Acceptance and adoption of transoral robotic surgery in Germany.

PURPOSE: Since its introduction over a decade ago, the use of robotic surgery (RS) in head and neck surgery has widely spread around the globe, with very differential adoption of this novel surgical technique in different parts of the world. In this study, we analyze the acceptance and adoption of robotic surgery in the head and neck in Germany. MATERIALS AND METHODS: A cross-sectional analysis using a questionnaire evaluating the acceptance and adoption of RS was performed. Questionnaires were distributed to all chairmen /-women of Otorhinolaryngology, Head and Neck Surgery Departments in Germany. RESULTS: A total of 107 respondents completed the questionnaire (65.2%). At university hospitals, 71.4% of the respondents indicated that a robotic system was available, and 21.4% responded that robotic surgery was performed at their institution; 22.7% and 0.04%, respectively, at non-university hospitals. The overall adoption rate was 0.8%. The most common cases performed were TORS resection in the oropharynx. Main reasons for not adopting this technique were costs, lack of interest and available co-operations. CONCLUSION: This study provides evidence of the extent of adoption of TORS in Germany; main perceived barriers to adoption are costs with lack of cost-covering reimbursement and insufficient co-operations with other disciplines as well as hospital administration resulting in a very low adoption rate of this technique over the past decade. Results from this study may assist in decision-making processes on adopting this technique in the future.

[Immunotherapy Against Head and Neck Cancer Stem Cells]. / Immuntherapie gegen Tumorstammzellen bei Plattenepithelkarzinomen im Kopf-Hals-Bereich.

Immunotherapy against head and neck cancer stem cells Immunologic therapies like antibodies in solid tumors like squamous cell cancer of the head and neck are administered either alone or in combination with radiation and chemotherapy. Despite some respectable successes, the effect of this therapy reaches its limits due the ability of the tumor to escape the immune system. Cancer stem cells seem to play an important role in this process due to their intrinsic resistance to conventional therapy and the ability to regenerate tumor heterogeneity. This way they substantially contribute to the formation of recurrences and metastases. Therefore, future immunotherapies should target specifically this subpopulation, possibly in combination with other therapeutic modalities. In this review the immunologic features of cancer stem cells and their potential as target for immunotherapies is summarized.

Epidemiology of laryngeal carcinoma in Germany, 1998-2011.

Constituting 25-30 % of all head and neck cancer cases, laryngeal carcinoma is the most prevalent entity. Major risk factors of laryngeal cancer are smoking and excessive alcohol consumption. This study presents the recent developments in the incidence of laryngeal cancer from 1998 to 2011 in Germany. Laryngeal carcinoma was identified using International Statistical Classification of Diseases and Related Health Problems (ICD10) from German population-based cancer registries. The incidence was provided by the Robert Koch Institute, and the mortality data were derived from German death statistics for further evaluation. Both descriptive and analytical analyses were conducted. From 1998 to 2011, a total of 14,847 laryngeal carcinoma cases were reported, in 13,195 men and 1652 women. Glottic carcinoma represented the main entity, constituting 69 % of male cases and 50 % of female cases. For men, a decline in incidence was observed starting in 2006. The incidence rate for women remained stable for the period of observation. The incidence of laryngeal cancer resembles the development of smoking behaviour in Germany. To maintain the positive trend of the male population and to reduce the incidence in women, it is crucial to continue and to improve the prevention of smoking campaigns in Germany.

Intensity modulated perioperative HDR brachytherapy for recurrent and/or advanced head and neck metastases.

Recurrent neck metastases following surgery and full dose adjuvant radiotherapy of squamous cell head and neck cancer remain a clinical challenge. After revision neck dissection and chemotherapy re-irradiation dosage is often limited and survival prognosis deteriorates. Here, adjuvant high-dose rate intensity modulated perioperative brachytherapy (HDR IMBT) offers a second full radiation dose with a limited volume of normal tissue radiation in the neck. In this retrospective study patients were identified who underwent revision surgery and perioperative HDR IMBT for recurrent neck metastases. Survival rates were estimated and the scarce literature on interstitial brachytherapy of the neck was reviewed. From 2006 to 2014, nine patients were treated for recurrent or palliative neck metastases using salvage surgery and HDR IMBT. Eight patients received previous surgery and external beam radiotherapy with or without chemotherapy. Two and five year overall survival was calculated to be 78 and 67 %, respectively. HDR IMBT is a salvage treatment option for selected cases in the neck following surgical revision or last-line treatment strategies. In the literature and this small cohort radiation toxicity and the risk of "carotid blow-out" seemed to be low.

Diagnostic Value of the Magnetic Resonance Imaging With Intratympanic Gadolinium Administration (IT-Gd MRI) Versus Audio-Vestibular Tests in Menière's Disease: IT-Gd MRI Makes the Difference.

OBJECTIVE: Our aim was to evaluate the validity and reliability of clinically relevant tests in the diagnosis of Menière's disease (MD) according to the criteria formulated during 2015 as well as their efficacy in detecting endolymphatic hydrops (EH). The focus was on: three-dimensional fluid-attenuated inversion recovery-SPectral Attenuated Inversion Recovery (3D-FLAIR-SPAIR) sequences using 3 Tesla magnetic resonance imaging (3T MRI) performed 24 hours after intratympanic Gadolinium injection (IT-Gd) in comparison with the functional tests pure tone audiometry (PTA), caloric test, video head impulse test (vHIT), and cervical-vestibular-evoked-myogenic-potentials (cVEMP). STUDY DESIGN: Retrospective study. SETTING: Tertiary care center. PATIENTS: Primary eligibility criteria were given clinical suspicion of MD and the performance of an IT-Gd MRI leading to a group of 31 patients and 52 ears to be analyzed separately. MAIN OUTCOME MEASURE (S): Reanalysis of the raw diagnostic data leading to comparability of IT-Gd MRI, PTA, caloric test, vHIT, and cVEMP concerning their valency for clinically diagnosed MD and quantifiability of EH. RESULTS: Considering sensitivity, specificity, and the likelihood-ratio only the IT-Gd MRI displayed results qualifying it as a viable device for MD-diagnostics in regards to the criteria of 2015 (p = 0.01), it even provides direct imaging evidence for the underlying pathology of the disease. Furthermore, the comparison between MRI images and test results of caloric test, vHIT and cVEMP revealed that neither of these diagnostic functional tests serves as a reliable indicator for EH. CONCLUSIONS: It appears that the diagnosing process of MD would benefit from turning IT-Gd MRI into a standard diagnostic procedure in cases of suspected MD, displaying better results than caloric test, vHIT, and cVEMP.

ENT COBRA ONTOLOGY: the covariates classification system proposed by the Head & Neck and Skin GEC-ESTRO Working Group for interdisciplinary standardized data collection in head and neck patient cohorts treated with interventional radiotherapy (brachytherapy).

PURPOSE: Clinical data collecting is expensive in terms of time and human resources. Data can be collected in different ways; therefore, performing multicentric research based on previously stored data is often difficult. The primary objective of the ENT COBRA (COnsortium for BRachytherapy data Analysis) ontology is to define a specific terminological system to standardized data collection for head and neck (H&N) cancer patients treated with interventional radiotherapy. MATERIAL AND METHODS: ENT-COBRA is a consortium for standardized data collection for H&N patients treated with interventional radiotherapy. It is linked to H&N and Skin GEC-ESTRO Working Group and includes 11 centers from 6 countries. Its ontology was firstly defined by a multicentric working group, then evaluated by the consortium followed by a multi-professional technical commission involving a mathematician, an engineer, a physician with experience in data storage, a programmer, and a software expert. RESULTS: Two hundred and forty variables were defined on 13 input forms. There are 3 levels, each offering a specific type of analysis: 1. Registry level (epidemiology analysis); 2. Procedures level (standard oncology analysis); 3. Research level (radiomics analysis). The ontology was approved by the consortium and technical commission; an ad-hoc software architecture ("broker") remaps the data present in already existing storage systems of the various centers according to the shared terminology system. The first data sharing was successfully performed using COBRA software and the ENT COBRA Ontology, automatically collecting data directly from 3 different hospital databases (Lübeck, Navarra, and Rome) in November 2017. CONCLUSIONS: The COBRA Ontology is a good response to the multi-dimensional criticalities of data collection, retrieval, and usability. It allows to create a software for large multicentric databases with implementation of specific remapping functions wherever necessary. This approach is well-received by all involved parties, primarily because it does not change a single center's storing technologies, procedures, and habits.

Overexpression of p68 mRNA in head and neck squamous cell carcinoma cells.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) are aggressively growing tumors with only marginal improvement in outcome despite ongoing developments in treatment protocols. This problem has been associated with a lack of therapy individualization on tumor biological properties. MATERIALS AND METHODS: mRNA expression profiles of HNSCC and normal epithelial cells were compared in order to identify genes associated with cancer formation. Differential display was used to trace gene fragments showing differential expression in HNSCC cells, which were than isolated, re-amplified, cloned and sequenced. RESULTS: A 131-bp-long fragment was identified to be overexpressed in HNSCC cells that revealed a 99.3% homology with p68 mRNA. The differential expression was confirmed by Northern hybridization. CONCLUSION: The data presented suggest an involvement of p68 in the process of malignant transformation or progression of HNSCC.

Nasal RANTES and eotaxin production pattern in response to rhinovirus infection.

Tissue eosinophilia is a hallmark of nasal polyposis and its pathogenesis is an area of high interest. RANTES and eotaxin are both known to recruit eosinophils, however, the mechanisms triggering their induction are still uncertain, and viral infections have been suggested to be involved in this process. Therefore, we investigated whether rhinovirus infection is a stimulus for RANTES and eotaxin expression and production. Fibroblasts were cultured from healthy nasal mucosa obtained during endonasal surgery. Cultured cells were infected with human rhinovirus-16 for one to 72 hours. Following total RNA isolation and reverse transcription, RANTES- and eotaxin-mRNA levels were analyzed. In addition, RANTES and eotaxin secretion was measured in culture supernatants by means of an ELISA. Rhinovirus infection induces RANTES-mRNA expression as early as one hour after infection, persisting for up to 72 hours. Eotaxin-mRNA profiles did not alter significantly from control. Protein production was confirmatory for both chemokines, indicating distinct translational latency. Our data suggest that RANTES functions as a host defence mechanism responding to rhinovirus infection, thus supporting a linkage between rhinovirus infections and the pathogenesis of nasal polyposis.

ENT COBRA (Consortium for Brachytherapy Data Analysis): interdisciplinary standardized data collection system for head and neck patients treated with interventional radiotherapy (brachytherapy).

PURPOSE: Aim of the COBRA (Consortium for Brachytherapy Data Analysis) project is to create a multicenter group (consortium) and a web-based system for standardized data collection. MATERIAL AND METHODS: GEC-ESTRO (Groupe Européen de Curiethérapie - European Society for Radiotherapy & Oncology) Head and Neck (H&N) Working Group participated in the project and in the implementation of the consortium agreement, the ontology (data-set) and the necessary COBRA software services as well as the peer reviewing of the general anatomic site-specific COBRA protocol. The ontology was defined by a multicenter task-group. RESULTS: Eleven centers from 6 countries signed an agreement and the consortium approved the ontology. We identified 3 tiers for the data set: Registry (epidemiology analysis), Procedures (prediction models and DSS), and Research (radiomics). The COBRA-Storage System (C-SS) is not time-consuming as, thanks to the use of "brokers", data can be extracted directly from the single center's storage systems through a connection with "structured query language database" (SQL-DB), Microsoft Access(®), FileMaker Pro(®), or Microsoft Excel(®). The system is also structured to perform automatic archiving directly from the treatment planning system or afterloading machine. The architecture is based on the concept of "on-purpose data projection". The C-SS architecture is privacy protecting because it will never make visible data that could identify an individual patient. This C-SS can also benefit from the so called "distributed learning" approaches, in which data never leave the collecting institution, while learning algorithms and proposed predictive models are commonly shared. CONCLUSIONS: Setting up a consortium is a feasible and practicable tool in the creation of an international and multi-system data sharing system. COBRA C-SS seems to be well accepted by all involved parties, primarily because it does not influence the center's own data storing technologies, procedures, and habits. Furthermore, the method preserves the privacy of all patients.

Electrofusion generates diverse DC-tumour cell hybrids for cancer immunotherapy.

BACKGROUND: Hybrid cells generated from dendritic cells (DC) and tumour cells provide tumour-associated antigens (TAA) in a polyvalent mode. The present study was designed to investigate the hybrid cell generation by dendritic cells and different tumour cell lines to establish an electrofusion protocol with an optimal fusion setting. MATERIALS AND METHODS: Hybrid cells from mature DC and tumour cells were generated by electrofusion. Fusion efficiency was determined by flow cytometry, as well as by light and fluorescence microscopy analyses. RESULTS: The gradual electrofusion process constituted different human dendritic cell tumour cell hybrids of high diversity depending on electrical and non-electrical parameters. Factors influencing fusion frequency were determined by specific cell staining with mAbs, FACS analysis and trypan blue dye exclusion. CONCLUSION: Increased fusion efficiency was associated with reduced viability. The protocol presented in this work might be helpful for future fusion studies as a prerequisite for comparable in vitro and human vaccination trials.

Perioperative image-adapted brachytherapy for the treatment of paranasal sinus and nasal cavity malignancies.

PURPOSE: Sinonasal malignancies are a rare group of cancers often associated with late presentation and poor prognosis. In the past, there was little progress regarding survival rate, and often, multimodal treatment regimens are required. The aim of this study was to evaluate the clinical outcome of perioperative image-adapted brachytherapy (IABT) as part of a multidisciplinary treatment regimen for the therapy of sinonasal cancer. METHODS AND MATERIALS: Since 2006, patients with sinonasal cancer at the University Hospital of Schleswig-Holstein Campus Luebeck, Germany, were offered a multimodal treatment concept including head and neck surgery, perioperative IABT with or without external beam radiation therapy, and chemotherapy. In a retrospective study, such patients were analyzed for survival rate, tumor control, and toxicity of the interdisciplinary treatment. RESULTS: Thirty-five consecutive patients were analyzed. The majority of patients (63%) were treated for a primary tumor and 62% presented with tumor Stages III-IV. The mean follow-up time with IABT was 28 months. Overall survival estimate was 72% after 3 years. Disease-specific survival, disease-free survival, and local control rates were 83%, 63%, and 67%, respectively. On univariate analysis, a significant better disease-free survival rate was found in patients treated for primary, but not recurrent, sinonasal cancer (p = 0.006). The overall treatment toxicities were mainly classified Grade I. CONCLUSIONS: Interdisciplinary perioperative IABT is associated with excellent locoregional control and survival rates. IABT is well tolerated and shows low toxicity. Furthermore, visual acuity can be preserved in advanced cases. The implementation of perioperative IABT into multimodal treatment regimens improves the oncologic outcome.

Antimicrobial peptides in oral cancer.

There is increasing evidence that antimicrobial peptides (AMPs) are differentially regulated in cancers such as oral squamous cell carcinomas (OSCC). Data showing that AMPs influence the growth of tumor cells, exhibit direct cytotoxic activity towards cancer cells, function as a tumor suppressor gene or activate the adaptive immunity suggest that a dysregulation of AMPs may be associated with the development of cancer. There is no question that, with increasing resistance against conventional chemotherapy, novel anticancer agents are needed. It is interesting to speculate that natural AMP or synthetic derivatives can be used to develop novel strategies to fight cancer diseases and may represent a novel family of anticancer agents. However, future research is needed to employ the role of AMPs in cancer and to investigate their role as potential anticancer drugs.

Metalloproteinases and their inhibitors: influence on tumor invasiveness and metastasis formation in head and neck squamous cell carcinomas.

BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in tumor invasiveness. This study investigates the expression status of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in head and neck squamous cell carcinomas (HNSCC). METHODS: Of 48 laryngeal squamous cell carcinoma (LSCC) biopsies and 10 HNSCC cell lines, mRNA was isolated, reversely transcribed, and subjected to polymerase chain reaction (PCR) amplifying MMP-1, MMP-2, MMP-9, MMP-10, TIMP-1, and TIMP-2. Silver nitrate-stained gel electrophoresis demonstrated MMP and TIMP expression status. Exemplary immunohistochemistry and zymography confirmed translation and enzyme activity. RESULTS: Densitometric analysis revealed MMP-2 expression and lymph node metastases to be positively and TIMP-1 and TIMP-2 to be negatively correlated with lymph node metastases. TIMP-2 expression and tumor size were negatively correlated. MMP-1, MMP-9, and MMP-10 expression were not correlated to metastasis formation or tumor size. CONCLUSIONS: Our results suggest that MMP-2 expression enhances, whereas TIMP-1 and TIMP-2 both suppress, cancer spread in LSCC.

The role of RANTES in nasal polyposis.

BACKGROUND: Characteristic infiltrates of eosinophils are a hallmark of nasal polyps (NPs). Several studies suggest that members of the CC chemokine family may be involved in this process. RANTES (regulated on activation, normal t-cell-expressed and secreted) is a member of the CC chemokine family with chemotactic activity on mainly eosinophils and T lymphocytes. Thus, RANTES is an interesting target for the recruitment of eosinophils and T lymphocytes into the nose. The degree of the tissue eosinophilia has been reported to correlate with the severeness of the symptomatology of the disease and the extension on the lower respiratory tract, as well as with the probability of the recurrence of NPs. Therefore, we hypothesized that high numbers of eosinophils correlate with high levels of RANTES and that associated atopic diseases modify this correlation. METHODS: Total RNA was extracted from NP homogenates, reverse transcribed and RANTES mRNA expression analyzed using semiquantitative reverse transcription polymerase chain reaction and Northern blot analysis. Histological studies divided NPs in an eosinophilic and low eosinophilic group. Additionally, RANTES protein concentration was measured in homogenates by a RANTES-specific enzyme-linked immunosorbent assay. RESULTS: This study has clearly shown that RANTES is expressed and secreted in NPs. The group with a high tissue eosinophilia had a significant higher RANTES gene expression and protein production than NPs without tissue eosinophilia. The isolated coincidence of acetylsalicyl acid intolerance with chronic hyperplastic sinusitis/NP additionally increased significantly the RANTES amounts in NPs. CONCLUSION: Increased RANTES leads to increased tissue eosinophilia. Associated acetylsalicylic acid intolerance seems to enhance the amount of RANTES in NPs and might explain in part the more severe clinical course in those patients. Thus, RANTES appears to play an important role in mobilization of eosinophils into the local inflamed tissue.