Clinical Impact of Rare and Compound Mutations of Epidermal Growth Factor Receptor in Patients With Non-Small-Cell Lung Cancer.

BACKGROUND: Standard therapy of advanced non-small-cell lung cancer harboring an activating mutation in the epidermal growth factor receptor (EGFR) gene is treatment with tyrosine kinase inhibitors (TKI). However, for rare and compound mutations of the EGFR gene, the clinical evidence of TKI therapy is still unclear. PATIENTS AND METHODS: A total of 2906 lung cancer samples were analyzed for EGFR mutations during routine analysis between 2010 and 2017. The samples have been investigated by Sanger sequencing and since 2014 by next-generation sequencing. RESULTS: We detected EGFR mutations in 408 specimens (14%). Among these, we found 41 samples with rare and 22 with compound mutations. In these 63 samples, 56 different rare EGFR mutations occurred. Information about the clinical outcome was available for 37. Among those with rare mutations, only one patient harboring the mutation p.G874D had disease that responded to first-generation TKI therapy. In contrast, the disease of all patients with compound mutations responded to first- or second-generation TKI therapy. Furthermore, we collected data on clinical relevance regarding TKI therapy from different databases and from an additional literature search, and only found data for 36 of the 56 detected rare mutations. CONCLUSION: Information about the clinical outcome of patients with rare and compound EGFR mutations remains limited. At present, second- and third-generation TKIs are available, which may represent new treatment strategies for these patients. Therefore, it is becoming increasingly important to maintain databases concerning rare EGFR mutations.

Three-dimensional force analysis of surgical manipulations at the long process of the incus.

PURPOSE: Surgical manipulation with application of inappropriate force may damage middle ear structures leading to hearing loss. This work analyzes the forces applied in simulated otosurgical exercises in a laboratory set-up by measuring the spatial components of applied forces with objective assessment criteria. With these criteria, the individual force characteristics applied by the surgeon can be quantified and an objective feedback can be given about their surgical maneuvers. METHODS: A natural size model of the human incus was mounted on a load cell to measure the spatial forces in all three directions during different manipulation tasks performed under the microscope by ten surgeons from our department having different levels of experience in otosurgery. The motions of the incus model and the instrument tip were recorded simultaneously with a video camera. RESULTS: Independent of surgical experience, a three-dimensional force pattern could be detected with components transverse to the desired force directions. The measured forces applied by trainees showed larger variations in magnitude, in spatial distribution and in temporal course than those applied by experienced surgeons. A better repeatability of identical tasks, constancy of force patterns and low peak force values could be seen in the group of experienced surgeons. CONCLUSIONS: The laboratory system presented in this study using simultaneous video and 3-D force registration allows the objective assessment of surgical manipulations, e.g., at the long process of the incus. Training with video and force feedback provides information about surgical techniques and skill development of surgeons and has the potential to shorten the learning curve and to diminish intra-operative risks to patients.

Effect of Tissue Heterogeneity on the Transmembrane Potential of Type-1 Spiral Ganglion Neurons: A Simulation Study.

Electric stimulation of the auditory nerve by cochlear implants has been a successful clinical intervention to treat the sensory neural deafness. In this pathological condition of the cochlea, type-1 spiral ganglion neurons in Rosenthal's canal play a vital role in the action potential initiation. Various morphological studies of the human temporal bones suggest that the spiral ganglion neurons are surrounded by heterogeneous structures formed by a variety of cells and tissues. However, the existing simulation models have not considered the tissue heterogeneity in the Rosenthal's canal while studying the electric field interaction with spiral ganglion neurons. Unlike the existing models, we have implemented the tissue heterogeneity in the Rosenthal's canal using a computationally inexpensive image based method in a two-dimensional finite element model. Our simulation results suggest that the spatial heterogeneity of surrounding tissues influences the electric field distribution in the Rosenthal's canal, and thereby alters the transmembrane potential of the spiral ganglion neurons. In addition to the academic interest, these results are especially useful to understand how the latest tissue regeneration methods such as gene therapy and drug-induced resprouting of peripheral axons, which probably modify the density of the tissues in the Rosenthal's canal, affect the cochlear implant functionality.

On the origin of ear clicks during deglutition or pressure equalization.

To explore the origin of clicking sounds in the ear during deglutition or other pharyngeal movements, which are interpreted differently in the literature. Experimental study at a tertiary referral centre. Acoustic phenomena during a forced opening test of the Eustachian tube (ET) were studied in a temporal bone model. Additionally, in vivo experiments were carried out in healthy volunteers for ruling out movements of the ossicular chain or the drumhead as potential causes of clicks. Thus, acoustic recordings were performed parallel to stapedius or tensor reflex measurements or pneumatic video endoscopies of the tympanic membrane. Obviously the acoustic signals (clicks) appear when the tube opens, which could be visualized and acoustically recorded during forced opening tests in temporal bone experiments. Middle ear muscle contractions with movements of the tympanic membrane did not cause any click events. Together with the results of a previous paper (9) we interpret the clicks as disruptions of fluid or mucus films covering the mucosa during the ET opening. The final goal of our studies is to use such clicks as indicators of ET openings in a new tube function test, which has to be elaborated.

Multicenter Clinical Trial of Vibroplasty Couplers to Treat Mixed/Conductive Hearing Loss: First Results.

OBJECTIVE: To evaluate the safety and effectiveness of round window (RW), oval window (OW), CliP and Bell couplers for use with an active middle ear implant. METHODS: This is a multicenter, long-term, prospective trial with consecutive enrollment, involving 6 university hospitals in Germany. Bone conduction, air conduction, implant-aided warble-tone thresholds and Freiburger monosyllable word recognition scores were compared with unaided preimplantation results in 28 moderate-to-profound hearing-impaired patients after 12 months of follow-up. All patients had previously undergone failed reconstruction surgeries (up to 5 or more). In a subset of patients, additional speech tests at 12 months postoperatively were used to compare the aided with the unaided condition after implantation with the processor switched off. An established quality-of-life questionnaire for hearing aids was used to determine patient satisfaction. RESULTS: Postoperative bone conduction remained stable. Mean functional gain for all couplers was 37 dB HL (RW = 42 dB, OW = 35 dB, Bell = 38 dB, CliP = 27 dB). The mean postoperative Freiburger monosyllable score was 71% at 65 dB SPL. The postimplantation mean SRT50 (speech reception in quiet for 50% understanding of words in sentences) improved on average by 23 dB over unaided testing and signal-to-noise ratios also improved in all patients. The International Outcome Inventory for Hearing Aids (IOI-HA)quality-of-life questionnaire was scored very positively by all patients. CONCLUSION: A significant improvement was seen with all couplers, and patients were satisfied with the device at 12 months postoperatively. These results demonstrate that an active implant is an advantage in achieving good hearing benefit in patients with prior failed reconstruction surgery.

The measurement of Eustachian tube function in a hyperbaric chamber using an ear canal microphone.

OBJECTIVE: The purpose of this study was to further the understanding of the opening of the Eustachian tube in relation to changes in barometric pressure. DESIGN: An ear canal microphone was used to measure the specific sounds related to tube opening and possible eardrum movements. Five subjects with normal tube function were examined in a hyperbaric chamber (up to 304 kPa). All active and passive equalization events were recorded and correlated with the subjectively perceived pressure regulation in the measured ear. RESULTS: The signals recorded were clear and reproducible. The acoustic analysis distinguished between the different kinds of equalization. Subjective impressions were confirmed by the recorded frequency of acoustic phenomena (clicks). During compression, the sequence of active equalization manoeuvres was in a more regular and steady pattern than during decompression, when the click sounds varied. CONCLUSION: The study established a simple technical method for analyzing the function of the Eustachian tube and provided new information about barometric pressure regulation of the middle ear.

Positioning Accuracy in Otosurgery Measured with Optical Tracking.

OBJECTIVES: To assess positioning accuracy in otosurgery and to test the impact of the two-handed instrument holding technique and the instrument support technique on surgical precision. To test an otologic training model with optical tracking. STUDY DESIGN: In total, 14 ENT surgeons in the same department with different levels of surgical experience performed static and dynamic tasks with otologic microinstruments under simulated otosurgical conditions. METHODS: Tip motion of the microinstrument was registered in three dimensions by optical tracking during 10 different tasks simulating surgical steps such as prosthesis crimping and dissection of the middle ear using formalin-fixed temporal bone. Instrument marker trajectories were compared within groups of experienced and less experienced surgeons performing uncompensated or compensated exercises. RESULTS: Experienced surgeons have significantly better positioning accuracy than novice ear surgeons in terms of mean displacement values of marker trajectories. The instrument support and the two-handed instrument holding techniques significantly reduce surgeons' tremor. The laboratory set-up presented in this study provides precise feedback for otosurgeons about their surgical skills and proved to be a useful device for otosurgical training. CONCLUSIONS: Simple tremor compensation techniques may offer trainees the potential to improve their positioning accuracy to the level of more experienced surgeons. Training in an experimental otologic environment with optical tracking may aid acquisition of technical skills in middle ear surgery and potentially shorten the learning curve. Thus, simulated exercises of surgical steps should be integrated into the training of otosurgeons.

"Physiological" Ear Clicking: Its Origin and Potential Usability as a Test Tool for the Eustachian Tube Function.

OBJECTIVE: To explore the origin of "physiological" ear clicks during deglutition or other pharyngeal movements, which, in contrast to disturbing frequent clicks under pathologic conditions, mostly remain unnoticed by the patient. STUDY DESIGN: Clinical experimental study at a tertiary referral center. METHODS: Ear clicks were recorded by a microphone sealing the external ear canal parallel to endoscopic or manometric evaluations of the Eustachian tube function. RESULTS: Obviously, the acoustic signals (clicks) appear when the tube opens. The clicks might be explained by a disruption of fluid or mucus films covering the mucosa. As in our tests clicks could be recorded regularly, they might potentially be used as indicators in a new tube function test, which has to be elaborated.

Regional Pattern of Dementia and Prevalence of Hearing Impairment in Germany.

OBJECTIVES: To determine the association between hearing impairment and dementia. DESIGN: Cross-sectional study. SETTING: Claims data of the Allgemeine Ortskrankenkasse, the largest public health insurance company in Germany. PARTICIPANTS: Age-stratified sample of all insured persons aged 65 and above in the first quarter of 2007 (N = 1,338,462). MEASUREMENTS: Metaregression analysis on the association between regional prevalence of dementia and hearing impairment controlled for major vascular risk factors, including hypertension, hypercholesterolemia, diabetes mellitus, and cerebrovascular disease. Dementia and hearing impairment diagnoses were defined according to International Classification of Diseases, Tenth Revision, codes. Ninety-five regions were distinguished according to the two-digit postal code of the place of residence. RESULTS: A significant association was found between regional prevalences of dementia and hearing impairment that was preserved when controlling for major vascular risk factors (P = .003). Regional dementia prevalence increased by approximately 0.23% when the prevalence of hearing impairment increased by 1 standard deviation. CONCLUSION: The relationship between hearing impairment and dementia has been repeatedly demonstrated on the individual level. The results of the current study confirm that this relationship also exists on a regional level. These findings underscore the potential role of hearing impairment as a risk factor for dementia that will be relevant for the management of elderly patients in general practice.

Can nasal decongestants improve eustachian tube function?

OBJECTIVE: To evaluate the effect of nasal decongestants on eustachian tube (ET) opening. STUDY DESIGN: A prospective nonrandomized study. SETTING: A tertiary referral center. PATIENTS: Twenty-four patients (44 ears) with intact eardrums, 39 patients (43 ears) having a noninfected eardrum defect, and six patients with an upper airway infection. INTERVENTIONS: Nasal or intratympanal (in perforated ears) application of a nasal decongestant (xylometazoline 0.1%). MAIN OUTCOME MEASURES: Change of tube opening quality (yes or no; better or worse) measuring tube opening parameters (pressure, latency) using the Estève method and pressure equalization tests (swallowing at negative and positive external ear canal pressures). RESULTS: In most cases, nasal decongestion or intratympanal use of decongestants have no effect on ET opening. Improvement in tube opening is rather an exception and, in a minority of patients, a reduced ET function was evident. CONCLUSION: Our acute studies revealed no improvement in eustachian ventilatory tube function with the administration of nasal decongestants.

Conservative management of post-intubation tracheal tears-report of three cases.

Iatrogenic tracheal rupture is a rare complication after intubation. We present three patients with tracheal tears. In all of these patients, a common finding was a lesion of the posterior tracheal wall with postoperative subcutaneous and emphysema as the first clinical sign of the rupture. Diagnosis and follow-up were based on clinical and endoscopic findings and chest computed tomography (CT) scans. In our cases with progressive subcutaneous and mediastinal emphysema or dyspnea, we performed a tracheotomy and bypassed the lesion with a tracheostomy tube to avoid an increase in air leakage into the mediastinum. Under broad-spectrum antibiotic therapy, no mediastinitis occurred and all patients survived without sequelae. Closure of tracheostomy was scheduled for 1-2 months after tracheal injury. Analysis of surgical and anesthesiological procedures revealed no abnormalities and the accumulation of tracheal injuries was considered as accidental. We found that in clinically stable patients with spontaneous breathing and with no mediastinitis, a conservative management of tracheal tears is a safe procedure.

Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial.

BACKGROUND: Tracheal intubation without muscle relaxants is usually performed with remifentanil and propofol or sevoflurane. Remifentanil 1.0 to 4.0 µg·kg(-1) and propofol 2.0-3.0 mg·kg(-1) or sevoflurane up to 8.0 Vol% provide acceptable, i.e. excellent or good intubating conditions. We hypothesized that sevoflurane 1.0 MAC would provide acceptable intubating conditions when combined with propofol and remifentanil. METHODS: Eighty-three patients to be intubated were randomised to two groups. The SEVO group received propofol 1.5 mg kg(-1), remifentanil 0.30 µg kg min(-1) and sevoflurane 1.0 MAC; the MR group received the same doses of propofol and remifentanil plus rocuronium 0.45 mg kg(-1). We evaluated intubation and extubation conditions, mean arterial pressure (MAP), heart rate (HR) and bispectral index (BIS). The vocal cords were examined for injury by videolaryngoscopy before and 24 hours after surgery. RESULTS: ACCEPTABLE INTUBATING CONDITIONS WERE SEEN MORE FREQUENTLY WITH ROCURONIUM THAN WITH SEVOFLURANE: 97% versus 82%; p = 0.03; the subscore for vocal cords was comparable: 100% versus 98%. MAP before intubation decreased significantly compared with the MAP at baseline to the same extent in both groups; ephedrine IV was given in 15 (SEVO) versus 16 (MR) patients; p = 0.93. BIS at tracheal intubation was 27 (13-65) in the SEVO group, 29 (14-62) in the MR group; p = 0.07. Vocal cord injuries (oedema, haematoma) were similar: 4 patients in each group. CONCLUSIONS: Overall intubating conditions were better when rocuronium was used; the subscore for vocal cords was comparable. The incidence of side effects was the same in the two groups. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT 01591031.

Polydimethylsiloxane for injection laryngoplasty: two cases necessitating tracheotomy.

The surgical treatment of glottic insufficiency due to lesions of the recurrent laryngeal nerve has become a routine procedure in the last few decades. In particular, injection laryngoplasty with polydimethylsiloxane (PDMS) has proved to be an easy, effective and safe method for vocal fold medialization. It is a biologically inert substance having almost ideal properties as a filler; complications related to its intralaryngeal use such as migration, or granuloma formation are extremely rare and allergic reactions have not been reported as yet. We discuss two cases representing the first description of acute severe complications after injection laryngoplasty with PDMS.

Would an endosteal CI-electrode make sense? Comparison of the auditory nerve excitability from different stimulation sites using ESRT measurements and mathematical models.

UNLABELLED: Regarding potential endosteal cochlear implant electrodes, the primary goal of this paper is to compare different intra- and extra-cochlear stimulation sites in terms of current strengths needed for stimulating the auditory nerve. Our study was performed during routine cochlear implantation using needle electrodes for electric stimulation and by visually recording electrically elicited stapedius reflexes (ESRT) as a measure for the stimulus transfer. Of course this rather simple setup only allows rough estimations, which, however, may provide further arguments whether or not to proceed with the concept of an endosteal electrode. In addition, a mathematical model is being developed. In a pilot study, intra-operative electric stimuli were applied via a needle electrode commonly used for the promontory stimulation test. Thus, stapedius reflex thresholds (ESRTs), electrically elicited via the needle from different points inside and outside the cochlea served as indicators for the suitability of different electrode positions towards the modiolus. Tests were performed on 11 CI-recipients. In addition, the extension of electrical fields from different stimulation sites is simulated in a mathematical cochlea model. In most patients ESRT measurements could be performed and evaluated. Thus an "endosteal" stimulation seems possible, although the current intensities must be higher than at intraluminal stimulation sites. Moreover, our model calculations confirm that the extension of electric fields is less favourable with increasing distance from the electrode to the ganglion nerve cells. In terms of hearing, the concept of an endosteal electrode should only be promoted, if its superiority for hearing preservation can be proven, e.g. in animal experiments. However, for other indications like the electric suppression of tinnitus, further research seems advisable. LEVELS OF EVIDENCE: N/A.

Laryngeal injuries following endotracheal intubation in ENT surgery: predictive value of anatomical scores.

Endotracheal intubation has been associated with a threefold higher incidence of laryngopharyngeal complaints following anesthesia in comparison to laryngeal mask airway. Such complaints, including hoarseness and sore throat, have been reported in up to 90% of patients within 24 h of extubation. The purpose of this study was to determine which preoperatively documented clinical and anatomic parameters are predictive of laryngo-pharyngeal trauma resulting from elective endotracheal intubation. Fifty-three patients undergoing ENT procedures requiring general anesthesia with endotracheal intubation were recruited. Pre and postoperative laryngostroboscopic examination was performed and findings correlated to preoperative clinical and anatomic parameters. Readily assessed anatomic parameters including height (>180 cm) and weight (>80 kg) correlated significantly to the Eckerbom grade of intubation-associated acute laryngeal injury (rs = 0.374; p = 0.006 and rs = 0.278; p = 0.044, respectively). The mandibular protrusion test also correlated significantly to the Eckerbom grade (rs = 0.462, p = 0.001) while the upper-lip-bite test showed significant correlation to impaired vocal fold oscillation (rs = 0.288, p = 0.036), with injury prediction sensitivities of 37.5 and 39.4%, respectively. No parameters correlated to subjective complaints (n = 5, 9.2%). This study provides suggestions on how to improve the classification of intubation-associated laryngeal injuries as well as providing the basis for larger clinical trials in other surgical subspecialties.

Comparative Study between the Surgeon's Intraoperative Evaluation and Histopathology for Diagnosis of Laryngeal Lesions.

Objective. To compare the surgeon's evaluation and histopathology for diagnosis of laryngeal lesions. Material. A clinical survey was distributed to laryngeal surgeons, ENT clinicians, and students in 2013 at the Department of Otorhinolaryngology in Rostock. Participants were asked to anonymously identify laryngeal pathologies and to assess the severity of the lesion starting from hyperplasia and inflammation over moderate dysplasia to early laryngeal cancer. Images of similar clinical laryngeal lesions were demonstrated in a multiple-choice modus to assess the surgeon's intraoperative evaluation. The questionnaires were digitally processed and evaluated. The results were correlated with histopathology and compared between experienced laryngeal surgeons, clinicians inexperienced in laryngeal surgery, and medical students from the Medical Faculty of the University of Rostock. Results. Sensitivity and specificity varied among the various groups, being highest in experienced laryngeal surgeons. In this group, sensitivity, specificity, positive and negative predictive value, and accuracy were 85%, 56%, 44%, 90%, and 65%, respectively. In 4% and 31%, laryngeal disease was underdiagnosed and overdiagnosed, respectively. In this group, Kappa statistics resulted in Kappa 0.32 (P < 0.001). Conclusion. This clinical survey clearly demonstrates that conformity between histopathology and evaluation of the laryngeal lesion depends on the surgeon's experience.

Anesthesia with Propofol versus Sevoflurane: Does the Longer Neuromuscular Block under Sevoflurane Anesthesia Reduce Laryngeal Injuries?

Anesthesia can be maintained with propofol or sevoflurane. Volatile anesthetics increase neuromuscular block of muscle relaxants. We tested the hypothesis, that sevoflurane would cause less vocal cord injuries than an intravenous anesthesia with propofol. In this prospective trial, 65 patients were randomized in 2 groups: SEVO group, anesthesia with sevoflurane, and TIVA group, total intravenous anesthesia with propofol. Intubating and extubating conditions were evaluated. Vocal cord injuries were examined by stroboscopy before and 24 and 72 h after surgery; hoarseness and sore throat were assessed up to 72 h after surgery. Hoarseness and sore throat were comparable between both groups (not significant). Similar findings were observed for vocal cord injuries: 9 (SEVO) versus 5 (TIVA) patients; P = 0.36; the overall incidence was 24%. Type of vocal cord injuries: 9 erythema and 5 edema of the vocal folds. Neuromuscular block was significantly longer in the SEVO group compared with the TIVA group: 71 (range: 38-148) min versus 52 (range: 21-74) min; P < 0.001. Five patients (TIVA group) versus 11 patients (SEVO group) needed neostigmine to achieve a TOF ratio of 1.0 (P = 0.14). Under anesthesia with propofol laryngeal injuries were not increased; the risk for residual curarization, however, was lower compared with sevoflurane.

Distribution of circulating natural killer cells and T lymphocytes in head and neck squamous cell carcinoma.

OBJECTIVE: Natural killer (NK) cells are capable of eliminating malignantly transformed cells without prior sensitization. In contrast to NK-cells, T lymphocytes possess antitumourous activity that is restricted to major histocompatibility complex (MHC) recognition. The aim of this study was to determine the causes of the different distributions of these cell types in the peripheral blood of patients with head and neck squamous cell carcinomas (HNSCC). METHODS: A cohort of 105 subjects was divided into three clinical groups: non-treated HNSCC patients, treated relapse-free HNSCC patients and healthy control subjects. Peripheral blood mononuclear cells (PBMC) were isolated from venous blood, subsets were depleted, flow cytometric counts were made and subsequently correlation analyses with clinical parameters were performed. RESULTS: Treated relapse-free HNSCC patients have a significantly increased mean proportion of NK-cells in PBMC of 26.39% (p<0.001), whereas T lymphocytes and natural killer-T-(NKT) cells of treated patients have a significantly decreased mean proportion in PBMC of 55.15% (p<0.05) at least 12 months after treatment. This inverse redistribution of these two subsets is reflected in a significantly increased mean NK/T-ratio of 0.54 (p<0.05) in treated patients. The NK/T-ratio correlates with the systemic invasiveness of the type of therapy patients undergo and is highest after surgery with adjuvant radiochemotherapy (0.64, rs=0.334, p<0.01). This appears to be a post-therapeutic long-term effect in treated patients, as they had a mean relapse-free period until venous puncture of 47.9 months in our study. We also demonstrated age-dependent changes in the peripheral distribution of T- and NK-cells. CONCLUSION: These findings reveal new aspects in understanding tumour biology and interactions with the cellular immune system which provide novel starting points for further research.

Cochlear implants.

Cochlear implants have evolved to become the treatment of choice for severely hearing-impaired patients. Speech signals are picked up by a microphone, processed and then delivered to the stimulating electrodes (the current maximum number being 22) that are placed on an electrode array implanted into the scala tympani of the cochlea. The target cells of electrical stimulation, the spiral ganglion cells (SGCs), are located some distance away in the central axis of the cochlea. SGCs start to degenerate after the onset of deafness. Additionally, fibrous tissue is formed around the electrode array after implantation. If cochlear implants are to deliver sound that is closer to natural hearing, the number of independent stimulation channels has to be increased. Optimization of the interface between the electrode array and the surrounding tissue is, therefore, the focus of current research. Promising approaches relating to cells, micro- and nanosystems will be reviewed.