Disease phenotypes in adult patients with suspected undifferentiated autoinflammatory diseases and PFAPA syndrome: Clinical and therapeutic implications.

BACKGROUND: Undifferentiated autoinflammatory diseases are characterized by recurrent or persistent fever, usually combined with other inflammatory manifestations, and negative or inconclusive genetic studies for monogenic autoinflammatory disorders. AIMS: To define and characterize disease phenotypes in adult patients diagnosed in an adult reference center with undifferentiated autoinflammatory diseases, and to analyze the efficacy of the drugs used in order to provide practical diagnostic and therapeutic recommendations. METHODS: Retrospective study (2015-2022) of patients with undifferentiated autoinflammatory diseases among all patients visited in our reference center. Demographic, clinical, laboratory features and detailed therapeutic information was collected. RESULTS: Of the 334 patients with a suspected autoinflammatory disease, 134 (40%) patients (61% women) were initially diagnosed with undifferentiated autoinflammatory diseases. Mean age at disease onset and at diagnosis was 28.7 and 37.7 years, respectively. In 90 (67.2%) patients, symptoms started during adulthood. Forty-four (32.8%) patients met diagnostic/classification criteria for adult PFAPA syndrome. In the remaining patients, four additional phenotypes were differentiated according to the predominant manifestations: a) Predominantly fever phenotype (n = 18; 13.4%); b) Predominantly abdominal/pleuritic pain phenotype (n = 9; 6.7%); c) Predominantly pericarditis phenotype (n = 18; 13.4%), and d) Complex syndrome phenotype (n = 45; 33.6%). Prednisone (mainly on demand), colchicine and anakinra were the drugs commonly used. Overall, complete responses were achieved with prednisone in 41.3%, colchicine in 40.2%, and anakinra in 58.3% of patients in whom they were used. By phenotypes, prednisone on demand was more effective in adult PFAPA syndrome and colchicine in patients with the abdominal/pleuritic pain pattern and PFAPA syndrome. Patients with complex syndrome achieved complete responses with prednisone (21.9%), colchicine (25.7%) and anakinra (44.4%), and were the group more often requiring additional immunosuppressive drugs. CONCLUSIONS: The analysis of the largest single-center series of adult patients with undifferentiated autoinflammatory diseases identified and characterized different disease phenotypes and their therapeutic approaches. This study is expected to contribute to increase the awareness of physicians for an early identification of these conditions, and to provide the best known therapeutic options.

The impact of margins in laryngeal cancer patients treated with transoral laser microsurgery: a systematic review and meta-analysis.

PURPOSE: In laryngeal squamous cell carcinoma (LSCC) treated with transoral laser microsurgery (TOLMS), the status of margins significantly affected local control. When a positive or close margin is present, there is no ubiquitous consensus regarding further treatments. The rationale of the present systematic review and meta-analysis is to investigate the survival impact of the status of the margins in patients affected by LSCC treated with TOLMS. DATA SOURCES: PubMed, EMBASE, and Cochrane Library. METHODS: We performed a systematic search, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Inclusion criteria were: patients affected by LSCC, staged according to the American Joint Committee on Cancer Staging System and treated by TOLMS without any previous treatment; margins status (close, positive, negative) and the adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of overall survival, disease-specific survival, and disease-free survival has to be reported. RESULTS: Nine studies were deemed eligible for the qualitative analysis, and 3 for the quantitative analysis to investigate the association between margin status and OS. The cumulative number of patients was 3130. The sample size ranged from 96 to 747 patients. The follow-up period ranged from 0 to 201 months. The meta-analysis results show that positive margins have an aHR of 1.30 yet with CI range (0.56 to 2.97). CONCLUSIONS: Our current meta-analysis results are unable to definitively assess the real impact of resection margins on OS. Few authors provide accurate data regarding position and types of margins. Further prospective or high-quality studies are required.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

An atlas of cells in the human tonsil.

Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil.

Survivin/BIRC5 as a novel molecular effector at the crossroads of glucose metabolism and radioresistance in head and neck squamous cell carcinoma.

BACKGROUND: Metabolic reprogramming and abnormal glucose metabolism are hallmarks of head and neck squamous cell carcinoma (HNSCC). Certain oncogenes can promote cancer-related metabolic changes, but understanding their crosstalk in HNSCC biology and treatment is essential for identifying predictive biomarkers and developing target therapies. METHODS: We assessed the value of survivin/BIRC5 as a radioresistance factor potentially modulated by glucose for predicting therapeutic sensitivity and prognosis of HNSCC in a cohort of 32 patients. Additionally, we conducted in vitro experiments to explore the role of survivin/BIRC5 in glucose metabolism concerning radiation response. RESULTS: Tumoral BIRC5 expression is associated with serum glucose and predicts locoregional disease-free survival and lower BIRC5 mRNA levels are associated with better outcomes. Upregulation of BIRC5 by radiation depends on glucose levels and provokes a pro-tumoral and radioresistant phenotype in surviving cells. CONCLUSIONS: Survivin/BIRC5 might be independently associated with the risk of recurrence in patients with HNSCC.

Laryngeal EBV-positive Inflammatory Follicular Dendritic cell/fibroblastic Reticular cell Tumour.

Epstein-Barr virus-positive Inflammatory follicular dendritic cell/fibroblastic reticular cell tumour (EBV-IFDC/FRCT) is a rare neoplasm that occurs almost exclusively in the liver or spleen. Extra-hepatosplenic presentation is infrequent and exceptional cases have been described arising in the gastrointestinal tract or in the pharynx. However, EBV-IFDC/FRCT cases have not been previously reported in the larynx. This report describes a case of a 32-year-old woman who arrived to the emergency department due to progressive dyspnea with associated inspiratory stridor and non-productive cough. Direct laryngoscopy showed a nodular tumour arising on the left posterior subglottic mucosa obstructing 90% of the airway. A preoperative dual energy contrast enhanced computed tomography (CECT) was performed demonstrating a low attenuation lesion on virtual non-contrast (VNC) images and vivid iodine uptake on the iodine map. The tumour was excised and the histopathological analysis led to the diagnosis of an EBV-IFDC/FRCT. A fibre-optic laryngoscopy six months after the surgery did not show any abnormalities. Although the vast majority of EBV-IFDC/FRCT occur in the liver or spleen, some extra hepatosplenic tumours have been reported affecting the head and neck region. We describe here the first case arising in the larynx, as well as the usefulness of preoperative dual energy imaging techniques to assess these lesions, thus providing information that could have management implications.

Consensus for voice quality assessment in clinical practice: guidelines of the European Laryngological Society and Union of the European Phoniatricians.

INTRODUCTION: To update the European guidelines for the assessment of voice quality (VQ) in clinical practice. METHODS: Nineteen laryngologists-phoniatricians of the European Laryngological Society (ELS) and the Union of the European Phoniatricians (UEP) participated to a modified Delphi process to propose statements about subjective and objective VQ assessments. Two anonymized voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 3/4. The statements with ≥ 3/4 score by 60-80% of experts were improved and resubmitted to voting until they were validated or rejected. RESULTS: Of the 90 initial statements, 51 were validated after two voting rounds. A multidimensional set of minimal VQ evaluations was proposed and included: baseline VQ anamnesis (e.g., allergy, medical and surgical history, medication, addiction, singing practice, job, and posture), videolaryngostroboscopy (mucosal wave symmetry, amplitude, morphology, and movements), patient-reported VQ assessment (30- or 10-voice handicap index), perception (Grade, Roughness, Breathiness, Asthenia, and Strain), aerodynamics (maximum phonation time), acoustics (Mean F0, Jitter, Shimmer, and noise-to-harmonic ratio), and clinical instruments associated with voice comorbidities (reflux symptom score, reflux sign assessment, eating-assessment tool-10, and dysphagia handicap index). For perception, aerodynamics and acoustics, experts provided guidelines for the methods of measurement. Some additional VQ evaluations are proposed for voice professionals or patients with some laryngeal diseases. CONCLUSION: The ELS-UEP consensus for VQ assessment provides clinical statements for the baseline and pre- to post-treatment evaluations of VQ and to improve collaborative research by adopting common and validated VQ evaluation approach.

Manifestaciones otorrinolaringológicas en la viruela del mono / Otorhinolaryngological manifestations in monkeypox

Antecedentes y objetivo En la actual emergencia sanitaria declarada por la Organización Mundial de la Salud (OMS) por viruela del mono se han detallado pocos datos sobre las manifestaciones otorrinolaringológicas (ORL) de dicha enfermedad. El propósito del estudio pretende describir las características clínicas de las manifestaciones ORL de la viruela del mono. Material y métodos Análisis descriptivo de 11 pacientes consecutivos con odinodisfagia o lesiones de la cavidad oral derivados al área de urgencias de ORL de un hospital terciario con factores de riesgo epidemiológicos que pudieran sugerir infección por viruela del mono. Se describen los hallazgos clínicos, diagnósticos y de tratamiento. Resultados El 90,9% de los pacientes habían tenido contacto sexual de riesgo previo. El cuadro de presentación predominante incluía fiebre de más de 38°C con odinodisfagia intensa. El examen físico mostraba úlceras y lesiones exudativas de presentación variable en la vía aerodigestiva superior. El frotis de las lesiones confirmó positividad en la reacción en cadena de la polimerasa (PCR) para viruela del mono en todos los pacientes. Conclusiones La infección por virus de viruela del mono puede presentarse en el área ORL con múltiples manifestaciones que precisan de un grado de sospecha epidemiológico alto y la confirmación con PCR para llegar a un diagnóstico de certeza. (AU)

Background and objective In the current health emergency declared by the World Health Organization (WHO) for monkeypox, few data on the otorhinolaryngological (ENT) manifestations of the disease have been detailed. The purpose of this study is to describe the clinical features of the ENT manifestations in monkeypox. Material and methods Descriptive analysis of 11 consecutive patients with odynodysphagia or oral cavity lesions referred to the ENT emergency department of a tertiary hospital with epidemiological risk factors suggestive of monkeypox infection. Clinical, diagnostic, and treatment findings are described. Results 90.9% of the patients had previous unsafe sexual contact. The predominant presenting features included fever over 38°C with severe odynodysphagia. Physical examination showed ulcers and exudative lesions of variable presentation in the upper respiratory tract. Smear of the lesions confirmed polymerase chain reaction (PCR) positivity for monkeypox in all patients. Conclusions Monkeypox virus infection can occur in the ENT area with multiple manifestations that require a high degree of epidemiological suspicion and confirmation with PCR to reach a diagnosis of certainty. (AU)

Otorhinolaryngological manifestations in monkeypox.

BACKGROUND AND OBJECTIVE: In the current health emergency declared by the World Health Organization (WHO) for monkeypox, few data on the otorhinolaryngological (ENT) manifestations of the disease have been detailed. The purpose of this study is to describe the clinical features of the ENT manifestations in monkeypox. MATERIALS AND METHODS: Descriptive analysis of 11 consecutive patients with odynodysphagia or oral cavity lesions referred to the ENT emergency department of a tertiary hospital with epidemiological risk factors suggestive of monkeypox infection. Clinical, diagnostic and treatment findings are described. RESULTS: 90.9% of the patients had previous unsafe sexual contact. The predominant presenting features included fever over 38 °C with severe odynodysphagia. Physical examination showed ulcers and exudative lesions of variable presentation in the upper respiratory tract. Smear of the lesions confirmed polymerase chain reaction (PCR) positivity for monkeypox in all patients. CONCLUSIONS: Monkeypox virus infection can occur in the ENT area with multiple manifestations that require a high degree of epidemiological suspicion and confirmation with PCR to reach a diagnosis of certainty.

Artificial Intelligence for Upper Aerodigestive Tract Endoscopy and Laryngoscopy: A Guide for Physicians and State-of-the-Art Review.

OBJECTIVE: The endoscopic and laryngoscopic examination is paramount for laryngeal, oropharyngeal, nasopharyngeal, nasal, and oral cavity benign lesions and cancer evaluation. Nevertheless, upper aerodigestive tract (UADT) endoscopy is intrinsically operator-dependent and lacks objective quality standards. At present, there has been an increased interest in artificial intelligence (AI) applications in this area to support physicians during the examination, thus enhancing diagnostic performances. The relative novelty of this research field poses a challenge both for the reviewers and readers as clinicians often lack a specific technical background. DATA SOURCES: Four bibliographic databases were searched: PubMed, EMBASE, Cochrane, and Google Scholar. REVIEW METHODS: A structured review of the current literature (up to September 2022) was performed. Search terms related to topics of AI, machine learning (ML), and deep learning (DL) in UADT endoscopy and laryngoscopy were identified and queried by 3 independent reviewers. Citations of selected studies were also evaluated to ensure comprehensiveness. CONCLUSIONS: Forty-one studies were included in the review. AI and computer vision techniques were used to achieve 3 fundamental tasks in this field: classification, detection, and segmentation. All papers were summarized and reviewed. IMPLICATIONS FOR PRACTICE: This article comprehensively reviews the latest developments in the application of ML and DL in UADT endoscopy and laryngoscopy, as well as their future clinical implications. The technical basis of AI is also explained, providing guidance for nonexpert readers to allow critical appraisal of the evaluation metrics and the most relevant quality requirements.

[Otorhinolaryngological manifestations in monkeypox]. / Manifestaciones otorrinolaringológicas en la viruela del mono.

Background and objective: In the current health emergency declared by the World Health Organization (WHO) for monkeypox, few data on the otorhinolaryngological (ENT) manifestations of the disease have been detailed. The purpose of this study is to describe the clinical features of the ENT manifestations in monkeypox. Material and methods: Descriptive analysis of 11 consecutive patients with odynodysphagia or oral cavity lesions referred to the ENT emergency department of a tertiary hospital with epidemiological risk factors suggestive of monkeypox infection. Clinical, diagnostic, and treatment findings are described. Results: 90.9% of the patients had previous unsafe sexual contact. The predominant presenting features included fever over 38 °C with severe odynodysphagia. Physical examination showed ulcers and exudative lesions of variable presentation in the upper respiratory tract. Smear of the lesions confirmed polymerase chain reaction (PCR) positivity for monkeypox in all patients. Conclusions: Monkeypox virus infection can occur in the ENT area with multiple manifestations that require a high degree of epidemiological suspicion and confirmation with PCR to reach a diagnosis of certainty.

Persistent lymph nodes after curative chemoradiotherapy for head and neck cancer: imaging predictors of response for decision-making.

PURPOSE: To identify response predictors in patients with head and neck squamous cell carcinoma (N + HNSCC) and persistent lymph nodes after curative chemoradiotherapy treatment (CCRT). MATERIALS AND METHODS: Consecutive patients with N + HNSCC treated with CCRT and persistent lymph nodes at first follow-up between 2015 and 2021 were identified and analyzed. Complete response was defined as the absence of lymph node metastatic involvement in patients with salvage lymphadenectomy or the absence of progression after 1 year of successive follow-ups. Tumour type and location, staging, and human papillomavirus (HPV) status were considered for analysis. The number and size of lymph nodes, type, shape, enhancement and margins on diagnostic and follow-up CT were also analyzed. RESULTS: The cohort included 46 patients with 134 pathological lymph nodes. Logistic regression models showed the following variables to be significant: performance of salvage lymphadenectomy (OR 0.094, [CI 95% 0.004-0.61], p = 0.037); the type of lymphadenopathy on diagnostic CE-CT (solid vs. cystic) (N1: OR = 4.11, [CI 95% 1.11-17.93], p = 0.042 and N3: OR 6.42, [CI 95% 1.2-42.56], p = 0.036); the change of shape (round to oval) on the follow-up CE-CT (OR 9.76, [CI 95% 1.79-8.57], p = 0.016) and the time in days between CCRT and the first follow-up CE-CT (OR 1.06, [CI 95% 1.004-1.13], p = 0.048). CONCLUSIONS: In our experience, the presence of solid lymph nodes on pre-treatment CT and the change in shape from round to oval on post-treatment CT are predictors of response to treatment in patients with N + HNSCC persistent lymph nodes after CCRT. Increasing the temporal interval between treatment and follow-up CT should be considered to avoid unnecessary nodal dissections.

CO2-TOLMS for laryngeal cancer in the elderly, pushing the boundaries of partial laryngectomy.

INTRODUCTION: CO2 transoral laser microsurgery (CO2-TOLMS) has pushed the indications of partial surgery of the larynx regardless the age of the patient. OBJECTIVE: To evaluate the complications and the oncologic and functional outcomes of CO2-TOLMS in patients older and younger than 70 years. METHODS: Retrospective analysis of 1244 consecutive laryngeal carcinomas treated with CO2-TOLMS. Complications, length of hospitalization, functional and survival outcomes were evaluated. RESULTS: The mean age was 64.2 ±â€¯11.1 years (20-96). Four hundred and sixteen patients were older than 70 years and 104 older than 80 years. The main location was the glottis (912), followed by the supraglottis (332). There were no differences in pT classification between the age groups. No differences were observed in voice outcomes. A higher rate of signs of aspiration at the glottic location was observed for those older than 70 years (2.1 % vs 5 %, p = 0.027). The need for definitive gastrostomy in supraglottic tumours was higher in those older than 70 years (0 % vs 6.5 %, p: 0.001). In the glottis, no differences in tracheostomy or gastrostomy rates were observed. Five-year overall survival was lower in the older than 70 years. No differences in disease-specific survival were observed in early stages for both locations, but a lower survival was observed in stage III glottic cancer for the older than 70 years. CONCLUSIONS: CO2-TOLMS is a valid treatment for laryngeal carcinomas in the elderly, with a reduced number of complications and good functional and oncologic outcomes.

Semaphorin-3F/Neuropilin-2 Transcriptional Expression as a Predictive Biomarker of Occult Lymph Node Metastases in HNSCC.

The expression of the semaphorin-3F (SEMA3F) and neuropilin-2 (NRP2) is involved in the regulation of lymphangiogenesis. The present study analyzes the relationship between the transcriptional expression of the SEMA3F-NRP2 genes and the presence of occult lymph node metastases in patients with cN0 head and neck squamous cell carcinomas. We analyzed the transcriptional expression of SEMA3F and NRP2 in a cohort of 53 patients with cN0 squamous cell carcinoma treated with an elective neck dissection. Occult lymph node metastases were found in 37.7% of the patients. Patients with occult lymph node metastases (cN0/pN+) had significantly lower SEMA3F expression values than patients without lymph node involvement (cN0/pN0). Considering the expression of the SEMA3F-NRP2 genes, patients were classified into two groups according to the risk of occult nodal metastasis: Group 1 (n = 34), high SEMA3F/low NRP2 expression, with a low risk of occult nodal involvement (14.7% cN0/pN+); Group 2 (n = 19), low SEMA3F or high SEMA3F/high NRP2 expression, with a high risk of occult nodal involvement (78.9% cN0/pN+). Multivariate analysis showed that patients in Group 2 had a 26.2 higher risk of lymph node involvement than patients in Group 1. There was a significant relationship between the transcriptional expression values of the SEMA3F-NRP2 genes and the risk of occult nodal metastases.

Deep brain stimulation as a palliative treatment for myorhythmia: A case of failure.

BACKGROUND AND PURPOSE: Myorhythmia is a hyperkinetic movement disorder that derives from a disruption of the Guillain-Mollaret triangle, due to an identifiable structural lesion. It is often disabling and with disappointing control under medical treatment. METHODS: Herein, a case of myorhythmia secondary to a vascular insult in the brainstem is reported and an unsuccessful attempt to palliate it with functional neurosurgery. RESULTS: A 67-year-old man displayed a repetitive, rhythmic, slow 2-3 Hz movement, 6 months after suffering a pontomesencephalic hypertensive haematoma. The kinetic phenomenon affected the orbicular and low facial muscles, the neck, the thorax and the upper limbs. Furthermore, he exhibited tremor of the soft palate and pendular nystagmus. On T2-weighted magnetic resonance imaging, hypertrophic degeneration of the inferior olivary complex was seen. He was diagnosed with secondary myorhythmia and multiple pharmacological treatments were tested, but failed. Ultimately, deep brain stimulation with bilateral electrodes placed in the thalamic ventralis intermedius nucleus was offered. Unfortunately, no alleviation of the symptoms was achieved other than mild improvement in involuntary eye movements. CONCLUSIONS: This is the first case to report the use of deep brain stimulation for myorhythmia. Better understanding of the pathophysiology of this condition, and localization of the pacemaker, may allow identification of reliable neurosurgical therapeutic targets.