Procoagulant platelets promote immune evasion in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive tumor entity, in which immune checkpoint (IC) molecules are primarily synthesized in the tumor environment. Here, we report that procoagulant platelets bear large amounts of such immunomodulatory factors and that the presence of these cellular blood components in TNBC relates to pro-tumorigenic immune cell activity and impaired survival. Mechanistically, tumor-released nucleic acids attract platelets into the aberrant tumor microvasculature where they undergo procoagulant activation, thus delivering specific stimulatory and inhibitory IC molecules. This concomitantly promotes pro-tumorigenic myeloid leukocyte responses and compromises anti-tumorigenic lymphocyte activity, ultimately supporting tumor growth. Interference with platelet-leukocyte interactions prevented immune cell misguidance and suppressed tumor progression, nearly as effective as systemic IC inhibition. Hence, our data uncover a self-sustaining mechanism of TNBC in utilizing platelets to misdirect immune cell responses. Targeting this irregular multicellular interplay might represent a novel immunotherapeutic strategy in TNBC without side effects of systemic IC inhibition.

ART and AutoART ECAP measurements and cochlear nerve anatomy as predictors in adult cochlear implant recipients.

PURPOSE: The purpose of this retrospective study is to compare the results of electrically evoked compound action potential (ECAP) measurements using automatic auditory response telemetry (AutoART) with those obtained by ART in adults. The study also aimed to evaluate the predictive value of intraoperative ART and AutoART ECAPs for speech intelligibility (SI) and hearing success (HS), and to determine if cochlear nerve (CN) cross-sectional area (CSA) obtained preoperatively by magnetic resonance imaging (MRI) scans could predict ART and AutoART ECAPs and SI and HS outcome. METHODS: The study analyzed and correlated ART and AutoART ECAP thresholds at electrodes E2, E6, and E10, as well as averaged ECAP thresholds over electrodes E1-E12, using data from 32 implants. Correlations were also examined for ART and AutoART ECAP slopes. In addition, averaged ART and AutoART ECAP thresholds and slopes over all 12 electrodes for each participant were correlated with CN CSA measured from MRI sequences. SI of the monosyllabic Freiburg Speech Test at 65 dB sound pressure level was examined along with averaged ART and AutoART thresholds and slopes over all 12 electrodes. A parallel analysis was performed for HS, derived from the difference between baseline and 6-month SI. Finally, correlations between CN CSA and SI, as well as CN CSA and HS were examined. RESULTS: The results of the study showed a significant positive correlation between ART and AutoART ECAP thresholds and as well as slopes for E2, E6, E10 and averaged thresholds and slopes of E1-E12. However, no significant correlation was observed between ART and AutoART averaged ECAP thresholds and slopes and either SI and HS or CN CSA. Furthermore, no significant correlation was found between CN CSA and SI and HS. CONCLUSION: While AutoART is a reliable and safe program for measuring ECAPs in adults, the study found no preoperative prognostic information on intraoperative ECAP results using parameters extracted from current MRI sequences or pre-/intraoperative information on subsequent hearing outcome using ECAP and CN CSA.

Significance of endolymphatic sac surgery with and/or without simultaneous cochlea implant surgery in respect of vertigo control and speech perception in patients with Menière's disease.

PURPOSE: The focus on treating patients with Menière's Disease (MD) lies on the reduction of vertigo attacks and the preservation of sensory function. Endolympathic hydrops is considered as an epiphenomenon in MD, which can potentially be altered by endolymphatic sac surgery (ESS). Purpose of the study was to investigate the influences on vertigo control through manipulation of the perilymphatic system with or without ESS. METHODS: Retrospective data analysis of 86 consecutive patients with MD according to current diagnostic criteria after endolymphatic sac surgery alone (ESSalone; n = 45), cochlear implantation (CI) alone (CIalone; n = 12), and ESS with CI (ESS + CI; n = 29), treated at a tertiary referral center. MAIN OUTCOME MEASURES: vertigo control, speech perception pre- and postoperatively. RESULTS: Gender, side, and preoperative treatment were similar in all groups. Age was younger in the ESSalone-group with 56.2 ± 13.0 years (CIalone = 64.2 ± 11.4 years; ESS + CI = 63.1 ± 9.7 years). Definitive MD was present in all the CIalone, in 79.3% of the ESS + CI and in 59.6% of the ESSalone-patients. Likewise, vertigo control rate was 100% in the CIalone, 89.7% in the ESS + CI and 66.0% in the ESSalone-group. CONCLUSIONS: Vertigo control was improved in all three groups, however, superior in groups treated with CI, potentially contributed by the manipulation of both the endo- and perilymphatic systems. A more systematic characterization of the patients with larger case numbers and documentation of follow up data would be needed to evaluate a clinical effect more properly.

Comparison of speech perception in bimodal cochlear implant patients with respect to the cochlear coverage.

BACKGROUND: The hearing success of patients with bimodal fitting, utilizing both a cochlear implant (CI) and a hearing aid (HA), varies considerably: While some patients benefit from bimodal CI and HA, others do not. OBJECTIVES: This retrospective study aimed to investigate speech perception in bimodally fitted patients and compare it with the cochlear coverage (CC). METHODS: The CC was calculated with the OTOPLAN software, measuring the cochlear duct length on temporal bone CT scans of 39 patients retrospectively. The patients were categorized into two groups: CC ≤ 65% (CC500) and CC > 65% (CC600). Monaural speech intelligibility for monosyllables at a sound pressure level (SPL) of 65 dB in a free-field setting was assessed before and after CI at various time points. The two groups, one with preoperative HA and one with postoperative CI, were compared. Additionally, speech intelligibility was correlated with CC in the entire cohort before CI and at the last available follow-up (last observation time, LOT). RESULTS: Overall, there was no significant difference in speech intelligibility between CC500 and CC600 patients, with both groups demonstrating a consistent improvement after implantation. While CC600 patients tended to exhibit earlier improvement in speech intelligibility, CC500 patients showed a slower initial improvement within the first 3 months but demonstrated a steeper learning curve thereafter. At LOT, the two patient groups converged, with no significant differences in expected speech intelligibility. There was no significant relationship between unimodal/unilateral free-field speech intelligibility and CC. Interestingly, patients with a CC of 70-75% achieved the highest speech intelligibility. CONCLUSION: Despite of the lack of a significant correlation between CC and speech perception, patients appeared to reach their maximum in unimodal/unilateral speech perception primarily at a coverage level of 70-75%. Nevertheless, further investigation is warranted, as CC500 was associated with shorter cochlear duct length, and different types of electrodes were used in both groups.

5'-Ectonucleotidase CD73/NT5E supports EGFR-mediated invasion of HPV-negative head and neck carcinoma cells.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) of malignant cells is a driving force of disease progression in human papillomavirus-negative (HPV-negative) head and neck squamous cell carcinomas (HNSCC). Sustained hyper-activation of epidermal growth factor receptor (EGFR) induces an invasion-promoting subtype of EMT (EGFR-EMT) characterized by a gene signature ("'EGFR-EMT_Signature'") comprising 5´-ectonucleotidase CD73. Generally, CD73 promotes immune evasion via adenosine (ADO) formation and associates with EMT and metastases. However, CD73 regulation through EGFR signaling remains under-explored and targeting options are amiss. METHODS: CD73 functions in EGFR-mediated tumor cell dissemination were addressed in 2D and 3D cellular models of migration and invasion. The novel antagonizing antibody 22E6 and therapeutic antibody Cetuximab served as inhibitors of CD73 and EGFR, respectively, in combinatorial treatment. Specificity for CD73 and its role as effector or regulator of EGFR-EMT were assessed upon CD73 knock-down and over-expression. CD73 correlation to tumor budding was studied in an in-house primary HNSCC cohort. Expression correlations, and prognostic and predictive values were analyzed using machine learning-based algorithms and Kaplan-Meier survival curves in single cell and bulk RNA sequencing datasets. RESULTS: CD73/NT5E is induced by the EGF/EGFR-EMT-axis and blocked by Cetuximab and MEK inhibitor. Inhibition of CD73 with the novel antagonizing antibody 22E6 specifically repressed EGFR-dependent migration and invasion of HNSCC cells in 2D. Cetuximab and 22E6 alone reduced local invasion in a 3D-model. Interestingly, combining inefficient low-dose concentrations of Cetuximab and 22E6 revealed highly potent in invasion inhibition, substantially reducing the functional IC50 of Cetuximab regarding local invasion. A role for CD73 as an effector of EGFR-EMT in local invasion was further supported by knock-down and over-expression experiments in vitro and by high expression in malignant cells budding from primary tumors. CD73 expression correlated with EGFR pathway activity, EMT, and partial EMT (p-EMT) in malignant single HNSCC cells and in large patient cohorts. Contrary to published data, CD73 was not a prognostic marker of overall survival (OS) in the TCGA-HNSCC cohort when patients were stratified for HPV-status. However, CD73 prognosticated OS of oral cavity carcinomas. Furthermore, CD73 expression levels correlated with response to Cetuximab in HPV-negative advanced, metastasized HNSCC patients. CONCLUSIONS: In sum, CD73 is an effector of EGF/EGFR-mediated local invasion and a potential therapeutic target and candidate predictive marker for advanced HPV-negative HNSCC.

Vestibular and audiometric results after endolymphatic mastoid shunt surgery in patients with Menière's disease.

PURPOSE: Treatment of Menière's Disease (MD) comprises an array of both non-destructive and destructive treatment options. In patients who are therapy-refractory to non-destructive medical treatment, endolymphatic mastoid shunt surgery (EMSS) is both recommended and debated controversially. The aim of this study was to investigate safety in terms of hearing, vestibular function, complication rate, and efficacy with regards to vertigo control of EMSS in patients with MD according to the current diagnostic criteria of 2015. METHODS: Retrospective analysis of 47 consecutive patients with definite or probable MD with description of demographic parameters, pre- and postoperative MD treatment, pre- and postoperative audiometric (pure tone audiometry) and vestibular (caloric testing) results. The parameters were compared between patients with and without postoperative vertigo control. RESULTS: 31/47 patients (66.0%) had improved vertigo control postoperatively. Postoperative hearing and vestibular preservation were predominantly stable. No significant differences between patients with improved vertigo control and patients with no change or worse vertigo episodes were found. In the treatment refractory group, 4 patients required a revision EMSS and 6 a destructive MD treatment (5 gentamicin intratympanically, 1 labyrinthectomy). No peri- or postsurgical complications were reported. CONCLUSIONS: EMSS was found to be beneficial in two thirds of the patients with definite or probable Morbus Menière and a safe procedure regarding hearing and vestibular preservation with no postoperative complications. Therefore, EMSS should be considered before inducing destructive treatment options, such as intratympanic gentamicin application or labyrinthectomy.

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.

Parameters for estimating the feasibility of implantation of a semi-implantable bone conduction device (SIBCD) in children and adolescents.

PURPOSE: In children and adolescents, preoperative planning for a semi-implantable bone conduction device (SIBCD) is crucial. The geometric changes of the new version of a common SIBCD should enable a higher rate of successful implantation due to its flatter actuator. Thus, this radioanatomic study compared the rate of successful implantation of both device versions at the traditional mastoidal localization and two alternative sites, retrosigmoidal, and parietal, and investigated parameters helping to estimate the feasibility. METHODS: A retrospective analysis of 136 CT scans of 0 to 20-year-old patients, evaluation of demographic parameters, radioanatomy, and assessment of head diameter was conducted. The feasibility was investigated for certain age groups at three implantation sites. Prediction of feasible implantation by means of different parameters was calculated. RESULTS: A significant higher implantation rate was observed with the new device for all three sites and age groups. The age group of 6-8 years (n = 19) had most striking differences with a 58.1% rate of successful implantation with the new device without spacer (80% with spacer) at the mastoidal localization, whereas none with the old implant. Head diameter was identified as the most predictive parameter regarding all implantation sites (mastoidal: p = 0.030; retrosigmoidal: p = 0.006; parietal: p < 0.0001), age for the mastoidal (p < 0.0001) and retrosigmoidal (p < 0.0001), and gender for the parietal site (p = 0.001). CONCLUSION: The geometric changes of the actuator lead to a higher rate of successful implantation in all age-groups and all three localizations with reducing the requirement for spacers. Parameters age and head diameter might aid in estimating the rate of successful implantation in young patients and may be a novel tool to assist in the decision-making process for a SIBCD.

[Speech perception as a function of cochlear coverage-comparison in bimodally hearing cochlear implant patients. German version]. / Sprachverstehen in Abhängigkeit von der cochleären Abdeckung ­ Vergleich bei bimodal versorgten Cochleaimplantatpatienten.

BACKGROUND: Hearing success in bimodally hearing patients with a cochlear implant (CI) and a hearing aid (HA) exhibits different results: while some benefit from bimodal CI and HA, others do not. OBJECTIVE: The aim of this study was to investigate hearing success in terms of speech perception in bimodally fitted patients in relation to the cochlear coverage (CC) of the CI electrodes. MATERIALS AND METHODS: Using the OTOPLAN software (CAScination AG, Bern, Switzerland), CC was retrospectively measured from CT scans of the temporal bone of 39 patients, who were then categorized into two groups: CC ≤ 65% (CC500) and CC > 65% (CC600). Monaural speech intelligibility for monosyllables at a sound pressure level (SPL) of 65 dB in open field was assessed at various timepoints, preoperatively with HA and postoperatively with CI, and compared between the groups. In addition, speech intelligibility was correlated with CC in the entire cohort before surgery and during follow-up (FU). RESULTS: Overall, no significant differences in speech intelligibility were found between CC500 and CC600 patients at any of the FU timepoints. However, both CC500 and CC600 patients showed a steady improvement in speech intelligibility after implantation. While CC600 patients tended to show an earlier improvement in speech intelligibility, CC500 patients tended to show a slower improvement during the first 3 months and a steeper learning curve thereafter. The two patient groups converged during FU, with no significant differences in speech intelligibility. There was no significant relationship between unimodal/unilateral free-field speech intelligibility and CC. However, patients with a CC of 70-75% achieved maximum speech intelligibility. CONCLUSION: Despite a nonsignificant correlation between CC and speech discrimination, patients seem to reach their maximum in unimodal/unilateral speech understanding mainly at 70-75% coverage. However, there is room for further investigation, as CC500 was associated with a shorter cochlear duct length (CDL), and long and very long electrodes were used in both groups.

A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) is both a driver oncogene and a therapeutic target in advanced head and neck squamous cell carcinoma (HNSCC). However, response to EGFR treatment is inconsistent and lacks markers for treatment prediction. This study investigated EGFR-induced epithelial-to-mesenchymal transition (EMT) as a central parameter in tumor progression and identified novel prognostic and therapeutic targets, and a candidate predictive marker for EGFR therapy response. METHODS: Transcriptomic profiles were analyzed by RNA sequencing (RNA-seq) following EGFR-mediated EMT in responsive human HNSCC cell lines. Exclusive genes were extracted via differentially expressed genes (DEGs) and a risk score was determined through forward feature selection and Cox regression models in HNSCC cohorts. Functional characterization of selected prognostic genes was conducted in 2D and 3D cellular models, and findings were validated by immunohistochemistry in primary HNSCC. RESULTS: An EGFR-mediated EMT gene signature composed of n = 171 genes was identified in responsive cell lines and transferred to the TCGA-HNSCC cohort. A 5-gene risk score comprising DDIT4, FADD, ITGB4, NCEH1, and TIMP1 prognosticated overall survival (OS) in TCGA and was confirmed in independent HNSCC cohorts. The EGFR-mediated EMT signature was distinct from EMT hallmark and partial EMT (pEMT) meta-programs with a differing enrichment pattern in single malignant cells. Molecular characterization showed that ITGB4 was upregulated in primary tumors and metastases compared to normal mucosa and correlated with EGFR/MAPK activity in tumor bulk and single malignant cells. Preferential localization of ITGB4 together with its ligand laminin 5 at tumor-stroma interfaces correlated with increased tumor budding in primary HNSCC tissue sections. In vitro, ITGB4 knock-down reduced EGFR-mediated migration and invasion and ITGB4-antagonizing antibody ASC8 impaired 2D and 3D invasion. Furthermore, a logistic regression model defined ITGB4 as a predictive marker of progression-free survival in response to Cetuximab in recurrent metastatic HNSCC patients. CONCLUSIONS: EGFR-mediated EMT conveyed through MAPK activation contributes to HNSCC progression upon induction of migration and invasion. A 5-gene risk score based on a novel EGFR-mediated EMT signature prognosticated survival of HNSCC patients and determined ITGB4 as potential therapeutic and predictive target in patients with strong EGFR-mediated EMT.

Liquid BIOpsy for MiNimal RESidual DiSease Detection in Head and Neck Squamous Cell Carcinoma (LIONESS)-a personalised circulating tumour DNA analysis in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) remain a substantial burden to global health. Cell-free circulating tumour DNA (ctDNA) is an emerging biomarker but has not been studied sufficiently in HNSCC. METHODS: We conducted a single-centre prospective cohort study to investigate ctDNA in patients with p16-negative HNSCC who received curative-intent primary surgical treatment. Whole-exome sequencing was performed on formalin-fixed paraffin-embedded (FFPE) tumour tissue. We utilised RaDaRTM, a highly sensitive personalised assay using deep sequencing for tumour-specific variants, to analyse serial pre- and post-operative plasma samples for evidence of minimal residual disease and recurrence. RESULTS: In 17 patients analysed, personalised panels were designed to detect 34 to 52 somatic variants. Data show ctDNA detection in baseline samples taken prior to surgery in 17 of 17 patients. In post-surgery samples, ctDNA could be detected at levels as low as 0.0006% variant allele frequency. In all cases with clinical recurrence to date, ctDNA was detected prior to progression, with lead times ranging from 108 to 253 days. CONCLUSIONS: This study illustrates the potential of ctDNA as a biomarker for detecting minimal residual disease and recurrence in HNSCC and demonstrates the feasibility of personalised ctDNA assays for the detection of disease prior to clinical recurrence.

Analysis of genetic variants of frequently mutated genes in human papillomavirus-negative primary head and neck squamous cell carcinoma, resection margins, local recurrences and corresponding circulating cell-free DNA.

BACKGROUND: Head and neck squamous cell carcinoma remains a substantial burden to global health. Despite evolving therapies, 5-year survival is <50% and unlike in other cancers, reliable molecular biomarkers to guide treatment do not exist. METHODS: We performed targeted panel next-generation sequencing to analyse somatic variants from primary and recurrent tumour tissue, corresponding resection margins and cell-free DNA from intra-operatively collected plasma samples from eight patients with human papillomavirus-negative head and neck squamous cell carcinoma. Patients were primarily treated with curative-intent surgery and received subsequent adjuvant treatment. RESULTS: The most frequently mutated gene was TP53. Other mutated genes included NOTCH1, NF1 and CDKN2A among others. A total of 20.8% of variants were shared between primary tumour and resection margin. Out of all the variants detected, 37.5% were shared between cell-free DNA and primary tumour, whereas 12.5% were commonly found in cell-free DNA, primary tumour and resection margin. Mutational profiling was able to distinguish between a locoregional recurrence and a second primary tumour by identifying a different TP53 mutation in the primary tumour compared to the recurrent tumour in addition to private FBXW7 and CTNNB1 mutations. We also identified identical TP53 and PIK3CA mutations in another primary tumour and corresponding recurrence. CONCLUSION: Molecular profiling of cell-free DNA and resection margins has potential applications in clinical practice to guide future treatment decisions.

From the Bottlecap to the Bottleneck: Frequent Esophageal Impaction of Bottlecaps Among Young Males in a Small University Town.

There have been few reports of ingestion of bottlecaps worldwide. However, all of these seemed to be unlikely accidental ingestions with a comic side effect. In contrast to this, the authors of this study found an accumulation of bottlecap ingestions in a small university town. Hence, we conducted a study to investigate the nature of these ingestions. We conducted a retrospective cohort study in a tertiary referral center in a small German university town (Göttingen). All patients that were admitted for esophageal foreign bodies were screened for accidental ingestion of bottlecaps and included in the study at hand. Overall, there were 14 cases of bottlecap ingestion within 12 years. Patients were exclusively male, average age was 23.0 ± 4.2 years, ranging from 18.3 to 35.6 years. In 13 out of 14 cases, association to a fraternity was found. Young men, particularly those belonging to a fraternity, should be beware of bottlecap ingestion when consuming beer in risky rituals in small university towns. Alternatively, competitive beer drinking may generally be avoided.

Variation of the cochlear anatomy and cochlea duct length: analysis with a new tablet-based software.

PURPOSE: In cochlear implantation, thorough preoperative planning together with measurement of the cochlear duct length (CDL) assists in choosing the correct electrode length. For measuring the CDL, different techniques have been introduced in the past century along with the then available technology. A tablet-based software offers an easy and intuitive way to visualize and analyze the anatomy of the temporal bone, its proportions and measure the CDL. Therefore, we investigated the calculation technique of the CDL via a tablet-based software on our own cohort retrospectively. METHODS: One hundred and eight preoperative computed tomography scans of the temporal bone (slice thickness < 0.7 mm) of already implanted FLEX28™ and FLEXSOFT™ patients were found eligible for analysis with the OTOPLAN software. Measurements were performed by two trained investigators independently. CDL, angular insertion depth (AID), and cochlear coverage were calculated and compared between groups of electrode types, sex, sides, and age. RESULTS: Mean CDL was 36.2 ± 1.8 mm with significant differences between sex (female: 35.8 ± 0.3 mm; male: 36.5 ± 0.2 mm; p = 0.037), but none concerning side or age. Differences in mean AID (FLEX28: 525.4 ± 46.4°; FLEXSOFT: 615.4 ± 47.6°), and cochlear coverage (FLEX28: 63.9 ± 5.6%; FLEXSOFT: 75.8 ± 4.3%) were significant (p < 0.001). CONCLUSION: A broad range of CDL was observed with significant larger values in male, but no significant differences concerning side or age. Almost every cochlea was measured longer than 31.0 mm. Preoperative assessment aids in prevention of complications (incomplete insertion, kinking, tipfoldover), attempt of atraumatic insertion, and addressing individual necessities (hearing preservation, cochlear malformation). The preferred AID of 720° (two turns of the cochlea) was never reached, opening the discussion for the requirement of longer CI-electrodes versus a debatable audiological benefit for the patient in his/her everyday life.

Functional results with active middle ear implant or semi-implantable bone conduction device in patients with comparable hearing loss.

OBJECTIVE: In patients with conductive (CHL) or mixed hearing loss (MHL), hearing rehabilitation with an implantable hearing system, active middle ear implant (AMEI) or a semi-implantable bone-conduction device (SIBCD), is an option when conventional hearing aids are insufficient, or patients are unable to wear them. DESIGN: Retrospective analysis of 20 consecutive patients (24 implants) with a comparison of demographic characteristics and audiometric results (air-bone gap = ABG, effective hearing gain = EHG, functional hearing gain = FHG, Freiburg Monosyllabic Test in quiet, Oldenburg Sentence Test in noise = OLSA). STUDY SAMPLE: Patients, eligible for both devices, who received either AMEI or SIBCD due to CHL or MHL. RESULTS: Analysis showed no significant differences in post-operative functional hearing results between the group of AMEI vs. SIBCD (ABG-reduction: 31.6 ± 12.4 dB HL vs. 28.0 ± 11.8 dB HL; p = 0.702; EHG: -1.6 ± 7.7 dB HL vs. -1.2 ± 4.2 dB HL; p = 0.090; FHG: 33.4 ± 12.6 dB HL vs. 26.1 ± 11.7 dB HL; p = 0.192; Freiburg: 83.0 ± 15.6% vs. 83.6 ± 14.2%; Freiburg-improvement: 57.7 ± 26.8% vs. 68.2 ± 19.7%; p = 0.294; OLSA: -2.7 ± 3.0 SNR vs. -1.4 ± 3.6 SNR; OLSA-improvement: 2.6 ± 2.1 dB vs. 3.7 ± 2.8 dB; p = 0.323). Four patients had the AMEI explanted due to insufficient functioning and later received a SIBCD. CONCLUSIONS: Due to more challenging anatomical conditions, a surgical technique for the AMEI is more complex. However, functional results are comparable to the SIBCD. Therefore, proper patient counselling and cautious choice of the device are mandated before surgery.

Factors influencing outcomes in selective neck dissection in 661 patients with head and neck squamous cell carcinoma.

BACKGROUND: Selective neck dissection (SND) is the surgical treatment of choice in squamous cell carcinoma of the head and neck (HNSCC) with suspected or manifest metastases in the cervical lymph nodes. For SND to be successful, treated lymph node levels should be selected according to anatomic considerations and the extent of the disease. Aim of this study was to identify neck dissection levels that had an impact on individual prognosis. METHODS: We conducted a retrospective review of SND as part of primary treatment of HNSCC. Overall survival (OS) and regional control rates (RCR) were calculated for all patients treated at one academic tertiary referral center. RESULTS: 661 patients with HNSCC were included, 644 underwent ipsilateral and 319 contralateral SND. Average follow-up was 78.9 ± 106.4 months. 67 (10.1%) patients eventually developed nodal recurrence. Tumor sites were oral cavity (135), oropharynx (179), hypopharynx (118) and larynx (229). Tumor categories pT1-pT4a, and all clinical and pathological nodal categories were included. Multivariate analysis indicated improved OS rates for patients undergoing SND in ipsilateral levels I and V as well as level III contralaterally. Analysis for tumor origin showed that SND in ipsilateral level I showed significantly improved OS in HNSCC of the oral cavity. CONCLUSION: The dissection of ipsilateral level I in oral cavity cancer was of particular relevance in our exploratory, retrospective analysis. To clarify the relevance for the determination of the extent of SND, this should be investigated prospectively in a more homogenous patient cohort.

Nasal Septal Perforation Closure by "Sandwich Grafts": Technique, Initial Results.

Nasal septal perforation closure represents a considerable surgical challenge. Many techniques rely on the implantation of foreign materials that pose a persisting threat of infection. The authors have identified a reliable technique closing septal perforations by an autologous "sandwich graft." It is layered around a piece of auricular cartilage, covered with temporal fascia, thus emulating the physiological layers of the nasal septum. Finally, the prepared graft is then sewn into the perforation in an underlay technique and kept in place by septal splints for 4 weeks. The technique is easily feasible and strives to reconstruct the nasal as physiological as possible. The data obtained from a case series of 11 patients highlights the efficacy of the technique.

[Hearing tests in practice : Audiometric masking in pure-tone and speech audiometry]. / Hörtests in der Praxis : Vertäubung in der Ton- und Sprachaudiometrie.

Correct execution of hearing tests is essential for audiologic diagnostics and selection of treatment by the ENT physician. Especially in the case of pure-tone and speech audiometry, incorrectly performed audiometric masking can lead to false measurement results. Often, hearing that is too good is feigned by overhearing in the contralateral ear. Herein, a masking strategy is described by which errors in the execution of masking can be recognized and corrected. The aim of this paper is to identify and prevent the most common errors made during the masking process in pure-tone and speech audiometry.

[ToSkORL: self- and objective assessment of examination skills in the head and neck region]. / ToSkORL: Selbst- und Fremdeinschätzung bei der Untersuchung des Kopf-Hals-Bereichs.

BACKGROUND: A central goal of medical school is acquisition of theoretical and practical competences. However, evidence on how capacity acquisition can be measured for special examination techniques is scarce. ToSkORL (Teaching of Skills in Otorhinolaryngology) is a project aimed at scientifically and didactically investigating students' self-evaluation skills in otorhinolaryngologic and head and neck examination techniques. METHODS: During the examination techniques course, a standardized oral and practical exam for nine different techniques was conducted. Using Likert scales, self-evaluation was based on questionnaires before the clinical skills exam and objective evaluation was performed by the examiners during the examination using a checklist. Self- and objective evaluation were correlated. Nine different examination skills were assessed 42 times each by a total of 91 students. RESULTS: Self-evaluation of competence in the different examination skills varied widely. Nevertheless, self- and objective evaluation correlated well overall, independent of age and gender. Students highly interested in otorhinolaryngology rated their own skills higher but tended toward overestimation. For examination items with intermediate difficulty, the highest divergences between self- and objective evaluation were found. CONCLUSION: Student self-evaluations are an appropriate instrument for measuring competences in otorhinolaryngologic examinations. Instructors should focus on items with allegedly intermediate difficulty, which are most often over- and underestimated.

Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years?

EpCAM (epithelial cell adhesion molecule) was discovered four decades ago as a tumor antigen on colorectal carcinomas. Owing to its frequent and high expression on carcinomas and their metastases, EpCAM serves as a prognostic marker, a therapeutic target, and an anchor molecule on circulating and disseminated tumor cells (CTCs/DTCs), which are considered the major source for metastatic cancer cells. Today, EpCAM is reckoned as a multi-functional transmembrane protein involved in the regulation of cell adhesion, proliferation, migration, stemness, and epithelial-to-mesenchymal transition (EMT) of carcinoma cells. To fulfill these functions, EpCAM is instrumental in intra- and intercellular signaling as a full-length molecule and following regulated intramembrane proteolysis, generating functionally active extra- and intracellular fragments. Intact EpCAM and its proteolytic fragments interact with claudins, CD44, E-cadherin, epidermal growth factor receptor (EGFR), and intracellular signaling components of the WNT and Ras/Raf pathways, respectively. This plethora of functions contributes to shaping intratumor heterogeneity and partial EMT, which are major determinants of the clinical outcome of carcinoma patients. EpCAM represents a marker for the epithelial status of primary and systemic tumor cells and emerges as a measure for the metastatic capacity of CTCs. Consequentially, EpCAM has reclaimed potential as a prognostic marker and target on primary and systemic tumor cells.