Monitoring mepolizumab treatment in chronic rhinosinusitis with nasal polyps (CRSwNP): Discontinue, change, continue therapy?

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-IL-5 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 should be monitored, what follow-up documentation is necessary, and when it should be discontinued if necessary. MATERIALS AND 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 discontinuation of therapy when using mepolizumab for the indication CRSwNP in the German healthcare system are given on the basis of a documentation sheet. CONCLUSION: 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.

Hypermethylated SHOX2 in circulating cell-free DNA post renal cell carcinoma surgery as TNM-independent biomarker for recurrence risk.

INTRODUCTION: Adjuvant immune checkpoint inhibitor trials in renal cell carcinoma (RCC) call for improved recurrence risk stratification. Due to limitations of circulating tumor DNA (ctDNA) use in RCC, the use of hypermethylated SHOX2 gene (mSHOX2) in circulating cell-free DNA is explored as a surrogate marker for identifying high-risk patients after RCC surgery. METHODS: Liquid biopsies were collected post-surgery from 45 RCC patients (mean duration 4.3 days). Real-time polymerase chain reaction was used to analyze SHOX2 methylation in circulating cell-free DNA. Patients were categorized as mSHOX2 positive or negative by cut-off. Metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using Cox regression and Log-rank analyses (median follow-up time: 60 months). RESULTS: 17 patients were mSHOX2 positive, showing unfavorable OS/CSS (Log-rank P = 0.004 and 0.02) and nearly 6-fold higher recurrence risk (hazard ratio 5.89, 95% CI 1.46-23.8). Multivariable Cox analysis confirmed mSHOX2 as an independent recurrence risk factor, disregarding TNM-based stratification. CONCLUSIONS: mSHOX2 effectively identifies high-risk RCC patients post-surgery, indicating minimal residual disease. This easy to implement biomarker has potential for guiding of adjuvant therapy decisions.

Circulating Cell-Free SHOX2 DNA Methylation Is a Predictive, Prognostic, and Monitoring Biomarker in Adjuvant and Palliative Anti-PD-1-Treated Melanoma.

BACKGROUND: The majority of metastatic melanoma patients initially do not respond or acquire resistance to anti-programmed cell death 1 (PD-1) immunotherapy. Liquid biopsy biomarkers might provide useful early response information and allow for personalized treatment decisions. METHODS: We prospectively assessed circulating cell-free SHOX2 DNA methylation (SHOX2 ccfDNAm) levels and their dynamic changes in blood plasma of melanoma patients by quantitative methylation-specific polymerase chain reaction. Patients were treated with either palliative (n = 42) or adjuvant (n = 55) anti-PD-1 immunotherapy. Moreover, we included n = 126 control patients without evidence of malignant disease. We analyzed SHOX2 ccfDNAm status prior to and 4 weeks after palliative treatment initiation with regard to outcome [objective response, progression-free survival (PFS), and overall survival (OS)]. In the adjuvant setting, we associated longitudinal SHOX2 ccfDNAm status with disease recurrence. RESULTS: Sensitivity was 60% with 25/42 melanoma patients showing increased SHOX2 ccfDNAm levels, whereas specificity was 98% with 123/126 (P < 0.001) control patients having SHOX2 ccfDNAm levels below cut-off. Pretreatment SHOX2 ccfDNAm status did not correlate with outcome; however, SHOX2 ccfDNAm negativity 4 weeks after palliative treatment initiation was strongly associated with improved survival [PFS: hazard ratio (HR) = 0.25, P = 0.002; OS: HR = 0.12, P = 0.007]. Pretreatment positive patients who reached SHOX2 ccfDNAm clearance after 4 weeks of immunotherapy showed an exceptionally beneficial outcome. SHOX2 ccfDNAm testing allowed for an early detection of distant metastases in adjuvant-treated melanoma patients. CONCLUSIONS: Our study suggests SHOX2 ccfDNAm to be an early predictor of outcome in anti-PD-1 treated melanoma patients. SHOX2 ccfDNAm testing may aid individualized treatment decision-making.

CD52 mRNA expression predicts prognosis and response to immune checkpoint blockade in melanoma.

The immune-modulating protein CD52 attenuates lymphocyte function and is associated with autoimmune disorders, for example, multiple sclerosis (MS). CD52 represents a therapeutic target in MS and chronic lymphocytic leukemia (CLL). Its expression has prognostic and predictive value in CLL and is prognostic in breast cancer. Its significance in melanoma is unclear. We analyzed CD52 mRNA expression data from tumor bulk tissues of N = 445 untreated melanoma patients from The Cancer Genome Atlas (TCGA) Research Network and of N = 121 melanoma patients undergoing anti-PD-1 immune checkpoint blockade (ICB) with regard to outcome (overall survival [OS], disease control [DC], and progression-free survival [PFS]), single-cell RNA-Seq data of N = 4645 cells from N = 19 melanoma tissues, and N = 15,457 cells from normal skin provided by N = 5 donors. Higher CD52 mRNA expression was associated with favorable OS (hazard ratio (HR) = 0.820, [95% CI 0.734-0.916], p < .001) in non-ICB-treated melanoma and with PFS (HR = 0.875, [95% CI 0.775-0.989], p = .033) and DC (p = .005) in ICB-treated melanoma. CD52 expression correlated significantly with distinct immune cell subsets and correlated negatively with immune checkpoint expression in T cells. Moreover, our results suggest CD52 expression by a certain type of tissue-resident macrophages. CD52 mRNA was expressed in a small subgroup (8%) of immune checkpoint coexpressing melanoma cells. CD52 expression is associated with features of ICB response in melanoma. Concomitant ICB and anti-CD52 treatment requires critical review.

[Clinical Management of Choanal Atresia]. / Klinisches Management der Choanalatresie.

Choanal atresia (CA) is a rare congenital anomaly of the nasal airway with an incidence of 1/5000 to 1/9000, which may occur unilateral (uCA) or bilateral (bCA). bCA manifests as an acute emergency immediately after birth by airway obstruction and paradoxical cyanosis, whereas uCA may present with a heterogeneous clinical picture in addition to unilateral nasal airway obstruction. Fiber endoscopic examination and cranial computed tomography are the gold standard in the diagnosis of CA. CA often occurs in association with congenital malformation syndromes, among which CHARGE syndrome stands out. Due to cardiopulmonary instability and difficult intubation conditions, syndromic CA patients should be considered as a separate risk group. After securing the airway, bCA must be treated surgically without delay, whereas correction of uCA should not be performed until after six months of age. Endoscopic techniques are the surgical standard in the treatment of CA. Different approaches can be distinguished: transnasal puncture of the atresia plate with subsequent extension medially and laterally, creation of a septal window with subsequent resection of the posterior vomer and atresia plate, and elevation of mucoperiosteal flaps with subsequent opening of the atresia plate. The transpalatal approach should only be employed in anatomically complex cases. The use of conventional choanal stents in the primary treatment of CA is increasingly rejected and should be reserved for high-risk constellations. Similarly, local application of mitomycin C should be avoided.

PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma.

PD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). PD-L1 promoter methylation is an epigenetic mechanism that has been shown to regulate PD-L1 mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of PD-L1 promoter methylation status (mPD-L1) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified mPD-L1 in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising N = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-γ stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. mPD-L1 hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as PD-L1 hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, PD-L1 promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon γ. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC.

The Apoptosis Inhibitor Protein Survivin Is a Critical Cytoprotective Resistor against Silica-Based Nanotoxicity.

Exposure to nanoparticles is inevitable as they become widely used in industry, cosmetics, and foods. However, knowledge of their (patho)physiological effects on biological entry routes of the human body and their underlying molecular mechanisms is still fragmented. Here, we examined the molecular effects of amorphous silica nanoparticles (aSiNPs) on cell lines mimicking the alveolar-capillary barrier of the lung. After state-of-the-art characterization of the used aSiNPs and the cell model, we performed cell viability-based assays and a protein analysis to determine the aSiNP-induced cell toxicity and underlying signaling mechanisms. We revealed that aSiNPs induce apoptosis in a dose-, time-, and size-dependent manner. aSiNP-induced toxicity involves the inhibition of pro-survival pathways, such as PI3K/AKT and ERK signaling, correlating with reduced expression of the anti-apoptotic protein Survivin on the protein and transcriptional levels. Furthermore, induced Survivin overexpression mediated resistance against aSiNP-toxicity. Thus, we present the first experimental evidence suggesting Survivin as a critical cytoprotective resistor against silica-based nanotoxicity, which may also play a role in responses to other NPs. Although Survivin's relevance as a biomarker for nanotoxicity needs to be demonstrated in vivo, our data give general impetus to investigate the pharmacological modulation of Survivin`s functions to attenuate the harmful effects of acute or chronic inhalative NP exposure.

Circulating Cell-Free SEPT9 DNA Methylation in Blood Is a Biomarker for Minimal Residual Disease Detection in Head and Neck Squamous Cell Carcinoma Patients.

BACKGROUND: Tumorous SEPT9 (septin 9, SEPTIN9) circulating cell-free DNA (ccfDNA) methylation in blood plasma is a powerful biomarker for diagnosis, molecular staging, prognosis, and recurrence monitoring in head and neck squamous cell carcinoma (HNSCC) patients. The present study aimed to evaluate the clinical performance of SEPT9 ccfDNA methylation to detect post-surgical minimal residual disease (MRD) in patients with localized or locally advanced HNSCC treated with curative intent. METHODS: We applied quasi-digital methylation-specific real-time PCR to quantify SEPT9 ccfDNA methylation levels 2 to 30 days post-surgically in plasma from n = 219 prospectively enrolled HNSCC patients. We tested the associations of SEPT9 ccfDNA methylation with clinicopathological parameters and used Kaplan-Meier and Cox proportional hazards analyses for univariate, pairwise bivariate, and multivariate analyses of disease-free survival. RESULTS: Of 219 patients, 26.5% (58/219) were post-surgically SEPT9 ccfDNA methylation positive. SEPT9 ccfDNA methylation positivity was significantly associated with tumor site, American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC; 8th edition) tumor stage, nodal category and extracapsular extension, lymphatic and vascular invasion, and surgical margin. Bivariate Cox proportional hazards analysis proved post-surgical SEPT9 ccfDNA methylation positivity to be an independent prognostic factor tested together with AJCC/UICC tumor stage (SEPT9: hazard ratio [HR] = 2.43, 95% CI, 1.37-4.30, P = 0.002; AJCC/UICC stage: HR = 1.48, 95% CI, 1.11-1.98, P = 0.008). CONCLUSIONS: Post-surgical SEPT9 ccfDNA methylation may aid to identify high-risk HNSCC patients who could benefit from an intensified adjuvant treatment and surveillance.

Cochlear implantation impairs intracochlear microcirculation and counteracts iNOS induction in guinea pigs.

Introduction: Preservation of residual hearing remains a great challenge during cochlear implantation. Cochlear implant (CI) electrode array insertion induces changes in the microvasculature as well as nitric oxide (NO)-dependent vessel dysfunction which have been identified as possible mediators of residual hearing loss after cochlear implantation. Methods: A total of 24 guinea pigs were randomized to receive either a CI (n = 12) or a sham procedure (sham) by performing a cochleostomy without electrode array insertion (n = 12). The hearing threshold was determined using frequency-specific compound action potentials. To gain visual access to the stria vascularis, a microscopic window was created in the osseous cochlear lateral wall. Cochlear blood flow (CBF) and cochlear microvascular permeability (CMP) were evaluated immediately after treatment, as well as after 1 and 2 h, respectively. Finally, cochleae were resected for subsequent immunohistochemical analysis of the iNOS expression. Results: The sham control group showed no change in mean CBF after 1 h (104.2 ± 0.7%) and 2 h (100.8 ± 3.6%) compared to baseline. In contrast, cochlear implantation resulted in a significant continuous decrease in CBF after 1 h (78.8 ± 8.1%, p < 0.001) and 2 h (60.6 ± 11.3%, p < 0.001). Additionally, the CI group exhibited a significantly increased CMP (+44.9% compared to baseline, p < 0.0001) and a significant increase in median hearing threshold (20.4 vs. 2.5 dB SPL, p = 0.0009) compared to sham after 2 h. Intriguingly, the CI group showed significantly lower iNOS-expression levels in the organ of Corti (329.5 vs. 54.33 AU, p = 0.0003), stria vascularis (596.7 vs. 48.51 AU, p < 0.0001), interdental cells (564.0 vs. 109.1 AU, p = 0.0003) and limbus fibrocytes (119.4 vs. 18.69 AU, p = 0.0286). Conclusion: Mechanical and NO-dependent microvascular dysfunction seem to play a pivotal role in residual hearing loss after CI electrode array insertion. This may be facilitated by the implantation associated decrease in iNOS expression. Therefore, stabilization of cochlear microcirculation could be a therapeutic strategy to preserve residual hearing.

CTLA4 DNA methylation is associated with CTLA-4 expression and predicts response to immunotherapy in head and neck squamous cell carcinoma.

BACKGROUND: The majority of patients with recurrent or metastasized head and neck squamous cell carcinoma (HNSCC) do not benefit from immune checkpoint blockade (ICB) while several patients experience severe and persistent immune-mediated side effects. Therefore, predictive biomarkers are urgently needed to allow for a personalized treatment. In this study, we investigated DNA methylation of the immune checkpoint gene CTLA4 with regard to its predictive value. METHODS: We analyzed CTLA4 promoter methylation in tumors of HNSCC patients (N = 29) treated with ICB at the University Medical Center Bonn with regard to response to ICB and progression-free survival. We further analyzed a second cohort (N = 138) of patients that did not receive ICB with regard to CTLA4 promoter methylation, CTLA-4 protein expression, and immune cell infiltrates. Finally, we tested inducibility of CTLA-4 protein expression in HNSCC cells using the DNA methyltransferase inhibitor decitabine. RESULTS: Lower CTLA4 promoter methylation correlated with response to ICB and prolonged progression-free survival. We could show that not only tumor infiltrating immune cells, but also HNSCC cells harbor cytoplasmic and nuclear CTLA-4 expression. CTLA4 promoter methylation inversely correlated with infiltrates of CD3+, CD4+, CD8+, and CD45+ immune cells. CTLA4 methylation did not correlate with protein expression in tumors, however, decitabine treatment led to decreased CTLA4 methylation and an induction of CTLA4 mRNA and CTLA-4 protein expression in HNSCC cell lines. CONCLUSIONS: Our results indicate that CTLA4 DNA hypomethylation is a predictive biomarker for response to ICB in HNSCC. Our study warrants further analyses of the predictive value of CTLA4 DNA methylation in clinical trials of anti-PD-1 and/or anti-CTLA-4 immunotherapy in HNSCC.

ICOS DNA methylation regulates melanoma cell-intrinsic ICOS expression, is associated with melanoma differentiation, prognosis, and predicts response to immune checkpoint blockade.

BACKGROUND: Inducible T cell costimulator ICOS is an emerging target in immuno-oncology. The aim of this study was to investigate the epigenetic regulation of ICOS in melanoma by DNA methylation. METHODS: We comprehensively investigate ICOS DNA methylation of specific CpG sites and expression pattern within the melanoma microenvironment with regard to immune correlates, differentiation, clinical outcomes, and immune checkpoint blockade (ICB) response. RESULTS: Our study revealed a sequence-contextual CpG methylation pattern consistent with an epigenetically regulated gene. We found a cell type-specific methylation pattern and locus-specific correlations and associations of CpG methylation with ICOS mRNA expression, immune infiltration, melanoma differentiation, prognosis, and response to ICB. High ICOS mRNA expression was identified as a surrogate for enriched immune cell infiltration and was associated with favorable overall survival (OS) in non-ICB-treated patients and predicted response and a prolonged progression-free survival (PFS) following ICB therapy initiation. ICOS hypomethylation, however, significantly correlated with poor OS in non-ICB patients but predicted higher response and prolonged PFS and OS in ICB-treated patients. Moreover, we observed cytoplasmic and sporadically nuclear tumor cell-intrinsic ICOS protein expression. Tumor cell-intrinsic ICOS protein and mRNA expression was inducible by pharmacological demethylation with decitabine. CONCLUSION: Our study identified ICOS DNA methylation and mRNA expression as promising prognostic and predictive biomarkers for immunotherapy in melanoma and points towards a hitherto undescribed role of ICOS in tumor cells.

Exploiting Vitamin D Receptor and Its Ligands to Target Squamous Cell Carcinomas of the Head and Neck.

Vitamin D (VitD) and its receptor (VDR) have been intensively investigated in many cancers. As knowledge for head and neck cancer (HNC) is limited, we investigated the (pre)clinical and therapeutic relevance of the VDR/VitD-axis. We found that VDR was differentially expressed in HNC tumors, correlating to the patients' clinical parameters. Poorly differentiated tumors showed high VDR and Ki67 expression, whereas the VDR and Ki67 levels decreased from moderate to well-differentiated tumors. The VitD serum levels were lowest in patients with poorly differentiated cancers (4.1 ± 0.5 ng/mL), increasing from moderate (7.3 ± 4.3 ng/mL) to well-differentiated (13.2 ± 3.4 ng/mL) tumors. Notably, females showed higher VitD insufficiency compared to males, correlating with poor differentiation of the tumor. To mechanistically uncover VDR/VitD's pathophysiological relevance, we demonstrated that VitD induced VDR nuclear-translocation (VitD < 100 nM) in HNC cells. RNA sequencing and heat map analysis showed that various nuclear receptors were differentially expressed in cisplatin-resistant versus sensitive HNC cells including VDR and the VDR interaction partner retinoic acid receptor (RXR). However, RXR expression was not significantly correlated with the clinical parameters, and cotreatment with its ligand, retinoic acid, did not enhance the killing by cisplatin. Moreover, the Chou-Talalay algorithm uncovered that VitD/cisplatin combinations synergistically killed tumor cells (VitD < 100 nM) and also inhibited the PI3K/Akt/mTOR pathway. Importantly, these findings were confirmed in 3D-tumor-spheroid models mimicking the patients' tumor microarchitecture. Here, VitD already affected the 3D-tumor-spheroid formation, which was not seen in the 2D-cultures. We conclude that novel VDR/VitD-targeted drug combinations and nuclear receptors should also be intensely explored for HNC. Gender-specific VDR/VitD-effects may be correlated to socioeconomic differences and need to be considered during VitD (supplementation)-therapies.

Randomized, placebo-controlled study on efficacy, safety and tolerability of drug-induced defibrinogenation for sudden sensorineural hearing loss: the lessons learned.

PURPOSE: Disturbance of cochlear microcirculation is discussed as final common pathway of various inner ear diseases. Hyperfibrinogenemia causing increased plasma viscosity is a possible factor for a critical reduction of cochlear blood flow that might lead to sudden sensorineural hearing loss (SSHL). The aim was to determine the efficacy and safety of drug-induced defibrinogenation by ancrod for SSHL. METHODS: Double-blind, randomized, placebo-controlled, multicenter, parallel group, phase II (proof-of-concept) study (planned enrollment: 99 patients). Patients received an infusion of ancrod or placebo (day 1) followed by subcutaneous administrations (day 2, 4, 6). Primary outcome was the change in pure tone audiogram air conduction average until day 8. RESULTS: The study was terminated early due to slow recruiting (31 enrolled patients: 22 ancrod, 9 placebo). A significant improvement of hearing loss was registered in both groups (ancrod: - 14.3 dB ± 20.4 dB, - 39.9% ± 50.4%; placebo: - 22.3 dB ± 13.7 dB, - 59.1% ± 38.0%). A statistically significant group-difference was not detected (p = 0.374). Placebo response of 33.3% complete and 85.7% at least partial recovery was observed. Plasma fibrinogen levels were reduced significantly by ancrod (baseline: 325.2 mg/dL, day 2: 107.2 mg/dL). Ancrod was tolerated well, no adverse drug reaction was of severe intensity, no serious adverse events occurred. CONCLUSION: Ancrod reduced fibrinogen levels that support its mechanism of action. The safety profile can be rated positively. Since the planned number of patients could not be enrolled, no efficacy conclusion can be drawn. The high rate of placebo response challenges clinical trials for SSHL and needs to be considered in future investigations. Trial registrations This study was registered in the EU Clinical Trials Register, EudraCT-No. 2012-000066-37 at 2012-07-02.

DNA methylation of GITR, OX40, 4-1BB, CD27 , and CD40 correlates with BAP1 aberrancy and prognosis in uveal melanoma.

Uveal melanoma represents an aggressive tumor that responds mostly poorly to established melanoma treatments. Comprehensive methylation profiling of the next-generation immunotherapeutic target genes, for example, members of the tumor necrosis factor receptor superfamily, might allow for the development of companion predictive biomarkers. We have analyzed CpG sites within the immune checkpoint genes GITR, OX40, 4-1BB, CD 27, and CD40 probed by the Illumina Infinium HumanMethylation450 BeadChip in N = 80 uveal melanomas included in The Cancer Genome Atlas with regard to BAP1 aberrancy, mRNA expression, and overall survival. In all analyzed immune checkpoint genes, BAP1 aberrancy was associated with decreased CpG methylation levels. We identified specific CpG sites that significantly correlated with BAP1 aberrancy, mRNA expression levels, and overall survival. Our results suggest epigenetic regulation of the analyzed immune checkpoint genes via DNA methylation in uveal melanoma and provide rationale for methylation testing in biomarker programs in clinical trials.

The German hearing in noise test with a female talker: development and comparison with German male speech test.

PURPOSE: The aim of the study was to develop the German Hearing in Noise Test (HINT) with female speaker by fulfilling the recommendations by International Collegium of Rehabilitative Audiology (ICRA) for using a female speaker to create new multilingual speech tests and to determine norms and to compare these norms with German male speech tests-the male speakers HINT and the Oldenburg Sentence Test (OLSA). METHODS: The HINT with a female speaker consists of the same speech material as the male speaking HINT. After recording the speech material, 10 normal hearing subjects were included to determine the performance-intensity function (PI function). 24 subjects were part of the measurements to determine the norms and compare them with the norms of male HINT and OLSA. Comparably, adaptive, open-set methods under headphones (HINT) and sound field (OLSA) were used. RESULTS: Acoustic phonetic analysis demonstrated significant difference in mean fundamental frequency, its range and mean speaking rate between both HINT speakers. The calculated norms by three of the tested four conditions of the HINT with a female speaker are not significantly different from the norms with a male speaker. No significant effect of the speaker's gender of the first HINT measurement and no significant correlation between the threshold results of the HINT and the OLSA were determined. CONCLUSIONS: The Norms for German HINT with a female speaker are comparable to the norms of the HINT with a male speaker. The speech intelligibility score of the HINT does not depend on the speakers' gender despite significant difference of acoustic-phonetic parameters between the female and male HINT speaker's voice. Instead, the speech intelligibility rating must be seen as a function of the used speech material.

Hearing rehabilitation for unilateral deafness using a cochlear implant: the influence of the subjective duration of deafness on speech intelligibility.

BACKGROUND: For patients with single sided deafness (SSD) or severe asymmetric sensorineural hearing loss (ASHL), cochlear implantation remains the only solution to restore bilateral hearing capacity. Prognostically, the duration of hearing loss in terms of audiological outcome is not yet clear. Therefore, the aim of this study was to retrospectively investigate the influence of subjective deafness duration on postoperative speech perception after cochlear implantation for SSD as well as its impact on quality of life. MATERIALS AND METHODS: The present study included a total of 36 adults aged 50.2 ± 15.5 years who underwent CI for SSD/ASHL at our clinic between 2010 and 2015. Patients were audiometrically assessed at 3 and 12-36 months postoperatively. Test results were correlated with self-reported duration of deafness. Quality of life was assessed by questionnaire. RESULTS: Mean duration of deafness was 193.9 ± 185.7 months. The side-separated hearing threshold showed an averaged target range between 30 and 40 dB HL. Freiburg monosyllable test increased from 0% pre-operatively to 20% after 3 months (p = 0.001) and to 50% after 12-36 months (p = 0.002). There was a significant correlation between audiometric outcome and subjective deafness duration at 12-36 months postoperatively (r = - 0.564; p = 0.02) with a cutoff for open-set monosyllable recognition at a duration of deafness of greater than 408 months. Quality of life was significantly improved by CI. CONCLUSIONS: CI implantation in unilaterally deafened patients provides objective and subjective benefits. Duration of deafness is unlikely to be an independent negative predictive factor and thus should not generally be considered as contraindication.

The Vitamin D Receptor-BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer.

Treatment success of head and neck squamous cell carcinoma (HNSCC) is often hindered by cisplatin resistance. As inherent and acquired therapy resistance counteracts improvement in long-term survival, novel multi-targeting strategies triggering cancer cell apoptosis are urgently required. Here, we identify the vitamin D receptor (VDR) as being significantly overexpressed in tumors of HNSCC patients (n = 604; p = 0.0059), correlating with tumor differentiation (p = 0.0002), HPV status (p = 0.00026), and perineural invasion (p = 0.0087). The VDR, a member of the nuclear receptor superfamily, is activated by its ligand vitamin D (VitD) and analogs, triggering multiple cellular responses. As we found that the VDR was also upregulated in our cisplatin-resistant HNSCC models, we investigated its effect on overcoming cisplatin resistance. We discovered that VitD/cisplatin combinations synergistically killed even cisplatin-resistant cells at clinically achievable levels. Similar results were obtained for the clinically used VitD analog Maxacalcitol. Moreover, VitD/cisplatin combinations inhibited tumor cell migration by E-cadherin upregulation. Signaling pathway analyses revealed that VitD co-treatments triggered cancer cell death by increasing the expression of the pro-apoptotic BCL-2 family protein BIM. BIM's pro-apoptotic activity in HNSCC cells was confirmed by ectopic overexpression studies. Importantly, BIM expression is positively associated with HNSCC patients' (n = 539) prognosis, as high expression correlated with improved survival (p = 0.0111), improved therapy response (p = 0.0026), and remission (p = 0.004). Collectively, by identifying, for the first time, the VDR/BIM axis, we here provide a molecular rationale for the reported anti-cancer activity of VitD/analogs in combination therapies. Our data also suggest its exploitation as a potential strategy to overcome cisplatin resistance in HNSCC and other malignancies by inducing additional pro-apoptotic pathways.

Nectin-4 is widely expressed in head and neck squamous cell carcinoma.

PURPOSE: Nectin-4 has been successfully established as a target molecule in locally advanced and metastatic bladder cancer. An antibody-drug conjugate (enfortumab-vedotin) directed against nectin-4 has shown marked tumor remission rates in this tumor type, which is known for high expression rates of nectin-4. As head and neck cancer and urothelial carcinomas share morphological and molecular similarities, we aimed to evaluate Nectin-4 expression in head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: A previously described and clinically characterized cohort of HNSCC (n = 159) was analyzed by immunohistochemistry for Nectin-4 expression. The expression data was correlated to clinico-pathological parameters including patient outcome. RESULTS: Nectin-4 was found in 86.2% of HNSCC, with medium/high expression seen in 32.7% of cases. Non smokers and p16 positive HNSCC showed a higher expression of Nectin-4 (p < 0.005). There was no correlation of Nectin-4 with grading or tumor stage. Nectin-4 positive tumors showed a significant better survival (log rank p = 0.006). CONCLUSIONS: Similar to urothelial carcinoma, Nectin-4 is found in the majority of HNSCC, which clearly warrants further studies to clarify if HNSCC also respond to targeted therapy with enfortumab-vedotin. Moreover, expression of Nectin-4 is associated with HPV infection and may serve as a prognostic marker in HNSCC.

MR-lymphangiography identifies lymphatic pathologies in patients with idiopathic recurrent cervical swelling.

Background: Idiopathic recurrent cervical swelling may be caused by lymphatic abnormalities. Methods: Ten patients (9 females, mean age 51.2 ± 7) with idiopathic recurrent cervical swelling underwent MR-lymphangiography (MRL). MR-lymphangiograms were evaluated regarding lymphatic anatomy and flow. Individualized treatment was recommended according to MRL-findings. Results: 8/10 patients presented with left-sided, 2/10 with right-sided swelling. Pathological lymph-flow was identified in all cases: thoracic duct dilatation in patients with left-sided and right lymphatic duct dilatation in right-sided swelling, accessory thoracic lymphatics in 7/10 and reflux in 8/10 cases. In two cases, a lymphatic thrombus was identified.After treatment, symptoms resolved completely in 6/10 cases and partially in 1/10 cases. The remaining three patients have intermittent swellings but have no treatment wish. Conclusion: Idiopathic recurrent cervical swelling can be caused by lymphatic anomalies. MRL displays impaired lymphatic drainage, lymphatic vessel dilatation, and chylolymphatic reflux as hallmarks of this condition and may aid in targeted treatment planning.