[Mutation signatures in head and neck squamous cell carcinoma : Pathogenesis and therapeutic potential]. / Mutationssignaturen beim Kopf- und Hals-Tumor : Pathogenese und Potenzial für die Therapie.

BACKGROUND: The pathogenesis of head and neck squamous cell carcinoma (HNSCC) is a complex and multistage process which results from the interaction of exogenous and endogenous cellular processes. Each of these processes leaves a characteristic pattern of mutations on the tumor genome, a so-called mutational signature. STATE OF THE ART: The subject of current studies is to decipher specific signatures of mutational processes operating during HNSCC pathogenesis and to address their prognostic value. Computational analysis of genomic sequencing data by The Cancer Genome Atlas (TCGA) revealed mutational signatures 1, 2, 4, 5, 7, and 13 as the main players in HNSCC pathogenesis. Signature 16 was first discovered in human papillomavirus (HPV)-negative oral and oropharyngeal tumors. In many studies, an association of signature 16 with alcohol and tobacco consumption as well as with an unfavorable prognosis was described.

Early nasal reconstruction after skin-preserving excision of squamous cell carcinoma of the nasal vestibule.

Surgery for early-stage squamous cell carcinoma of the nasal vestibule (SCCNV) may lead to facial disfigurement. We wanted to investigate if skin-preserving excision of SCCNV with reconstruction is oncologically, aesthetically, and functionally justifiable in cases with proximity to the skin. From 2010 to 2016, 16 patients underwent skin-preserving excision of T1-2 N0 SCCNV by a lateral rhinotomy approach at a tertiary referral center. The inner nose was reconstructed using a mucoperichondrial septal flap for the inner lining and a septal pivot flap and/or auricular cartilage grafting for the framework. Nasal appearance was measured on pre- and postoperative photographs. Median follow-up was 5.4 years. Three (19%) patients received adjuvant radiotherapy. Two (12.5%) recurrences occurred locally, but not at the site of preserved skin. The Kaplan-Meier estimate of local control rate after 5 years was 83%. All patients could be salvaged, giving an ultimate control rate of 100%. Nasal tip projection decreased by 6.7% (p < 0.001), and it was retained normal or near normal in 87.5% of patients. Nasal axis changed by 1.7° (p = 0.5). Nasal deviation occurred in 6.25% (1/16) of patients, and minor alar retraction in 6.25% of patients (1/16). Nasal breathing was normal or close to normal in 75% (12/16) of patients. Skin-preserving excision of SCCNV is oncologically justifiable in selected cases even in proximity to nasal skin. Early inner nasal reconstruction preserves nasal form and function to a high degree. This technique is a suitable alternative to rhinectomy and to avoid the sequelae of radiotherapy in selected cases.

Topographic bone thickness maps to evaluate the intuitive placement of titanium miniplates for nasal prostheses.

The aim of this study was to evaluate the intuitive placement of titanium miniplates. The hypothesis was that virtual planning can improve miniplate placement. Twenty patients were included in the study. These patients were fitted with 21 titanium miniplates (16 y-plates, three t-plates, and two u-plates) to retain nasal prostheses between 2005 and 2017. Colour-coded topographic bone thickness maps (TBTMs) were created in fused pre- and postoperative computed tomography. Implants were virtually transposed at the position of highest bone thickness. The bone thickness index (BTI) was calculated as the sum of points assigned at each screw (1 point per millimetre up to 4 mm, and 5 points for greater values) divided by the number of screws. One plate broke after 2.8 years, thus plate survival after 5 years was 91% using the Kaplan-Meier method. The BTI for all 21 plates increased from 3.4 to 4.1 points using virtual transposition (P<0.001). No significant changes were observed in t- and u-plates, but the median BTI increased from 3.1 to 4.1 points (P<0.0005) in 16 y-plates. The change was substantial (≥0.5 points) in 9/16 y-plates. Therefore, the hypothesis that virtual planning improves implant placement was accepted.

Measurement of bone thickness at the site of titanium miniplates used to retain nasal prostheses in fused computed tomographic data.

Our aim was to investigate the bone thickness at the site of titanium miniplates inserted to retain nasal prostheses. We studied 13 patients who had had titanium miniplates inserted for retention of nasal prostheses with a total of 60 titanium bone screws. A trajectory along each bone screw was segmented in fused computed tomographic (CT) data. Bone thickness was measured along this trajectory on the preoperative CT. The median bone thickness at the positions of the screws implanted on the frontal process of the maxillary bone was 1.4 (range 0.2-6.9) mm (mean 1.8). The median (range) values for men and women were 1.4 (0.2-6.9) mm and 1.3 (0.2-3.3) mm, respectively. The thickest bone was at the cranial part of the frontal process of the maxilla with a median of 2.0 (range 0.3-4.1) mm. However, differences in sex and position were not significant. None of the implant miniplates lost osseointegration. Despite the low bone stock at the lateral aspect of the pyriform aperture, survival of implanted titanium miniplates was 100% in this study group.

Primary surgical treatment of nasal vestibule cancer - therapeutic outcome and reconstructive strategies.

OBJECTIVE: The treatment strategy of squamous cell carcinoma of the nasal vestibule (SCCNV) is controversial. The objective of this study is to investigate the role of surgery, which is the preferred treatment option at our institution. DESIGN: This was a monocentric prospective study of patients that were diagnosed with SCCNV between 2005 and 2013. MATERIAL AND METHODS: Twenty-six patients were included. Tumors were staged using the UICC (7th edition) TNM classification of nasal cavity cancer and the classification proposed by Wang. The primary treatment was surgery in all patients. Survival data were statistically analyzed using the Kaplan-Meier method. The median follow-up time was 6 years. RESULTS: Using the UICC classification, 9/26 tumors were staged as pT1 (35%), 7/26 as pT2 (27%), and 10/26 as pT4a (39%). Using the classification by Wang, 9/26 tumors were staged as pT1 (35%), 15/26 as pT2 (58%), and 2/26 as pT3 (8%). Reconstruction was performed using an implant-retained prosthesis in 50% of patients and by plastic surgery in the remaining 50%. Only 2/26 patients (8%) needed adjuvant radiation therapy. The five-year recurrence-free survival (RFS) was 86.7%, disease-specific survival was 96.2% and overall survival was 91.8% after five years. CONCLUSION: Surgery in SCCNV gives an excellent prognosis and minimized the need for radiotherapy.

Quality of life after nasal cancer resection - surgical versus prosthetic rehabilitation.

BACKGROUND: Nose reconstruction following resection of nasal carcinomas is controversial. The objective of this study is to investigate the effect of surgical reconstruction versus prosthetic rehabilitation on patient quality of life (QOL). DESIGN: This was a monocentric prospective study of patients diagnosed with nasal carcinoma from 2003 to 2013. QOL was evaluated using two organ-specific questionnaires (Rhinoplasty Outcome Evaluation [ROE] and the Functional Rhinoplasty Outcome Inventory-17 [FROI-17]) and a generic questionnaire, the Short-Form 36 Health Survey (SF-36). MATERIAL AND METHODS: Sixty-four patients were included. Patients completed the ROE, FROI-17, and SF-36 questionnaires after nasal reconstruction. Questionnaires were completed by 62.8% of the 51 alive patients. RESULTS: Recurrence-free survival (RFS) was 89.9%, disease-specific survival was 94.5%, and overall survival was 75.5% after five years according to the Kaplan-Meier method. Considering initial tumor stage, early stage patients had a significantly higher self-confidence score in FROI-17 subgroup analysis. In contrast, advanced stage patients showed a significantly higher score for social functioning in SF-36. Prosthetically fitted patients scored highly on the ROE questionnaire showing a high degree of aesthetic satisfaction. Surgically reconstructed patients showed a high degree of self-confidence on the FROI-17 questionnaire. However, the organ-specific ROE and FROI-17 scores were not significantly different between patients who received surgical reconstruction and prosthetic rehabilitation after oncological resection. When comparing the rehabilitation method as a function of tumor stage, there was significantly better score for physical functioning in early stage surgically reconstructed patients in the SF-36, but no significant differences in organ-specific QOL. CONCLUSION: Surgical reconstruction and prosthetic rehabilitation after nasal cancer resection have the same effect on organ- and non-organ-specific QOL.

[Prosthetic treatment of nasal septal perforations : Results with custom-made silicone buttons]. / Epithetische Versorgung von Nasenseptumperforationen : Ergebnisse mit individuell angepassten Obturatoren aus Silikon.

BACKGROUND: Perforations of the nasal septum can be very disturbing for patients due to increased crust formation, nose bleeds, obstruction of nasal breathing and whistling sounds during nasal breathing. The aim of this study was to evaluate how the symptom burden can be alleviated by custom-made silicone buttons derived from an impression mold. MATERIAL AND METHODS: A retrospective study was carried out to evaluate 45 patients with symptomatic septal perforations, who have been treated over a period of 8 years. The magnitude and localization of the perforations were measured on the impression molds as well as in situ in 28 patients. The symptoms were rated on a visual analogue scale (VAS) before and after treatment (response 64%). RESULTS: No correlation was found between the size of the perforation and the distance from the nasal opening. Of the patients 31 (69%) still had the septal button in situ at the time of the last follow-up. The magnitude and localization of the perforation were not found to be predictors of treatment success. The following symptoms showed a highly significant improvement: crust formation (VAS median 75 vs. 31), nose bleeds (VAS median 50 vs. 0), obstruction of nasal breathing (VAS median 84 vs. 14) and whistling breathing sounds (VAS median 69 vs. 0). Unpleasant odor and symptoms of sinusitis did not show significant changes. The long-term septal button carriers rated the improvement with a median of 91% on the VAS. CONCLUSION: The success of prosthetic closing of septal perforations by a custom-made button still cannot be accurately predicted. The majority of patients were extraordinarily satisfied because the symptom burden could be significantly reduced.

[Diabetes mellitus as a prognostic marker in oropharyngeal and laryngeal squamous cell carcinoma]. / Diabetes mellitus als prognostischer Marker beim Oropharynx- und Larynxkarzinom.

Recent experimental and clinical studies have provided compelling evidence that diabetes mellitus (DM) is an important risk factor in various cancers, and may affect both pathogenesis and prognosis. Additionally, antidiabetic agents such as metformin exhibit an antitumorigenic effect. However, to date there is insufficient knowledge about the role of DM in the pathogenesis and prognosis of head and neck squamous cell carcinoma (HNSCC).In a retrospective monocentric study including 424 patients with SCC of the oropharynx (OPSCC) or larynx (LaSCC), the impact of DM on clinical and histopathologic parameters was investigated. The authors found a rising incidence of DM among LaSCC patients (<10 % until 2005 and 20 % since 2006) and a significant association between DM and clinical and histopathologic features (age, gender, tumor size, and pathologic grading), which depended on the anatomic site. Moreover, a clear trend toward unfavorable progression-free and overall survival of HNSCC patients with DM upon current treatment modalities was evident.The presented data support a relative increase in patients with DM, particularly for LaSCC. This might have a sustained influence on treatment decisions and management, and should be considered in future clinical trials. A better understanding of the cellular and molecular traits of HNSCC in DM could pave the way for innovative therapeutic strategies in terms of personalized medicine.

[The epigenome. Target for innovative therapies in head and neck carcinoma]. / Das Epigenom. Zielstruktur für innovative Therapiekonzeptebeim Kopf- und Halskarzinom

BACKGROUND: The pathogenesis of head and neck squamous carcinoma (HNSCC) is a complex and multistage process, which is characterized by the accumulation of genetic and epigenetic aberrations. Most of our knowledge concerning the regulation of gene expression by the epigenome is based on changes in DNA methylation and post-translational histone modifications that affect the phenotypic plasticity of cells under physiological and pathological conditions. STATE OF THE ART: Numerous experimental studies have unraveled the impact of epigenetic alterations during initiation and malignant progression of HNSCC and substantiate their contribution in the context of tumor stem cells and treatment resistance. Due to their stability epigenetic modifications serve as promising diagnostic and prognostic biomarkers, and the reversible nature makes key regulators attractive targets for innovative treatment options.

[Percutaneous titanium implants for bone conduction hearing aids: experience with 283 cases]. / Perkutane Titanimplantate für Knochenleitungshörgeräte: Erfahrungen mit 283 Fällen.

BACKGROUND: By virtue of direct bone conduction, percutaneous bone-anchored hearing implants offer a high level of wearing comfort, as well as audiologically superior signal transmission due to less dampening. Over the years, titanium implants have been optimized and the surgical technique developed into a minimally invasive intervention without soft tissue reduction. This study aims to investigate the success rates of the various percutaneous implant systems. MATERIALS AND METHODS: This retrospective study includes 191 patients who received a total of 283 percutaneous titanium implants for bone conduction hearing systems during the period from 01.01.1989 until 31.12.2013. Patient age ranged from 2 to 81 years (mean 36 years). The mean follow-up duration was 5.2 years. RESULTS: The overall osseointegration success rate was 92.6% and ranged from 90.5 to 100% for the various implant systems (p = 0.6). For children and adolescents, the success rate was 86.8%, compared to 95.2% in adults (p = 0.023). Classical soft tissue reduction was received by 185 patients, mainly via the dermatome technique. The linear incision technique was used in 3.8% of cases and the technique without soft tissue reduction in 3.7% of cases. Revision surgery for soft tissue problems was performed in 4.2% of cases. CONCLUSION: Success rates in adults were significantly higher than those in children and adolescents. Although success rates improved with the development of new systems, this did not reach statistical significance. Minimally invasive surgery without soft tissue reduction is considered state of the art.

Clinical investigation of flat panel CT following middle ear reconstruction: a study of 107 patients.

OBJECTIVES: After middle ear reconstruction using partial or total ossicular replacement prostheses (PORP/TORP), an air-bone gap (ABG) may persist because of prosthesis displacement or malposition. So far, CT of the temporal bone has played the main role in the diagnosis of reasons for postoperative insufficient ABG improvement. Recent experimental and clinical studies have evaluated flat panel CT (fpCT) as an alternative imaging technique that provides images with high isovolumetric resolution, fewer metal-induced artefacts and lower irradiation doses. METHODS: One hundred and seven consecutive patients with chronic otitis media with or without cholesteatoma underwent reconstruction by PORP (n = 52) or TORP (n = 55). All subjects underwent preoperative and postoperative audiometric testing and postoperative fpCT. RESULTS: Statistical evaluation of all 107 patients as well as the sole sub-assembly groups (PORP or TORP) showed a highly significant correlation between hearing improvement and fpCT-determined prosthesis position. FpCT enables detailed postoperative information on patients with middle ear reconstruction. CONCLUSIONS: FpCT is a new imaging technique that provides immediate feedback on surgical results after reconstructive middle ear surgery. Specific parameters evaluated by fpCT may serve as a predictive tool for estimated postoperative hearing improvement. Therefore this imaging technique is suitable for postoperative quality control in reconstructive middle ear surgery. KEY POINTS: • Flat panel CT offers advantages with regard to artefacts and radiation dose. • FpCT provides higher isovolumetric resolution of temporal bone and middle ear implants. • FpCT allows prediction of the postoperative hearing outcome in patients. • FpCT is an important tool for immediate postoperative quality control. • FpCT improves postoperative management of patients with complications following ossicular replacement.

[Grafts with microvascular anastomosis. Their use in the head and neck region following radiotherapy and vessel depletion]. / Mikrovaskulär anastomosierte Transplantate. Verwendung in der Kopf-Hals-Region nach Bestrahlung und Gefäßdepletion.

Surgical tumor removal is often the treatment of choice in patients with head and neck squamous cell carcinoma. Depending on the extent of tumor resection, large defects are often produced in the individual head and neck regions, necessitating reconstructive surgery to avoid further functional impairment. In principle, this decision depends on the size and location of the defect, the aesthetic importance of the region and the functional significance of the area to be replaced. Reconstructive free flap procedures in patients who have undergone radiotherapy or exhibit vessel depletion in the neck due to multiple previous surgical interventions are particularly challenging. In order to ensure the best possible outcomes of surgical oncology therapies under difficult circumstances, this paper discusses the important factors and variables that can increase the success rate of microvascular grafts in irradiated or multiply resected patients.

Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus.

First-line treatment of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC) is based on platinum, 5-fluorouracil (5-FU) and the monoclonal antiEGFR antibody cetuximab. However, in most cases this chemoimmunotherapy does not cure the disease, and more than 50% of HNSCC patients are dying because of local recurrence of the tumors. In the majority of cases, HNSCC overexpress the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome. In this study, we engineered an EGFR-targeted oncolytic measles virus (MV), armed with the bifunctional enzyme cytosine deaminase/uracil phosphoribosyltransferase (CD/UPRT). CD/UPRT converts 5-fluorocytosine (5-FC) into the chemotherapeutic 5-FU, a mainstay of HNSCC chemotherapy. This virus efficiently replicates in and lyses primary HNSCC cells in vitro. Arming with CD/UPRT mediates efficient prodrug activation with high bystander killing of non-infected tumor cells. In mice bearing primary HNSCC xenografts, intratumoral administration of MV-antiEGFR resulted in statistically significant tumor growth delay and prolongation of survival. Importantly, combination with 5-FC is superior to virus-only treatment leading to significant tumor growth inhibition. Thus, chemovirotherapy with EGFR-targeted and CD/UPRT-armed MV is highly efficacious in preclinical settings with direct translational implications for a planned Phase I clinical trial of MV for locoregional treatment of HNSCC.

Flat panel CT following stapes prosthesis insertion: an experimental and clinical study.

OBJECTIVES: Anatomical information of the middle and inner ear is becoming increasingly important in post-operative evaluation especially after stapesplasty with unsuccessful improvement of the air-bone gap (ABG). So far computed tomography (CT) has been the first choice for detection of reasons for recurrent hearing loss. CT has the disadvantage of metal-induced artefacts after insertion of middle ear implants and of a relatively high irradiation dose. METHODS: Flat panel CT (fpCT) was performed in three temporal bone specimen after experimental insertion of different stapes prostheses, aiming to validate the accuracy of fpCT of the middle and inner ear. Additionally, 28 consecutive patients, supplied with different stapes prostheses underwent post-operative fpCT to compare the pre- and post-operative hearing results with the determined prosthesis position in the middle and inner ear. RESULTS: In all cases, fpCT showed a statistically significant correlation between hearing improvement and prosthesis position. This technique provided detailed post-operative information of the implant position in patients and temporal bone specimen. CONCLUSIONS: The new imaging technique of fpCT allows the immediate and almost artefact-free evaluation of surgical results following stapesplasty. Further benefits are a lower irradiation dose and higher isovolumetric resolution compared with standard CT. KEY POINTS: Flat panel computed tomography (fpCT) helps otosurgeons design precise stapes protheses. fpCT allows a prediction of the postoperative hearing outcome in patients. fpCT is an adequate imaging technique for immediate postoperative quality control. Postoperative management of patients with prosthesis-related complications is more appropriate.

[Differential diagnosis of headaches in otorhinolaryngology]. / Differenzialdiagnose von Kopfschmerzen in der HNO-Heilkunde.

Facial pain and headaches are heterogeneous, therefore, a differential diagnosis, interdisciplinary survey and mapping of the pain symptoms are essential for determination of treatment concepts. This requires an otorhinolaryngology (ENT) adapted zoning of the various pains in the head and neck in line with the classification of the International Headache Society (IHS). In this review, idiopathic, symptomatic and neuralgic facial pain and headaches will be differentiated and classified according to their location from the ENT medical point of view. This provides otolaryngologists with a simplified, targeted diagnosis and subsequent indication for therapy.