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OBJECTIVES: Airway reconstruction for laryngo tracheal stenosis (LTS) improves dyspnoea. There is little evidence relating to impact upon voice and swallowing. We explored voice and swallowing outcomes in adults with LTS before and after reconstructive surgery. DESIGN: Outcome measures were collected pre-reconstructive surgery, two-weeks post-surgery and up to 4-6 months post-surgery. SETTING: Tertiary referral centre. PARTICIPANTS: With ethical approval, twenty consecutive adult (≥18 years) LTS patients undergoing airway reconstruction were prospectively recruited. MAIN OUTCOME MEASURES: These included physiological values (maximum phonation time (MPT) and fundamental frequency; penetration aspiration score, residue score), clinician-reported (GRBAS, functional oral intake score, 100ml Water Swallow Test) and patient-reported outcomes (Voice Handicap Index-10, Reflux Symptoms Index, Eating Assessment Tool, Dysphagia Handicap Index). RESULTS: The observational study identified patient-reported and clinician-reported voice and swallow difficulties pre- and post-surgery; median and interquartile range are reported at each time point: Voice Handicap Index-10 23 (8-31); 20.5 (9-33.5), 24.5 (12.5-29); Dysphagia Handicap Index 9 (0-37); 13 (7-44); 15 (4-34); GRBAS grade 1(1-2); 2 (1-2.5); 2(1-2); 100ml Water Swallow Test volume score 16.7 (11.1-20); 14.3 (12.5-16.7); 16.7 (14.3-20.0); 100ml Water Swallow Test capacity score 16.3 ± 9.0; 11.0 ± 4.1; 12.5 ± 2.6. CONCLUSIONS: We present the first prospective data on voice and swallowing outcomes in adults with LTS before and after reconstructive surgery. The variability of the outcomes was higher than expected but importantly, for many the voice and swallow outcomes were not within normal limits before surgery. The clinical value of the study demonstrates the need for individual assessment and management of LTS patients' voice and swallowing.
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Transtornos de Deglutição , Laringoestenose , Cirurgia Plástica , Estenose Traqueal , Adulto , Humanos , Deglutição/fisiologia , Estenose Traqueal/cirurgia , Estudos Prospectivos , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/cirurgia , Constrição Patológica , Laringoestenose/complicações , Laringoestenose/cirurgia , ÁguaRESUMO
INTRODUCTION: Sarcoidosis is a chronic granulomatous disease of unknown aetiology and laryngeal involvement is seen in a small percentage of cases. Dysphagia is a common but under-reported symptom. Little is known about how dysphagia typically presents or is managed in the context of this fluctuating disease. We present our case series using an SLT-led model of assessment and management. METHODS: A literature search was conducted for any articles that reported both laryngeal sarcoidosis and dysphagia. We then analysed a case series of laryngeal sarcoidosis patients treated at Charing Cross Hospital. We report on multidimensional swallowing evaluation and rehabilitative interventions. RESULTS: Seventeen papers report both laryngeal sarcoidosis and dysphagia, with only one paper giving details on the nature of the dysphagia and the treatment provided. In our case series (n = 7), patients presented with FOIS Scores ranging from 5 to 7 pre-operatively (median = 6). Aspiration (median PAS Score = 6 and Range = 3-8) and pharyngeal residue were common. Sensory issues were also prevalent with most unaware of the extent of their difficulties. Management interventions included safe swallowing advice, compensatory strategies, exercises and close surveillance given their potential for repeated surgical interventions. CONCLUSION: Laryngeal sarcoidosis is a rare condition. Dysphagia is under-reported and our experience highlights the need for specialist dysphagia intervention. Further research is required to understand dysphagia management requirements in the context of this fluctuating disease process.
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Transtornos de Deglutição , Laringe , Sarcoidose , Deglutição , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Humanos , Sarcoidose/complicaçõesRESUMO
OBJECTIVES: In most cases, suspension laryngoscopy (SL) is efficient, bloodless and with minimal post-procedure discomfort. We aimed to identify predictive patient factors for acceptable surgical views at SL as well as quantify our tertiary airway unit's complication rates. DESIGN: Prospective cohort study of 150 consecutive microlaryngoscopy procedures involving SL over an 8-month period between November 2019 and July 2020. Patients were assessed preoperatively for pre-existing oral, temporomandibular, dental, pharyngeal or laryngeal pathology, interincisor distance and qualitative gross limitations to neck extension and forward head posture. Intraoperatively, the laryngoscopic view was graded by anaesthetic and surgical teams, and complications were recorded on patient interview in recovery. SETTING: Tertiary adult airway service for predominantly benign pathology. RESULTS: Adequate surgical views were obtained in 149/150 procedures. BMI had a weak positive correlation with a more difficult view (r = .22, p = .008) but did not correlate with a statistically significant increase in any complication. There was a weak negative correlation between age and interincisor gap (r = -.20, p = .014), and wider mouth opening correlated very weakly with a lower incidence of sore throat (r = -.19, p = .023). Gross macroglossia showed a significant moderate positive correlation with tongue symptoms (r = .45, p = 1.611 × 10-8 ). CONCLUSION: In the context of an experienced airway unit with a high caseload of predominantly benign pathology, SL is very effective and safe with low associated morbidity and no mortality. The most common complication of SL is temporary sore throat and there remain recognised risks of temporary tongue and dental symptoms.
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Intubação Intratraqueal/métodos , Doenças da Laringe/cirurgia , Laringoscopia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVES: Airway reconstruction for laryngotracheal stenosis (LTS) encompasses several procedures. Dysphagia is a well-recognised sequela of LTS and airway surgery, however studies have employed mostly non-validated assessments post-operatively in small, heterogenous samples, perpetuating uncertainty around the contributions of LTS and its management to impaired deglutition. Consequently, considerable variation in LTS perioperative nutritional management exists. Our objective was to characterise baseline and post-operative dysphagia with instrumental assessment in an LTS cohort undergoing airway reconstruction and provide a gold-standard management framework for its management. DESIGN, SETTING, PARTICIPANTS AND MAIN OUTCOME MEASURES: We performed a retrospective cohort study of adult airway reconstruction procedures from 2016-2020 at our quaternary centre. Patient background, LTS aetiology, procedure type, tube feeding duration, length of stay and serial Functional Oral Intake Scale (FOIS) and International Dysphagia Diet Standardisation Initiative (IDDSI) scores were noted. Baseline, post-operative day one and post-stent removal Fibreoptic Endoscopic Evaluation of Swallow (FEES) generated Penetration Aspiration Scale (PAS) scores. RESULTS: Forty-four patients underwent forty-six reconstructions. Baseline incidence of penetration-aspiration was considerably higher than the general population and worsened in the immediate post-operative period, however FOIS and PAS scores generally returned to baseline by discharge. Post-operative FOIS correlated negatively with tracheostomy or airway stent placement. At discharge, 80% tolerated soft or normal diet and 93% were feeding tube independent. CONCLUSIONS: We present the largest adult airway reconstruction cohort with instrumental swallow assessment perioperatively. LTS patients have a higher incidence of underlying dysphagia but swallowing tends to return to baseline with appropriate postoperative rehabilitation. Such practice may avoid the complications, costs and morbidity of prolonged nutritional support.
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Transtornos de Deglutição/cirurgia , Laringoestenose/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Estenose Traqueal/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVES: Sarcoidosis is a multisystemic inflammatory disease with extrathoracic manifestations, most commonly affecting the young and middle-aged, female and Black populations. Diagnosis usually requires evidence of non-caseating granulomata and, when treated, prognosis is usually favourable. We aim to establish the incidence, clinical features and optimal treatment of ENT manifestations of this disease. DESIGN: We performed a PubMed literature review to determine the evidence base supporting this. RESULTS: ENT manifestations are present in 5%-15% of patients with sarcoidosis, often as a presenting feature, and require vigilance for swift recognition and coordinated additional treatment specific to the organ. Laryngeal sarcoidosis presents with difficulty in breathing, dysphonia and cough, and may be treated by speech and language therapy (SLT) or intralesional injection, dilatation or tissue reduction. Nasal disease presents with crusting, rhinitis, nasal obstruction and anosmia, usually without sinus involvement. It is treated by topical nasal or intralesional treatments but may also require endoscopic sinus surgery, laser treatment or even nasal reconstruction. Otological disease is uncommon but includes audiovestibular symptoms, both sensorineural and conductive hearing loss, and skin lesions. CONCLUSIONS: The consequences of ENT manifestations of sarcoidosis can be uncomfortable, disabling and even life-threatening. Effective management strategies require good diagnostic skills and use of specific therapies combined with established treatments such as corticosteroids. Comparisons of treatment outcomes are needed to establish best practice in this area.
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Otopatias/patologia , Doenças da Laringe/patologia , Doenças Nasais/patologia , Sarcoidose/patologia , Diagnóstico Diferencial , Otopatias/diagnóstico , Otopatias/tratamento farmacológico , Humanos , Doenças da Laringe/diagnóstico , Doenças da Laringe/tratamento farmacológico , Doenças Nasais/diagnóstico , Doenças Nasais/tratamento farmacológico , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológicoRESUMO
Vaccinia virus (VACV) continues to be used in immunotherapy for the prevention of infectious diseases and treatment of cancer since its use for the eradication of smallpox. However, the current method of editing the VACV genome is not efficient. Here, we demonstrate that the CRISPR-Cas9 system can be used to edit the VACV genome rapidly and efficiently. Additionally, a set of 8,964 computationally designed unique guide RNAs (gRNAs) targeting all VACV genes will be valuable for the study of VACV gene functions.
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Sistemas CRISPR-Cas , Genoma Viral , Biologia Molecular/métodos , Recombinação Genética , Vaccinia virus/genética , Tecnologia Farmacêutica/métodosAssuntos
Doenças da Laringe/terapia , Sarcoidose/terapia , Adolescente , Adulto , Biópsia , Feminino , Humanos , Laringoscopia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE OF REVIEW: This review addresses the challenges faced by transgender women in achieving congruence between gender identity and voice characteristics and emphasizes the importance of a multidisciplinary approach involving therapeutic and surgical interventions. RECENT FINDINGS: Recent literature on gender-affirming vocal care emphasizes key themes such as assessment, voice feminization therapy, and various surgical techniques, including glottoplasty and its modifications. Recent publications focused on outcomes, duration, and impact on vocal quality and scrutinized complications associated with surgical interventions. SUMMARY: Most publications in the last 18âmonths advocate for the integration of voice therapy and surgery for optimal outcomes. Utilising a combined approach is significantly more effective in terms of fundamental frequency gain compared to therapy alone. Modified Wendler's glottoplasty remains the preferred and most reliable surgical intervention. However, surgery is not without its complications and vocal trade-offs, in particular, its impact on vocal projection and the risk of long-term dysphonia. Postsurgery rehabilitation improves long-term outcomes. Recent publications on alternative surgical approaches, namely laser reduction glottoplasty and feminization laryngoplasty, show promise but the results are more difficult to generalise. FUTURE DIRECTION: Prospective multicentre studies with standardized protocols are needed to establish best evidence-based practices.
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Pessoas Transgênero , Qualidade da Voz , Humanos , Feminino , Laringoplastia/métodos , Masculino , Treinamento da VozRESUMO
OBJECTIVES: The development of artificial intelligence-powered language models, such as Chatbot Generative Pre-trained Transformer (ChatGPT) or Large Language Model Meta AI (Llama), is emerging in medicine. Patients and practitioners have full access to chatbots that may provide medical information. The aim of this study was to explore the performance and accuracy of ChatGPT and Llama in treatment decision-making for bilateral vocal fold paralysis (BVFP). METHODS: Data of 20 clinical cases, treated between 2018 and 2023, were retrospectively collected from four tertiary laryngology centers in Europe. The cases were defined as the most common or most challenging scenarios regarding BVFP treatment. The treatment proposals were discussed in their local multidisciplinary teams (MDT). Each case was presented to ChatGPT-4.0 and Llama Chat-2.0, and potential treatment strategies were requested. The Artificial Intelligence Performance Instrument (AIPI) treatment subscore was used to compare both Chatbots' performances to MDT treatment proposal. RESULTS: Most common etiology of BVFP was thyroid surgery. A form of partial arytenoidectomy with or without posterior transverse cordotomy was the MDT proposal for most cases. The accuracy of both Chatbots was very low regarding their treatment proposals, with a maximum AIPI treatment score in 5% of the cases. In most cases even harmful assertions were made, including the suggestion of vocal fold medialisation to treat patients with stridor and dyspnea. ChatGPT-4.0 performed significantly better in suggesting the correct treatment as part of the treatment proposal (50%) compared to Llama Chat-2.0 (15%). CONCLUSION: ChatGPT and Llama are judged as inaccurate in proposing correct treatment for BVFP. ChatGPT significantly outperformed Llama. Treatment decision-making for a complex condition such as BVFP is clearly beyond the Chatbot's knowledge expertise. This study highlights the complexity and heterogeneity of BVFP treatment, and the need for further guidelines dedicated to the management of BVFP.
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PURPOSE: To describe the development and implementation of an enhanced recovery programme for patients undergoing total laryngectomy. METHODS: A feasibility study set in a tertiary head and neck unit in London, United Kingdom. The programme was developed based on Enhanced Recovery After Surgery (ERAS) Society guidelines for head and neck cancer surgery and local expert group consensus. An ERAS 'booklet' was devised which accompanied all laryngectomy patients during their inpatient stay. Contributors included otolaryngologists, anaesthetists, dieticians, physiotherapists, speech and language therapists and nurses. A 12-month pilot study was undertaken. The main outcome measures were feasibility and adherence. RESULTS: An enhanced recovery programme for 25 people undergoing total laryngectomy was successfully piloted in a tertiary referral head and neck unit. Median length of stay was reduced in the post-ERAS group by 1.5 days. No statistically significant difference in length of stay, time to first gastrografin swallow, rate of fistula nor postoperative normalcy of eating between the pre and post-ERAS patients who underwent laryngectomy was observed. Clavien-Dindo-grouped complication rates were significantly higher in the post-ERAS group. CONCLUSION: This enhanced recovery programme for patients undergoing laryngectomy is the first of its kind in the literature. Implementation has been demonstrated feasible. Further longitudinal studies are required to reliably inform us on ERAS programmes' effects on laryngectomy outcomes.
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Laringectomia , Complicações Pós-Operatórias , Humanos , Estudos de Viabilidade , Tempo de Internação , Projetos Piloto , Complicações Pós-Operatórias/epidemiologia , Resultado do TratamentoRESUMO
The airway epithelium is a protective barrier that is maintained by the self-renewal and differentiation of basal stem cells. Increasing age is a principle risk factor for chronic lung diseases, but few studies have explored age-related molecular or functional changes in the airway epithelium. We retrieved epithelial biopsies from histologically normal tracheobronchial sites from pediatric and adult donors and compared their cellular composition and gene expression profile (in laser capture-microdissected whole epithelium, fluorescence-activated cell-sorted basal cells, and basal cells in cell culture). Histologically, pediatric and adult tracheobronchial epithelium was similar in composition. We observed age-associated changes in RNA sequencing studies, including higher interferon-associated gene expression in pediatric epithelium. In cell culture, pediatric cells had higher colony formation ability, sustained in vitro growth, and outcompeted adult cells in a direct competitive proliferation assay. Our results demonstrate cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states.
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OBJECTIVES: To determine the number of patients with idiopathic subglottic stenosis (iSGS) who have contracted coronavirus disease 2019 (COVID-19), the impact of the pandemic on patients' attitudes on seeking help and attending hospitals, as well as the delays in the offer of treatment from the local health care systems. METHODS: A 29-question survey was distributed to an international mailing list of patients with subglottic stenosis to assess the patient experience during the COVID-19 pandemic. RESULTS: A total of 543 patients with iSGS participated. Fewer than 1 in 10 patients with iSGS have experienced COVID-19 symptoms, which were predominantly mild to moderate, with only 2 hospitalizations. Most patients with iSGS (80.0%) have not been advised they are high risk for COVID-19, despite 36.5% of patients with iSGS being obese (body mass index of 30+). Delays to surgeries and in-office procedures have impacted 40.1% of patients currently receiving treatment, with 38.8% of patients increasingly struggling to breathe as a result. Anxiety and stress are increasing among patients, with 3 in 4 (75.2%) reporting they are anxious about travelling by public transport, contracting the virus in hospital and infecting loved ones (69.0% and 71.9%, respectively). Of greater concern is that 23.1% with increasing dyspnea state they are staying away from hospital despite their deteriorating health. CONCLUSIONS: The COVID-19 pandemic has had an impact on the physical and psychological health of patients with iSGS. Surgeons managing cases of laryngotracheal stenosis need to offer appropriate support and communication to these high risk patients. During the pandemic, this should include self-isolation if they are dyspneic or on treatments that may have reduced their immunity. In addition, they should offer safe clinical pathways to airway assessment and treatments, if they become necessary. To minimize unnecessary travel, much of the clinical monitoring can be carried out remotely, using telephone or video-based consultations, in conjunction with local health professionals.
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Ansiedade/psicologia , COVID-19/epidemiologia , Dispneia/fisiopatologia , Laringoestenose/fisiopatologia , Estresse Psicológico/psicologia , Adulto , Idoso , Ansiedade/epidemiologia , COVID-19/diagnóstico , COVID-19/fisiopatologia , COVID-19/terapia , Gerenciamento Clínico , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Laringoestenose/epidemiologia , Laringoestenose/psicologia , Laringoestenose/terapia , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Educação de Pacientes como Assunto , SARS-CoV-2 , Grupos de Autoajuda , Estresse Psicológico/epidemiologia , Inquéritos e Questionários , Telemedicina , Tempo para o TratamentoRESUMO
PURPOSE: Bariatric surgery improves several obesity-related comorbidities. Laryngotracheal stenosis is a rare condition that is usually managed with repeated endoscopic airway interventions and reconstructive airway surgery. The outcome of these definitive operations is worse in individuals with obesity. There are no studies investigating the effect of weight loss following bariatric surgery in the management of laryngotracheal stenosis. MATERIALS AND METHODS: In an observational study, consecutive patients with a BMI over 35 kg/m2 and laryngotracheal stenosis were prospectively recruited to a bariatric and airway stenosis database in two tertiary care centres. Patients were treated with laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy and control subjects were managed conservatively. RESULTS: A total of eleven patients with an initial body mass index of 43 kg/m2 (37-45) were enrolled to this study. Six patients underwent bariatric surgery and five subjects were treated conservatively. After 12 months, the total weight loss of patients undergoing bariatric surgery was 19.4% (14-24%) whilst 2.3% (1-3%) in the control group. The annual number of endoscopic airway interventions following bariatric surgery reduced (p = 0.002). Higher weight loss in patients led to less frequent interventions compared to control subjects (p = 0.004). Patients undergoing laryngotracheal reconstruction following bariatric surgery needed less endoscopic intervention, an annual average of 1.9 interventions before vs 0.5 intervention after. Conservatively managed control subjects required more frequent endoscopic intervention, 1.8 before vs 3.4 after airway reconstruction. CONCLUSION: Bariatric surgery reduced the number of endoscopic airway interventions and enabled patients to undergo successful definitive airway reconstructive surgery.
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Cirurgia Bariátrica , Derivação Gástrica , Laparoscopia , Obesidade Mórbida , Comorbidade , Constrição Patológica , Gastrectomia , Humanos , Morbidade , Obesidade/complicações , Obesidade/cirurgia , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Redução de PesoRESUMO
AIMS: To describe the use of laser, endoscopic balloon dilatation with jet ventilation anaesthesia in the treatment of pregnant women with idiopathic subglottic stenosis. MATERIALS AND METHODS: This is a case review of pregnant women with idiopathic subglottic stenosis, presenting to a tertiary referral centre with worsening breathlessness. Data were extracted from patient case notes. RESULTS: Four women underwent surgical management of subglottic stenosis in pregnancy. One patient required two procedures during the course of their pregnancy due to restenosis. All women had improvement in symptoms post-operatively and went on to deliver healthy babies at term. CONCLUSION: Endoscopic balloon dilatation of idiopathic subglottic stenosis is a safe and viable treatment option in pregnancy and should be offered as first-line treatment in symptomatic women.
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OBJECTIVE: The COVID-19 pandemic has led to unprecedented demands on healthcare with many requiring intubation. Tracheostomy insertion has often been delayed and the enduring effects of this on voice, swallow, and airway outcomes in COVID-19 tracheostomy patients are unknown. The aim of this study was to prospectively assess these outcomes in this patient cohort following hospital discharge. METHODS: All COVID-19 patients who had undergone tracheostomy insertion, and were subsequently decannulated, were identified at our institution and followed up 2 months post-discharge. Patient-reported (PROMS) and clinician-reported outcome measures, endoscopic examination, and spirometry were used to assess voice, swallow, and airway outcomes. RESULTS: Forty-one patients were included in the study with a mean age of 56 years and male:female ratio of 28:13. Average duration of endotracheal intubation was 24 days and 63.4% of tracheostomies were performed at day 21 to 35 of intubation. 53.7% had an abnormal GRBAS score and 30% reported abnormal swallow on EAT-10 questionnaire. 81.1% had normal endoscopic examination of the larynx, however, positive endoscopic findings correlated with the patient self-reported VHI-10 (P = .036) and EAT-10 scores (P = .027). 22.5% had spirometric evidence of fixed upper airway obstruction using the Expiratory-Disproportion Index (EDI) and Spearman correlation analysis showed a positive trend between abnormal endoscopic findings and EDI scores over 50 (P < .0001). CONCLUSION: The preliminary results of this study reveal a high incidence of laryngeal injury among patients who underwent intubation and tracheostomy insertion during the COVID-19 pandemic. As these patients continue to be followed up, the evolution of these complications will be studied. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E1918-E1925, 2021.
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COVID-19/cirurgia , Deglutição/fisiologia , Complicações Pós-Operatórias/fisiopatologia , Ventilação Pulmonar/fisiologia , Traqueostomia , Qualidade da Voz/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/fisiopatologia , COVID-19/fisiopatologia , Correlação de Dados , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/fisiopatologia , Feminino , Seguimentos , Humanos , Intubação Intratraqueal , Laringe/lesões , Laringe/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espirometria , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognised cause of various systemic fibro-inflammatory conditions. However, laryngeal involvement as a primary feature is extremely rare. We aimed to report on a case series of such patients and examine the global literature relating to laryngeal involvement. METHODS: Having previously reported a case of IgG4-RD laryngeal pseudotumour, we describe a case series of further 4 patients with primary laryngeal IgG4-RD managed by our UK quaternary airway service and provide a brief overview of laryngeal IgG4-RD. RESULTS: Including our cases, 14 cases of primary laryngeal IgG4-RD have been reported. Vocal cord involvement is relatively uncommon. Repeat biopsies may be required to achieve histological diagnosis. Remission is achievable by commencement of immunomodulatory treatment, following which laryngeal reconstruction may be necessary. CONCLUSION: Laryngeal involvement is a rare presentation of IgG4-RD, itself a rare and difficult-to-diagnose condition. A high and prolonged index of suspicion is necessary from both surgical and pathological specialists for correct diagnosis and management.
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BACKGROUND: Local recurrence and remote metastasis are major challenges to overcome in order to improve the survival of patients with cancer after surgery. Oncolytic viruses are a particularly attractive option for prevention of postsurgical disease as they offer a non-toxic treatment option that can directly target residual tumor deposits and beneficially modulate the systemic immune environment that is suppressed post surgery and allows residual disease escape from control. Here, we report that a novel Vaccinia virus (VV), VVΔTKΔN1L (with deletion of both thymidine kinase (TK) and N1L genes) armed with interleukin 12 (IL-12), can prolong postoperative survival when used as a neoadjuvant treatment in different murine and hamster surgical models of cancer. METHODS: A tumor-targeted replicating VV with deletion of TK gene and N1L gene (VVΔTKΔN1L) was created. This virus was armed rationally with IL-12. The effect of VVΔTKΔN1L and VVΔTKΔN1L-IL12 on modulation of the tumor microenvironment and induction of tumor-specific immunity as well the feasibility and safety as a neoadjuvant agent for preventing recurrence and metastasis after surgery were assessed in several clinically relevant models. RESULTS: VVΔTKΔN1L can significantly prolong postoperative survival when used as a neoadjuvant treatment in three different surgery-induced metastatic models of cancer. Efficacy was critically dependent on elevation of circulating natural killer cells that was achieved by virus-induced cytokine production from cells infected with N1L-deleted, but not N1L-intact VV. This effect was further enhanced by arming VVΔTKΔN1L with IL-12, a potent antitumor cytokine. Five daily treatments with VVΔTKΔN1L-IL12 before surgery dramatically improved postsurgical survival. VVΔTKΔN1L armed with human IL-12 completely prevented tumor recurrence in surgical models of head and neck cancer in Syrian hamsters. CONCLUSIONS: These data provide a proof of concept for translation of the regime into clinical trials. VVΔTKΔN1L-IL12 is a promising agent for use as an adjuvant to surgical treatment of solid tumors.