Changes in Vestibular Function in Patients With Head-and-Neck Cancer Undergoing Chemoradiation.

INTRODUCTION: While the cochleotoxicity of cisplatin has been well investigated, less is known about the effects of platinum-based chemotherapy on the vestibular system. In particular, there is a lack of prospective studies using modern laboratory vestibular testing that examine the effects of cisplatin on the semicircular canals and on the otolith organs. The aim of the present study was, therefore, to investigate the vestibulotoxic effect of cisplatin in patients with head and neck tumors who are undergoing chemoradiation. METHODS: Forty-five patients undergoing cisplatin-based chemoradiation for head and neck cancer received a vestibular assessment consisting of anamnesis, a horizontal video head impulse test (vHIT), ocular and cervical vestibular evoked myogenic potential testing, as well as pure tone audiometry. This assessment was performed before therapy, 6 weeks after therapy, and 3 months after therapy. RESULTS: Video head impulse test showed a significantly reduced median gain 6 weeks after chemoradiation. In addition, significantly more refixational saccades could be detected after therapy. Vestibular evoked myogenic potential testing results also revealed significant changes, whereas pure tone audiometry did not. None of the patients mentioned "dizziness" during the follow-up examinations. CONCLUSION: We demonstrated a vestibulotoxic effect of cisplatin-based chemoradiation in patients with head and neck cancer. Future studies are needed to better understand cisplatin-induced vestibulotoxicity and to identify possible vestibuloprotective substances. Still, before and after chemoradiation, patients should undergo not only auditory testing but also vestibular testing in order to detect potential vestibular loss as soon as possible and to quickly initiate vestibular physiotherapy.

A new form of irritant rhinitis to filtering facepiece particle (FFP) masks (FFP2/N95/KN95 respirators) during COVID-19 pandemic.

Filtering facepiece particle (FFP) masks are important items of personal protective equipment in fighting COVID-19 pandemic. They shall protect the wearer of the mask from particles, droplets, and aerosols, but they also can prevent the spread of aerosol-transmitted viruses if the wearer becomes infected. Most often, FFP respirators consist of multiple layers of non-woven fabric made from polypropylene. Worldwide, FFP respirators are subject to various regulatory standards that specify physical properties and performance characteristics. During the SARS-CoV-2 pandemic, health authorities have temporarily repealed standards for respirators. We report on 46 patients that presented with rhinitis-like symptoms strongly associated to the use of FFP masks. Some of them were obliged to use FFP masks in their work environment. Nasal endoscopy showed edemata of the nasal mucosa that significantly decreased after a period of non-use of FFP masks. Subjectively reported symptom levels decreased after cessation of FFP use for 3 or more days. The presence of polypropylene fibres isolated from nasal rinsing solution was significantly associated with the use of FFP masks in our patients. Material safety and performance deregulation of FFP masks can pose a health risk. Thus, especially health care professionals and other individuals with occupational need for FFP masks should be aware of possible hazards that come with COVID-19 pandemic protection measures.

DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) is linked to gene expression and survival in laryngeal cancer.

BACKGROUND: Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). RESULTS: Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts (p = 0.016 and < 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 (p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients (p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression. CONCLUSIONS: The data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies.

Influence of static magnetic fields on human myoblast/mesenchymal stem cell co­cultures.

The results of surgical repair of extensive muscle tissue defects are still of primary concern, leaving patients with residual cosmetic and functional impairments. Therefore, skeletal muscle tissue engineering attempts to grow functional neo­tissue from human stem cells to promote tissue regeneration and support defect closure. Despite intensive research efforts, the goal of stable induction of myogenic differentiation in expanded human stem cells by using clinically feasible stimuli, has not yet been reached to a sufficient extent. Therefore, the present study investigated the differentiation potential of static magnetic fields (SMFs), using co­cultures of human satellite cells and human mesenchymal stem cells (MSCs). It has previously been demonstrated that SMFs may act as a promising myogenic stimulus. Tests were performed on co­cultures with and without SMF exposure, using growth medium [high growth factor concentrations (GM)] and differentiation medium [low growth factors concentrations (DM)]. AlamarBlue® assay­based cell proliferation analysis revealed no significant difference between co­cultures with, vs. without SMF stimulation, regardless of growth factor concentrations in the cell culture medium. To determine the degree of differentiation in co­cultures under stimulation with SMFs, semi­quantitative gene expression measurements of the following marker genes were performed: Desmin, myogenic factor 5, myogenic differentiation antigen 1, myogenin, adult myosin heavy chain 1 and skeletal muscle α1 actin. In neither GM nor DM was a steady, significant increase in marker gene expression detected. Verifying the gene expression findings, immunohistochemical antibody staining against differentiation markers revealed that SMF exposure did not enhance myogenic maturation. Therefore, SMF treatment of human satellite cell/MSC co­cultures did not result in the desired increase in myogenic differentiation. Further studies are required to identify a suitable stimulus for skeletal muscle tissue engineering.

Heated air humidification versus cold air nebulization in newly tracheostomized patients.

BACKGROUND: After tracheostomy, the airway lacks an essential mechanism for warming and humidifying the inspired air with the consequent functional impairment and discomfort. The purpose of this study was to compare airway hydration with cold-air nebulization versus heated high-flow humidification on medical interventions and tracheal ciliary beat frequency (CBF). METHODS: Newly tracheostomized patients (n = 20) were treated either with cold-air nebulization or heated humidification. The number of required tracheal suctioning procedures to clean the trachea and tracheal CBF were assessed. RESULTS: The number of required suctions per day was significantly lower in the heated humidification group with medians 3 versus 5 times per day. Mean CBF was significantly higher in the heated humidification group (6.36 ± 1.49 Hz) compared to the cold-air nebulization group (3.99 ± 1.39 Hz). CONCLUSION: The data suggest that heated humidification enhanced mucociliary transport leading to a reduced number of required suctioning procedures in the trachea, which may improve postoperative patient care.

Innovative Surgery for Obstructive Sleep Apnea: Nerve Stimulator.

Obstructive sleep apnea (OSA) as a multifactorial disease is treated with continuous positive airway pressure (CPAP) as the gold standard. Yet, if patients suffer from CPAP incompliance, traditional OSA surgery only targets morphological changes of the upper airway while neglecting functional issues. With the advent of upper airway stimulation, and in particular hypoglossal nerve stimulation as a treatment option, a highly effective, clinically proven and functional therapy with good evidence is available. This article gives a comprehensive overview of current and upcoming hypoglossal nerve stimulation systems (Inspire, ImThera, and Nyxoah), the specific advantages of this approach, the selection criteria and screening process, relevant clinical data, and a description of the different implantation procedures. Upper airway stimulation and hypoglossal nerve stimulation appears to be a long-term, low-morbidity treatment for moderate-to-severe OSA patients suffering from CPAP incompliance.

Effect of selective small molecule inhibitors on MMP-9 and VEGFR-1 expression in p16-positive and -negative squamous cell carcinoma.

The identification of molecular targets in the therapy of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a primary aim of cancer research. Matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor receptor (VEGFR) have important roles in the development of HNSCC. The tyrosine kinase inhibitors, nilotinib, dasatinib, erlotinib and gefitinib are well established in the targeted therapy of tumors other than HNSCC. The present study aimed to investigate the alteration of MMP-9 and VEGFR-1 expression patterns following treatment with these tyrosine kinase inhibitors in p16-positive and -negative squamous carcinoma cells. MMP-9 and VEGFR-1 expression was evaluated using an ELISA in HNSCC 11A, HNSCC 14C and p16-positive CERV196 tumor cell lines, following treatment with nilotinib, dasatinib, erlotinib and gefitinib. A statistically significant reduction in MMP-9 and VEGFR-1 expression was observed in the p16-negative HNSCC 11A cells following treatment with all inhibitors (P<0.05). VEGFR-1 expression was significantly increased in p16-positive SCC cells following treatment with nilotinib, dasatinib, erlotinib and gefitinib (P<0.05). The expression of MMP-9 and VEGFR-1 was significantly altered by treatment with nilotinib, dasatinib, erlotinib and gefitinib in vitro. The results of the present study are attributed to the efficacy of the tested drugs and present potential compensatory strategies of cancer cells to avoid the antiangiogenic properties of the tested tyrosine kinase inhibitors in vitro.

Impact of Small Molecules on ß-Catenin and E-Cadherin Expression in HPV16-positive and -negative Squamous Cell Carcinomas.

BACKGROUND: The validation of potential molecular targets in head and neck squamous cell carcinoma (SCC) is mandatory. ß-Catenin and E-cadherin are crucial for cancer progression through epithelial-mesenchymal transition. We analyzed the effect of the tyrosine kinase inhibitors nilotinib, dasatinib, erlotinib and gefitinib on ß-catenin and E-cadherin expression in SCC with respect to human papillomavirus (HPV) status. MATERIALS AND METHODS: Expression of ß-catenin and E-cadherin in cell lines UMSCC 11A, UMSCC 14C and CERV196 under the influence of tyrosine kinase inhibitors were analyzed by enzyme-linked immunosorbent assay. RESULTS: All agents reduced ß-catenin and E-cadherin expression of HPV16-negative cells. Increased E-cadherin expression was observed after treatment with gefitinib and dasatinib in HPV16-positive cells. CONCLUSION: All substances, nilotinib, dasatinib, erlotinib and gefitinib have a significant impact on ß-catenin and E-cadherin expression in both HPV16-positive and HPV16-negative cells in vitro. Alterations of ß-catenin and E-cadherin could provide novel insights for future targeted therapies of head and neck SCC.

[Using a Standardized Questionnaire for Coagulation Assessment in Children Undergoing Tonsillectomy]. / Standardisierte Gerinnungsanamnese vor Tonsillektomie und Adenotomie im Kindesalter.

Introduction A 2006 position paper suggests assessing coagulation status via a standardized questionnaire instead of performing routine coagulation testing for children undergoing tonsillectomy/adenotomy. The aim of the presented study was to evaluate whether this paradigm change led to a change in the incidence of secondary bleeding. Methods Descriptive statistical analysis of existing clinical data was performed to evaluate the incidence and characteristics of secondary bleeding in children after tonsillectomy/adenotomy in 2003 vs. 2009. Result In 2003, 352 children underwent surgery. Secondary bleeding occurred in 25 cases (7.1%), 18, (6.1%) of which required surgical treatment. In 2009, 20 out of 293 children who had undergone tonsillectomy/adenotomy suffered from secondary bleeding, 14 required (4.7%) surgical treatment. There was no significant difference in the incidence of bleeding between those years. In 5 children who suffered from secondary bleeding in 2003, preoperative diagnostic blood coagulation testing was performed, none of them showed abnormal results. Furthermore, none of the diagnostic blood coagulation tests performed after secondary bleeding in both groups showed any abnormalities. Conclusion Using a standardized questionnaire instead of a diagnostic blood coagulation testing for preoperative coagulation assessment does not have an influence on the incidence of secondary bleeding after tonsillectomy/adenotomy. The results of this study suggest that secondary bleeding is not is not caused by abnormal hemostasis.

Targeted Therapies in HPV-positive and -negative HNSCC - Alteration of EGFR and VEGFR-2 Expression In Vitro.

BACKGROUND: Angiogenesis plays a crucial role in the formation and progression of tumor growth in head and neck squamous cell carcinoma (HNSCC). The tyrosine kinase receptors epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are essential for mediation of pro-angiogenic signals. Nilotinib, dasatinib, erlotinib and gefitinib are tyrosine kinase inhibitors and approved as targeted therapies for several tumor entities other than HNSCC. In this study, we sought to evaluate the alteration of EGFR and VEGFR-2 expression by these tyrosine kinase inhibitors with respect to the human papillomavirus (HPV)-status in squamous cell carcinoma (SCC) tumor cells. MATERIALS AND METHODS: Expression patterns of EGFR and VEGFR-2 were determined by enzyme linked immunosorbent assay (ELISA) in HNSCC 11A, HNSCC 14C and p-16-positive CERV196 tumor cell lines. These cells were incubated with nilotinib, dasatinib, erlotinib and gefitinib (5-20µmol/l) and compared to a chemonaive control. The incubation time was 24, 48, 72 and 96 h. RESULTS: All tested substances led to a statistically significant reduction (p<0.05) of EGFR protein expression levels in HPV-negative cells compared to the negative control. Surprisingly, a statistically significant increase in VEGFR-2 expression was observed after exposure to all tested substances especially after exposure to erlotinib treatment. CONCLUSION: Nilotinib, dasatinib, erlotinib and gefitinib cause significant changes in protein expression of EGFR and VEGFR-2 in vitro. Besides the anti-angiogenic impact of the substances, as shown for the decrease of EGFR expression, we also observed an increase of VEGFR-2 expression. These contradictive effects could be interpreted as a compensatory up-regulation by the tumor cell.

Tonsillectomy with Uvulopalatopharyngoplasty in Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a very common disorder (prevalence 2-7% in women, 7-14% in men). It impairs the quality of life and increases mortality. Conservative treatment with continuous positive airway pressure is highly effective, but patient compliance is variable. Surgical treatments are controversial, as only a few are supported by evidence from controlled clinical trials. METHODS: Adult patients with OSA, CPAP intolerance, and oropharyngeal obstruction were included in the trial. All underwent polysomnography (PSG) and were randomly allotted to one of two groups. Patients in the treatment group underwent tonsillectomy with uvulopalatopharyngoplasty (TE-UPPP) within one month. All patients had a follow-up PSG at three months, and all PSGs were evaluated in blinded fashion. The primary outcome variable was the apneahypopnea index (AHI) as determined by PSG. Other outcome variables were subjective symptoms (daytime sleepiness, quality of life), complications, and patient satisfaction. RESULTS: 42 patents were included in the trial (23 in the treatment group, 19 in the control group). The baseline AHI was 35.7 ± 19.4/hr in the control group and 33.7 ± 14.6/hr in the treatment group. The corresponding figures at 3 months were 28.6 ± 19.4/hr in the control group and 15.4 ± 14.1/hr in the treatment group (p = 0.036). The intervention also led to significant improvement in daytime sleepiness and in snoring, according to the patients' and their bed partners' assessment. 97% of the patients who underwent surgery were satisfied with the outcome. 65% of them needed no further treatment for OSA. CONCLUSION: TE-UPPP significantly improved apnea/hypopnea, daytime sleepiness, and snoring compared to control (i.e., no) treatment. It is a safe and effective treatment for OSA..

Effect of TH2 cytokines and interferon gamma on beat frequency of human respiratory cilia.

BACKGROUND: In asthmatic airways secondary ciliary dyskinesia contributes to impaired mucociliary clearance. To investigate underlying mechanisms, we studied the effects of cytokines associated with asthma phenotype on the ciliary beat frequency (CBF) in a cell culture model of ciliated human respiratory epithelial cells. METHODS: Nasal respiratory epithelial cells of 21 patients were used to prepare multicellular cells (spheroids) in the presence of the T helper (TH) 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13, and the TH1 cytokine interferon gamma (IFN-γ). CBF was determined by high-speed video microscopy. RESULTS: Addition of IL-4 and IL-13 and IL-4 + IL-13 decreased the mean CBF by 17, 21, and 22%, respectively, compared with untreated controls. Addition of IL-5 and IL-9 lead to an increase in mean CBF (20 and 10%, respectively). Lower concentrations of IFN-γ (0.1 and 1 ng/ml) decreased mean CBF and higher concentrations (10 ng/ml) increased CBF by 6%. Addition of IFN-γ to IL-13 reversed the effect of IL-13 on the CBF of spheroids. CONCLUSION: Cytokines directly influence the ciliary function of respiratory epithelium and contribute to the impaired mucociliary clearance in asthmatic disease. Our study encourages further research to investigate IFN-γ as a treatment option in diseases with impaired mucociliary clearance like asthma.

CpG-Oligodeoxynucleotides in Chronic Rhinosinusitis Cell Culture.

UNLABELLED: In chronic rhinosinusitis (CRS) an important feature is the infiltration of eosinophils, triggered by T-helper type 2 cells (TH2). Binding of the CpG oligodeoxynucleotide (CpG-ODN) ligand to toll-like receptor 9 (TLR9) induces a shift from a TH2- to a TH1-type response. We evaluated the hypothesis that CpG-ODN could reduce the predominantly TH2-driven response in our cultures. MATERIALS AND METHODS: Twenty samples from CRS patients with (CRSwNP) and without nasal polyposis (CRSsNP) were cultivated. The expression of interleukin 5 (IL-5), eotaxin 3 and matrix metalloprotease 9 (MMP-9) were evaluated with and without CpG-ODN. RESULTS: Addition of CpG did not influence the expression of IL-5 and eotaxin-3 DNA. Elevated MMP-9 expression in cultures from CRSwNP and CRSsNP patients could be established. CONCLUSION: CpG does not reduce the attraction of eosinophils since no reduced IL-5 expression was measured in our cultures. Yet, MMP-9 - an important factor in tissue remodelling - was elevated in cultures from CRS patients.

Clinical Outcome and Quality of Life After a Multimodal Therapy Approach to Ear Keloids.

IMPORTANCE: Keloids are fibroproliferative scars that can cause a huge psychological burden and severe problems for patients, such as depression. Many treatment options exist; however, recurrence rates, especially with monotherapy, remain high. OBJECTIVE: To investigate the recurrence rate and changes in quality of life after multimodal therapy. DESIGN, SETTING, AND PARTICIPANTS: A total of 33 patients with 42 auricle keloids (24 female and 9 male patients; mean [SD] age, 27 [17] years) were enrolled in a prospective cohort study and underwent intramarginal keloid excision and multimodal therapy. Patients were observed postoperatively in the outpatient Department of Otorhinolaryngology-Head and Neck Surgery, University Hospital of Mannheim, from August 1, 2007, through September 30, 2014, with a mean (SD) follow-up of 30 (19) months (through August 31, 2014). A retrospective analysis of clinical outcomes was performed from September 1 through November 15, 2014. INTERVENTIONS: Excision followed by 6 intralesional corticosteroid injections at 4- to 6-week intervals and individually customized pressure splints applied at least 5 nights a week for 6 months. MAIN OUTCOMES AND MEASURES: Keloid recurrence rate and subjective handling of the pressure splint were evaluated during clinical visits. Quality of life was measured after the end of therapy with a 3-part questionnaire, including the Glasgow Benefit Inventory (GBI). RESULTS: After excluding 4 patients (with 5 keloids) for nonadherence to treatment, 3 of 37 keloids recurred, for a recurrence rate of 8% among 29 patients. Insecure handling of the pressure splint significantly correlated with a higher relapse rate (mean subjective handling score in patients with a relapse, 3.60; P = .02). Four of 8 patients with recurrent keloids had poor adherence to adjuvant pressure therapy, which suggests an association between keloid recurrence and adherence to adjuvant pressure therapy. Patients received the 3-part questionnaire by mail to collect data on quality of life. Of 43 patients approached, 33 treated with multimodal therapy completed the questionnaire for a return rate of 77%. Improvement in quality of life after keloid treatment was significant in recurrence-free patients, with a mean GBI score of 22.53 (P < .001). CONCLUSIONS AND RELEVANCE: The present study showed an improvement in quality-of-life scores after multimodal therapy for keloids. Because poor adherence to the use of ear splints correlated with a higher recurrence rate of keloids, efforts are needed to improve adherence and minimize recurrence. LEVEL OF EVIDENCE: 3.

Targeting mTOR and AREG with everolimus, sunitinib and sorafenib in HPV-positive and -negative SCC.

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy. It is the most common neoplasm appearing in the upper aerodigestive tract and the sixth most common cancer worldwide. The five-year survival rate remains poor despite advances in surgery, radiation and chemotherapy. Furthermore, the incidence of human papillomavirus (HPV)-associated oropharyngeal cancer is rising. Thus, innovative therapy approaches are imperative in order to improve the situation. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) and sorafenib and sunitinib, multityrosine kinase inhibitors, have been notably effective in the therapy of different tumor entities. The modest side-effects and oral application of the drugs might improve patient compliance. Expression levels of mTOR and Amphiregulin (AREG) in p16-positive and -negative SCC (squamous cell carcinoma) and the effect of everolimus, sorafenib or sunitinib on the expression levels of these target proteins were assessed. As far as we are aware of, this is one of the first in vitro studies to evaluate the effect of these small-molecule drugs with regard to the p16 status of SCC cells. MATERIALS AND METHODS: p16-negative HNSCC 11A and 14C cells and p16-positive CERV196 cells were exposed to different concentrations of everolimus, sorafenib and sunitinib for 2-8 days. Expression levels of mTOR and AREG were determined by enzyme-linked immunosorbent assay (ELISA) and compared against a chemonaïve control. RESULTS: AREG and mTOR were expressed in all tested cell lines. CERV196 displayed a remarkable increase of mTOR expression compared to p16-negative HNSCC. On the contrary, AREG levels were reduced by 50% in CERV196. Everolimus, sorafenib and sunitinib significantly reduced mTOR expression. Everolimus significantly decreased AREG expression independently of the HPV status. Sunitinib and sorafenib increased AREG expression in HNSCC 11A and 14C but not in CERV196. CONCLUSION: The applied drugs showed remarkable suppression of mTOR expression, which might delay tumor progression. Interestingly, sorafenib and sunitinib increased AREG in HNSCC 11A and 14C, which could be a possible evasive mechanism following incubation with these drugs. On the contrary, p16-positive CERV196 showed increased susceptibility to sorafenib and sunitinib concerning suppression of AREG expression. Further studies are required to evaluate the HPV-dependent differences of therapy response and the possible consequences for treatment options.

Small molecules alter VEGFR and PTEN expression in HPV-positive and -negative SCC: new hope for targeted-therapy.

BACKGROUND/AIM: Prognosis for patients with head and neck squamous cell carcinoma (HNSCC) is poor in most cases and has not improved despite advances in therapy. Novel therapeutic approaches are mandatory in order to improve the situation. Everolimus, an inhibitor of mammalian target of rapamycin, as well as the multi-tyrosine kinase inhibitors sorafenib and sunitinib, has demonstrated a substantial therapeutic effect in various types of human cancer with moderate side-effects. Expression of vascular endothelial growth factor receptor (VEGFR) 1 and 2, and of the tumor-suppressor protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN) were evaluated in chemonaïve human papillomavirus (HPV)-positive and -negative squamous cell carcinoma (SCC) and after exposure to everolimus, sorafenib or sunitinib. MATERIALS AND METHODS: p16-positive CERV196 and p16-negative HNSCC 11A and 14C cells were incubated with different drug concentrations for 48-192 h. Expression of VEGFR1 and -2 as well as PTEN were determined by enzyme-linked immunosorbent assay and was compared to a chemonaïve control. RESULTS: VEGFR1 and -2, as well as PTEN, were expressed in all three cell lines. Sunitinib, sorafenib and everolimus significantly reduced the expression of VEGFR1 and -2, especially in p16-positive CERV196 cells. Sunitinib appeared to be more effective in reducing VEGFR1 and -2 expression than sorafenib and everolimus. PTEN levels were remarkably lower in HPV-positive CERV196 cells. PTEN expression increased significantly under sunitinib and sorafenib in HNSCC 11A and CERV196 cells. Everolimus, on the other hand, led to a significant decrease of PTEN expression in these cell lines. CONCLUSION: The tested drugs displayed a remarkable anti-angiogenic effect by inhibition of VEGFR1 and -2 expression. Sunitinib and sorafenib were able to increase PTEN expression, which might induce apoptosis of cancer cells. HPV-positive CERV196 cells were characterized by an increased susceptibility to these small-molecule drugs. Further studies are imperative to scrutinize HPV status-dependent differences in drug response and possible implications for future treatment options.

Matrix metalloproteinase-2 and -14 in p16-positive and -negative HNSCC after exposure To 5-FU and docetaxel In Vitro.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world. While the incidence of HNSCC associated with tobacco and alcohol abuse is falling, the incidence of HNSCC associated with human papilloma virus (HPV) is rising. Proliferation, cell migration and formation of metastases are dependent on interactions between the tumor cells, tumor stromal cells and the extracellular matrix (ECM). Degradation of the ECM is a crucial step in the process of local tumor infiltration and formation of locoregional and distant metastases. Matrix metalloproteinases (MMPs) are a family of enzymes that are able to degrade the ECM. Locally advanced HNSCC with cervical node metastases are treated with docetaxel in induction chemotherapy (ICT) combined with platinum-based chemotherapy and 5-fluorouracil (5-FU) as standard clinical anti-neoplastic regimens. This study evaluated the expression of MMP-14 and MMP-2 in HPV-positive (CERV196) and HPV-negative squamous cell carcinoma (HNSCC 11A and 14C) and the alteration of expression levels after exposure to either docetaxel or 5-FU. MATERIALS AND METHODS: Tumor cells were exposed to 5-FU or docetaxel in concentrations of 1.0 and 5.0 µmol/ml. MMP-protein expression was evaluated by enzyme-linked immunosorbent assay (ELISA) after 2, 3, 5, 8 and 10 days of incubation. RESULTS: Docetaxel exposure significantly decreased MMP-14 expression in HNSCC 11A and especially 14C but not in CERV196 apart from an apoptotic process. 5-FU had no significant effect on MMP-14 expression independent of the HPV-status. Significant alterations of MMP-2 could be detected in HNSCC 11A only. CONCLUSION: Although neither of the applied drugs were selective inhibitors of MMP-expression, surprisingly docetaxel significantly decreased MMP-14 in HNSCC 14C and 11A in this study. Interestingly, HPV-positive CERV196 was not sensitive to decreased MMP-14 or -2 expression following incubation with 5-FU or docetaxel.

Interleukin 4, interleukin 6 and osteopontin-serological markers of head and neck malignancy in primary diagnostics: A pilot study.

The progression of head and neck squamous cell carcinoma (HNSCC) is stimulated by various angiogenic peptides and growth factors. A correlation between tumor progression and the secretion of various serological mediators in patients with malignant tumors of the head and neck is of major interest for tumor diagnostics, evaluation of the therapy response and it may predict prognosis by specifying the individual tumor biology. Established chemotherapeutic regimes for head and neck tumors usually consist of platinum-based chemotherapeutic drugs and 5-fluorouracil (5-FU). The present pilot study sought to assess the eligibility of seven serological factors as biomarkers for malignant tumors of the head and neck: Platelet-derived growth factor, vascular endothelial growth factor, epidermal growth factor receptor, osteopontin, granulocyte-colony stimulating factor, interleukin-4 (IL-4) and IL-6. The serum levels of each factor in 20 patients receiving concomitant radiochemotherapy with cisplatin or carboplatin and 5-FU with curative intent were determined prior and subsequent to chemotherapy and were compared with 40 healthy controls. Another aim of the pilot study was to investigate whether the serum of patients showed significant differences in the concentrations of the analyzed factors at the start of concomitant radiochemotherapy compared with the controls, whether those markers indicated a neoplastic process and whether concomitant radiochemotherapy with cisplatin or carboplatin and 5-FU induced significant alterations of concentration compared with pre-therapeutic levels. The included patients were histopathologically diagnosed with HNSCC and the average age was 62.3 years. The serum samples of the patients were obtained during the course of regular pre- and post-chemotherapeutic blood draws one week prior to the start of radiochemotherapy and one week following the completion of chemotherapy. The healthy controls were collected from patients of the Sleep Laboratory of the Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital (Mannheim, Germany) without clinical evidence or laboratory signs of inflammation or history of a malignant disease. The average age was 50.3 years. The serological level of each factor was ascertained by enzyme-linked immunosorbent assay in duplicate. Serum levels of IL-4, IL-6 and osteopontin were significantly increased in patients with HNSCC compared with those in chemotherapy-naive healthy controls. IL-4 and osteopontin showed no significant therapy-associated alterations. Notably, IL-6 levels significantly increased post-therapeutically. Using logistic regression with osteopontin and IL-4, an individual risk-profile for random samples was calculated. IL-4, IL-6 and osteopontin appear to be suitable indicators of the neoplastic process as they are significantly increased in HNSCC patients compared with the control group. With the exception of IL-6, whose levels were in fact increased following therapy, a significant therapy-associated alteration of these factors was missing. Therefore, these serological markers failed to predict the therapy response, but they may be valuable as a screening instrument in primary diagnostics.

Anti-inflammatory effects of polihexanide and polyethylene glycol in an in vitro study in chronic rhinosinusitis.

The majority of patients affected by chronic rhinosinusitis (CRS) suffer from eosinophilic infiltration. We hypothesised that polihexanide and polyethylene glycol as an antiseptic might alter the eosinophil-associated IL-5 and eotaxin-3 expression in CRS and also the expression of MMP-9, being involved in the tissue-remodelling in CRS. After obtaining samples from 10 CRS patients with (CRSwNP) and without nasal-polyposis (CRSsNP) and 2 patients with inverted-papilloma undergoing functional endoscopic sinus surgery (FESS), the expression of interleukin-5, eotaxin-3 and MMP-9 were evaluated by an ELISA assay with and without the tested agent. CRSwNP showed a significantly increased expression of IL-5. Polihexanide seems not to alter the attraction of eosinophils in patients with CRS via IL-5 expression. Also elevated levels of MMP-9 could not be reduced to normal values. But there exists statistically significant evidence that the self-amplification process of eosinophils via eotaxin-3 could be influenced by the administration of polihexanide.