Claude Fischer

Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality

The incidence of human papilloma virus (HPV) induced oropharyngeal squamous cell carcinoma (OPSCC) increases in the western countries. These OPSCC show distinct molecular characteristics and are characterized by an overexpression of p16, considered a surrogate marker for HPV infection. When compared to patients with p16 negative OPSCC, patients with HPV induced p16 positive OPSCC show a significantly better prognosis, which is reported to be caused by increased radiosensitivity. The objective of the present study was to analyze the impact of p16 expression status on the prognosis of OPSCC treated by either radiotherapy (RT) or primary surgery. Results are based upon a tissue microarray (TMA) of 365 head neck squamous cell carcinomas (HNSCC) including 85 OPSCC with clinico‐pathological and follow‐up data. p16 positivity correlated significantly with oropharyngeal tumor localization (p < 0.001). Patients with p16 positive OPSCC exhibited a significantly better overall survival than those with p16 negative tumors (p = 0.007). In a multivariate analysis, survival benefit of patients with p16 positive OPSCC was independent of clinico‐pathological parameters such as cT and cN classification and treatment modality. The improved prognosis of p16 positive OPSCC is found after RT as well as after surgery.

Enhanced Expression of ANO1 in Head and Neck Squamous Cell Carcinoma Causes Cell Migration and Correlates with Poor Prognosis

Head and neck squamous cell carcinoma (HNSCC) has the potential for early metastasis and is associated with poor survival. Ano1 (Dog1) is an established and sensitive marker for the diagnosis of gastrointestinal stromal tumors (GIST) and has recently been identified as a Ca2+ activated Cl− channel. Although the ANO1 gene is located on the 11q13 locus, a region which is known to be amplified in different types of human carcinomas, a detailed analysis of Ano1 amplification and expression in HNSCC has not been performed. It is thus still unclear how Ano1 contributes to malignancy in HNSCC. We analyzed genomic amplification of the 11q13 locus and Ano1 together with Ano1-protein expression in a large collection of HNSCC samples. We detected a highly significant correlation between amplification and expression of Ano1 and showed that HNSCC patients with Ano1 protein expression have a poor overall survival. We further analyzed the expression of the Ano1 protein in more than 4′000 human samples from 80 different tumor types and 76 normal tissue types and detected that besides HNSCC and GISTs, Ano1 was rarely expressed in other tumor samples or healthy human tissues. In HNSCC cell lines, expression of Ano1 caused Ca2+ activated Cl− currents, which induced cell motility and cell migration in wound healing and in real time migration assays, respectively. In contrast, knockdown of Ano1 did not affect intracellular Ca2+ signaling and surprisingly did not reduce cell proliferation in BHY cells. Further, expression and activity of Ano1 strongly correlated with the ability of HNSCC cells to regulate their volume. Thus, poor survival in HNSCC patients is correlated with the presence of Ano1. Our results further suggest that Ano1 facilitates regulation of the cell volume and causes cell migration, which both can contribute to metastatic progression in HNSCC.

Three-dimensional imaging of the larynx for pre-operative planning of laryngeal framework surgery

Modern laryngeal framework surgery (LFS) requires an exact understanding of the laryngeal biomechanics and precise pre-operative planning, for which bi-planar imaging is not sufficient. The aim of the study was to test whether MIMICS®, a commercially available software package for three-dimensional (3D) rendering of high-resolution computerised tomography (HRCT), is suitable for 3D imaging of the larynx, analysis of laryngeal biomechanics and pre-operative planning. We examined four cadaver larynx and one patient larynx. In the five larynges, all relevant structures and landmarks could be 3D visualised. Superimposing of two HRCT scans shows that when the arytenoids move from ‘respiration’ to ‘phonation’, they perform a rotating, translating and tilting motion. Moreover, we could demonstrate that the vocal fold elongates by 7% with cricothyroid approximation. We conclude that MIMCS® is well suited for 3D imaging of the larynx, analysis of laryngeal biomechanics and pre-operative planning of LFS procedures.

Co-overexpression of p21 and Ki-67 in head and neck squamous cell carcinoma relative to a significantly poor prognosis

Head and neck squamous cell carcinomas (HNSCC) are treated by surgery or radiotherapy. Tumor cell death–related markers, such as p21 and Ki‐67, may predict response to therapy and improve treatment choice. We evaluated and compared the effect of their coexpression between patients treated by surgery or radiotherapy.

Developing a 3D model of the laryngeal cartilages using HRCT data and MIMICS’s segmentation software

Abstract Discussions relating to the biomechanics of the larynx are still generally controversial. The purpose of this study is to develop a 3D model of the larynx based on high-resolution computer tomography (HRCT) data identifying and visualizing anatomical landmarks and structures of the larynx. We examined four fresh cadaver larynges with HRCT. The DICOM (Digital Imaging and Communication in Medicine) data were post-processed with the software package MIMICS® for three-dimensional visualization. All relevant structures of the laryngeal cartilages could be identified on HRCT and visualized in a 3D model. We conclude that 1) HRCT provides excellent data for three-dimensional visualization of the laryngeal anatomy, and 2) the combined technology of HRCT and MIMICS® is useful to study the biomechanics on 3D images and for preoperative planning of laryngeal framework surgery.

Hydroxyapatite versus titanium implant: Comparison of the functional outcome after vocal fold medialization in unilateral recurrent nerve paralysis

Results of medialization thyroplasty for treatment of unilateral vocal fold paralysis are often unsatisfactory. This study compares glottal closure and voice quality after use of 2 different medialization implant types: VoCoM and TVFMI.

Results of concurrent radio-chemotherapy for the treatment of head and neck squamous cell carcinoma in everyday clinical practice with special reference to early mortality

BackgroundRandomized controlled trials have established concurrent chemo-radiotherapy as the preferred treatment option for inoperable local-regionally advanced head and neck squamous cell carcinomas (HNSCCs). Because many patients have multiple co-morbidities and would not fulfill the eligibility criteria of clinical trials, the results need to be re-evaluated in daily clinical practice with special reference to early mortality.Methods167 consecutive patients with HNSCC who received concurrent chemo-radiotherapy at the Basel University Hospital between 1988 and 2006 were analyzed retrospectively with a special focus on early deaths and risk factors for an unfavorable outcome.ResultsIn our cohort, the 3- and 5-year overall survival rates were 54% and 47%, respectively. The therapy was associated with relevant toxicity and an early mortality rate of 5.4%. Patients dying early were analyzed individually for the cause of death. Patients with elevated white blood cell counts (HR: 2.66 p = 0,016) and vascular co-morbidities (HR: 5.3, p = 0,047) showed significantly worse survival rates. The same factors were associated with a trend toward increased treatment-related mortality. The 3-year survival rate improved from approximately 43% for patients treated before the year 2000 to 65% for patients treated after the year 2000 (Fisher’s exact test p = 0.01).ConclusionsAlthough many patients who received concurrent chemo-radiotherapy would not have qualified for clinical trials, the outcome was favorable and has significantly improved in recent years. However the early mortality was slightly worse than what is described in the literature.

Analysis of the EGFR Mutation Status in Head and Neck Squamous Cell Carcinoma before Treatment with Gefitinib

Background: The efficacy of chemotherapy in metastatic and recurrent squamous cell carcinomas of the head and neck (HNSCC) remains unsatisfactory. Gefitinib offers a new therapeutic option with comparable results and better tolerability than chemotherapy. We conducted this study to see if mutations in the epidermal growth factor receptor (EGFR) might predict the therapeutic benefit in HNSCC patients. Patients and Methods: In a pilot trial, 8 patients with metastatic or recurrent HNSCC were treated palliatively with gefitinib (500 mg/day orally). Forceps biopsies were taken to confirm tumor recurrence and to perform an EGFR mutation analysis. Results: The EGFR status could be determined in 6 of the 8 patients. 5 patients had no EGFR gene mutation, and 1 patient showed a silent guanine-to-adenosine mutation in position 2607. Even without any relevant mutation in the EGFR, we observed partial remission in 3 of 6 patients treated with gefitinib. We also observed that an additional 4 patients had stable disease for at least 10 weeks. The median progression-free survival was 6.25 months, and the median overall survival was 7.39 months. Conclusion: In HNSCC, there are tumor responses to gefitinib without protein-altering mutations in the EGFR gene.

Abstract 1082: The amplification and overexpression of the calcium activated chloride channel TMEM16A (aka DOG1) has a prognostic role in patients with head and neck squamous cell carcinoma

Introduction: The calcium activated chloride channel TMEM16A, which is also known as DOG1, is used as a sensitive marker for the diagnosis of gastrointestinal tumors (GIST). Its expression has also been described in head and neck squamous cell carcinomas (HNSCC) and in esophageal SCC. Surprisingly, until recently (2008) its role as chloride channel was not known. The TMEM16A gene is localized very close to the Cyclin D1 gene (CCND1), which is a putative target gene of the 11q13 amplicon. Aim of this study was the analysis of the genomic and expression status of TMEM16A in HNSCC. Methods: We applied fluorescence in-situ hybridization (FISH) and immunohistochemistry to a tissue microarray (TMA) containing tissue specimens from 216 primary tumors from the oral cavity, 40 local recurrences and 76 neck dissections. We validated our results on a second cohort consisting of additional 158 HNSCCs. In order to analyze the prognostic role of TMEM16A, a subset of 365 primary tumors with complete follow-up data was selected. Results: We found genomic amplification of the TMEM16A gene in 13% of the primary head and neck squamous cell carcinomas and in 12% of the local recurrences. Although the prevalence of TMEM16A protein expression was lower (8%), a strong correlation between TMEM16A amplification and overexpression was found (p Conclusions: TMEM16A positivity characterizes a small subgroup of HNSCC with poor survival. The strong correlation between genomic amplification and expression suggests that TMEM16A is one of the driving genes of the 11q13 amplicon in HNSCC. Additional studies may show how this chloride channel can be used as a therapeutic target in patients with TMEM16A positive tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1082. doi:10.1158/1538-7445.AM2011-1082