Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Mepolizumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem ­ Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der AGs Klinische Immunologie, Allergologie und Umweltmedizin und Rhinologie und Rhinochirurgie der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC).

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-IL5 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 is to be monitored, what follow-up documentation is necessary, and when it should be terminated if necessary. 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 termination of therapy when using mepolizumab for the indication CRSwNP in the German health care system are given on the basis of a documentation sheet. CONCLUSIONS: 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.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Dupilumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the nasal and paranasal mucosa. A Type-2 inflammation is described as the most common endotype. Since October 2019 the anti-IL-4/-IL-13 antibody dupilumab has been approved in Germany as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps, when systemic corticosteroids alone or surgery do not provide adequate disease control. While recommendations for the use of dupilumab in CRSwNP exist at both national and international levels, until now it has not been adequately established, how therapy should be monitored and when it should be discontinued in the German Health Care System. METHODS: A literature search was performed analyzing previous data on the treatment of CRSwNP with dupilumab 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 05/2022 were included. RESULTS: Based on international literature and previous experience, recommendations are given by an expert panel for follow-up and possible therapy breaks, therapy intervals or termination of therapy when using dupilumab for the indication CRSwNP in the German health care system based on a documentation form. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens new non-surgical therapy approaches with biologics for patients with severe courses. The authors give recommendations for follow-up, possible therapy breaks, therapy intervals and a termination for dupilumab treatment as add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

No acute effects of an exposure to 50 ppm methyl methacrylate on the upper airways.

PURPOSE: The German MAK value of methyl methacrylate has been fixed at 50 ppm. The aim of this study was to evaluate possible acute effects of an exposure to 50 ppm methyl methacrylate on the upper airways of human subjects. METHODS: Twenty healthy subjects were exposed to 50 ppm methyl methacrylate and to air (sham) in an exposure chamber for 4 h according to a crossover design. Symptoms were assessed by the SPES questionnaire. Olfactory thresholds for n-butanol and mucociliary transport time were measured before and after exposure. Concentrations of interleukin 1ß and interleukin 8 were determined in nasal secretions taken after exposure. mRNA levels of interleukins 1ß, 6 and 8, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and cyclooxygenases 1 and 2 were measured in nasal epithelial cells, obtained after exposure. Possible effects were investigated by semiparametric and parametric crossover analyses. RESULTS: The score of the item "irritation to the nose" was slightly elevated following exposure to methyl methacrylate (p ≤ 0.01). Olfactory functioning was not impaired. Mucociliary transport time did not change. Neither concentrations of interleukins in nasal secretions nor mRNA levels were elevated. CONCLUSION: Only minor irritating effects on the nose were observed. The acute exposure to 50 ppm methyl methacrylate did not cause any adverse effects. However, the results cannot be extrapolated to chronic exposure.

[Catch me if you can: endoscopic remove of a needle from the jejunum]. / Catch me if you can: Endoskopische Bergung einer Sicherheitsnadel aus dem tiefen Dünndarm.

INTRODUCTION: The ingestion of foreign bodies is a frequently observed problem in daily clinical practice. In order to avoid complications such as perforation, endoscopic removal of potentially penetrating foreign bodies should be attempted quickly. The use of various endoscopic techniques has been reported for this purpose. However, extraction of foreign bodies from the mid gastrointestinal tract has rarely been reported. CASE REPORT: We present the case of a patient who had swallowed a safety needle which could safely be removed from the jejunum by means of double-balloon enteroscopy (DBE). The combination of a thin p-type enteroscope with a thick t-type overtube was used in order to improve the manoeuvrability of the endoscope. The needle was pulled into the overtube which served as a protective shield during the retrieval of the endoscope. CONCLUSION: Our case report describes the potential of removing foreign bodies from the deep small bowel by pulling them into the overtube of a double-balloon enteroscope. If the suspicion of foreign body impaction in the small bowel is made, it may be advisable to primarily choose a balloon enteroscopy system. Through this, quick and deep insertion can be combined with a safe removal of the foreign body.

Low-dose aspirin desensitization in individuals with aspirin-exacerbated respiratory disease.

BACKGROUND: Nasal polyposis frequently occurs within the clinical picture of aspirin-exacerbated respiratory disease (AERD). A derailed arachidonic acid metabolism is regarded to be part of the pathophysiology of AERD, and aspirin desensitization is the only causal therapeutic option, so far. The optimal maintenance dose of aspirin desensitization to prevent nasal polyp recurrence on the one hand and to minimize aspirin-related side-effects, on the other hand, is still a matter of debate. The aim of this trial was to investigate the efficacy and safety of a low-dose aspirin desensitization protocol. METHODS: After sinus surgery, 70 individuals with AERD were randomly allocated to a prospective double-blind placebo-controlled aspirin desensitization protocol with a maintenance dose of 100 mg daily. The primary outcome was polyp relapse after 36 months. Nasal endoscopy status, quality of life, and patients' symptom score as well as aspirin-related side-effects were monitored. RESULTS: Due to the high dropout rate, only 31 individuals were evaluated. After 36 months, nasal polyp relapse was less frequent (P = 0.0785) and the polyposis score was lower (P = 0.0702) in the therapy group. Quality of life obviously improved (P = 0.0324), clinical complaints (P = 0.0083) were significantly reduced, and no severe aspirin-related side-effects were observed. CONCLUSION: Aspirin desensitization with a maintenance dose of 100 mg daily has a positive impact on nasal polyp relapse and seems to be a safe and suitable therapy to improve clinical complaints and the quality of life of individuals with AERD.

[Correction of complex facial scars]. / Die Behandlung komplexer Narben im Gesicht.

Correction of complex facial scars frequently requires individualized, multimodal strategies, which are composed of various therapeutic measures. This report provides information on techniques for correction of contractures, atrophic scars, scars within hair-bearing regions of the face and auricular keloids. Additionally, we present adjuvant procedures in a subject-related manner.

No evidence for a correlation of glutathione S-tranferase polymorphisms and chronic rhinosinusitis.

OBJECTIVE: Cellular detoxification mechanisms are mandatory for cellular protection against oxidative stress and reactive oxygen species. One major group of antioxidative active enzymes involved in cellular detoxification are the Glutathione S-Transferases (GST). Multiple subtypes like GSTM1, GSTP1, and GSTT1 and variants of them are known, arising from allelic variations of the GST loci. Moreover, functional variants occur in high percentages and have been associated with diseases like bronchial asthma and bronchial hyperresponsiveness. The interplay of oxidative stress, detoxifying genes like GSTs and the genesis of respiratory tract illness is under contradictory debate. In this study, we analysed the potential association of GST-polymorphisms and chronic rhinosinusitis (CRS). METHODS: In total 170 nasal tissue samples, 49 tissue samples from patients with CRS without nasal polyps, 69 tissue samples from CRS with nasal polyps and 52 healthy tissue controls of the inferior turbinate were analysed for their individual GST-status. Genotypes for GSTM1 (null versus present), GSTT1 (null versus present), and GSTP1 (Ile105Val) were determined by Polymerase Chain Reaction. The respective genotypes were correlated to the incidence of CRS with and without nasal polyps in aspirin-tolerant and intolerant patients and to the individual health status concerning asthma and allergies. RESULTS: No correlation between any GST-polymorphism and CRS with and without nasal polyps or allergies or asthma or aspirin-intolerance was observed. CONCLUSION: Our results do not suggest that there is a relevant genetic predisposition considering the individual GST-status for the susceptibility of nasal respiratory epithelia leading to CRS.

No acute effects of an exposure to 50 ppm acetaldehyde on the upper airways.

OBJECTIVE: German MAK value of acetaldehyde has been fixed at 50 ppm to prevent from irritating effects. The threshold value is mainly based on animal experiments. The aim of this study was to evaluate acute effects of an exposure to 50 ppm acetaldehyde on the upper airways of human subjects. METHODS: Twenty subjects were exposed to 50 ppm acetaldehyde and to air in an exposure chamber for 4 h according to a crossover design. Subjective symptoms were assessed by questionnaire. Olfactory threshold for n-butanol and mucociliary transport time were measured before and after exposure. Concentrations of interleukin 1beta and interleukin 8 were determined in nasal secretions taken after exposure. mRNA levels of interleukins 1beta, 6 and 8, tumour necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and cyclooxygenases 1 and 2 were measured in nasal epithelial cells, gained after exposure. Possible effects were investigated by semiparametric and parametric crossover analyses. RESULTS: Exposure to acetaldehyde did not cause any subjective irritating symptoms. Olfactory threshold did not change. Mucociliary transport time increased insignificantly after exposure to acetaldehyde. Neither concentrations of interleukins in nasal secretions nor mRNA levels of inflammatory factors were higher after exposure to acetaldehyde. CONCLUSION: An acute exposure to 50 ppm acetaldehyde did not cause any adverse effects in test subjects.

Incidence of childhood cancer of the head and neck in Germany.

BACKGROUND: Only very limited data are available in the literature on the incidence of childhood cancer of the head and neck worldwide. METHODS: Based on data obtained from the national German Childhood Cancer Registry, a total of 370 malignancies of the head and neck in children under the age of 15 (199 boys and 171 girls), which were reported to this institution between 1994 and 2003, were analysed in this study. RESULTS: The overall incidence of malignancies of specific sites of the head and neck in Germany is 4.48 per 100000 children. The most frequently observed entities, representing primary tumours, are soft tissue sarcomas (0.39/100000), lymphomas (0.09/100000) and thyroid carcinoma (0.07/100000). The most commonly affected organs are the thyroid (1.21/100000), orbita (0.91/100000), nasopharynx (0.66/100000), tonsils (0.43/100000) and paranasal sinuses (0.14/100000). Overall, boys are more frequently affected than girls; however, incidence increases in girls with age and exceeds that of boys in the age group between 10 and 14 years. CONCLUSIONS: This is a first statistical evaluation detailing cumulative incidences of various histologic types of malignancies of the head and neck including age and gender distribution as well as organ-specific localization in children below the age of 15 in Germany.

[Tonsillectomy technique: bipolar scissors vs raspatory: results of a case control study in 138 patients]. / Tonsillektomie mit Koagulationsschere oder Raspatorium: Ergebnisse einer Fallkontrollstudie bei 138 Patienten.

BACKGROUND: Postoperative bleeding is the major complication in tonsillectomy, and pain the most common side effect. The use of bipolar scissors versus blunt dissection tonsillectomy were compared in this study in order to evaluate postoperative bleeding and pain, as well as operative time. METHODS: In this case control study, 138 patients with the diagnosis of chronic tonsillitis, mononucleosis or a peritonsillar abscess were divided into two groups. A total of 78 patients were operated using bipolar scissors while 60 patients underwent tonsillectomy by blunt dissection. Operating time, frequency of postoperative bleeding and the postoperative pain score were compared between these two groups. RESULTS: The average operating time in the bipolar scissor group showed a tendency to be shorter than in the blunt dissection group (mean 4.1 min), although this did not reach a level of statistical significance. No differences were seen in pain scores or in the incidence of postoperative bleeding. CONCLUSION: The data documented in this study show that tonsillectomy with bipolar scissors might represent a surgical option to reduce surgical time in a larger patient group. Postoperative pain and the incidence of postoperative bleeding did not show any statistical difference between the two surgical techniques.

Individual monitoring of aspirin desensitization.

BACKGROUND: Patients with aspirin-sensitive rhinosinusitis, which is frequently associated with intrinsic bronchial asthma, can be desensitized by long-term treatment with oral aspirin. The exact mechanisms of this desensitization remain obscure, but modulations of the eicosanoid pathway occur and can be monitored with the help of a practicable in vitro assay on mixed leukocyte cultures. OBJECTIVE: To monitor the effect of low-dose aspirin desensitization therapy, 100 mg/d, objectively by an in vitro assay. DESIGN: In a prospective study, 30 patients with aspirin intolerance, who were treated following a desensitization protocol with a dose of oral aspirin of only 100 mg/d were followed up for 1 year and reassessed every 3 months clinically and in vitro. RESULTS: Twenty-five patients showed a normalization of in vitro eicosanoid levels during this period, 4 showed some improvement, and 1 showed no therapeutic effect on eicosanoid release. Clinical follow-up revealed a low recurrence rate of nasal polyposis, with recurrent disease only in 4 individuals who also showed no normalization of eicosanoid release levels. Furthermore, a reduction of the average incidence of purulent episodes of sinusitis was seen after 1 year. Of 12 patients with asthma, 9 experienced marked improvement in pulmonary function. Of 16 individuals with a marked impairment of nasal breathing, 14 felt an increase of nasal patency, and 7 of 11 patients with pretreatment hyposmia had an improved sense of smell after 1 year. CONCLUSIONS: Desensitization therapy in patients with aspirin-sensitive rhinosinusitis can be successfully performed with low oral doses of aspirin, and the individual course throughout the desensitization can be monitored with the help of an in vitro analysis of eicosanoid release from mixed leukocyte cultures.

Expression and localization of cyclooxigenases (Cox-1 and Cox-2) in nasal respiratory mucosa. Does Cox-2 play a key role in the immunology of nasal polyps?

INTRODUCTION: Cyclooxygenases 1 (Cox-1) and 2 (Cox-2) play a key role in arachidonic acid metabolism and in the regulation of eicosanoid production. The balance of prostaglandin and leukotrien release in respiratory mucosa is a crucial factor in the development of Sampter's triad in NSAID (aspirin-) intolerant patients and possibly also relevant in the pathophysiology and immunology of chronic rhinosinusitis (CRS) and nasal polyposis in NSAID tolerant patients. METHODS: 36 surgical specimens were immunohistochemically labeled for Cox-1 and Cox-2. Specimens were taken from chronically inflamed mucosa (n=13) and from nasal polyps (n=10) during endonasal sinus surgery. Controls were obtained from healthy nasal respiratory mucosa (n=13), harvested during turbinate surgery in patients with nasal obstruction without inflammatory disease. RESULTS: Analysis revealed that Cox-1 and Cox-2 were labeled in all 23 inflamed / polypoid tissue specimens and in all 13 controls. In chronically inflamed tissue the expression of Cox-1 and Cox-2 was strongly labeled in the respiratory epithelial lining and in mucosal glandular ducts. In nasal polyps the expression pattern of Cox-1 was similar, but Cox-2 was much less intensely labeled in the superficial epithelial cellular lining. Controls showed homogenious labeling of Cox-1 and Cox-2 in both tissues with little intensity. CONCLUSIONS: These data suggest that Cox-2 is downregulated in epithelial cells of nasal polyps. Cox-1 and 2 are present in high concentrations in ductal structures of mucosal glands. The significance of these findings has to be discussed with regard to the regulatory function of Cox-2 in eicosanoid release and the role of the latter in the immunology and pathophysiology of nasal polyps.

[Cysts of the thoracic canal. Apropos of a subclavicular site]. / Kystes du canal thoracique. A propos d'une localisation sus-claviculaire.

The authors report a case of cystic dilatation of the terminal portion of the thoracic duct which clinically corresponded to a swelling in the root of the left side of the neck. Pathogeny and evolutive mode of this exceptional affection are ill known. Echography and scanography show the cystic nature of the mass. Diagnosis is made by direct puncture which can prove the chylous nature of the content and permits the opacification of the cyst. Lymphography shows the type of junction with the thoracic duct.

Acute effects of an exposure to 100 ppm 1-methoxypropanol-2 on the upper airways of human subjects.

The German MAK value of 1-methoxypropanol-2 has been fixed at 100 ppm. The aim of this study was to evaluate possible acute effects of an exposure to 100 ppm 1-methoxypropanol-2 on the upper airways of human subjects. Twenty subjects were exposed in a crossover design to 100 ppm 1-methoxypropanol-2 and to air in an exposure chamber for 4h. Subjective symptoms were assessed by questionnaire. Olfactory thresholds for n-butanol and mucociliary transport time were measured before and after exposure. Concentrations of interleukin 1ß and interleukin 8 were determined in nasal secretions taken after exposure. mRNA levels of interleukins 1ß, 6 and 8, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and cyclooxygenases 1 and 2 were measured in nasal epithelial cells, obtained after exposure. Possible effects were investigated by semiparametric and parametric cross-over analyses. Subjects did not have any subjective irritating symptoms. The olfactory threshold was slightly elevated following exposure to 1-methoxypropanol-2. Mucociliary transport time did not change. Neither concentrations of interleukins in nasal secretions nor mRNA levels except for interleukin 1ß were higher after exposure to 1-methoxypropanol-2. In conclusion, the acute exposure to 100 ppm 1-methoxypropanol-2 did not cause clear-cut adverse effects in test subjects.

[A rare manifestation of sarcoidosis]. / Seltene Manifestation einer Sarkoidose.

This article reports the case of a 14-year-old boy who was presented in the case conference with symptoms of decreased visual acuity, scintillating scotomas and photophobia. Physical examination revealed right facial paralysis, parotid gland swelling, high fever and poor general condition. Ophthalmoscopy revealed anterior and posterior uveitis including macular edema and chorioretinal infiltrates. Angiography revealed a dense pattern of hyperfluorescent lesions and these observations resulted in the diagnosis of Heerfordt syndrome. Under systemic prednisolone therapy, symptoms were reduced and visual acuity recovered.

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment.

BACKGROUND Trifunctional antibodies, such as catumaxomab (anti-EpCAM×anti-CD3) and ertumaxomab (anti- HER-2/neu×anti-CD3), transiently link immune effector cells to tumour cells, which results in cellular cytotoxicity towards the tumour cells. A functional immune system is therefore essential for effective anti-tumour activity. However, the commonly observed haematotoxicity of chemotherapeutics and radiation therapy may be associated with some degree of immunosuppression. Combining chemotherapy and trifunctional antibodies in cancer treatment requires understanding of the impact of chemotherapeutics on immune cell function and, thus, on the activity of trifunctional antibodies. METHODS The effect of chemotherapeutic treatment on trifunctional antibody-mediated anti-tumour activity was assessed in vitro. Blood samples were collected from 12 head and neck squamous cell carcinoma patients after chemotherapy (5-fluorouracil, cisplatin) and radiotherapy, and from one healthy control donor. The immune cell status was analysed and mononuclear cells (MNC) were isolated. The potency of catumaxomab and ertumaxomab was assessed in a cytotoxicity assay using MNC isolated from each patient sample in co-culture with a tumour target cell line. The release of infl ammatory cytokines was also monitored in the cell culture supernatant. RESULTS Most patients included in this study had decreased immune cell counts during the course of chemotherapy. Nonetheless, an effective and concentration-dependent anti- tumour activity mediated by trifunctional antibodies was demonstrated using these patient immune effector cells. The immune response activity of the patient immune cells was not impaired one week after cisplatin administration or even three days after the last 5-fluorouracil treatment. CONCLUSION This study shows for the first time that immune effector cells from cancer patients undergoing standard chemotherapy and radiotherapy can be activated by trifunctional antibodies for efficient killing of tumour cells.

Initial experience with intraoperative ultrasound in navigated soft tissue operations of the neck and below the base of the skull.

AIM: Ultrasound (US) is a cost effective and time saving examination method for diseases of the neck,and can be used without any known side effects or limitations. US tied into modern navigation devices may significantly improve intraoperative orientation in regions with soft tissue characteristics. METHODS: 22 patients with soft tissue tumours of the head and neck underwent surgical procedures assisted by CAS system LandmarX (Medtronic) in combination with the US system DynaVievP II (Aloka). Clinical feasibility of using intraoperative US in navigated surgical procedures has been investigated by paying particular attention to the surgical approach, possible interferences from surgical instruments and time consumption. RESULTS: In the case of soft tissue shift, US can provide a sequence of a section of the operative field and, without delay, an instant comparison with the preoperative imaging data set. The feasibility of using this method is severely limited by the additional preparation required, the unfamiliar handling during surgery, and design-related matters. CONCLUSIONS: Integrating US into a navigation device could provide additional useful information for a more controlled resection of soft tissue disease of the neck and below the base of the skull.

[Chronic rhinosinusitis. What is new from the last 25 years?]. / Chronische Rhinosinusitis. Was gibt es Neues in den letzten 25 Jahren?

Chronic rhinosinusitis (CRS) appears to be of increasing relevance epidemiologically. Despite progress in elucidating the role of eosinophilia as well as aspirin intolerance and eicosanoid mediators, the pathophysiology remains obscure. Endonasal sinus surgery has become the treatment of the choice for CRS patients with and without nasal polyposis, particularly if conservative treatment fails. Long-term studies indicate that a minimally invasive approach with microscopic and endoscopic procedures is preferable to radical surgery. Powered instrumentation or computer-aided surgery are still controversially discussed, but certainly can be very helpful in the hands of an experienced surgeon, especially to minimize surgical trauma and save surgical time. The complex therapeutic concept needs to be individually tailored to the disease of the patients and to the heterogeneous etiologic aspects.