Monitoring mepolizumab treatment in chronic rhinosinusitis with nasal polyps (CRSwNP): Discontinue, change, continue therapy?

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL-5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy should be monitored, what follow-up documentation is necessary, and when it should be discontinued if necessary. MATERIALS AND METHODS: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries, and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. RESULTS: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals, and possible therapy breaks as well as discontinuation of therapy when using mepolizumab for the indication CRSwNP in the German healthcare system are given on the basis of a documentation sheet. CONCLUSION: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

The Multifaceted Role of Confocal Laser Endomicroscopy in Head and Neck Surgery: Oncologic and Functional Insights.

(1) Background: Confocal laser endomicroscopy (CLE) has emerged as a transformative tool in head and neck surgery, with applications spanning oncologic insights and functional evaluations. This study delves into CLE's potential in these domains. (2) Methods: We performed CLE in head and neck oncologic surgery, focusing on tumor margin identification and precise resection. We also employed CLE for functional assessment in allergic rhinitis, observing real-time mucosal changes during nasal provocation testing. (3) Results: In oncologic surgery, CLE enabled real-time visualization of tumor margins and cellular patterns, aiding resection decisions. In allergic rhinitis assessment, CLE captured dynamic morphological alterations upon allergen exposure, enhancing understanding of mucosal reactions. (4) Conclusions: The integration of CLE with evolving technologies such as deep learning and AI holds promise for enhanced diagnostic accuracy. This study underscores CLE's expansive potential, highlighting its role in guiding surgical choices and illuminating inflammatory processes in the head and neck.

Technical Note: First Use of Endonasal Confocal Laser Endomicroscopy - Feasibility and Proof of Concept

Abstract Introduction Probe-based confocal laser endomicroscopy (p-CLE) is a method for real-time in vivo visualization of mucosal changes on a cellular level. Due to the size of the endoscopes, it was mainly used in the gastrointestinal tract so far. First investigations on head and neck carcinoma described the oropharyngeal application. The further miniaturization of the laser probe now allows endonasal application and, thus, first experiences with the investigation of endonasal neoplasms. Objectives The aim of the present investigation is to elucidate, based on the morphological criteria validated in the oropharynx, whether these criteria be transferred in a similar way to the endonasal mucosa. Methods We conducted p-CLE (Cellvizio, Paris, France) with intravenous fluorescein staining in endoscopic sinus surgery in a patient with sinonasal inverted papilloma and a histologically confirmed squamous cell carcinoma. We compared the cellular visualization of pathological changes with those of healthy mucosa in the same specimen, and also with our former findings in the oropharynx. Results Endonasal p-CLE proved to be quite feasible in the surgical setting, and the transfer of malignancy criteria in analogy to histological examination could be optically retraced. Furthermore, additional criteria for tissue dignity assessment were obtained. Conclusion Our results suggest that endonasal application of p-CLE represents a valuable extension of the diagnostic repertoire available to date by an additional realtime analysis of the nasal mucosa. This is of particular value in surgically challenging anatomical areas such as the paranasal sinuses.

Technical Note: First Use of Endonasal Confocal Laser Endomicroscopy - Feasibility and Proof of Concept.

Introduction Probe-based confocal laser endomicroscopy (p-CLE) is a method for real-time in vivo visualization of mucosal changes on a cellular level. Due to the size of the endoscopes, it was mainly used in the gastrointestinal tract so far. First investigations on head and neck carcinoma described the oropharyngeal application. The further miniaturization of the laser probe now allows endonasal application and, thus, first experiences with the investigation of endonasal neoplasms. Objectives The aim of the present investigation is to elucidate, based on the morphological criteria validated in the oropharynx, whether these criteria be transferred in a similar way to the endonasal mucosa. Methods We conducted p-CLE (Cellvizio, Paris, France) with intravenous fluorescein staining in endoscopic sinus surgery in a patient with sinonasal inverted papilloma and a histologically confirmed squamous cell carcinoma. We compared the cellular visualization of pathological changes with those of healthy mucosa in the same specimen, and also with our former findings in the oropharynx. Results Endonasal p-CLE proved to be quite feasible in the surgical setting, and the transfer of malignancy criteria in analogy to histological examination could be optically retraced. Furthermore, additional criteria for tissue dignity assessment were obtained. Conclusion Our results suggest that endonasal application of p-CLE represents a valuable extension of the diagnostic repertoire available to date by an additional real-time analysis of the nasal mucosa. This is of particular value in surgically challenging anatomical areas such as the paranasal sinuses. Further investigation and validation will be necessary.

[Confocal laser endomicroscopy - first application and validation of malignancy criteria]. / Endonasale konfokale Laserendomikroskopie ­ erste Anwendung und Validierung von Malignitätskriterien.

OBJECTIVES: Confocal laser endomicroscopy (CLE) is a method for real-time in vivo visualization of mucosal changes on a cellular level. First investigations on head and neck carcinoma described the oropharyngeal application. The aim of this investigation is to elucidate, based on the criteria validated in the oropharynx, whether these can be transferred to endonasal mucosa. METHODS: CLE was performed with intravenous fluorescein staining in endoscopic sinus surgery in one patient with sinonasal inverted papilloma and another with squamous cell carcinoma. We compared cellular visualization of pathological changes to those of healthy mucosa in the same specimen as well to our former findings in the oropharynx. RESULTS: Endonasal CLE proved to be well feasible in the surgical setting and the transfer of malignancy criteria in analogy to histological examination could be optically retraced. Furthermore, additional criteria for tissue dignity assessment were obtained. CONCLUSION: Our results suggest that endonasal CLE represents a valuable extension of the diagnostic repertoire available to date by an additional real-time analysis of nasal mucosa. This is of particular value in surgically challenging anatomical areas such as the paranasal sinuses. Further investigation and validation will be necessary.

Fluorescein- and EGFR-Antibody Conjugated Silica Nanoparticles for Enhancement of Real-time Tumor Border Definition Using Confocal Laser Endomicroscopy in Squamous Cell Carcinoma of the Head and Neck.

Intraoperative definition of tumor free resection margins in head and neck cancer is challenging. In the current proof-of-principle study we evaluated a novel silica nanoparticle-based agent for its potential use as contrast enhancer. We synthesized silica nanoparticles with an average size of 45 nm and modified these particles with the fluorescence stain fluorescein isocyanate (FITC) for particle detection and with epidermal growth factor receptor (EGFR)-targeting antibodies for enhanced tumor specificity. The nanoparticles exhibited good biocompatibility and could be detected in vitro and in vivo by confocal laser scanning microscopy. Additionally, we show in an ex vivo setting that these modified nanoparticles specifically bind to tumor samples and could be detected using a handheld confocal fluorescence endomicroscope. From a clinical point of view, we believe that this method could be used for tumor border contrast enhancement and for better intraoperative definition of R-0 tumor resection.

An acute exposure to ozone impairs human olfactory functioning.

INTRODUCTION: Ozone is a ubiquitous and irritant gas. We questioned whether an acute exposure to 0.2 ppm ozone impaired olfactory functioning. METHODS: Healthy, normosmic subjects were exposed according to a parallel group design either to 0.2 ppm ozone (n = 15) or to sham (n = 13) in an exposure chamber for two hours. Possible irritating effects were assessed by questionnaire (range 0-5). The detection threshold of n-butanol was measured with the Sniffin' Sticks test before and after exposure. Olfactory thresholds were logarithmized and a two-way analysis of variance (ANOVA) with repeated measurements was carried out to test the effects of exposure (ozone vs. sham) and time (before vs. after exposure). Additionally, nasal secretions were taken at a preliminary examination and after exposure to determine interleukins 1ß and 8. RESULTS: No irritating effects to the upper airways were observed. In the ozone group, the median score for cough increased from 0 to 2 at the end of exposure (sham group 0 and 0, respectively, p < 0.001). The ANOVA showed a main effect for ozone exposure (F (1, 26) = 27.6, p = 0.0002), indicating higher olfactory thresholds in the ozone group. Concentrations of interleukins in nasal secretions did not increase following ozone exposure. CONCLUSIONS: This study shows a clear impairment of olfactory functioning following an acute exposure to 0.2 ppm ozone.

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.

Aspirin Exacerbated Respiratory Disease.

Aspirin exacerbated respiratory disease (AERD) has been defined as a non-steroidal anti-inflammatory drug (NSAID)-triggered hypersensitivity, non-allergic bronchial asthma and chronic rhinosinusitis (CRS) with nasal polyps. The underlying pathophysiology of AERD is not completely understood so far. An altered arachidonic acid metabolism and dysregulated enzyme activity are regarded to be causal. AERD is characterized by recalcitrant CRS with recurrent nasal polyps after sinus surgery, accompanied by difficult to treat bronchial asthma and adverse reaction after NSAID ingestion such as nasal blockage, itching, laryngospasm and severe asthma attacks. Affected individuals suffer from poor quality of life. Besides functional endoscopic sinus surgery, the application of topical and systemic steroids and symptomatic therapy, aspirin desensitization is the only causative treatment option. The diagnostic approach to AERD, the ideal desensitization protocol and especially the following daily maintenance dose is part of an ongoing debate. This article summarizes the current knowledge about the pathophysiology, focuses on modern diagnostic approaches of AERD and discusses various aspirin desensitization protocols with respect to efficacy as well as to undesirable side effects.

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis.

BACKGROUND: The body of knowledge regarding rhinosinusitis(RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS). METHODS: Evidence-based reviews with recommendations(EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR)was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus. RESULTS: The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS)with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AECRS), and pediatric RS. CONCLUSION: As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too often the foundation upon which these recommendations are based is comprised of lower level evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed.

Effect of endoscopic brow lift on contractures and synkinesis of the facial muscles in patients with a regenerated postparalytic facial nerve syndrome.

BACKGROUND: Delayed recovery after facial palsy results in aberrant nerve regeneration with symptomatic movement disorders, summarized as the postparalytic facial nerve syndrome. The authors present an alternative surgical approach for improvement of periocular movement disorders in patients with postparalytic facial nerve syndrome. The authors proposed that endoscopic brow lift leads to an improvement of periocular movement disorders by reducing pathologically raised levels of afferent input. METHODS: Eleven patients (seven women and four men) with a mean age of 54 years (range, 33 to 85 years) and with postparalytic facial nerve syndrome underwent endoscopic brow lift under general anesthesia. Patients' preoperative condition was compared with their postoperative condition using a retrospective questionnaire. Subjects were also asked to compare the therapeutic effectiveness of endoscopic brow lift and botulinum toxin type A. RESULTS: Mean follow-up was 52 months (range, 22 to 83 months). No intraoperative or postoperative complications occurred. During follow-up, patients and physicians observed an improvement of periorbital contractures and oculofacial synkinesis. Scores on quality of life improved significantly after endoscopic brow lift. Best results were obtained when botulinum toxin type A was adjoined after the endoscopic brow lift. Patients described a cumulative therapeutic effect. CONCLUSIONS: These findings suggest endoscopic brow lift as a promising additional treatment modality for the treatment of periocular postparalytic facial nerve syndrome-related symptoms, leading to an improved quality of life. Even though further prospective investigation is needed, a combination of endoscopic brow lift and postsurgical botulinum toxin type A administration could become a new therapeutic standard.

Low SPINK5 expression in chronic rhinosinusitis.

OBJECTIVES/HYPOTHESIS: Chronic rhinosinusitis (CRS) is a multifactorial disease that probably arises as a result of genetic diversity and environmental factors. SPINK5 is a serine protease inhibitor, which is supposed to be an important regulator of epithelial barrier maintenance. The role of SPINK5 polymorphisms and expression in CRS, especially in individuals with aspirin intolerance, is unclear. STUDY DESIGN: SPINK5 single-nucleotide polymorphisms (SNPs) and SPINK5 expression levels were correlated with CRS without (CRSsNP) and with nasal polyps (CRSwNP), aspirin intolerance, asthma, and allergies. METHODS: One hundred four nasal tissue samples, 15 from patients with CRSsNP, 59 from patients with CRSwNP, and 30 from healthy controls of the inferior turbinate, were analyzed for their SPINK5 status. Genotypes of four SPINK5 single nucleotide polymorphism (SNPs; G1258A, G2475T, A2915G, and A1103G), as well as SPINK5 mRNA expression levels, were determined by polymerase chain reaction. RESULTS: No correlation between any SPINK5 SNP and CRSsNP, CRSwNP, or allergies and asthma was observed. The heterozygous SNPs G1258A and A1103G were observed more frequently in aspirin-intolerant patients; the homozygous (A/A) genotype of SNP 1258 and the homozygous (G/G) genotype SNP 1103 were less frequent. There was no correlation between the analyzed SNPs and the level of SPINK5 expression. It was noted that in individuals with CRSwNP, aspirin intolerance, and allergies, SPINK5 expression was lowered. CONCLUSIONS: G1258A and A1103G polymorphisms are distinctive for the aspirin intolerance syndrome. Lowered SPINK5 expression might be a contributing factor leading to CRS, and appears to be characteristic for patients suffering from aspirin intolerance and from allergies.

Systematic intraoperative application of confocal endomicroscopy for early detection and resection of squamous cell carcinoma of the head and neck: a preliminary report.

OBJECTIVE: To use intraoperative confocal endomicroscopy for early detection and resection of squamous cell carcinoma (SCC) of the head and neck. A preliminary report. DESIGN: Prospective case series. SETTING: Tertiary referral hospital. PATIENTS: Fifteen consecutive patients with SCC of the oral cavity, hypopharynx, and larynx were included from the Department of Otolaryngology-Head and Neck Surgery, HSK Dr Horst Schmidt Kliniken GmbH, Wiesbaden, Germany INTERVENTIONS: Confocal endomicroscopy was performed during diagnostic and therapeutic procedures with a prototype of a rigid laser endoscope in combination with the already available technology of autofluorescence. MAIN OUTCOME MEASURES: Real-time visualization of cellular and subcellular details during endoscopy. Diagnostic scores were applied to differentiate dysplastic and malignant mucosal changes of SCC of the head and neck from normal squamous cell mucosa using this method. Results were correlated with the well-established gold standard, histologic analysis. RESULTS: Dysplastic and malignant changes of head and neck squamous cell mucosa were endoscopically determined by this unique in vivo application of confocal laser endomicroscopy using a rigid probe. CONCLUSIONS: We present preliminary and descriptive data using this novel technology in vivo. Considering the impact of a virtual real-time histologic analysis, this technology points to a very promising development. It may carry potential for quicker intraoperative diagnosis, less need for multiple frozen sections, and more precise resection margins.

Radiotherapy and wound healing: principles, management and prospects (review).

Radiation therapy is a major therapeutic modality in the management of cancer patients. Over 60% of these patients receive radiotherapy at some point during their course of treatment and over 90% will develop skin reactions after therapy. Problematic wound healing in radiation-damaged tissue constitutes a major surgical difficulty and despite all efforts, irradiated skin remains a therapeutic challenge. This review provides an overview of the fundamental principles of radiation therapy with regards to the wound healing in normal and irradiated skin. Furthermore, it presents techniques that describe how to prevent and manage skin side effects as well as prospects that may improve cutaneous wound repair in general and in irradiated skin.

Keloids: Fundamental principles and prospects (Review).

Wound healing is a very complex process of interactions between different cells, growth factors, blood elements and extracellular matrix. Keloids represent one of the possible complications in the fundamental process of cutaneous wound repair. Despite all efforts, keloids remain a therapeutic challenge since no treatment is as yet considered 100% effective. Growth factors, discovered in the late 1970s, have been shown to influence dermal regeneration. However, the exogenous application of growth factors to chronic wounds has not proven to be effective in healing them. Additionally, genetic analysis has not revealed any single gene that might cause keloids; as such, classic gene therapy is not a feasible option for the treatment of keloids. A new approach is so-called somatic gene therapy. This review provides an overview of the fundamentals of wound healing and of keloids, and presents new possibilities that may improve cutaneous wound repair.

Confocal endomicroscopy: a novel application for imaging of oral and oropharyngeal mucosa in human.

Confocal endomicroscopy is an emerging technique for intravital visualization of neoplastic lesions, but its use has so far been limited to the gastrointestinal (GI) tract. This study was designed to assess the feasibility of in vivo confocal endomicroscopy of different regions of the oropharyngeal mucosa and to evaluate different contrast agents. We examined five different regions of the human oropharynx in vivo, and images were collected in real time by using a confocal laser endoscope as formerly described for the GI tract. Additionally ex vivo specimens were examined using a topical contrast agent. Confocal scanning was performed at 488-nm illumination for excitation of exogenously applied fluorophores (topical acriflavine and intravenous fluorescein). Confocal endomicroscopy allowed for visualization of cellular and subcellular structures of the anterior human oropharyngeal region. Fluorescein staining yielded architectural details of the surface epithelium and also subepithelial layers. Images taken at increasing depth beneath the epithelium showed the mucosal capillary network. Acriflavine strongly contrasted the cell nuclei of the surface epithelium. The findings correlated well with the histology of biopsy specimens. This is the first report showing that the use of fluorescence confocal endomicroscopy represents a promising method to examine cellular details in vivo in different oropharyngeal regions in human.

Histological and radiological signs indicative for chronic sinus mucosal inflammation in Graves' ophthalmopathy.

Orbital decompression and, in some cases, decompression of the optic nerve are the principal surgical procedures used for treatment of moderate or severe Graves' orbitopathy (GO). Histological examination of the surgical specimens of the ethmoid revealed a wide spectrum of inflammatory mucosal changes. The charts of 68 GO patients (55 female and 13 male; age range: 14 - 85 years) were retrospectively reviewed. Lund - Mackay scores were calculated for each patient based on findings of pre-operative computer tomography (CT) sinus scans, and the incidence of histological changes associated with polypoid and eosinophilic inflammation was assessed. Files did not reveal any evidence of chronic rhinosinusitis with or without nasal polyps based on endoscopic findings. Sinus opacification on CT (of any extent) was found in 20 out of the 68 patients (29.4%). On histological exam, histological changes of the sinus mucosa indicative for chronic rhinosinusitis were found in 31 out of the 68 GO patients (45.5%). A histological examination of the sinus mucosa indicative for chronic polypoid inflammation was present in 25 patients. Fourteen out of these 25 patients showed mucosal tissue eosinophilia on histology. Six patients had mucosal changes suggesting chronic non-polypoid inflammation with tissue eosinophilia on histological exam. The incidence of chronic rhinosinusitis in individuals without GO ranges between 10 and 15%. The incidence of histological changes of the sinus mucosa indicative for chronic rhinosinusitis described in this investigation suggests that chronic inflammatory disease is considerably more frequent in GO patients, when compared to the incidence of chronic rhinosinusitis in individuals without GO. Additionally, our data underline that CT imaging of the paranasal sinuses underestimates (29.4%) the incidence of inflammatory changes of the sinus mucosa (45.5%) of any extent in GO patients.

Cochlear implant and hearing aid: a new approach to optimizing the fitting in this bimodal situation.

More and more patients with residual hearing on the contralateral side are becoming candidates for cochlear implants (CI) surgery due to increasing CI. The major benefits of regular binaural hearing are spatial hearing, localization, and signal source discrimination in both quiet and noisy surroundings. In most of the reports, hearing aid fitting was carried out without balancing both the devices. Twelve children and eight adults with residual hearing on the non-operated side were binaurally fitted. Our fitting procedure for the hearing aid was based on the desired sensation level [i/o] method. A loudness scaling was used to adjust the loudness perception monaurally and to balance the volume of both devices. Speech audiometry in quiet and noisy surroundings was conducted both monaurally and in the bimodal mode. The fitting was modified according to the respective test results. In all children and six adults, a measurable gain and/or a subjective improvement of speech perception was achieved. Two adult patients did not accept the new fitting. In seven younger children, loudness scaling was impossible to perform because of age. This was also the case with speech audiometry for two children. A structured bimodal fitting using loudness scaling for both the cochlear implant and the hearing aid results in a subjective and objective amelioration of the patient's hearing and speech perception.