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Summary Background Sinonasal mucosal melanoma (SNMM) is a rare disease entity comprising 0.4–1.3% of all melanomas. Surgery with free margins has been the primary treatment over decades. Neither the addition of radiotherapy nor chemotherapy could significantly improve outcome rates of this devastating malignancy. This study presents our clinical experience with SNMM over a 19-year period and summarizes the current body of literature on SNMM. Methods This retrospective analysis included 12 patients with SNMM treated from 2001 to 2019 at an academic center. Additionally, a literature review of the last 29 years on treatment and survival data of SNMM was conducted. Results Main initial symptoms were epistaxis and nasal obstruction. Of the patients 9 underwent endoscopic surgery, 6 received adjuvant therapy. 3 patients who did not undergo surgery, received chemoradiotherapy, radiotherapy alone, and chemotherapy alone, respectively. At the time of diagnosis 2 patients had distant metastases and 4 patients developed distant metastases during the course of the disease. Mean overall survival (OS) was 30.6 months, 3‑year and 5‑year OS were 25%, and 18.2%, respectively. Conclusion Unspecific symptoms and hidden anatomic locations lead to delayed diagnosis and increased rates of metastatic dissemination. Distant metastasis is the main treatment failure in SNMM. Surgery with free margins remains the primary treatment for SNMM. Adjuvant radiotherapy might improve local control in individual cases but efficient systemic therapy is needed to improve outcome rates. To evaluate and define more effective targeted treatment options and improve outcome rates, homogeneous data and prospective multicentric analysis are needed.

Purpose Radiochemotherapy (RCT) is an effective standard therapy for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Nonetheless, toxicity is common, with patients often requiring dose modifications. Methods To investigate associations of RCT toxicities according to CTCAE version 5.0 and subsequent therapy modifications with short- and long-term treatment outcomes, we studied all 193 patients with HNSCC who received RCT (70 Gy + platinum agent) at an academic center between 03/2010 and 04/2018. Results During RCT, 77 (41%, 95% CI 34–49) patients developed at least one ≥ grade 3 toxicity, including seven grade 4 and 3 fatal grade 5 toxicities. The most frequent any-grade toxicities were xerostomia (n = 187), stomatitis (n = 181), dermatitis (n = 174), and leucopenia (n = 98). Eleven patients (6%) had their radiotherapy schedule modified (mean radiotherapy dose reduction = 12 Gy), and 120 patients (64%) had chemotherapy modifications (permanent discontinuation: n = 67, pause: n = 34, dose reduction: n = 7, change to other chemotherapy: n = 10). Objective response rates to RCT were 55% and 88% in patients with and without radiotherapy modifications (p = 0.003), and 84% and 88% in patients with and without chemotherapy modifications (p = 0.468), respectively. Five-year progression-free survival estimates were 20% and 50% in patients with and without radiotherapy modifications (p = p = 0.88), respectively. Conclusions Reductions of radiotherapy dose were associated with impaired long-term outcomes, whereas reductions in chemotherapy intensity were not. This suggests that toxicities during RCT should be primarily managed by modifying chemotherapy rather than radiotherapy.

Background Generally, it is known that men are affected more frequently by nonmelanoma skin cancer (NMSC) than women. The aim of our study was to investigate the effect of sex on the characteristics of NMSCs of the pinna at the population that our center serves and to compare it with the international data. Methods We analyzed retrospectively the data of 225 patients with NMSC of the pinna. Sex‐specific differences were investigated for basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) subgroups. Results The ratio of BCC to cSCC was determined in male patients at 1:1.3, in contrast in females it was identified at 4:1 (P = .001). Conclusion In our study, a new aspect of the sex‐dependent distribution of cSCC and BCC of the pinna was demonstrated. Women are affected four times more frequently by BCC than by cSCC, whereas in men this ratio is approximately equal.

Summary Background The outcome of patients with cancer of the head and neck is significantly improved by increased interdisciplinary cooperation. The main focus of this study was a comparison of epidemiologic factors (age, sex, origin, staging) of patients with head and neck cancer in Styria, with those for patients throughout Austria. Methods A retrospective data analysis of collected archived tumor board protocols of the Comprehensive Cancer Center (CCC) Graz included the patient’s age, sex, area of residence, TNM stage, reasons for inoperability, comorbidities and performance status by ECOG (Eastern Cooperative Oncology Group), was performed. This study focuses on 340 patients who presented with a head and neck malignancy for the first time. Results In the period from January 2014 to December 2015 a total of 252 men (74.1%) and 88 women (25.9%) with malignant head and neck tumors, were presented in the tumor board for the first time. The mean age at diagnosis was 63.4 years. In 45.5% the patients already demonstrated advanced tumor stages (T4 = 27.9%, T3 = 17.6%). Most newly diagnosed neoplasms were cancers of the oropharynx (24.1%), larynx (19.4%) and oral cavity (18.8%) and 36.5% were considered to be inoperable. Curative and palliative treatments were initiated in 83.2% and 16.9%, respectively. Conclusion The region of south Styria showed a higher incidence of T3 and T4 tumors of the oropharynx than the average Austrian population. Measures to increase awareness of this problem should be initiated to support general otorhinolaryngologists and general practitioners in detecting oropharyngeal cancers at an earlier stage.

Squamous cell carcinoma is the most common type of throat cancer. Treatment options comprise surgery, radiotherapy, and/or chemo(immuno)therapy. The salivary microbiome is shaped by the disease, and likely by the treatment, resulting in side effects caused by chemoradiation that severely impair patients’ well-being. High-throughput amplicon sequencing of the 16S rRNA gene provides an opportunity to investigate changes in the salivary microbiome in health and disease. In this preliminary study, we investigated alterations in the bacterial, fungal, and archaeal components of the salivary microbiome between healthy subjects and patients with head and neck squamous cell carcinoma before and close to the end point of chemoradiation (“after”). We enrolled 31 patients and 11 healthy controls, with 11 patients providing samples both before and after chemoradiation. Analysis revealed an effect on the bacterial and fungal microbiome, with a partial antagonistic reaction but no effects on the archaeal microbial community. Specifically, we observed an individual increase in Candida signatures following chemoradiation, whereas the overall diversity of the microbial and fungal signatures decreased significantly after therapy. Thus, our study indicates that the patient microbiome reacts individually to chemoradiation but has potential for future optimization of disease diagnostics and personalized treatments.

The purpose of the present study was to evaluate the prognostic significance of the pre- treatment C-reactive protein (CRP) level in a cohort of 503 patients with oral and oropharyngeal cancer treated at a tertiary academic center between 2000 and 2017. Cancer-specific survival (CSS), overall survival (OS) and loco-regional control (LC) were calculated using Kaplan-Meier analysis. To evaluate the prognostic value of the CRP level for the clinical endpoints, univariate and multivariate Cox regression models were applied. The median follow-up period was 61 months. Patients were divided into elevated CRP (&ge, 5 mg/L) and normal CRP groups, according to pre-treatment plasma levels. An increased CRP level was significantly associated with shorter CSS (p &lt, 0.001, log-rank test), as well as with shorter OS (p &lt, 0.001, log-rank test) and loco-regional control (p = 0.001, log-rank test). In addition, multivariate analysis identified CRP as an independent predictor for CSS (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.08&ndash, 2.35, p = 0.020) as well as for OS (HR 1.62, 95%CI 1.17&ndash, 2.24, p = 0.004) and LC (HR 1.50, 95%CI 1.06&ndash, 2.14, p = 0.023). In subgroup analysis, Kaplan Meier curves revealed that an elevated pre-treatment CRP level was a consistent prognostic factor for poor CSS (p = 0.003, log-rank test), OS (p = 0.001, log-rank test), and LC (p = 0.028, log-rank test) in patients treated with definitive (chemo-) radiotherapy, whereas a significant association in patients undergoing surgery and postoperative radiotherapy was not detected. The pre-treatment CRP level seems to represent a prognostic factor for CSS, OS, and LC in patients with oral and oropharyngeal cancer, particularly in those treated with definitive (chemo-) radiotherapy. Additional large-scale prospective studies are warranted to confirm and extend our findings.

Background Results from publications evaluating discrepancies between clinical staging data in relation to pathological findings demonstrate that a significant number of head and neck squamous cell carcinoma (HNSCC) patients are not correctly staged. The aim of this retrospective study was to analyze potential discrepancies of radiological assessment versus pathological data of regional lymph node involvement and to compare the results with data published in the literature. Patients and methods In a retrospective analysis we focused on patients with HNSCC routinely treated by surgery plus postoperative radiotherapy between 2002 and 2012. For inclusion, complete pre-operative clinical staging information with lymph node status and patho-histological information on involved lymph node regions as well as survival outcome data were mandatory. We included 87 patients (UICC stage III-IV 90.8%) for which the aforementioned data obtained by CT or MRI were available. Overall survival rates were estimated by the Kaplan–Meier method. The Pearson correlation coefficient and Spearman’s rank correlation coefficient (non-linear relationship) was calculated. Results Discrepancies at the level of overall tumour stage assessment were noticed in 27.5% of all cases. Thereof, 5.7% were assigned to patho-histological up-staging or down-staging of the primary tumour. At the lymph node level, 11.5% of the patients were downstaged, and 10.3% were upstaged. Conclusions The study showed that in approximately one-fifth (21.8%) of the patients, lymph node assessment by CT or MRI differs from the pathologic staging, an outcome that corresponds well with those published by several other groups in this field.

Ginger (Zingiber officinale Roscoe) is used for a wide array of conditions in traditional medicine in Asia, but little is known about the effect on head and neck cancer. In this study, the effect of two major pharmacologically active compounds of ginger, 6-gingerol and 6-shogaol, were studied on head and neck cancer cell lines. Furthermore, experiments in combination with established treatment methods for head and neck cancer were performed. Proliferation assays showed a dose-dependent reduction of cell viability. Flow cytometry analysis revealed the induction of apoptosis. Western blot analysis indicated that the antiapoptotic protein survivin was suppressed after treatment. Although a combination of 6-shogaol with cisplatin exhibited no synergistic effect, the combination with irradiation showed a synergistic reduction of clonogenic survival. In conclusion, ginger compounds have many noteworthy effects on head and neck cancer cell lines. In particular, the enhancement of radiosensitivity is remarkable.

Objectives Despite the excellent overall survival of 92%-97% in early glottic cancer, recurrence rates of 13%-20% have not improved in the last decades. The engulfment and cell motility protein 3 (ELMO3) have been described as prognostic marker in patients with lung cancer. The aim of this study was to investigate the expression of ELMO3 in early laryngeal cancer patients treated with TLM and to evaluate its prognostic significance on clinical outcome. Design, setting and participant Forty-eight patients with glottic carcinoma (T1N0M0) that underwent primary treatment with TLM between 1994 and 2012 were analysed. ELMO3 expression of the tumour was assessed using immunohistochemistry and correlated with clinical data. Main outcome measure Overall survival, disease-specific survival (DSS) and disease-free survival (DFS) rates Results Positive ELMO3 expression was found in 23% of the patients and was correlated with poor DSS and DFS (P

Background To date, no studies have successfully shown that a highly specific, blood-based tumour marker to detect clinically relevant HPV-induced disease could be used for screening, monitoring therapy response or early detection of recurrence. This study aims to assess the clinical performance of a newly developed HPV16-L1 DRH1 epitope-specific serological assay. Methods In a multi-centre study sera of 1486 patients (301 Head and Neck Squamous Cell Carcinoma (HNSCC) patients, 12 HIV+ anal cancer patients, 80 HIV-positive patients, 29 Gardasil-9-vaccinees, 1064 healthy controls) were tested for human HPV16-L1 DRH1 antibodies. Analytical specificity was determined using WHO reference-sera for HPV16/18 and 29 pre- and post-immune sera of Gardasil-9-vaccinees. Tumour-tissue was immunochemically stained for HPV-L1-capsidprotein-expression. Findings The DRH1-competitive-serological-assay showed a sensitivity of 95% (95% CI, 77.2–99.9%) for HPV16-driven HNSCC, and 90% (95% CI, 55.5–99.7%) for HPV16-induced anal cancer in HIV-positives. Overall diagnostic specificity was 99.46% for men and 99.29% for women ≥ 30 years. After vaccination, antibody level increased from average 364 ng/ml to 37,500 ng/ml. During post-therapy-monitoring, HNSCC patients showing an antibody decrease in the range of 30–100% lived disease free over a period of up to 26 months. The increase of antibodies from 2750 to 12,000 ng/ml mirrored recurrent disease. We can also show that the L1-capsidprotein is expressed in HPV16-DNA positive tumour-tissue. Interpretation HPV16-L1 DRH1 epitope-specific antibodies are linked to HPV16-induced malignant disease. As post-treatment biomarker, the assay allows independent post-therapy monitoring as well as early diagnosis of tumour recurrence. An AUC of 0.96 indicates high sensitivity and specificity for early detection of HPV16-induced disease. Funding The manufacturer provided assays free of charge.

The coniotomy is a potentially life-saving measure in a “can’t intubate, can’t ventilate” situation. In order to provide security in an emergency, the advantages and disadvantages of the current methods as a surgical approach or with needle catheter systems based on Seldinger techniques are presented in a detailed description and classification along the current guidelines. Specific anatomical features in relation to coniotomy are taught and indications and contraindications are dealt with. The reader is familiarized with different methods of the step-by-step procedure. From an interdisciplinary point of view, the chapter provides both beginners and experienced surgeons with an orientation aid between possible complications of a coniotomy and the avoidance of suffocation thanks to successful surgical performance.

Objective The incidence of oropharyngeal squamous cell carcinoma (OPSCC), especially human papillomavirus (HPV)-associated, is increasing worldwide. Immunotherapy become available for patients with carcinomas in the head and neck region, however without ideal biomarker. Markers like PD-L1 vary in the clone of the antibody used, and the method of evaluation. Adequate and reliable immune cells characterization and evaluation is still not found. Furthermore, studies analyzing representativeness of different tissue samples are scarce. We analyzed small biopsy, lymph node (LN) metastasis and resected OPSCC, in regards of tumor infiltrating lymphocyte (TIL) density, PD-L1 and p16 expression. Material and methods Patients with OPSCC diagnosed from 2000 to 2016, with small biopsy, resection specimen and LN metastasis samples were selected. We analyzed TILs on hematoxylin-eosin stain, and PD-L1 and p16 expression in tumor cells. Concordance between different tumor locations was evaluated. Results 93 patients, with 65 small biopsies, 72 resection specimens, and 70 LN metastases were included. TILs, p16 and PD-L1 demonstrated very high concordance. Additionally, PD-L1 expression in the small biopsies was more representative of the PD-L1 expression in the resection specimens, than the LN samples. Conclusion TILs density can be reliably assessed using hematoxylin-eosin stain with high concordance between the small biopsy, resection specimen and LN metastasis. Evaluation of concordance of p16 expression is very high, nevertheless some cases might be misdiagnosed on a small biopsy or lymph node metastasis. Evaluation of PD-L1 expression is very reliable on the biopsy specimen. Different PD-L1 clones and methods of evaluation still remain to be addressed.

Background Cigarette smoking is a major risk factor for head and neck squamous cell carcinoma. Still, the effect of cigarette smoke on the molecular level is unclear. The aim of the present study was to investigate the early effects of cigarette smoke on carcinogenesis of head and neck squamous cell carcinoma. Methods Human oral keratinocytes were exposed for 1 week to standardized cigarette smoke extract, and subsequently RT‐quantitative PCR array was performed. Protein expression of dysregulated genes was determined by immunohistochemistry in tissue samples of oral squamous cell carcinoma, oral leukoplakia, and tonsil mucosa. Results RT‐PCR revealed upregulation of ITGA‐2 and MMP‐1, whereas TEK receptor tyrosine kinase was downregulated in human oral keratinocytes. ITGA‐2 and MMP‐1 were significantly overexpressed in tissue samples of oral squamous cell carcinoma in comparison to normal mucosa (P

Summary Background After publishing promising results for the treatment of patients with human papilloma virus (HPV) positive oropharyngeal cancer with radiochemotherapy regarding 2‑year survival, we present an update of the disease-specific and disease-free survival after 5 years. Patients and methods A total of 29 patients of which 18 were HPV negative and 11 HPV positive with squamous cell carcinoma of the oropharynx received radiation therapy with or without chemotherapy (cisplatin) or immunotherapy (cetuximab) between 2007 and 2009. At time of the present analysis, six patients are still alive including four with HPV positive and two with HPV negative oropharyngeal carcinoma, while 15 out of 16 patients with HPV negative tumors died and 1 died of another cause with evidence of disease. Results Since the 2‑year disease-specific survival of patients with HPV positive cancer of the oropharynx was published with 100% versus 30.4% in HPV negative tumors, we now present the 5‑year disease-specific survival after treatment, which was 85.7% in HPV positive versus 11.1% in HPV negative patients. Conclusion We present the results of patients receiving radiochemo(immuno)therapy for oropharyngeal cancer regarding the HPV status, which is still promising.

Background Carcinogenesis is determined by various epigenetic events, such as histone deacetylation. The purpose of this study was to investigate the effect of the new histone deacetylase inhibitor resminostat on head and neck squamous cell carcinoma (HNSCC) cell lines. Methods The cytotoxicity of resminostat and cisplatin on HNSCC cell lines SCC25, CAL27, and FaDu was determined using CCK-8 cell proliferation assay and combination index analysis. Cells were irradiated with 2 to 8 Gray. Apoptosis was measured using flow cytometry and expression of Mcl-1, p-AKT, and survivin was investigated. Results Treatment with resminostat showed a decrease of cell proliferation of HNSCC cell lines. In addition, a synergistic effect with cisplatin as well as with radiation treatment could be observed. Induction of cell death and dose-dependent downregulation of survivin was evident in all cell lines. Conclusion Resminostat is a promising treatment of HNSCC because of its antiproliferative, chemosensitizing, and radiosensitizing effects. © 2017 Wiley Periodicals, Inc. Head Neck 39: 900–907, 2017

Objective Prognosis of patients with head and neck squamous cell carcinoma (HNSCC) is still poor. Novel therapeutic approaches are of great interest to improve the effects of radiochemotherapy. We evaluated the effects of tyrosine kinase inhibitor neratinib on HNSCC cell lines CAL27, SCC25 and FaDu as a single agent and in combination with irradiation and chemotherapy. Methods Effects of neratinib were evaluated in HNSCC cell lines CAL27, SCC25 and FaDu. Effect on cell viability of neratinib and combination with cisplatin and irradiation was measured using CCK-8 assays and clonogenic assays. Western blot analysis was performed to distinguish the effect on epithelial growth factor receptor (EGFR) and HER2 expression. Apoptosis was evaluated by flow cytometry analysis. Results Growth inhibition was achieved in all cell lines, whereas combination of cisplatin and neratinib showed greater inhibition than each agent alone. Apoptosis was induced in all cell lines. Combination of neratinib with irradiation or cisplatin showed significantly increased apoptosis. In clonogenic assays, significant growth inhibition was observed in all investigated cell lines. Conclusion Neratinib, as a single agent or in combination with chemo-irradiation may be a promising treatment option for patients with head and neck cancer. This article is protected by copyright. All rights reserved.

Reconstruction of the upper gastrointestinal tract presents a surgical challenge after esophagogastrectomy, especially when it includes hypopharyngolaryngectomy. Reconstruction is generally undertaken with interposed colon as a substitute conduit, but it carries several risks. Alternative reconstruction of the foregut with pedicled retrosternal jejunum anastomosed at the level of the base of the tongue is described.

Objectives Reliable prognostic markers are lacking for tongue carcinoma. C-reactive protein (CRP) and a ratio from neutrophils/lymphocytes (NLR) are biomarkers, associated with prognosis in solid cancers. Aim of this work was to investigate the role of CRP and NLR in prognosis of patients with tongue carcinoma. Design Retrospective cohort study. Setting We retrospectively analysed data of patients treated for tongue carcinoma at our institution. Levels of CRP, Neutrophils and Lymphocytes were measured pretherapeutic. Participants 197 patients treated for squamous cell carcinoma of the tongue between 2002 and 2015. Main outcome measures Overall survival, disease-free survival. Results Elevated CRP was significantly associated with shorter overall survival in our cohort in uni- and multivariate analysis. NLR was not associated with prognosis. Conclusion In the present study we could confirm the role of CRP as an independent prognostic marker in patients with tongue carcinoma. Incorporating this marker in prognostication could represent a valuable and moreover inexpensive tool for improved decisions making concerning therapy in the future.

Background Merkel cell carcinoma (MCC) is a rare and aggressive malignancy of the skin. Treatment options for MCC include surgery, radiotherapy, and chemotherapy. The purpose of this study was to assess the expression of Polo-like kinase 1 (PLK1) in MCC and the role of the inhibitor, BI2536, as a potential therapeutic option in MCC. Methods PLK1 expression was assessed in tissue samples from 28 patients with MCC and 5 healthy skin samples via immunohistochemistry and furthermore in the 2 MCC cell lines, MCC13 and MCC26, via immunoblotting. The impact of increasing doses of BI2536 alone and in combination with cisplatin or irradiation on cell viability was measured using the CCK-8 assay. Colony forming assays were performed to evaluate long-term effects of combination treatments. Additionally, the induction of apoptotic cell death was measured via flow cytometry. Results PLK1 is moderately to strongly expressed in 75% of the patients with MCC. The PLK1 inhibitor, BI2536, demonstrated marked inhibition of cell proliferation with IC50 in the low nM range (from 10.07–12.39 nM). Furthermore, BI2536 induces apoptosis in MCC cell lines and acts synergistically in combination with irradiation and cisplatin. Conclusion Because of the marked upregulation of PLK1 in MCC tumor samples and potent inhibition of cell proliferation using a specific clinically available inhibitor, targeting of PLK1 qualifies as a potential novel therapeutic strategy in MCC. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

This study aimed to assess the oral health status and dental care behaviours of patients treated for head and neck squamous cell carcinoma (HNSCC) in an Austrian tertiary hospital. Dental care behaviours, oral hygiene level, caries, and periodontal parameters were assessed in 48 patients treated for HNSCC >6 months ago. Only 52 % requested a dental check-up after HNSCC diagnosis and prior to treatment, and of those, 80 % received some type of dental treatment. At time-point of clinical examination, 69 % of the patients had consulted a dentist within the last year, but 88 % still needed dental treatment; 75 % had at least one tooth with caries and 78 % had moderate to severe periodontitis. Although it was recommended, only half of the patients did consult a dentist prior to HNSCC treatment and oral health appeared, in general, low prioritized. About 90 % of the current group of head and neck squamous cell carcinoma cancer patients presented large treatment needs, both in regard with caries and periodontal disease, about 20 months after cancer treatment.

Two-dimensional (2D) monolayer cell culture models are the most common method used to investigate tumor cells in vitro. In the few last decades, a multicellular spheroid model has gained attention due to its adjacency to tumors in vivo. The aim of the present study was to investigate immunohistochemical differences between these two cell culture systems. The FaDu, CAL27 and SCC25 head and neck squamous cell carcinoma (HNSCC) cell lines were seeded out in monolayer and multicellular spheroids. The FaDu and SCC25 cells were treated with increasing doses of cisplatin and irradiation. CAL27 cells were not used in theproliferation experiments, since the spheroids of CAL27 cells were not able to process the reagent in CCK-8 assays. Furthermore, they were stained to present alterations of the following antigens: Ki-67, vascular endothelial growth factor receptor, epithelial growth factor and survivin. Differences in growth rates and expression patterns were detected in certain HNSCC cell lines. The proliferation rates showed a significant divergence of cells grown in the three-dimensional model compared with cells grown in the 2D model. Overall, multicellular spheroids are a promising method to reproduce the immunohistochemical aspects and characteristics of tumor cells, and may show different response rates to therapeutic options.

Minor salivary gland carcinoma is a rare and heterogeneous type of cancer. Molecular prognostic and predictive markers are sparse. The aim of this study was to identify new prognostic and predictive markers in minor salivary gland carcinoma. 50 tissue samples of carcinomas of the minor salivary glands (adenoid cystic carcinoma n = 23, mucoepidermoid carcinoma n = 12, adenocarcinoma n = 10, carcinoma ex pleomorphic adenoma n = 2, salivary duct carcinoma n = 1, clear cell carcinoma n = 1, basal cell carcinoma n = 1) were immunohistochemically stained for β-catenin, cyclin D1 and PIN1. Expression patterns were analyzed and correlated to clinical outcome of 37 patients with complete clinical data. High expression of membranous β-catenin was linked to significantly better overall survival in patients with adenoid cystic carcinoma (log rank test, χ 2 = 13.3, p = .00397, Bonferroni corrected p = .024). PIN1 and cyclin D1 did not show any significant correlation to patients’ clinical outcome. Expression of β-catenin in adenoid cystic carcinoma of the minor salivary glands significantly correlates with better overall survival. Hence, evaluation of β-catenin might serve as a clinical prognostic marker.

Die Koniotomie (= Krikothyreotomie) bezeichnet die chirurgische Durchtrennung des Ligamentum conicum (= Ligamentum cricothyroideum), das sich zwischen Schild- und Ringknorpel des Larynx aufspannt. Da in diesem Bereich der Atemweg der Haut am nachsten kommt, kann dieser mit der Durchtrennung dieses Ligaments sehr schnell, sicher und komplikationsarm eroffnet und gesichert werden. Dies kann auf chirurgischem Weg oder mit Hilfe eines an die Seldinger-Technik angelehnten Nadel- Katheter-Systems auf »nichtchirurgischem« Weg erfolgen.

Die hochakute Luftnot durch eine Blockade der oberen Atemwege, die durch eine Intubation nicht zu beheben ist, zwingt den Arzt zu einer unmittelbaren chirurgischen Sicherung der Atemwege durch eine Koniotomie. Es wird daher zunachst das chirurgisch-interventionelle Vorgehen bei der Koniotomie vorgestellt, bevor die chirurgische Tracheostomie und die perkutan-dilatative Tracheostoma-Anlage dargestellt werden. Ein besonderes Augenmerk wird auf die Tracheotomie im Sauglings- und Kleinkindalter gelegt, da die medizinischen Fortschritte in der Neonatologie immer haufiger eine Tracheotomie erfordern.

Quality improvement of care for patients with head and neck cancer remains a constant objective for the multidisciplinary team of physicians managing these patients. The purpose of quality assurance (QA) for head and neck surgical oncology and surgical trials however differs. While QA for the general head and neck patient aims to improve global outcome through structural changes of health-care systems, QA for surgical trials pursues the goal to help providing meaningful results from a clinical trial through the definition of structure, process and outcome measures within the trial. Establishing a QA program for surgical trials is challenging largely due to the variation in the execution of surgical techniques. Within this article, we describe the surgical QA program, which was developed for the phase III European Organisation for Research and Treatment of Cancer (EORTC) 1420 study, a trial assessing swallowing function after transoral surgery compared with radiation therapy. We propose based on our experience to further develop surgical QA for surgical clinical trials by introducing two separate components, one adaptable and one non-adaptable. The adaptable is tailored to the scientific question and specific procedure; the non-adaptable consists of minimal structural requirements of the clinical unit to participate in surgical trials at EORTC as well as guidelines and incentives for protocol adherence based on our experience in EORTC 24954. Finally, we strongly believe that surgical QA designed for clinical trials may serve as a basis for the development of QA surgical guidelines in clinical practice.

This study aimed to undertake an initial, comparative analysis of the oral salivary microbiome of patients with oral and oropharyngeal squamous cell carcinoma versus healthy controls. This project, conceived as a pilot study, included 11 patients (1 female, 10 male, mean age 61.6 yrs., SD = 8.2 yrs.) and 11 healthy controls (1 female, 10 male, mean age 46.7 yrs., SD = 15.1 yrs.). Samples of saliva were analysed by high-throughput sequencing of the 16S rRNA gene using the MiSeq platform. Sequence data revealed microbial changes that may mirror disease progression and reflect clinical preconditions such as age, alcohol consumption, tumour size, lymph node status, smoking habit, and tumour HPV-positivity. Consequently, mapping microbial changes in patients with oral and oropharyngeal squamous cell carcinomas might improve our understanding of the pathobiology of the disease, and help in the design of novel diagnostic and treatment strategies.

Since the prognosis of head and neck squamous cell carcinoma (HNSCC) still remains poor, identifying novel chemotherapeutic agents is of outmost importance. The anticancer potential of quinoxalines has been described in various tumor entities. Caroverine, also a quinoxaline derivative, has been shown to suppress tumor promotion factors. The aim of this study was to evaluate the effect of caroverine on HNSCC cell lines. The HNSCC cell lines SCC9, SCC25, CAL27, and FaDu were incubated with caroverine alone or in combination with cisplatin, 5-fluorouracil (5-FU) or cetuximab. Cell viability was measured using the CCK-8 assay. The murine 3T3 fibroblast cell line was used to address tissue specificity. Apoptosis was visualized by immunohistochemistry. Caroverine showed a dose-dependent growth inhibition in all cell lines, IC50 values ranged from 75.69 to 179.80 µM. This effect was increased when caroverine was combined with cetuximab or 5-FU. Immunohistochemistry displayed more apoptosis after caroverine treatment compared to controls. Furthermore, caroverine alone had no growth inhibitory effect on 3T3 cells. For the first time, this study provides evidence that caroverine may serve as a supportive drug in the treatment of HNSCC patients.

Conclusion: Resveratrol shows a growth inhibitory effect in head and neck squamous cell carcinoma (HNSCC) cell lines and acts synergistically in combination with etoposide in three cell lines via the induction of apoptotic and necrotic cell death. Objective: In patients with recurrent/distant HNSCC, one of the limited treatment options is etoposide. The aim of this study was to investigate whether resveratrol is able to enhance the antiproliferative effect of etoposide in vitro synergistically. Methods: Dose-response curves of etoposide and resveratrol in three HNSCC cell lines were generated. Drug combinations in a fixed dose ratio were carried out and results were analyzed by the combination index method. Detection of apoptotic cells was performed by flow cytometry. Results: Both compounds show a dose- and time-dependent growth inhibitory effect as single agents after treatment. In combination experiments we observed distinct synergistic effects increasing over time in all three cell lines.

Background Malignant tumors of the salivary glands comprise about 3% to 5% of all head and neck carcinomas. The purpose of our study was to find possible predictive and/or prognostic markers for parotid cancer. Methods A total of 46 tissue samples of carcinomas of the parotid gland were immunohistochemically stained for s-catenin, cyclin D1, and PIN1. The factors were analyzed regarding their prognostic value for disease-free and overall survival. Results An overexpression of the cytoplasmatic s-catenin was linked to a statistically significant worse outcome regarding disease-free (p = .0296) and overall survival (p = .0416). The 5-year overall survival was 83.9% in patients without and 0% in patients presenting with overexpression of cytoplasmatic s-catenin. Additionally, Union Internationale Contre le Cancer (UICC) stage correlated with overall survival (p = .0306) and disease-free survival (DFS; p = .0473). Conclusion Multivariate analysis showed that overexpression of cytoplasmatic s-catenin and the UICC stage are 2 independent prognostic markers for survival in patients with parotid cancer. © 2014 Wiley Periodicals, Inc. Head Neck 37: 30–36, 2015

Cancer of the head and neck is one of the six most common malignancies, accounting for more than 600,000 case per year worldwide.

Carcinogenesis is determined by various epigenetic events, such as histone deacetylation. The purpose of this study was to investigate the effect of the new histone deacetylase inhibitor resminostat on head and neck squamous cell carcinoma (HNSCC) cell lines.The cytotoxicity of resminostat and cisplatin on HNSCC cell lines SCC25, CAL27, and FaDu was determined using CCK-8 cell proliferation assay and combination index analysis. Cells were irradiated with 2 to 8 Gray. Apoptosis was measured using flow cytometry and expression of Mcl-1, p-AKT, and survivin was investigated.Treatment with resminostat showed a decrease of cell proliferation of HNSCC cell lines. In addition, a synergistic effect with cisplatin as well as with radiation treatment could be observed. Induction of cell death and dose-dependent downregulation of survivin was evident in all cell lines.Resminostat is a promising treatment of HNSCC because of its antiproliferative, chemosensitizing, and radiosensitizing effects. © 2017 Wiley Periodicals, Inc. Head Neck 39: 900-907, 2017.

Thymoquinone (TQ) is the main bioactive constituent present in black seed oil (Nigella sativa); it has shown anti-inflammatory and anti-neoplastic effects in various cancer cell types. The aim of the present study was to investigate the effects of TQ on head and neck squamous cell carcinoma (HNSCC) cell lines, on its own and in combination with radiation and cisplatin, respectively. The SCC25 and CAL27 HNSCC cell lines were treated with TQ alone and in combination with cisplatin or radiation, respectively. Proliferation assays and clonogenic assays were performed. Apoptosis was detected by flow cytometry. TQ exhibited dose-dependent cytotoxicity via apoptosis in the investigated cell lines. In combination with cisplatin, TQ resulted in no significant increase in cytotoxicity. Combined with radiation, TQ significantly reduced clonogenic survival compared with each treatment method alone. TQ is a promising agent in the treatment of head and neck cancer due to its anti-proliferative and radiosensitizing properties. However, the combination of TQ with cisplatin showed no therapeutic benefit in vitro.

Arsenic trioxide (ATO) has been approved for the treatment of relapsed acute promyelocytic leukaemia. The aim of this study was to determine whether ATO would lead to cell death in head and neck squamous cell carcinoma (HNSCC) cell lines and whether it was able to enhance the cytotoxicity of cisplatin, a standard chemotherapeutic agent. The four HNSCC cell lines SCC9, SCC25, CAL27 and FADU were treated with ATO or cisplatin alone or with ATO and cisplatin in combination. Cytotoxicity assays, immunohistochemistry, western blot analysis and flow cytometry were carried out. Possible interactions between the two drugs were calculated using the Chou-Talalay equation. Ther results demonstrated a synergistic cytotoxic effect of the combination of ATO and cisplatin at high doses. The two agents induced apoptosis in all four HNSCC cell lines. In conclusion, this study showed that ATO is a promising therapeutic drug with cytotoxic effects in HNSCC. We demonstrated a synergistic effect in the combined treatment with cisplatin at high doses.

The correlation between p16 upregulation and high-risk HPV infection is well known in head and neck squamous cell cancer. However, no information is available on rare carcinomas of the minor salivary glands. We analyzed 38 samples of minor salivary gland malignancies. p16 expression was determined by immunohistochemistry, HPV DNA by using in situ hybridization to detect low (type 6 and 11) and high (type 16 and 18) risk HPV types. In 71% of samples p16 expression was found. Low-risk HPV DNA could not be detected in any of the samples, whereas high-risk HPV DNA was found in two samples of mucoepidermoid carcinoma, which also showed the highest immunoreactivity with p16. HPV infection does not seem to be a common event in minor salivary gland carcinoma. Upregulation of p16 is present in the majority of cases but only diffuse staining correlates with HPV 16 and 18 infections.

BACKGROUND: The purpose of this study was to evaluate the incidence and clinical significance of HPV (Human papilloma virus) infection in patients with head and neck cancer who had received radiotherapy in Eastern Austria. PATIENTS AND METHODS: 88 patients with head and neck cancer including 26 patients with oral cavity cancer, 45 patients with oropharyngeal cancer, seven patients with laryngeal carcinoma and ten patients with carcinoma of the hypopharynx were screened for high risk HPV by immunohistochemistry, PCR (Polymerase Chain Reaction) and in-situ hybridization. 29 out of 45 patients with a squamous cell carcinoma of the oropharynx received radiotherapy alone, radiotherapy in combination with cisplatin or cetuximab. RESULTS: Of the investigated 29 patients with oropharyngeal cancer receiving conservative treatment, 11 had a HPV-positive and 18 a HPV-negative tumor. Patients received radiation ± cisplatin or cetuximab, where the HPV-positive patients had a significant better response to treatment and overall survival (p = 0.015) as well as disease-free survival (p = 0.001) after therapy. CONCLUSION: Patients with oropharyngeal carcinoma and a positive HPV status respond considerably better to radiochemotherapy than patients with HPV-negative tumors. HPV screening is a simple procedure and can easily be implemented in routine pathology investigations and should be included in standard operational procedures for the diagnosis and therapy of head and neck cancer patients.

Background Activation of the hedgehog pathway may contribute to carcinogenesis. This study characterizes the expression pattern in squamous cell carcinoma of the skin and the head and neck. Methods Tissue microarrays were constructed with samples of squamous cell carcinoma of the skin and the head and neck. All tissue samples were immunohistochemically stained for 7 Hedgehog pathway molecules. Results Significant (p < .0001) overexpression of all evaluated molecules could be observed in the tumor samples compared with healthy control tissues. Expression of Gli-2 showed significant upregulation and that of Smoothened and Patched significant downregulation in head and neck compared with skin carcinoma. High expression of Sonic hedgehog correlates significantly (p = .001) with poor overall survival in patients with head and neck cancer. Conclusions Hedgehog signaling is differentially regulated in squamous cell carcinomas of the skin and the head and neck. Sonic hedgehog expression may serve as a prognostic factor in patients with head and neck cancer. © 2010 Wiley Periodicals, Inc. Head Neck, 2011

The anti-apoptotic protein Mcl-1 is highly expressed in various types of malignant tumors. Overexpression is reported to correlate with poor prognosis and disease progression. We report the expression levels of Mcl-1 in tumor samples of the parotid gland. A retrospective study containing 108 patients was performed. A tissue microarray of six malignancies of the parotid gland and pleomorphic adenoma as control was constructed. Parotid gland tumor samples were immunohistochemically stained for Mcl-1 and expression intensities were assessed. Statistical analysis included correlation to patients' clinical data and comparison of malignancies to the adenoma.All malignancies had significantly higher expression of Mcl-1 than the pleomorphic adenomas. The intensity, however, had no significant correlation to overall survival.Our immunohistochemical findings indicate that parotid gland malignancies produce high levels of Mcl-1 protein. Therefore, Mcl-1 might serve as a predictive co-marker in tumors of the parotid gland.

Background Esophageal, esophago-hypopharyngeal and esophago-tracheobronchial fistulae or strictures arising either de novo or following therapeutic interventions constitute serious therapeutic challenges. If conservative measures fail, pedicled muscular or myocutaneous flaps are life-saving assets. Methods During the last 10 years we treated 13 patients (11 males, 2 females; mean age: 59; range: 44–82y) with complex esophageal/hypopharyngeal problems by using pedicled muscle flaps. Results All had but one case of lye ingestion had underlying malignant disease, all but two of the latter had had chemo- and or radiotherapy. At the time of the intervention eight patients were in a critical, septic condition. There were 5 esophago-tracheal, 2 esophago-bifurcational, one esophago-colo-bronchial, and one hypopharyngo-tracheal fistula, as well as one pharyngo-cutaneous fistula all following resection/reconstruction and/or attempts of surgical closure. One patient had stricture following external irradiation, another one anastomotic stricture. We applied a total of 17 pedicled flaps: 10 pectoralis major flaps (7 of them myocutaneous, three split flaps), 5 deltoideo-pectoral myocutaneous flaps and 2 sternocleidomastoideus flaps. In 11 patients additional intermittent stenting was used. In 6 patients the respective condition healed, 4 patients could be discharged but had minor recurrent fistulae that could be handled conservatively, in three cases persisting sepsis and multiorgan failure could not be overcome. Conclusion Muscle flaps can be life-saving in large fistulae of the esophagus and the hypopharynx and are useful for refractory cervical stenosis. In presence of multiorgan dysfunction, however, healing of flaps however initially vital, is often impaired. Disclosure All authors have declared no conflicts of interest.

Our aim in this study was to identify prognostic factors and the optimal therapeutic management in patients with minor salivary gland carcinomas.Overall and disease-free survival and overall survival after recurrence in patients with adenoidcystic carcinoma (n = 25), mucoepidermoid carcinoma (n = 8), adenocarcinoma (n = 5), carcinoma ex pleomorphic adenoma (n = 4), and others (n = 5) were correlated to clinical data.Overall survival correlated to treatment modality (p = .039) and T classification (p = .003), whereas prolonged disease-free interval correlated to treatment (p.001) and T classification (p = .009). Overall survival after recurrence correlated to treatment of recurrence (p = .006) and initial T classification (p = .02). Multivariate analysis showed that overall survival after recurrence correlated to treatment of recurrence (p = .019) and initial T classification (p = 0.019). T classification was a prognostic factor for overall survival (p = .002) and disease-free interval (p = .002).The initial tumor classification is a clinical predictor for patients' overall and disease-free survival and overall survival after recurrence. Multimodal treatment significantly improves patients' overall survival.

Background/Aims: RCAS-1 is a transmembrane protein that is involved in the evasion of host immune surveillance by tumor cells. It has been found to be a valuable prognostic and diagnostic marker in a number of different malignancies. The objective of the study was to analyze the potency of RCAS-1 as a biomarker in the serum of patients with head and neck squamous cell carcinoma (HNSCC). Methods: ELISA was performed with prospectively collected serum samples from 60 patients with HNSCC (taken at the time of diagnosis, after 3 and 12 months) and from 31 healthy controls. To correlate serum levels with RCAS-1 expression in the tumor, immunohistochemical staining of RCAS-1 was done using a tissue microarray. Results: Surprisingly, median sRCAS-1 levels were basically identical between tumor patients and controls. Interestingly, patients with low RCAS-1 values at the time of diagnosis had better disease-free survival. 62% of tumor samples expressed RCAS-1 but we could not demonstrate a correlation between protein expression and serum levels. Conclusion: This study was the first to correlate RCAS-1 levels in the serum and in the tumor of the same patients. RCAS-1 seems to have prognostic properties although larger studies will be necessary to fully evaluate its role in HNSCC.

Background and objectives This retrospective study was performed to evaluate the status of p53 in pleomorphic adenomas and carcinomas ex pleomorphic adenoma in the parotid gland. As loss or mutation of p53 can cause malignant transformation, the possible degeneration of pleomorphic adenomas to carcinomas ex pleomorhic adenoma was investigated by mutational analysis. Methods Twenty-five Patients including 14 patients with pleomorphic adenomas and 11 patients with carcinoma ex pleomorphic adenoma of the parotid gland were examined for p53 status. DNA was extracted out of paraffin-embedded tissue and PCR was performed for the coding exons 2-11. Denaturing gradient gel electrophoresis (DGGE) was carried out for mutational analysis and DNA sequencing was performed in case of a suspected mutation. Results Fourteen pleomorphic adenomas and 11 carcinomas ex pleomorphic adenoma were screened for p53 status and potent mutations. Subsequent sequencing of the distinct exons showed no mutation. Conclusion We could not detect mutations of p53 neither in benign nor malignant parotid tumors and we therefore assume that p53 plays no role in the transformation from pleomorphic adenoma to carcinoma ex pleomorphic adenoma.

No data are available on the effects of the cyclooxygenase-2 (COX-2) inhibitor nimesulide in combination with irradiation on the survival of head-and-neck carcinoma cells.Two head-and-neck carcinoma cell lines (SCC9 and SCC25) were treated with nimesulide (50-600 microM) and irradiated concomitantly or sequentially. Early effects on cell survival were investigated by counting cell numbers, long-term effects by colony-forming assays. Cell-cycle effects were analyzed 24-72 h after treatment with nimesulide by flow cytometry.Unexpectedly, nimesulide solely inhibited cell proliferation without affecting colony-forming ability. In addition, no evidence for a radiosensitizing effect of nimesulide in short-term assays was seen. Nimesulide alone had no effect on clonogenic survival alone or in combination with radiation.Nimesulide differentially affects cell proliferation and clonogenic survival and may decrease the efficacy of radiotherapy. Short-term assays to assess tumor growth may not correctly predict the clinically relevant long-term effect of COX-2 inhibitors.