EPOS2020/EUFOREA expert opinion on defining disease states and therapeutic goals in CRSwNP.

Severe chronic rhinosinusitis with nasal polyps (CRSwNP), a form of diffuse bilateral (usually type 2) CRS, is a debilitating disease with a significant impact on quality of life (QoL). With novel knowledge and treatment options becoming available, there is a growing need to update or revise key definitions to enable communication across different specialties dealing with CRS, and to agree on novel goals of care in CRSwNP. The European Forum for Research and Education in Allergy and Airway diseases (EUFOREA) and EPOS expert members discussed how to measure treatment responses and set new treatment goals for CRSwNP. In this paper a consensus on a list of definitions related to CRSwNP is provided: control, remission, cure, recurrence/exacerbation, treatable traits, remodeling, progression, and disease modification. By providing these definitions, the involved experts hope to improve communication between all stakeholders involved in CRSwNP treatment for use in routine care, basic and clinical research and international guidelines aimed to harmonize and optimize standard of care of patients with CRSwNP in the future.

Mepolizumab improves sense of smell in severe chronic rhinosinusitis with nasal polyps: SYNAPSE.

BACKGROUND: Loss of smell is one of the most bothersome and difficult-to-treat symptoms in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). METHODOLOGY: SYNAPSE was a 52-week Phase III study of 4-weekly mepolizumab (100 mg subcutaneously) plus standard of care in adults with severe bilateral CRSwNP. This post hoc analysis assessed changes from baseline to study end in loss of smell visual analogue scale (VAS) symptom score, in patients stratified by several baseline clinical characteristics. SinoNasal Outcomes Test (SNOT)-22 sense of smell/taste item and University of Pennsylvania Smell Identification Test (UPSIT) scores were also assessed. RESULTS: SYNAPSE enrolled 407 patients (mepolizumab=206; placebo=201) with impaired sense of smell at baseline. Improvements from baseline to study end in loss of smell VAS score were greater with mepolizumab versus placebo (treatment difference: −0.37) and most notable in patients with fewer or more recent prior surgeries (treatment difference: 1 vs 2 vs more than 2 prior surgeries,−1.29 vs −0.23 vs −0.07; =3 years since last surgery, −0.89 vs 0.22). Approximately 25% of patients had baseline UPSIT scoresavailable; among those scoring =19 by study end. The SNOT-22 sense of smell/taste item score improved with mepolizumab versus placebo. CONCLUSIONS: Mepolizumab treatment improved patients' perceived sense of smell, as measured by loss of smell VAS score and SNOT-22 sense of smell/taste item score in patients with severe refractory CRSwNP.

The EUFOREA pocket guide for chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is known to affect around 5 % of the total population, with major impact on the quality of life of those severely affected (1). Despite a substantial burden on individuals, society and health economies, CRS often remains underdiagnosed, under-estimated and under-treated (2). International guidelines like the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) (3) and the International Consensus statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR) (4) offer physicians insight into the recommended treatment options for CRS, with an overview of effective strategies and guidance of diagnosis and care throughout the disease journey of CRS.

Optimized NGFR-derived hinges for rapid and efficient enrichment and detection of CAR T cells in vitro and in vivo.

Chimeric antigen receptor (CAR) T cell therapy has demonstrated unprecedented success with high remission rates for heavily pretreated patients with hematological malignancies. The hinge connecting the extracellular antigen recognition unit to the transmembrane domain provides the length and flexibility of the CAR constructs and ensures that the CAR can reach the target antigen and mediate recognition and killing of target cells. The hinge can also include specific amino acid sequences to improve CAR expression, influence T cell proliferation, and facilitate CAR T cell detection, enrichment, and even elimination. Here, we report the generation of two novel hinge domains derived from the low-affinity p75 chain of the human nerve growth factor receptor (NGFR), termed N3 and N4, which, when incorporated into the CAR backbone, allow detection as well as high-grade enrichment of CAR T cells with GMP-compatible immunomagnetic reagents. After optimizing the MACS protocol for excellent CAR T cell purity and yield, we demonstrated that N3- and N4-hinged CAR T cells are as efficacious as their CD8-hinged counterparts in vitro against hematological blasts and also in vivo in the control of acute monocytic leukemia in an immunodeficient mouse xenograft model. Thus, both hinges could potentially be an integral part of future CAR designs and universally applicable in clinical applications.

[Interdisciplinary surgery to the central skull base-current status]. / Interdisziplinäre Chirurgie der zentralen Schädelbasis ­ aktueller Stand.

BACKGROUND: The skull base is a surgically complex unit and is often only accessible via combined access routes. Newly developed surgical techniques using microsurgical visualization procedures and active instruments ("powered instruments") as well as multiport accesses enable new, less traumatic surgical corridors. This requires close interdisciplinary cooperation between ENT and neurosurgeons. Currently established access routes to the central skull base are systematized based on the authors' own clinical experience, and discussed in relation to the entity and the current study situation. MATERIALS AND METHODS: A retrospective, qualitative, and descriptive evaluation of the surgical reports of patients with pathologies of the central skull base who were jointly treated by neurosurgery and otorhinolaryngologic/head and neck surgery between 2006 and 2019 was performed. RESULTS: The surgical access routes to the central skull base can be categorized as so-called multiport access routes, partly also in combination, as follows: transnasal-transsphenoidal, subfrontal, subtemporal, transzygomatic, transpterygonal, transpetrous, translabyrinthine, and suboccipital. The choice of access route was based on the location and type of pathology, its inflammatory or space-occupying (benign or malignant tumor) nature, and the possibilities of functional preservation and complete removal. CONCLUSION: Due to the complexity of central skull base structures, the different tumor entities, and the required expertise of different medical specialties, surgery of the central skull base remains a challenge and should only be performed at special competence centers certified according to the criteria of the German Society of Skull Base Surgery.

[Symptoms, causes, and treatment options of geriatric nose]. / Symptome, Ursachen und Behandlungsmöglichkeiten der Altersnase.

With increasing age, structures of the internal and external nose change. Many elderly patients complain about rhinitis with nasal obstruction, endonasal crusting, epistaxis, intermittent rhinorrhea, and olfactory disorders. These symptoms are mainly caused by atrophy of the mucosa and the olfactory epithelium, but may also be an expression of drug side effects. Additionally, there are changes in the shape of the nose (continuous growth, altered elasticity of supporting structures) and in the dermis, which may develop tumors due to its sun-exposed position. These multiple internal and external changes of the nose can be summarized by the collective term "aging nose," whose treatment options are complex. These range from conservative (nasal care, medication changes, hemostatic measures) to surgical lines of therapy (septorhinoplasty, tumor excision, vascular ligation) and will require further scientific study in the future.

[Droplet exposure during tracheotomy : Case analysis and consequences with respect to COVID-19 patients]. / Tröpfchenexposition bei Tracheotomie : Fallanalyse und Konsequenzen in Bezug auf COVID-19-Patienten.

BACKGROUND: The COVID(coronavirus disease)-19 pandemic is characterized by high infectivity, droplet transmission, and high viral load in the upper respiratory tract. Severe disease courses are associated with interstitial pneumonia and ventilated patients, in whom tracheotomy (TT)-a droplet- and aerosol-producing medical intervention-is regularly necessary. TT as a potential infection risk for medical staff is scarcely found in the literature. Therefore, the aim of this study was to quantify droplet exposure of the surgical team during TT, to better define the requirements for personal protective equipment (PPE). MATERIALS AND METHODS: Surgical TT was performed in four non-infectious patients, during which the surgeon and his assistant both wore a surgical nasal mask with a transparent visor. After the procedure, the type, distribution, and number of droplets on the visor were determined macroscopically and microscopically. RESULTS: An average of 29 droplets were found on the middle third of the visor, 4 on the right third, and 13 on the left third, with an average droplet size of 571 µm (±â€¯381 µm). The smallest droplets were 55 µm, the largest 1431 µm. An increase in the number of droplets was found with increased ventilation during the procedure. Blood droplets were more common than secretion droplets. CONCLUSION: Contamination of the visor with droplets was demonstrated. Especially in the case of TT in highly infectious patients, e.g., COVID-19 patients, the use of hooded headgear in combination with breathing apparatus with air purification and power supply is recommended to ensure best protection from infection for the surgeon and the surgical assistant.

[Complications of anterior skull base surgery]. / Komplikationen bei Operationen an der Rhinobasis.

Anterior skull base operations are complex surgical procedures that are performed to treat serious and complicated diseases. Despite significant advances in surgical techniques, complications are relatively frequent and can be serious. Endoscopic skull base surgery seems to be associated with less complications than open techniques. Different classifications aimed at categorizing these complications have been suggested, the use of which can be recommended when reporting complication rates. The most relevant and frequent complications of anterior skull base surgery are hemorrhage, cerebrospinal fluid (CSF) leak, meningitis, and cranial nerve injury. Careful planning, close interdisciplinary cooperation, the competence of the skull base center and its members, and rigorous quality management are decisive for the avoidance of complications. With respect to the frequency and the seriousness of the complications, their meticulous and complete discussion with the patient before obtaining informed consent plays a central role.

EAACI Position paper on the standardization of nasal allergen challenges.

Nasal allergen challenge (NAC) is an important tool to diagnose allergic rhinitis. In daily clinical routine, experimentally, or when measuring therapeutic success clinically, nasal allergen challenge is fundamental. It is further one of the key diagnostic tools when initiating specific allergen immunotherapy. So far, national recommendations offered guidance on its execution; however, international divergence left many questions unanswered. These differences in the literature caused EAACI to initiate a task force to answer unmet needs and find a consensus in executing nasal allergen challenge. On the basis of a systematic review containing nasal allergen challenges of the past years, task force members reviewed evidence, discussed open issues, and studied variations of several subjective and objective assessment parameters to propose a standardized way of a nasal allergen challenge procedure in clinical practice. Besides an update on indications, contraindications, and preparations for the test procedure, main recommendations are a bilaterally challenge with standardized allergens, with a spray device offering 0.1 mL per nostril. A systematic catalogue for positivity criteria is given for the variety of established subjective and objective assessment methods as well as a schedule for the challenge procedure. The task force recommends a unified protocol for NAC for daily clinical practice, aiming at eliminating the previous difficulty of comparing NAC results due to unmet needs.

[Seasonal allergic conjunctivitis]. / Saisonale allergische Konjunktivitis.

Seasonal allergic conjunctivitis (SAC) is a frequent disease, which is often associated with allergic rhinitis and subsequently manifested as allergic rhinoconjunctivitis. In contrast to other types of chronic allergic conjunctivitis, the course of SAC is not sight-threatening. Pathogenetically, the underlying cause of SAC is an immunoglobulin E (IgE) mediated, Th2-driven type 1 hypersensitivity reaction. Clinically it presents with itching, light-red conjunctival injection as well as chemosis that exceeds the extent of conjunctival injection. The goals of treatment are relief of acute signs and symptoms, control of the underlying inflammatory process and utilization of preventive options. Dually effective local therapeutics combine the advantages of rapid action with a relatively long-lasting effect by a two-fold active approach. Specific immunotherapy is useful in selected patients.

[Seasonal and Perennial Allergic Rhinoconjunctivitis]. / Die saisonale und perenniale allergische Rhinokonjunktivitis.

Seasonsal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90% of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivitity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection,watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly.

Optimized human CYP4B1 in combination with the alkylator prodrug 4-ipomeanol serves as a novel suicide gene system for adoptive T-cell therapies.

Engineering autologous or allogeneic T cells to express a suicide gene can control potential toxicity in adoptive T-cell therapies. We recently reported the development of a novel human suicide gene system that is based on an orphan human cytochrome P450 enzyme, CYP4B1, and the naturally occurring alkylator prodrug 4-ipomeanol. The goal of this study was to systematically develop a clinically applicable self-inactivating lentiviral vector for efficient co-expression of CYP4B1 as an ER-located protein with two distinct types of cell surface proteins, either MACS selection genes for donor lymphocyte infusions after allogeneic stem cell transplantation or chimeric antigen receptors for retargeting primary T cells. The U3 region of the myeloproliferative sarcoma virus in combination with the T2A site was found to drive high-level expression of our CYP4B1 mutant with truncated CD34 or CD271 as MACS suitable selection markers. This lentiviral vector backbone was also well suited for co-expression of CYP4B1 with a codon-optimized CD19 chimeric antigen receptor (CAR) construct. Finally, 4-ipomeanol efficiently induced apoptosis in primary T cells that co-express mutant CYP4B1 and the divergently located MACS selection and CAR genes. In conclusion, we here developed a clinically suited lentiviral vector that supports high-level co-expression of cell surface proteins with a potent novel human suicide gene.

An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

BACKGROUND: The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. METHODS: In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. RESULTS: Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". CONCLUSIONS: The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

[Seasonal and perennial allergic rhinoconjunctivitis]. / Die saisonale und perenniale allergische Rhinokonjunktivitis.

Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90 % of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection, watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly.