[Therapeutic success of proton pump inhibitors in the therapy of contact granulomas]. / Therapieerfolg von Protonenpumpeninhibitoren bei der Therapie von Kontaktgranulomen.

According to the current S2k guideline "Gastroesophageal Reflux Disease (GERD)" of 05/2014, an empirical proton pump inhibitor (PPI) therapy in double standard dose (e. g. Pantoprazole 40 mg 2 ×/day) is recommended for the extraesophageal GERD manifestation (e. g. with formation of a contact granuloma, CG) for 8 weeks. However, valid study data don't exist.In a prospective study from 05.2015 to 12.2019 39 patients consecutively randomized with endoscopically proven KG received PPIs in single (1 × PPI, n = 22) or double standard dose (2 × PPI, n = 17) for 8 weeks. A possible gastrolaryngeal reflux as well as throat sensations, a tendency to clear the throat or a hoarseness were recorded at first presentation and at control after 4 months.This was archieved by videolaryngostroboscopy to detect hoarseness and to assess the development of the granuloma (progression, constant, remission < 50 %, > 50 % or complete). The two groups were compared.The granuloma disappeared or regressed in 40 % of the cases with 1 × PPIs and in 77 % of the cases with 2 × PPIs (p < 0.05) after therapy. At the control appointment 23 % of the patients with 1 × PPIs were completely symptom-free and 77 % of the patients with 2 × PPIs. Throat sensation was the most frequent symptom at first presentation with 64 %. In the control group after PPI therapy in single or double standard dose, throat sensations were only detectable in 33 % and 15 % in case of granuloma remission. However, if the granuloma was persistent, the symptoms could hardly be influenced.The therapy of a KG with PPIs in double standard dose is more effective than in single standard dose. These results must be confirmed on a larger collective.

Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate.

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene.

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13 × 10(-14) for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32-1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.

[Evaluation of treatment modalities for contact granulomas]. / Evaluation des Therapieerfolges bei Kontaktgranulomen.

INTRODUCTION: There are merely heterogenous therapy modalities for contact granulomas (CG) without evidenced efficacy. The intention of our study was to evaluate possible risk factors as well as to demonstrate therapeutic successful approaches. METHODS: Based on a retrospective analysis on 79 patients with CG we evaluated personal data for the first patient contact, for the first follow-up appointment (FA) averaged 3-4 months after the first contact, for the second follow-up appointment (SA) averaged 6-8 months after the first contact and for the last follow-up (LA) averaged 13 months after the first contact with collecting information concerning a possible gastrolaryngeal reflux disease as well as symptoms like harrumphing, hoarseness, hyperfunctional dysphonia as well as videostroboscopic signs. The therapeutic methods were prohibition of harrumphing, speech therapy, antazida therapy, surgical resection or a combination of therapy modalities. The group of FA and SA were divided into groups of complete remission group and incomplete remission group, symptoms and stroboscopic signs were statistically compared. RESULTS: Harrumphing was an important cofactor in developing a CG. Although we couldn't verify a superior therapy modality a complete remission was archieved in 2/3rd of the reviewed cases. Even if there was an incomplete remission of the contact granuloma we were able to show a reduction of symptoms. Surgical resections of CG showed a significantly higher recurrence rate. DISCUSSION: Even if we couldn't confirm a superior therapy modality we recommend a symptomatic therapy of CG with overall good remission rates. Primary surgical interventions are not advised owing to high recurrence rates.

[Subglottic pathologies]. / Subglottische Pathologien.

Subglottic pathologies are rare and show a clinical unspecific appearance i. e. through tissue increase around the cricoid or the cranial trachea. Typical symptoms are hoarseness, an overstimulated coughing, a globus laryngeus feeling as well as dyspnea or a stridor. Differential diagnosis include benign diseases like involving a posttraumatic status (e. g. stenosis), infection (i. e. pseudocroup), rheumatic disease (i. e. granulomatosis with polyangiitis) or benign tumor (i. e. papilloma, hemangioma or granular cell tumor). On the other hand, malignant diseases like the squamous cell carcinoma, a chondrosarcoma or the very rare laryngeal lymphoma manifestation must be considered as well. Idiopathic causes should also be taken into account. To secure the final diagnosis of such tumor formation a tissue sample should be histologically analyzed. The therapy is multimodal e. g. in close collaboration with internal medicine and ENT specialists.

[Laryngopharyngeal Reflux]. / Laryngopharyngealer Reflux.

The prevalence of laryngopharyngeal reflux (LPR) is around 31 % in the general population. Patients with a dysphonia or other laryngeal diseases are accompanied up to 50 % by an LPR. Typical reflux associated diseases of the larynx are a chronical laryngitis and a contact granuloma. The role of LPR is still not clarified in the development of a glottic carcinoma. There still doesn't exist evidence based data for the diagnosis of a LPR. Therefore LPR is usually clinically diagnosed by a combination of typical symptoms like hoarseness, chronic coughing, relapsing throat clearing, globus pharyngis and dysphagia as well as through the laryngoscopic characteristics like mucosal erythema, mucosal hyperplasia with plication of the interarytenoid region and an edema of the vocal cords. Occasionally the LPR can be ensured with the additional method of the pharyngeal 24-hour pH-monitoring. The therapy of the LPR is a multimodal for example dietary arrangements, medication with proton pump inhibitors and where indicated a surgical intervention. The treatment of a symptomatic patient is administered by proton pump inhibitors in a close dialog with the ENT practitioner and the gastroenterologist.

[Phonomicrosurgery - a retrospective analysis of 400 cases]. / Phonochirurgie ­ eine retrospektive Analyse von 400 Eingriffen.

Introduction Voice disorders caused by pseudotumors of the vocal folds or paralysis of the vocal folds with incomplete glottis closure frequently require phonomicrosurgery. These interventions were analyzed with regard to quality of voice after surgery and safety of the intervention. Methods Retrospective analysis of 400 consecutive phonomicrosurgery interventions. The following parameters were collected: distribution of pathologies of the vocal folds, rating of the voice quality by both the surgeon (RBH-system) and patient and videolaryngstroboscopy six weeks after the intervention compared to the state prior to surgery, complications and results of histological examination. Results In our collective vocal fold polyps (36 %), cysts (12 %) and paralysis (10 %) dominated. After the intervention the quality of voice improved in 90 % of all cases. In 14 % voice therapy was needed postoperatively because of hyperfunction.After vocal fold augmentation one patient developed an edema of the larynx and another patient a temporary paralysis of the vocal fold of the opposite side. The histological examination showed as incidental findings a malignant osteoclastic giant cell tumor, a granular cell tumor and a carcinoma in situ of the vocal fold requiring further surgery and follow up. Discussion Phonomicrosurgery is a safe and effective therapy. The histological examination is also useful in patients with macroscopically non suspicious lesions to recognize rare or malignant tumor entities. Patient observation with early detection as well as therapy of complications like edema of the larynx or vocal fold paralysis is recommended.

Do orofacial clefts represent different genetic entities?

OBJECTIVE: To contribute to the understanding of potential genetic differences between different cleft types. METHOD: Analysis of family history concerning cleft type and search for cleft-type-specific associations in candidate genes performed in 98 individuals from 98 families. RESULTS: In a given family, the cleft type of a second case was more often identical to the index case than expected by chance. Each type of cleft (cleft lip [CL], cleft lip and palate [CLP], cleft palate only [CP], and submucous cleft palate only [SMCP]) was associated with different genes. CONCLUSION: Family history indicates some specificity of cleft types. The observed phenotype-genotype associations were compatible with this interpretation in that significant associations occurred with disjoint sets of genes in each cleft type. These observations indicate that CL, CLP, CP, and SMCP might represent genetically different entities.

The Relation Between Endoscopic and Subjective Laryngopharyngeal Reflux Signs, Vocal Tract Discomfort, Voice Handicap, and Voice Disorder Type: Same Yet Different?

OBJECTIVES: This study aimed to investigate the relation between subjective voice-related symptoms and endoscopic findings in patients with different etiology of voice disorder and vocally healthy subjects with and without laryngopharyngeal reflux (LPR). STUDY DESIGN: Retrospective cross-sectional study. METHODS: The study involved 149 participants (106 female, 43 male) including 125 with various voice disorders (functional, structural, and neurogenic) and 24 vocally healthy individuals. For self-rating the German versions of the Voice Handicap Index (VHI), Vocal Tract Discomfort (VTD) Scale, and Reflux Symptom Index (RSI) were applied, while endoscopic evaluations utilized the Reflux Finding Score (RFS) and Reflux Sign Assessment (RSA). Statistical analyses incorporated ANOVA with Bonferroni posthoc tests to identify group variations. Correlations between VTD Scale, VHI, RSI, RFS, and RSA were evaluated using Pearson's correlation coefficient. To examine test sensitivity and specificity for the VTD Scale and RSA, we performed a receiver operating characteristics analysis. Youden's-Index was applied to determine the cut-off-value with best discriminatory abilities. The diagnosis of LPR was assumed when the criteria of RFS > 7 AND RSI > 13 was met. RESULTS: Significant differences for all voice diagnosis groups and vocally healthy individuals for RFS and all three self-rating questionnaires were found. Moreover, there was significant correlation between VTD Scale and VHI and RSI as well as RSI and RFS, which was moderate, negative in the group of persons with LPR. However, there was no significant difference for RSA results between the vocally healthy or any diagnosis group. CONCLUSION: Thus, the RFS may be more suitable to predict reflux and voice-related symptoms. The VTD Scale is a useful instrument in screening voice disorders but also LPR and can therefore be used as a tool for decision-making when transferring to a specialist.

Genetic and environmental risk factors for submucous cleft palate.

A multifactorial aetiology with genetic and environmental factors is assumed for orofacial clefts. Submucous cleft palate (SMCP), a subgroup of cleft palates with insufficient median fusion of the muscles of the soft palate hidden under the mucosa, has a prevalence of 1:1,250-1:5,000. We described the prevalence of risk factors among 103 German patients with the subtype SMCP and genotyped 24 single nucleotide polymorphisms (SNPs) from 12 candidate genes for orofacial clefts. Analysis of risk factors yielded a positive history for maternal cigarette smoking during pregnancy in 25.2% of the patients, and this was significantly more frequent than in the normal population. The group of patients differed in allele frequencies at SNP rs3917192 of the gene TGFB3 (nominal P = 0.053) and at SNP rs5752638 of the gene MN1 (nominal P = 0.075) compared with 279 control individuals. Our results indicate a potential role of maternal smoking during pregnancy for the formation of SMCP. The analysis of genetic variants hints at the contribution of TGFB3 and MN1 in the aetiology of SMCPs.

The Efficiency of (videolaryngo) stroboscopy in Detecting T1a Glottic Carcinoma and Its Preliminary Stages.

OBJECTIVE: The efficiency of laryngovideostroboscopy (LVS) in detecting premalignancies of the vocal fold and early glottic cancer was determined in a prospective monocentric study. In addition, the recovery rate of the mucosal membrane on the vocal fold after surgical intervention was determined by LVS. METHODS: We included 159 patients with a leukoplakia of the vocal folds and 50 healthy controls. Clinicopathological data and LVS characteristics (amplitude, mucosal wave, nonvibratory segment, glottic closure, phase symmetry, periodicity) at the lesion site were obtained and compared with the histopathological results. LVS parameters were recorded before cordectomy and in a 12-month follow-up interval. Patients who had prior laryngosurgery, radiotherapy, or laryngeal scarring were excluded. RESULTS: Absent or greatly reduced mucosal waves were found in all patients with an invasive carcinoma, in 94% with a severe intraepithelial neoplasia (SIN III), in 38% with a moderate squamous intraepithelial neoplasia (SIN II), in 32% with a mild squamous intraepithelial neoplasia (SIN I), and in 23% with a hyperkeratosis without dysplasia. The sensitivity and specificity of LVS in predicting an invasive carcinoma based on the absence or reduction of mucosal waves was 0.96 and 0.90, respectively. Following surgical intervention, the recovery rate of the mucosal wave and amplitude was 12% in the invasive carcinoma group, 36% in the SIN III group and up to 80% for both these parameters in the SIN I, SIN II, and hyperkeratosis groups. CONCLUSION: LVS is a valid tool to identify early glottic carcinoma and its high risk premalignancy carcinoma in situ (CIS). Even when there is no definitive differentiation between SIN I and II, the invasive character of a CIS and an invasive glottic carcinoma can be identified. Especially strobosopic signs of abnormal amplitude and/or mucosal waves, particularly phoniatric halt, are an early indication for a CIS or an invasive carcinoma.

Inhibition of radiation induced migration of human head and neck squamous cell carcinoma cells by blocking of EGF receptor pathways.

BACKGROUND: Recently it has been shown that radiation induces migration of glioma cells and facilitates a further spread of tumor cells locally and systemically. The aim of this study was to evaluate whether radiotherapy induces migration in head and neck squamous cell carcinoma (HNSCC). A further aim was to investigate the effects of blocking the epidermal growth factor receptor (EGFR) and its downstream pathways (Raf/MEK/ERK, PI3K/Akt) on tumor cell migration in vitro. METHODS: Migration of tumor cells was assessed via a wound healing assay and proliferation by a MTT colorimeritric assay using 3 HNSCC cell lines (BHY, CAL-27, HN). The cells were treated with increasing doses of irradiation (2 Gy, 5 Gy, 8 Gy) in the presence or absence of EGF, EGFR-antagonist (AG1478) or inhibitors of the downstream pathways PI3K (LY294002), mTOR (rapamycin) and MEK1 (PD98059). Biochemical activation of EGFR and the downstream markers Akt and ERK were examined by Western blot analysis. RESULTS: In absence of stimulation or inhibition, increasing doses of irradiation induced a dose-dependent enhancement of migrating cells (p < 0.05 for the 3 HNSCC cell lines) and a decrease of cell proliferation (p < 0.05 for the 3 HNSCC cell lines). The inhibition of EGFR or the downstream pathways reduced cell migration significantly (almost all p < 0.05 for the 3 HNSCC cell lines). Stimulation of HNSCC cells with EGF caused a significant increase in migration (p < 0.05 for the 3 HNSCC cell lines). After irradiation alone a pronounced activation of EGFR was observed by Western blot analysis. CONCLUSION: Our results demonstrate that the EGFR is involved in radiation induced migration of HNSCC cells. Therefore EGFR or the downstream pathways might be a target for the treatment of HNSCC to improve the efficacy of radiotherapy.

Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR(2A) and 5-HTR(2B) receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/B) antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor ß(1)- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR(2A) specifically in IPF. Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.