DNA methylation-based reclassification of olfactory neuroblastoma.

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.

Diagnóstico en la patología del olfato: revisión de la literatura / Diagnosis in smell pathology: literature review

La patología del olfato es una afección común en la población, principalmente en adultos mayores, que puede alterar de manera significativa la calidad de vida del paciente, pudiendo ser la manifestación inicial de enfermedades neurológicas como la enfermedad de Parkinson. A pesar de su relevancia, el sentido del olfato continúa siendo poco estudiado en clínica, no obstante la existencia de métodos simples validados para su evaluación. En este articulo realizamos una revisión y análisis de la literatura actual sobre el estudio clínico del olfato, con el objetivo de establecer las herramientas diagnósticas disponibles en la práctica clínica para su estudio.

Olfactory diseases are common to find in the population, mainly in older people, and it can affect significantly life quality. It can also be the first manifestation of neurological diseases, such as Parkinson disease. Despite its relevance, the sense of smell is still not studied although there are simple and validated methods available in the clinical practice. In this article, we make a review and analysis of the actual literature related to smell studies, so that we can establish available diagnosis tools in the clinical practice.

Função olfatória e qualidade de vida após a reabilitação do olfato em laringectomizados totais / Olfactory function and quality of life after olfaction rehabilitation in total laryngectomees

RESUMO Objetivo Avaliar os efeitos da reabilitação do olfato na função olfatória e na qualidade de vida de laringectomizados totais. Métodos Estudo clínico pré e pós-intervenção em laringectomizados totais submetidos à reabilitação do olfato pela técnica Nasal Airflow- Inducing Maneuver, por meio do Teste de Identificação do Olfato da Universidade da Pensilvânia, dos Questionários sobre a Acuidade Olfatória, do Questionário de Acompanhamento e do Questionário de Qualidade de Vida da Universidade de Washington. Resultados Foram incluídos 45 laringectomizados totais. Antes da reabilitação do olfato, 48,9% dos participantes tiveram o olfato classificado em anosmia, 46,8% apresentaram algum tipo de microsmia e 4,4% tiveram o olfato considerado normal. Depois da reabilitação, 4,4% dos participantes foram classificados como anosmia e 31,1% foram classificados dentro da normalidade. No Teste de Identificação do Olfato, o escore médio após a reabilitação apresentou melhora estatisticamente significante. Nos questionários sobre a acuidade olfatória após a reabilitação do olfato, os resultados demonstram melhora na frequência da percepção com relação ao olfato, paladar e à capacidade de sentir cheiros dos perfumes, alimentos, gás vazando e fumaça, após o aprendizado da manobra. Os escores do Questionário de Qualidade de Vida, embora já indicassem uma boa qualidade de vida antes da intervenção, apresentaram valores estatisticamente significantes após a reabilitação do olfato. Conclusão A reabilitação do olfato melhora a função olfatória e tem impacto positivo nas atividades de vida diária e na qualidade de vida dos laringectomizados totais.

ABSTRACT Purpose To evaluate the effects of olfaction rehabilitation in the olfactory function and quality of life of total laryngectomized patients. Methods Pre-post intervention clinical study conducted with total laryngectomees submitted to olfaction rehabilitation by means of the Nasal Airflow-Inducing Maneuver (NAIM) using the University of Pennsylvania Smell Identification Test (UPSIT), Olfactory Acuity Questionnaires, a Monitoring Questionnaire, and the University of Washington Quality of Life Questionnaire (UW-QOL). Results Participants were 45 total laryngectomees. Before olfaction rehabilitation, 48.9% of the participants had their olfactic abilities classified as anosmia, 46.8% as microsmia, and 4.4% were considered within the normal range. After olfaction rehabilitation, 4.4% of the participants were classified as anosmia and 31.1% were within the normal range. In the Smell Identification Test, the mean score after rehabilitation showed statistically significant improvement. Reponses to the Olfactory Acuity Questionnaires after rehabilitation showed improvement in the frequency of perception regarding smell, taste, and the ability to smell perfume, food, leaking gas, and smoke, after learning the maneuver. Although the scores in the Quality of Life Questionnaire already indicated good quality of life before the surgery, post-intervention values were statistically significant. Conclusion Olfaction rehabilitation improves olfactory function and has a positive impact on the activities of daily living and quality of life of total laryngectomized patients.

Olfactory function and quality of life after olfaction rehabilitation in total laryngectomees. / Função olfatória e qualidade de vida após a reabilitação do olfato em laringectomizados totais.

PURPOSE: To evaluate the effects of olfaction rehabilitation in the olfactory function and quality of life of total laryngectomized patients. METHODS: Pre-post intervention clinical study conducted with total laryngectomees submitted to olfaction rehabilitation by means of the Nasal Airflow-Inducing Maneuver (NAIM) using the University of Pennsylvania Smell Identification Test (UPSIT), Olfactory Acuity Questionnaires, a Monitoring Questionnaire, and the University of Washington Quality of Life Questionnaire (UW-QOL). RESULTS: Participants were 45 total laryngectomees. Before olfaction rehabilitation, 48.9% of the participants had their olfactic abilities classified as anosmia, 46.8% as microsmia, and 4.4% were considered within the normal range. After olfaction rehabilitation, 4.4% of the participants were classified as anosmia and 31.1% were within the normal range. In the Smell Identification Test, the mean score after rehabilitation showed statistically significant improvement. Reponses to the Olfactory Acuity Questionnaires after rehabilitation showed improvement in the frequency of perception regarding smell, taste, and the ability to smell perfume, food, leaking gas, and smoke, after learning the maneuver. Although the scores in the Quality of Life Questionnaire already indicated good quality of life before the surgery, post-intervention values were statistically significant. CONCLUSION: Olfaction rehabilitation improves olfactory function and has a positive impact on the activities of daily living and quality of life of total laryngectomized patients.

Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications.

CONTEXT: The olfactory phenotype in patients with idiopathic hypogonadotropic hypogonadism (IHH) ranges from complete anosmia (Kallmann syndrome) to normosmia (normosmic IHH). However, the true prevalence of intermediary olfactory phenotypes (hyposmia) in IHH patients has not yet been assessed, and systematic correlations with anatomical and genetic abnormalities have not been reported. OBJECTIVE: The objective of this study was to evaluate olfactory function in a large IHH cohort and correlate these findings with olfactory magnetic resonance imaging (MRI) and underlying genetic etiology. DESIGN AND SETTING: We conducted a cross-sectional case-control study at an academic referral center. PATIENTS: A total of 286 IHH patients (201 males and 85 females) and 2183 healthy historic controls (1011 males and 1172 females) were studied. MAIN OUTCOME MEASURES: We measured olfactory function using the University of Pennsylvania Smell Identification Test; in 208 subjects, the genetic etiology of IHH was ascertained by DNA sequencing; in a minor subset [39 of 286 subjects (13%)], olfactory structures were determined by MRI. RESULTS: In the IHH cohort, 31.5% were anosmic, 33.6% were hyposmic, and 34.9% were normosmic. Most hyposmic (seven of 11) subjects with MRI data exhibited olfactory structure abnormalities. Of hyposmic subjects, 39.5% harbored mutations in genes involved in either GnRH neuronal migration or GnRH secretion. CONCLUSIONS: IHH subjects display a broad spectrum of olfactory function, with a significant hyposmic phenotype in nearly one third of subjects. The hyposmic subjects harbor mutations in genes affecting GnRH neuronal migration and its secretion, suggesting a pathophysiological overlap between Kallmann syndrome and normosmic IHH. Accurate olfactory phenotyping in IHH subjects will inform the pathophysiology of this condition and guide genetic testing.

[Expert opinion of ORL for private accident insurance]. / HNO-ärztliche Begutachtung für private Unfallversicherungen.

The provisions and the aims of private accident insurance are not comparable to those of the statutory accident insurance. The ear nose throat- (ENT-)specialist is often consulted on the question of a possible causality between an accident and sequelae. Loss of smell, taste disorder and loss of hearing are specified in a table with a fixed percentage for compensation. The individual invalidity for ear ringing, vertigo and other disorders have to be determined separately from this table. In private accident insurance a probability bordering on absolute certainty must be given when establishing a possible causal connection whereby mental reactions are excluded from compensation and all sequelae have to have continued for at least 3 years. The occupation or specific skills of the injured person are not essential for the judgement. The current jurisdiction and conditions of private accident insurance for tinnitus and vertigo have to be taken into consideration.

Intranasal Helicobacter pylori colonization does not correlate with the severity of chronic rhinosinusitis.

OBJECTIVE: To investigate the prevalence of Helicobacter pylori (HP) in the nasal cavity of patients with chronic rhinosinusitis (CRS) and to correlate it with the severity of CRS. STUDY DESIGN AND SETTING: Intranasal HP was investigated using rapid urease (CLO) testing and immunohistochemical (IHC) analysis and confirmed with transmission electron microscopy. To evaluate the severity of sinusitis, CT scans were graded according to the Lund-MacKay scoring system, and CRS symptom scores were recorded. RESULTS: Twelve of 48 patients (25.0%) were positive, but only 1 of 29 (3.4%) controls was positive for both CLO testing and IHC analysis (P = 0.025). The mean preoperative CT grade (P = 0.439) and symptom scores (P = 0.515) were not related to the severity of CRS. CONCLUSIONS: Intranasal HP was more prevalent in patients with CRS than healthy controls. However, there was no significant correlation observed between the severity of sinusitis and intranasal HP colonization. SIGNIFICANCE: HP has a limited role in pathogenesis of CRS.

[Clinical research of patients with congenital anosmia].

OBJECTIVE: To report on a series of patients with congenital anosmia, and to discuss its classification and clinical characteristics. METHODS: Eight patients with congenital anosmia were reviewed retrospectively. Four of eight cases were congenital anosmia with other abnormalities, including three cases with Kallmann's syndrome, one with hypoplasia of nasal cavity and nasal sinus. Four cases were isolated congenital anosmia. A thorough medical and chemosensory history, physical examination, nasal endoscopy, T&T olfactory testing, olfactory event-related potentials and sinonasal computed tomography scan were performed in all patients. Magnetic resonance image of olfactory pathway was available in seven cases, and olfactory biopsies were done in two cases. RESULTS: All patients reported had never been able to smell anything. ENT physical examination and nasal endoscopy were normal, except one case with hypoplasia of nasal cavity. Subjective olfactory test indicated all of them were anosmia. No olfactory event-related potentials to maximum stimulus were obtained. Magnetic resonance imaging revealed the absence of olfactory bulbs and tracts in six cases, hypoplasia of bilateral olfactory bulbs and tracts in one case. Computed tomography scan indicated normal except hypoplasia of nasal cavity and sinus in one case. Three cases with Kallmann syndrome showed poor development of both primary and secondary sexual characteristics and had decreased serum luteinizing hormone, follicle-stimulating hormone, testosterone and estradiol. CONCLUSIONS: Diagnosis of congenital anosmia is established on chief complain, physical examination, nasal endoscopy, olfactory testing and olfactory imaging. Magnetic resonance imaging of olfactory pathway is indispensable.

Smell disorders in ENT clinic.

Olfactory disorders may have several causes. Nasal polyposis or chronic sinusitis can result in nasal obstructions that block the access of odorants to the olfactory epithelium, and this can explain the development of olfactory disorders. On the other hand, when nasal endoscopy has revealed that the nasal cleft is free of inflammatory or tumoural disease, olfactory disorders may be explained by neuroepithelial or central nervous system disturbances. This paper will provide information about current approaches to smell disorders in otorhinolaryngology. Major causes will be reviewed as outcomes after medical or surgical treatment. An algorithm will also be given to standardise clinical investigations, including psychophysical olfactory testing, imaging and electrophysiological examinations.

Screening of olfactory function using the Biolfa olfactory test: investigations in patients with dysosmia.

OBJECTIVE: To present a statistical evaluation of a new olfactory test, Biolfa. MATERIAL AND METHODS: The olfactory test was carried out in individuals with normal olfactory function (n=67; 31 males; mean age 27.4 years) and in patients with mild, moderate or severe hyposmia (n=155; 61 males; mean age 54.6 years). The main diagnoses of the hyposmic patients were upper respiratory tract infection (32%), nasal polyposis (24%), head trauma (8%), idiopathic (8%), old age (5%) and chronic rhinitis (5%). In the first part of the test, olfactory thresholds were measured for three different substances (eugenol, aldehyde C14 and phenyl ethyl alcohol). The second part comprised an odor identification test for determining olfactory function for a large panel of common odors of Southern European countries. RESULTS: Mean olfactory thresholds were determined for subjects with normal olfaction and hyposmic patients; there was a statistically significant relationship between olfactory thresholds and degree of olfaction (mild to moderate hyposmia versus severe hyposmia). For the odor identification test, a global score was determined to allow the differentiation of normosmic subjects from patients with mild, moderate or severe hyposmia. The principles of decision theory (i.e. analysis of the receiver operating characteristic curve) were applied to the problem of evaluating the ability of Biolfa to distinguish subnormal subjects from hyposmic subjects. CONCLUSION: This study provides a basis for the routine clinical use of Biolfa.

[Olfactory dysfunction. Epidemiology, pathophsiological classification, diagnosis and therapy]. / Riechstörungen. Epidemiologie, pathophysiologische Klassifikation, Diagnose und Therapie.

The present manuscript is the result of a collaborative effort within the framework of the Working Group of Olfactology and Gustology of the German Society for ENT, Head and Neck Surgery. It provides a comprehensive overview about the current views on the epidemiology, terminology, diagnostics, and therapy of olfactory dysfunction, and aims to offer a framework for the standardized procedures for the diagnosis and therapy of olfactory disorders.

Proposed classification scheme for quantitative olfactory function alterations.

Given the need for a clinical classification for daily patient examinations to refer to each type of quantitative alteration in the sense of smell, we have created a topographic classification of such alterations, establishing groups to distinguish among patients with decreased or total loss of olfaction. Because the classification is based on the diagnosis of the different causes of anosmia, it implicitly includes etiologic and topographic considerations. We have established 3 main groups on the basis of the site of the causal lesion: conduction, sensorineural, and mixed anosmias. In addition, within the sensorineural anosmias, we distinguish between the epithelial, retroepithelial, and central anosmias.

A review of olfactory dysfunctions in man.

Although a large number of individuals experience olfactory disorders following accidents, disease states, medical interventions, aging, and exposure to environmental chemicals and pollutants, few medical practitioners have the expertise or staff to provide appropriate clinical evaluation, treatment, counseling, or referral for such patients. The present review examines studies associated with the diagnosis and treatment of olfactory disorders, as well as ones noting olfactory signs as diagnostic markers for brain tumors and other serious problems. A basic taxonomy of smell dysfunctions is presented, along with a review of etiologic factors, including local diseases and mechanical obstruction of the airways, viral infections, trauma, congenital anomalies, endocrine disorders, tumors, psychiatric disorders, aging, drugs, environmental and industrial pollutants, iatrogenic factors, and miscellaneous diseases. A discussion of current disability compensation guidelines in the United States and Britain is also presented.