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.

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.

[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.

Bradykinin Receptor B1 and C-Reactive Protein as Prognostic Factors for Pharyngocutaneous Fistula Development After Laryngectomy.

Pharyngocutaneous fistulae (PCF) are one of the most common complications after laryngectomy. Predisposing risk factors have been studied, yet knowledge to determine which patients are prone to developing a fistula remains scarce. This study aims to establish prognostic parameters to identify individual patients at risk for PCF development. As PCF and inflammation seem to be interwoven, this work focuses on markers able to detect an inflammatory response. We retrospectively analyzed all patients who had undergone a laryngectomy at our clinic in the years 2007 to 2017 (n = 182). Immunohistochemical expression of bradykinin type 1 and 2 receptor and vascular endothelial growth factor receptor 2 was studied in all available tumor samples. Additionally, the clinical inflammation parameters 'body temperature', 'pain', 'c-reactive protein (CRP)', and 'leucocytes' were postoperatively tracked in all patients. The times between fistula diagnosis, therapeutic approach, and hospital discharge were recorded. We found a strong correlation between inflammation and the formation of a fistula. High bradykinin 1 receptor expression in the tumor samples correlated with postoperative PCF development. Persistently elevated CRP and leukocyte levels beyond the 6th postoperative day were also risk factors. A decreased time lapse between PCF diagnosis and surgical revision clearly correlated with a shorter hospital stay. In this study, we identified a bradykinin 1 receptor positive patient group at high risk for development of PCF. We recommend close monitoring for fistula formation in these patients to ensure timely intervention.

[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.

Quality of Voice and Prognostic Markers for the Recovery of Vocal Fold Paralysis After Thyroid Surgery.

OBJECTIVES: This study is set to analyze clinicopathological factors predicting the recovery of unilateral vocal fold paralysis (UVP) in patients after thyroid gland surgery. The quality of voice was additionally assessed in these patients. METHODS: The charts and videolaryngostroboscopy (VLS) examinations of 84 consecutive patients with a complete UVP after surgery of the thyroid gland were retrospectively reviewed. Patients were divided into 2 groups: patients who fully recovered from vocal fold paralysis and those who failed to recover after a follow-up of 12 months. The quality of voice was analyzed among other things by determining the Voice Handicap Index (VHI). RESULTS: The UVP fully recovered in 52 of 84 (61.9%) patients. Positive mucosal waves (pMWs) on the paralyzed side, a minimal glottic gap <3 mm seen at the first postoperative VLS, age ≤50 years, and surgery duration ≤120 minutes were associated factors for a complete recovery of nerve function. The voice parameters improved independently from recovery of the paralysis in 90% of the patients. CONCLUSIONS: For patients with a poor prognosis of a UVP, early intervention may be beneficial. Thus, predicting factors for a full recovery of vocal fold motion would be a valuable tool. In our cohort, about 60% of recoveries could have been predicted using the above-mentioned parameters. Good quality of voice was independently reached in 90% of the cases.

[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.

[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.

The Aurora-Kinase A Phe31-Ile polymorphism as possible predictor of response to treatment in head and neck squamous cell carcinoma.

Recently the Aurora-Kinases (Aurk) moved into the focus as novel disease related biomarkers and therapeutic targets. Elevated Aurora-Kinase expression has been found in a number of malignancies, amongst them HNSCC. For esophageal cancer, the AurkA Phe31-Ile polymorphism has previously been associated with tumor progression. Here we evaluated the treatment efficiency of HNSCC cell radiation as a function of Aurora-Kinases in HNSCC cell lines. Moreover, we investigated a potential sensitization to radiation by a cell treatment with the inhibitors Alisertib, Barasertib, Docetaxel and VX-680. In parallel the radiation dependent expression and regulation of AurkA/B, p-Akt Ser 473 and Survivin and the AurkA polymorphism were investigated in primary tumor samples. We identified a high-risk collective with elevated AurkA and Survivin or AurkA and p-Akt Ser 473 expression. High AurkA, AurkB, and p-Akt Ser 473 expression was exclusively found in the heterozygous cell line. We found a polymorphism dependent sensitivity to treatments with different Aurk inhibitors: The homozygous cell line UD-SCC-5 could be sensitized to radiation with Docetaxel in combination with any of the Aurora-Kinase inhibitors. In contrast, treatment with Docetaxel or radiation did not enhance the inhibitory effect of Barasertib or VX-680 in the heterozygous SAS cell line. These findings indicate that the Aurora-Kinase A Phe31-Ile-polymorphism is a possibly predictive factor for response to radiation in combination with Docetaxel and Aurora-Kinase inhibitor treatments.

[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.

Epidermal growth factor receptor variant III in head and neck squamous cell carcinoma is not relevant for targeted therapy and irradiation.

BACKGROUND: The epidermal growth factor receptor (EGFR) is an important regulator of cell growth and survival, and is highly variable in tumor cells. The most prevalent variation of the EGFR extracellular domain is the EGFR variant III (EGFRvIII). Some studies imply that EGFRvIII may be responsible for the poor response to the monoclonal EGFR-antibody Cetuximab, used therapeutically in head and neck squamous cell carcinoma (HNSCC). Due to inconsistent data in the literature regarding EGFRvIII prevalence and clinical relevance in HNSCC, especially its predictive value, we examined EGFRvIII-transfected cell lines and patient tissue samples. RESULTS: In contrast to other recent publications, we were able to demonstrate EGFRvIII expression in HNSCC. However, we noted that the different detection methods yielded inconsistent results. Furthermore, our EGFRvIII transfected and EGFR wild type cell lines exhibited similar characteristics and response rates in the performed in vitro experiments. MATERIALS AND METHODS: We conducted various inhibition and combined irradiation experiments using three EGFRvIII-transfected cell lines. Moreover, a patient cohort of 149 cases consisting of formalin fixed and paraffin embedded (FFPE) and fresh-frozen specimens was assayed via reverse transcriptase PCR (rtPCR) with gel electrophoresis and sequencing for EGFRvIII prevalence. In the rtPCR assays, we used five previously published EGFRvIII primers and EGFRvIII-positive glioblastoma tissue as a positive control. In addition, immunohistochemical staining was conducted. CONCLUSIONS: EGFRvIII can be detected in HNSCC patient samples. Nevertheless, the low prevalence and similar response rates to targeted drugs and irradiation in vitro cast doubt regarding the clinical relevance of EGFRvIII in HNSCC.

HNSCC cells resistant to EGFR pathway inhibitors are hypermutated and sensitive to DNA damaging substances.

Despite remarkable successes with targeted therapies in the treatment of cancer, resistance can occur which limits the clinical outcome. In this study, we generated and characterized resistant cell clones derived from two different head and neck squamous cell carcinoma (HNSCC) cell lines (Cal27, UD-SCC-5) by long-term exposure to five targeted- and chemotherapeutics (afatinib, MK2206, BEZ235, olaparib and cisplatin). The resistant tumor cell clones showed an increased ERK1/2 expression and an altered expression of the stem-cell markers CD44, ALDH1, Oct4, Sox2, Nanog and Bmi1. None of the single markers alone was predictive for resistance to all five targeted- and chemotherapeutics. Furthermore, long-term exposure of tumor cells to these five drugs resulted in an eightfold increase in the mutational rate compared to untreated cells. Interestingly, targeted- and chemotherapy resistant cell clones remained sensitive to irradiation. Lastly, clones that were resistant to afatinib, MK2206 or BEZ235 showed cross-resistance to further treatment with therapeutics that affect the same signaling pathway, but remained sensitive to those affecting different pathways such as cisplatin and olaparib. In contrast, cell clones which were once resistant to cisplatin or olaparib were found to be multidrug-resistant. These data might indicate that patients with HNSCC benefit more by a first line targeted therapy followed by cisplatin as a second line therapy.

HES1 mRNA expression is associated with survival in sinonasal squamous cell carcinoma.

OBJECTIVE: In squamous cell carcinoma of the pharynx and larynx, NOTCH1 downstream signaling has been shown to be activated. The NOTCH1 signaling pathway has not been examined in detail for sinonasal squamous cell carcinomas (SNSCCs). The aim of this study was to evaluate NOTCH1 signaling by mRNA expression analysis and to examine the occurrence of NOTCH1 mutations in SNSCC. STUDY DESIGN: In a retrospective study, we analyzed tissues from 44 SNSCCs and 56 head and neck squamous cell carcinomas (HNSCCs) at other locations. Expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 mRNA were measured by using quantitative real-time polymerase chain reaction (q-rtPCR). In SNSCC, NOTCH1 mutations were evaluated with sequencing of seven selected exons. RESULTS: Expression of NOTCH1, HEY1, and JAG1 at the mRNA level were significantly higher in tumor tissue compared with normal tissue. In SNSCC, the subgroup of patients with high expression (5th quintile) of HES1 mRNA was associated with better survival (P = .04); however these patients with high expression of HES1 mRNA had also a more favorable tumor stage and grade and more unfavorable resections representing potential confounders. CONCLUSIONS: Key components of NOTCH1 are upregulated at the mRNA level in HNSCCs. The mechanism, clinical significance, and potential therapeutic options should therefore be further evaluated.

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.