKGROUND: Considerations about implant surface wear and metal particles released during implant placement have been reported. However, little is known about implant surface macro- and microstructural components, which can influence these events. The aim of this research was to investigate accurately the surface morphology and chemical composition of commercially available dental implants, by means of multivariate and multidimensional statistical analysis, in order to predict their effect on wear onset and particle release during implant placement. METHODS: The implant surface characterization (roughness, texture) was carried out through Confocal Microscopy and SEM-EDS analysis; the quantitative surface quality variables (amplitude and hybrid roughness parameters) were statistically analyzed through post hoc Bonferroni's test for pair comparisons. RESULTS: The parameters used by discriminant analysis evidenced several differences in terms of implant surface roughness between the examined fixtures. In relation to the observed surface quality, some of the investigated implants showed the presence of residuals due to the industrial surface treatments. CONCLUSIONS: Many structural components of the dental implant surface can influence the wear onset and particles released during the implant placement.

Preservation of neurons in an AD 79 vitrified human brain.

Detecting the ultrastructure of brain tissue in human archaeological remains is a rare event that can offer unique insights into the structure of the ancient central nervous system (CNS). Yet ancient brains reported in the literature show only poor preservation of neuronal structures. Using scanning electron microscopy (SEM) and advanced image processing tools, we describe the direct visualization of neuronal tissue in vitrified brain and spinal cord remains which we discovered in a male victim of the AD 79 eruption in Herculaneum. We show exceptionally well preserved ancient neurons from different regions of the human CNS at unprecedented resolution. This tissue typically consists of organic matter, as detected using energy-dispersive X-ray spectroscopy. By means of a self-developed neural image processing network, we also show specific details of the neuronal nanomorphology, like the typical myelin periodicity evidenced in the brain axons. The perfect state of preservation of these structures is due to the unique process of vitrification which occurred at Herculaneum. The discovery of proteins whose genes are expressed in the different region of the human adult brain further agree with the neuronal origin of the unusual archaeological find. The conversion of human tissue into glass is the result of sudden exposure to scorching volcanic ash and the concomitant rapid drop in temperature. The eruptive-induced process of natural vitrification, locking the cellular structure of the CNS, allowed us to study possibly the best known example in archaeology of extraordinarily well-preserved human neuronal tissue from the brain and spinal cord.

Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network.

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.

Some inconsistencies in Demirjian's method.

Nowadays, given the massive migration movements toward and across EU countries, age assessment can be highly useful for estimating the real age of asylum seekers or in medico-legal assessments of age-disputed children charged with criminal acts. Demirjian et al.'s dental maturity score is currently a dental scoring system universally adopted for age assessment of unidentified children. Here we explore the biological compatibility of Demirjian's scores with respect to the estimation of certain chronological ages of forensic interest through an algorithm based on the theory of constrained graphs integrated with combinatory analysis. Rather than simply respect Demirjian's indications (direct method) on a sample of children, we followed a reverse procedure (indirect method) as follows: i. chronological age selection and identification of the corresponding maturity score (MS); ii. determination of all the possible combinations of dental maturity stages whose sum of the scores is equal to the MS under consideration; iii. checking for all such possible combinations the biological congruity of the state of maturity of each tooth compared to the chronological age initially chosen. By evidencing dental development inconsistencies, our mathematical approach explains why Demirjian's method typically overestimates age. Therefore, even if the method in question remains the recommended way to assess individual dental maturity, it should definitely be considered unsuitable for application in certain forensic scenarios, particularly as regards the most disputed age range 14-16 years.

Clinical Influence of Micromorphological Structure of Dental Implant Bone Drills.

BACKGROUND: Considerations about heat generation, wear, and corrosion due to some macrostructural bur components (e.g., cutting lips, rake angle, flute, and helix angle) have been widely reported. However, little is known about how the microstructural components of the implant drill surface can influence the implant drill lifetime and clinical performance. AIM: To investigate accurately the surface morphology of surgical bone drill, by means of multivariate and multidimensional statistical analysis, in order to assess roughness parameters able to predict the evolution of tribological phenomena linked to heat development, wear, and corrosion occurring in clinical use. MATERIALS AND METHODS: The surfaces of implant drills approximately 2.0mm in diameter made by five manufacturers were examined by means of confocal microscope with white light laser interferometry, obtaining several surface roughness parameters. Statistical multivariate analysis based on discriminant analysis showed, for each cut-off, the parameters which discriminate the manufacturers. RESULTS: The microstructural parameters used by discriminant analysis evidenced several differences in terms of drill surface roughness between the five manufacturers. CONCLUSIONS: The observed surface roughness difference of drills is able to predict a different durability and clinical performance especially in heat generation and wear onset.

Prognostic value of p27Kip1 expression in Basaloid Squamous Cell Carcinoma of the larynx.

BACKGROUND: Very few reports have investigated the role of cell cycle regulators as biomarkers in Basaloid Squamous Cell Carcinoma (BSCC) of the larynx, a definite morphologic, uncommon, very aggressive variant of squamous cell carcinoma. Lower expression of Ki67/Mib-1, a proliferation marker highly expressed in the majority of tumours, and p53, a tumour suppressor protein that can induce an arrest of the G1-S transition, was related to a better prognosis in laryngeal BSCC. In the head and neck, p27kip1, a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors, has emerged as an independent prognostic factor, able to identify low-expressing tumours with unfavourable course. Up to date the role of this protein was never studied in BSCC. Aim of our study was to investigate the potential prognostic value of p27kip1 levels and their correlation with Ki67/Mib-1 and p53 expression in BSCC of the larynx. METHODS: The retrospective study group consisted of 15 male and 1 female patients, affected by laryngeal BSCC, ranging in age from 44 to 69 years (mean 58). The tumour originated from the supraglottis in thirtheen cases and from the glottis in the remaining three. Ten patients had metastatic cervical lymph nodes at presentation and were classified as N+. Post surgical stage was IV in four patients, III in nine, II in two cases and I in the remaining one. Follow-up ranged from a minimum of 5 months up to 9 years. Paraffin-embedded tissue sections of each laryngeal tumour were analyzed for p27kip, Ki67/Mib-1 and p53 expression by immunohistochemistry. RESULTS: The immunohistochemical study showed p27kip1 expression in 40% of the patients with no evidence of disease (NED) and in none (0%) of the patients dead of disease (DOD), whilst p53 was expressed in 60% of patients in NED status and in 90% of patients in DOD status. Ki67/Mib-1 was positive in 80% of NED patients and in 100% of DOD patients. At multivariate analysis, performed by means of Discriminant analysis, low levels of p27kip1 expression significantly correlated with poor prognosis (P < 0.05). CONCLUSION: p27kip1 protein has been shown to be a significant independent prognostic factor in laryngeal SCC. In our series of laryngeal BSCC the resulting data seem to confirm the clinical prognostic relevance of p27kip1 low expression, which directly correlated with biological aggressiveness and consequent shortened survival.

The Relationship between molar dentoalveolar and craniofacial heights.

Excessive vertical growth of the posterior dentoalveolar region has been implicated in the etiology of the so-called long-face syndrome. In this study, we tested the hypothesis that molar dentoalveolar heights are positively related to vertical craniofacial features. Cephalometric measurements obtained from 82 adult subjects were entered as independent variables in a multiple regression model. Maxillary and mandibular molar dentoalveolar heights were entered as dependent variables. Approximately 70% of the total variance was explained by anterior lower facial height (ANS-Me) and the mandibular palatal plane angle (PP-MP). Increases of ANS-Me and PP-MP had opposite effects on the amount of molar dentoalveolar heights. The lowest values of molar dentoalveolar heights were found in subjects with a small ANS-Me distance but with a wide PP-MP angle. The findings suggest that individuals with a marked divergence of the jaws may also have a reduced molar dentoalveolar vertical development.

Medical liability, defensive medicine and professional insurance in otolaryngology.

BACKGROUND: This study aims at verifying relationships between the perception of medico-legal risks involved in the professional activity of Italian otolaryngologists, defensive medical behaviour and their understanding of professional liability insurance in matters of civil liability. One hundred specialists replied to a questionnaire pertaining to the psychological impact of medico-legal issues and to specific queries regarding insurance coverage, either privately stipulated or provided by the employer. Statistic analysis was carried out by χ(2) test and ANOVA multiple variance regression test, assuming P = 0.05 as the value of minimum statistical significance. RESULTS: It was found that in 50% of cases the behaviour of the doctor towards the patient had been decidedly influenced by concerns over medico-legal implications. In 29% of the sample these concerns had "often to always" influenced the choice of diagnostic procedures or treatment options, in order to safeguard themselves in case of legal dispute. The data obtained showed a statistically significant correlation between the level of concern (regarding potential medico-legal disputes) experienced by specialists on the one hand and variations in the doctor/patient relationship (P < 0.05) and the choice of defensive medical procedures (P < 0.05) on the other. Furthermore, the perception of the medico-legal problem was statistically related to the absence or poor knowledge of some insurance clauses, regarding posthumous coverage (72%), informed written consent (89%), and the coverage provided by the healthcare centre where the specialist is employed (32%) (P < 0.05). CONCLUSIONS: The results of this study indicate the necessity for a greater awareness of the actual guarantees provided by the insurance policy stipulated by specialists, to avoid inadequate coverage in the case of medico-legal disputes.

Early medical skull surgery for treatment of post-traumatic osteomyelitis 5,000 years ago.

Here we describe the findings of a unique example of the early techniques adopted in neurosurgery around 5000 years ago, consisting in a double well healed skull trephination associated with a post-cranial traumatic event occurring intra vitam to a young male from the Early Chalcolithic cemetery of Pontecagnano (South Italy, ca. 4,900 - 4,500 cal BP). Morphological, X-ray and 3D-CT scan skull-cap evaluation revealed that the main orifice was produced by scraping, obtained by clockwise rotary motion of a right-handed surgeon facing the patient, while the partial trephination was carried out by using a stone point as a drilling tool. In both cases, bone regrowth is indicative of the individual's prolonged postoperative survival and his near-complete recovery. The right femur shows a poorly healed mid-shaft fracture presumably induced by a high energy injury, and a resulting chronic osteomyelitis, affecting both femurs by hematogenous spread of the infection. Our observations on the visual and radiological features of skull and femur lesions, along with evidence on the timing of experimental bone regrowth vs. healing of lower limb fractures associated to long-term bone infections now suggest that this young man underwent a double skull trephination in order to alleviate his extremely painful condition induced by chronic osteomyelitis, which is thought to have been the cause of death.

Prevalence of tooth-size discrepancy among different malocclusion groups.

This study was designed to estimate the prevalence of tooth-size discrepancy as a factor of skeletal malocclusion in the orthodontic patient population of the Campania region. The study employed the pretreatment models of 94 patients. The mesiodistal diameters of teeth were measured by digital electronic calipers (accurate to 0.01 mm) and Bolton's indices were calculated. The sample was grouped into three malocclusion groups based on the values of Steiner cephalometric analysis. Multiple regression analysis data indicated a significant linear relationship (r2 = 0.99, P = 0.0000) for Bolton's posterior, anterior and total indices. The discriminant multivariate analysis, based on stepwise Wilke's lambda, revealed five variables capable of classifying 88.6% of the sample in the four malocclusion groups. As no relationship between the four groups identified by the discriminant analysis and the types of skeletal malocclusions exists, it was unequivocally concluded that there is no evidence of any predisposition for a tooth-size discrepancy in any of the malocclusion groups.