Georg Mathias Sprinzl

Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma

Co-culture of periodontal ligament (PDL) fibroblasts and SCC-25 oral squamous carcinoma cells (OSCC), results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs). Paracrin circuits between CAFs and OSCC cells were hypothesized to regulate the gene expression of matrix remodeling enzymes in their co-culture, which was performed for 7 days, followed by analysis of the mRNA/protein expression and activity of metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and other relevant genes. Interleukin1-β, transforming growth factor-β1, fibronectin and αvβ6 integrin have shown to be involved in the regulation of the MMP and TIMP gene expression in co-culture of CAFs and tumor cells. In addition, these cells also cooperated in activation of MMP pro-enzymes. It is particularly interesting that the fibroblast-produced inactive MMP-2 has been activated by the tumor-cell-produced membrane-type 1 matrix metalloproteinase (MT1-MMP). The crosstalk between cancer- and the surrounding fibroblast stromal-cells is essential for the fine tuning of cancer cells invasivity.

Fibroblasts produce brain-derived neurotrophic factor and induce mesenchymal transition of oral tumor cells

Summary Fibroblasts (Fibs) contribution to neoplastic progression, tumor growth, angiogenesis, and metastasis has been recently reported by several research groups. In this study it was investigated if fibroblasts are the source of brain-derived neurotrophic factor (BDNF), which plays a crucial role in the progression of oral squamous cell carcinoma. In a novel in vitro system oral Fibs were cultured with SCC-25 lingual squamous cell carcinoma cells for 7 days. Factors related with this interaction were investigated by quantitative PCR and western blot. In the co-culture, fibroblasts were converted to carcinoma-associated fibroblasts (CAFs), which in return initiated epithelial–mesenchymal transition (EMT) of SCC-25 cells. The induced CAFs produced increased levels of BDNF, which interacted with the increased-expressed neurothrophin receptor B (TrkB) on EMT-converted SCC-25 cells. Possible regulatory factors of BDNF expression (tumor necrosis factor-α and interleukin-1-β) were detected both in CAFs and EMT-tumor cells. In CAFs: IL-1β-, in SCC-25 cells TNF-α-gene-expression was significantly increased in co-culture conditions. Activated fibroblasts (CAFs) and mesenchymal transitioned tumor cells might use the BDNF-TrkB axis and its regulation to harmonize their interaction in the process of tumor progression.

First European Multicenter Results With a New Transcutaneous Bone Conduction Hearing Implant System: Short-Term Safety and Efficacy

Objective To investigate safety and efficacy of a new transcutaneous bone conduction hearing implant, over a 3-month follow-up period. Study Design Prospective, single-subject repeated-measures design in which each subject serves as his/her own control. Setting Departments of Otolaryngology at 4 hospitals in Germany and Austria. Patients Subjects were 12 German-speaking adults who suffered from conductive or mixed hearing loss. The upper bone conduction threshold limit was set to 45 dB HL at frequencies between 500 Hz and 4 kHz. Intervention Implantation of a transcutaneous bone conduction hearing implant. Main Outcome Measures Subjects’ speech perception (word recognition scores and SRT50%) and audiometric thresholds (air conduction, bone conduction and sound field at frequencies 500 Hz to 8 kHz) were assessed preoperatively, 1 month postoperatively and 3 months postoperatively. The subjects were monitored for adverse events and given a questionnaire to assess their satisfaction levels. Results Speech perception as measured by word recognition scores and SRT50% improved on average about 78.8% and 25 dB HL, respectively, 3 months after implantation. Aided thresholds also improved postoperatively at all tested frequencies and continued to improve from 1 to 3 months postoperatively. Air conduction and bone conduction thresholds showed no significant changes, confirming that subjects’ residual unaided hearing was not deteriorated by the treatment. Only minor adverse events were reported and resolved by the end of the study. Conclusion The new transcutaneous bone conduction implant was demonstrated to be safe and effective in adults up to 3 months of device use.

Distant metastasis of parotid gland tumors

The incidence of distant metastasis in head and neck cancer and especially in salivary gland cancer is relatively low in comparison to other malignancies. However, the presence of distant metastasis heralds a poor prognosis in head and neck cancer, with a median survival of 4.3–7.3 months. Treatment of these patients is usually performed in a palliative setting. Patients with malignant salivary gland tumors should have an X-ray or CT scan of the chest at their initial assessment to exclude the possibility of distant metastasis. The likelihood of developing distant metastasis is associated with high-grade tumors, such as adenoid cystic carcinoma, salivary duct carcinoma, high-grade mucoepidermoid carcinoma and tumors located in the submandibular gland, posterior tongue and pharyngeal tumors. A lower risk of developing distant metastasis is known for all other histological entities of salivary gland tumors. Nevertheless all patients who have a histologically confirmed malignant salivary gland tumor should have lifelong follow-up. On the basis of a clinical case regarding a patient with metastatic parotid gland cancer we present a review of the literature.

EGFR inhibition as a therapy for head and neck squamous cell carcinoma

Background: Improved understanding of disease biology of head and neck squamous cell carcinoma (HNSCC) with nearly universal expression of EGFR has led to the introduction of targeted therapies to interrupt signalling of this negative prognostic marker. Objective: We performed a literature review on the mechanisms and efficacy of anti-EGFR antibodies and EGFR tyrosine kinase inhibitors in patients with locally advanced or recurrent/metastatic HNSCC. Results/conclusion: Clinical trials in HNSCC have administered EGFR directed drugs as single agents, in combination with chemotherapy or radiotherapy and demonstrated a good safety profile with antitumour activity in a subgroup of patients. The biology of responsiveness is still unclear, although there is growing evidence of an association of skin toxicity or presence of shorter EGFR intron 1 cytosine–adenine repeats with positive outcome.

Tumor-produced, active Interleukin-1 β regulates gene expression in carcinoma-associated fibroblasts

Recently we described a co-culture model of periodontal ligament (PDL) fibroblasts and SCC-25 lingual squamous carcinoma cells, which resulted in conversion of normal fibroblasts into carcinoma-associated fibroblasts (CAFs), and in epithelial–mesenchymal transition (EMT) of SCC-25 cells. We have found a constitutive high interleukin-1β (IL1-β) expression in SCC-25 cells in normal and in co-cultured conditions. In our hypothesis a constitutive IL1-β expression in SCC-25 regulates gene expression in fibroblasts during co-culture. Co-cultures were performed between PDL fibroblasts and SCC-25 cells with and without dexamethasone (DEX) treatment; IL1-β processing was investigated in SCC-25 cells, tumor cells and PDL fibroblasts were treated with IL1-β. IL1-β signaling was investigated by western blot and immunocytochemistry. IL1-β-regulated genes were analyzed by real-time qPCR. SCC-25 cells produced 16 kD active IL1-β, its receptor was upregulated in PDL fibroblasts during co-culture, which induced phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1), and nuclear translocalization of NFκBα. Several genes, including interferon regulatory factor 1 (IRF1) interleukin-6 (IL-6) and prostaglandin-endoperoxide synthase 2 (COX-2) were induced in CAFs during co-culture. The most enhanced induction was found for IL-6 and COX-2. Treatment of PDL fibroblasts with IL1-β reproduced a time- and dose-dependent upregulation of IL1-receptor, IL-6 and COX-2. A further proof was achieved by DEX inhibition for IL1-β-stimulated IL-6 and COX-2 gene expression. Constitutive expression of IL1-β in the tumor cells leads to IL1-β-stimulated gene expression changes in tumor-associated fibroblasts, which are involved in tumor progression.

Identification of the rare EGFR mutation p.G796S as somatic and germline mutation in white patients with squamous cell carcinoma of the head and neck

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are involved in tumorigenesis and response to targeted therapies in distinct cancer types. Squamous cell carcinomas of the head and neck (HNSCC) show an incidence of EGFR mutations varying from 7% in Asians to 0% to 4% in white patients. Mutational screening predominantly focuses on the analysis of hotspot regions of EGFR (exons 19 and 21).

Health-related quality of life outcome of adult patients after otoplasty.

Prominent ears are relatively frequent. Decreased self-esteem, increased anxiety, behavioral problems and social avoidance may result from disfigurement. In modern medicine it is becoming increasingly important to measure the benefit of surgical intervention by its impact on the patients Quality of Life (QOL). Our study was performed in a retrospective manner at our institution including 40 adult patients with prominent ears. The Glasgow Benefit Inventory (GBI), a reproducible, valid and responsive questionnaire, was the basis of the used inquiry for detecting the changes in HRQOL after otoplasty. We showed an improvement in GBI subscores after intervention. There was no difference in GBI subscores between men and women. The follow-up time as well as critical life event and chronic concomitant disease have no influence on the GBI results. Otoplasty has a positive impact on the HRQOL of adult patients with prominent ears. The importance of this benefit is not only of individual nature. In times of healthcare economization, an amelioration of QOL followed by increased productivity at work of the individual is an important argument to justify health care expenditures. We believe that otoplasty is an appropriate therapy for selected adult patients burdened by prominent ears.

The impact of adenotonsillectomy on children's quality of life.

Objectives:  Although adenotonsillectomy is one of the most frequently performed surgical procedures in the pediatric population, there is little known about its impact on Health‐related Quality of Life (HRQL). The aim of this study was to measure children’s HRQL‐benefit after adenotonsillectomy.

Sheep as a Large Animal Model for Middle and Inner Ear Implantable Hearing Devices: A Feasibility Study in Cadavers

Objective Currently, no large animal model exists for surgical-experimental exploratory analysis of implantable hearing devices. In a histomorphometric study, we sought to investigate whether sheep or pig cochleae are suitable for this purpose and whether device implantation is feasible. Methods Skulls of pig and sheep cadavers were examined using high-resolution 128-slice computed tomography (CT) to study anatomic relationships. A cochlear implant and an active middle ear implant could be successfully implanted into the sheep’s inner and middle ear, respectively. Correct device placement was verified by CT and histology. The cochlear anatomy of the sheep was further studied by micro-CT and histology. Results Our investigations indicate that the sheep is a suitable animal model for implantation of implantable hearing devices. The implantation of the devices was successfully performed by access through a mastoidectomy. The histologic, morphologic, and micro-CT study of the sheep cochlea showed that it is highly similar to the human cochlea. The temporal bone of the pig was not suitable for these microsurgical procedures because the middle and inner ear were not accessible owing to distinct soft and fatty tissue coverage of the mastoid. Conclusion The sheep is an appropriate large animal model for experimental studies with implantable hearing devices, whereas the pig is not.