[Does aspirin therapy after desensitization still have a role in treatment of chronic rhinosinusitis with nasal polyposis in the era of biologics?] / Hat die ASS-Desaktivierung in Zeiten von Biologika noch einen Stellenwert bei chronischer Rhinosinusitis mit nasaler Polyposis?

The prevalence of analgesic intolerance syndrome (AIS), internationally known as NSAID-exacerbated respiratory disease (NERD), is reported to be 0.5-5.7% in the general population. The disease often begins with nasal symptoms, which are later joined by chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and respiratory hypersensitivity reactions following use of nonsteroidal anti-inflammatory drugs (NSAIDs). In the setting of chronic respiratory disease, the type 2 inflammatory endotype is predominant in approximately 80% of patients with CRSwNP, rendering biologics directed against interleukin (IL)-4, IL­5, IL-13, and IgE of high clinical interest, particularly in patients with severe CRSwNP and NERD. NERD is often associated with CRSwNP and asthma. Patients with CRSwNP and NERD have been treated, among other therapies, with aspirin therapy after desensitization (ATAD). With the approval of monoclonal antibodies for CRSwNP and asthma, the question arises as to what extent ATAD, which is associated with undesirable side effects, is still useful in the treatment of CRSwNP. In this manuscript, the use of ATAD in CRSwNP patients is discussed from different medical and socioeconomic points of view, both alternatively to or in combination with monoclonal antibodies. Accordingly, both ATAD and biologics continue to play a supporting role in modern treatment of CRSwNP in NERD patients, and should be used judiciously to complement each other.

[Neuroimmunology of allergic rhinitis part 2 : Interactions of neurons and immune cells and neuroimmunological units]. / Neuroimmunologie der allergischen Rhinitis Teil 2 : Interaktionen von Neuronen und Immunzellen und neuroimmunologische Einheiten.

Allergic rhinitis is an IgE-mediated, type­2 inflammatory disease. neuropeptides are released by neurons and interact with immune cells. Via colocalization, neuroimmune cell units such as nerve-mast cell units, nerve-type 2 innate lymphoid cell (ILC2) units, nerve-eosinophil units, and nerve-basophil units are formed. Markedly elevated tryptase levels were found in nasal lavage fluid and were strongly associated with neuropeptide levels. A close anatomical connection allows bidirectional communication between immune and neuronal cells. Transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin repeat 1 (TRPA1) are critically involved in immunological reactions in the setting of allergic rhinitis. Neuroimmunological communication plays an important role in the inflammatory process, so that allergic rhinitis can no longer be considered a purely immunological disease, but rather a combined neuroimmunological disease.

[Neuroimmunology of allergic rhinitis : Part 1: Cellular and humoral basic principles]. / Neuroimmunologie der allergischen Rhinitis : Teil 1: Zelluläre und humorale Grundlagen.

Allergic rhinitis (AR) is a very common disease with a high prevalence worldwide. It is an IgE-mediated type 2 inflammatory disease following exposure to inhalant allergens. A multitude of different neuropeptides including substance P, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), and neuromedin U (NMU) can be released via peripheral axon or central reflexes, interact with immune cells, and thus contribute to neurogenic inflammation which causes the nasal hyperreactivity (NHR) characteristic of AR. Independent production of neuroendocrine hormones and neuropeptides by immune cells has also been demonstrated. Neuro-immune cell units arise when immune and neuronal cells colocalize, for which typical anatomic regions are, e.g., the mast cell-nerve functional unit. The focus of this review is the elucidation of neuroimmune communication mechanisms in AR.

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.

Positionspapier: Empfehlungen zur Anwendung von Mepolizumab bei chronischer Rhinosinusitis mit Polyposis nasi (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 Hals-Chirurgie (DGHNO-KHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the paranasal sinus mucosa with eosinophilic inflammation as the most common endotype. The anti-IL5 antibody mepolizumab was approved for the treatment of severe CRSwNP in the EU in November 2021. METHODS: A literature search was performed to analyze the immunology of CRSwNP and determine the available evidence by searching Medline, Pubmed, and the German national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 12/2021 that investigated the effect of mepolizumab in CRSwNP were considered. RESULTS: Based on the international literature and previous experience, recommendations for the use of mepolizumab in CRSwNP in the German health care system are given by an expert panel on the basis of a documentation form. CONCLUSIONS: Understanding about the immunological basis of CRSwNP opens new non-surgical therapeutic approaches with biologics for patients with severe courses. Mepolizumab is approved since November 2021 for add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP who cannot be adequately controlled with systemic corticosteroids 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.

COVID-19 and chronic rhinosinusitis: management and comorbidity - what have we learned?

INTRODUCTION: Approximately 5%-12% of the population worldwide suffer from chronic rhinosinusitis (CRS). CRS is defined as a chronic respiratory disease and is considered to be a risk factor for COVID-19 patients. AREAS COVERED: A non-systematic literature research was conducted on COVID-19 and treatment options for CRSwNP. The latest international publications in medical databases, international guidelines, and the internet were reviewed. Since there were no publications on all aspects of this topic during the pandemic, we included our own experience in this report. Based on the conducted literature research in addition to our previously reported experience, we discuss the treatment of CRSwNP during the COVID-19 pandemic and what can be taken for future pandemics. EXPERT OPINION: Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Indications for surgical treatment of CRS should be critically evaluated and reserved for patients with complications and those with no other treatment options. For this purpose, COVID-19 status should be known if possible and, in case of unclear status (emergency), using appropriate personal protective equipment. Systemic corticosteroids should be avoided were possible. Biological treatment should be continued under careful monitoring in uninfected patients and should be temporarily interrupted during COVID-19 infection.

Early detection of Knudson's two-hits in preneoplastic renal cells of the Eker rat model by the laser microdissection procedure.

Hereditary renal cell carcinomas invariably develop by the age of 1 year in Eker rats. At the histological level, renal cell carcinomas develop through multiple stages from early preneoplastic lesions (e.g., phenotypically altered tubules) to adenomas. We previously reported that ionizing radiation induces additional tumors (large adenomas and carcinomas) in a linear dose-response relationship and that loss of heterozygosity (LOH) at chromosome 10, where the predisposing tuberous sclerosis (Tsc2) gene is localized, was found in the renal cell carcinomas which developed from hybrid F1 rats carrying the Eker mutation, indicating that in heterozygotes two events (one inherited, one somatic) are necessary to produce at least large adenomas and carcinomas. This study was designed to examine LOH in the earliest preneoplastic lesions, using a laser microdissection procedure. We could accurately dissect single altered renal tubules out of freeze-dried sections and clearly detected LOH in 4 of 19 altered tubules (21%). This is the first demonstration of LOH in single renal tubules. Our present results support the theory of a second, somatic mutation (second hit) as rate-limiting step of renal carcinogenesis in the Eker rat model of dominantly inherited cancer and the tumor suppressor nature of the Tsc2 gene function.

p53 codon 72 polymorphism and various human papillomavirus 16 E6 genotypes are risk factors for cervical cancer development.

Risk factors other than human papillomavirus (HPV) infection per se for cervical cancer development have been investigated recently. It was suggested that HPV 16 E6 variants and the p53 codon 72 arginine polymorphism could be progression markers. Indeed, it has been demonstrated that specific E6 variants and p53 arginine were both enriched in cancer. However, especially with regard to the latter, divergent results have been reported. Our aim was thus to investigate whether p53 arginine is important for cervical carcinogenesis by scaling up samples of the two European cohorts, the initial results of which were reported previously. In addition, we have assessed the occurrence of p53 codon 72 arginine, in combination with specific HPV 16 E6 genotypes. We found p53 arginine to be increased in cancer of both cohorts, consistent with our previous concept. Although specific E6 genotypes increased gradually with the severity of the lesion, p53 arginine was enriched in cancer only. Moreover, the frequency of the arginine allele was similar in groups with different E6 genotypes. It is concluded that p53 arginine is a risk factor for cervical cancer but probably acts independently of E6 variants.

Studies of cellular differentiation by automated cell separation. Two model systems: Friend virus-transformed cells and Hydra attenuata.

The automated high-speed analysis and separation of cells on the basis of spectroscopic parameters has been applied to studies of cellular differentiation in two systems. The temporal changes following induction of differentiation by dimethylsulfoxide in the Friend virus-transformed erythroid cells were quantitated by multiparameter analysis leading to the separation of discrete subpopulations. Thus, following induction, cell size decreased as measured by light scattering, the number of H-2 histocompatibility antigen sites decreased as measured by indirect fluorescent antibody binding, the number of lectin-binding sites per cell increased as measured by fluorescein-labeled concanavalin-A and the microviscosity of the hydrocarbon region of the plasma membrane increased as determined by the fluorescence emission anisotropy of the membrane probe 1,6-diphenyl-1,3,5-hexatriene. Cells were separated on the basis of several of these parameters and analyzed for their hemogloglobin content by benzidine staining. Examination of cells separated according to the anisotropy parameter showed that high anisotropy values were correlated with (a) small cell size, (b) positive staining with benzidine and (c) pronounced reactivity with fluorescent antibody to the erythrocyte protein spectrin. Disaggregated cells from Hydra attenuata were selectively stained with the dyes rhodanile blue, 7-(p-methoxybenzylamino)-4-nitrobenz-2-oxa-1,3-diazole and fluorescamine. Distribution analyses and preliminary separations indicated the feasibility of obtaining homogeneous classes of cell types in a viable state. The experiments with emission anisotropy represent the first analyses and separations of single cells on the basis of fluorescence polarization. Many other uses of this technique are anticipated.

Insulin receptor substrate-1 is over-expressed in glycogenotic but not in amphophilic preneoplastic hepatic foci induced in rats by N-nitrosomorpholine and dehydroepiandrosterone.

Insulin receptor substrate-1 (IRS-1) is over-expressed in preneoplastic glycogenotic hepatic foci (GSF) and is gradually down-regulated during progression of these lesions, via mixed cell foci (MCF), to the basophilic neoplastic phenotype. The aim of the present study was to investigate the effect of dehydroepiandrosterone (DHEA), a weak hepatocarcinogen and tumour enhancer, on IRS-1 expression. Hepatocellular lesions were induced by N-nitrosomorpholine followed by DHEA. Under these conditions, many glycogen-poor amphophilic (APF) and intermediate cell foci (ICF) appear, in addition to GSF and MCF. IRS-1 was over-expressed in 215 out of 295 GSF, in 50 out of 53 MCF and in a glycogen-rich mixed cell adenoma. IRS-1 expression was not shown in 147 APF, 51 ICF and 5 amphophilic hepatocellular adenomas, and 3 out of 5 hepatocellular carcinomas showed a weak IRS-1 expression. The results suggest a close association of IRS-1 over-expression with the glycogenotic hepatocellular phenotype. The modulation and enhancement of tumour progression by DHEA is associated with a shift from glycogenosis to amphophilia and basophilia, and a down-regulation of IRS-1 expression.

Cytochemical and biochemical studies on adenylate cyclase activity in preneoplastic and neoplastic liver tissue and cultured liver cells.

The ATP-analogue adenylyl(beta,gamma-methylene)diphosphonate was chosen as substrate for the cytochemical localization of adenylate cyclase (AC) activity. The tissues investigated covered normal rat liver and liver from carcinogen-treated animals with preneoplastic lesions and hepatocellular neoplasms, as well as cultured liver cells. The AC reaction product methylene diphosphonate was precipitated with Pb2+ immediately at the place of production. This approach permitted a precise localization of AC activity by light and electron microscopy. The specificity of the AC reaction was demonstrated by control reactions, including inhibition of AC with 2'5'-dideoxyadenosine and activation with forskolin, glucagon, and cholera toxin. Endogenous phosphatases were inhibited with tetramisole and NAD. In normal liver, AC activity was mainly localized in the sinusoidal membrane of hepatocytes. A distinct gradient in activity was observed within the liver lobule. Hepatocytes localized around the terminal hepatic venule showed a significant higher AC activity compared to hepatocytes near the portal tract. AC was clearly decreased in focal preneoplastic liver lesions of the glycogenotic-basophilic cell lineage leading to hepatocellular carcinomas. Cytochemically detected intensity of AC activity corresponded to data obtained by microbiochemical assays in laser-dissected tissue samples. A remarkable interdependence of AC activity and degree of differentiation was also seen in epithelial rat liver cell lines: Highly differentiated cells show high enzyme activity and vice versa, as shown by both cytochemical and biochemical examinations. It is concluded that alterations in cellular signal transduction caused by alterations in AC activity play an important role in hepatocarcinogenesis.

Hepatocellular glycogenosis and related pattern of enzymatic changes during hepatocarcinogenesis.

Systematic studies of the sequence of cellular changes during hepatocarcinogenesis induced predominantly in rats by stop experiments with N-nitrosomorpholine (NNM) led to the following main results and conclusions: The development of hepatocellular tumors is preceded by a multifocal hepatic glycogen storage disease (glycogenosis). Cytomorphological and cytochemical findings suggest a sequence of focal changes leading from clear and acidophilic glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas. The clear and acidophilic glycogen storage cells persisting after withdrawal of the carcinogen apparently represent a preneoplastic cell population, the neoplastic transformation of which is accompanied by a gradual reduction of glycogen and a concomitant increase in ribosomes (basophilia). The first appearance and frequency of the different liver lesions investigated was shown to depend on the dose of carcinogen administered. With increasing dose of NNM, the number of focal lesions considerably increased, and this was accompanied by an earlier development of mixed and basophilic cell populations. There was no indication of any reversibility of pronounced focal lesions under the experimental conditions chosen. On the contrary, the foci became larger and acquired phenotypic markers closer to neoplasia independent of further action of the carcinogen. Enzyme histochemically, the majority of the pronounced glycogen storage foci showed a reduction in the activities of glycogen phosphorylase and glucose-6-phosphatase while the activity of glucose-6-phosphate dehydrogenase, a key enzyme for the pentose phosphate pathway, was increased. The mixed cell foci, neoplastic nodules and carcinomas which emerged at later stages were characterized by a progressive shift away from glycogen metabolism towards glycolysis and the pentose phosphate pathway. as indicated by an increase in glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase activities. These changes in enzyme pattern are in keeping with a developmental sequence leading from glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas. Biochemical microanalysis of dissected glycogen storage foci and mixed cell foci revealed that the foci composed exclusively of storage cells contained on an average 100% more glycogen than the normal liver tissue. The overall glycogen content of the mixed cell foci, which were composed of both glycogenotic and glycogen-poor basophilic cells, was not distinguishable from that of normal tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Preliminary results in the immunization of Irus monkeys against dental caries.

Twelve Irus monkeys were divided into four groups which were immunized with placebo, two cell wall preparations and one vaccine containing a glucosyltransferase preparation of S. mutans. After 310 days of challenge by a cariogenic diet, the caries score in all the immunized animals was below that of the controls. Furthermore, the protected animals were characterized by a high specific serum titer against the antigens used for immunization and the extension of plaque seemed to be smaller when compared with the controls.

Isoenzyme shift from glucokinase to hexokinase is not an early but a late event in hepatocarcinogenesis.

The appearance of hepatocellular adenomas and carcinomas induced in rat liver with N-nitrosomorpholine is preceded by different types of preneoplastic foci consisting of phenotypically altered hepatocytes. The altered cells show changes in the activities of various enzymes including those of carbohydrate metabolism. Glucokinase is a type of hexokinase that is specific for hepatocytes. The enzyme plays a key role in glucose homeostasis in normal liver parenchyma and is replaced in the dedifferentiated hepatocytes of carcinomas by a low Km hexokinase. To determine the time course of the shift from glucokinase to this isoenzyme in the development of carcinomas, focal hepatic lesions were dissected from freeze-dried serial tissue sections by the laser-dissection method and studied by microbiochemical tests. In early clear and acidophilic cell foci that excessively stored glycogen (glycogenotic foci) a nearly normal glucokinase activity comparable with that of the surrounding hepatocytes was observed, whereas in the later appearing mixed cell foci a reduction in the activity of this enzyme without a compensatory increase in the hexokinase activity was found. A pronounced activity of hexokinase was only measurable in fully developed carcinomas. Since glucokinase is not modified at the post-transcriptional level, a gradual decrease in its mRNA during hepatocarcinogenesis can be assumed. A shift in gene expression from glucokinase to the isoenzyme hexokinase occurs only at the mixed cell foci/carcinoma transition step of the carcinogenic process.