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Translational research in head and neck oncology is subject to the same laws as all other solid tumors. It is based on the one hand on a solid framework of well prepared clinical studies and / or workflows according to consensus criteria with comparable documentation of clinical outcomes, while on the other on methodolgically solid and reproducible laboratory research within an effeciently interacting network. Translationally applicable single molecular markers from basic research [with the exception of p16(INK4a) as a surrogate marker for human papillomavirus (HPV)] have not found their way into clinical routine in head and neck squamous cell carcinoma (HNSCC). "Correlated gene sets" and "metagenes", including genetic profiling (omics) within clinically characterized patient groups, play an increasing role in the translational research of HNSCC. Although methodological problems currently hinder clinical oncological research, increasing focus on translational research can be observed.

There has been a growing body of evidence in recent years to indicate that the presence of cancer stem cells may be responsible for tumour development and early recurrence after conventional therapy strategies such as surgery, radiation, or chemotherapy. Although this concept of a small subpopulation of cancer cells with stem cell properties is not new as such and was already discussed by Virchow decades ago, the identification of cells of this kind in human malignancies was first successful in 1997 in acute myeloid leukemia. The recent identification of cancer stem cells and the detection of their fundamental signalling pathways (e.g. Hedgehog, Notch) may offer new therapeutic options in the future and become part of a therapeutic concept. In this article, we introduce the cancer stem cell model, provide an overview of current cancer stem cell markers in different human malignancies as well as head and neck squamous cell carcinoma, and discuss studies on the first targeted therapies against cancer stem cells and their signalling pathways.

Despite multiple medical and scientific achievements, cancer remains a leading cause of death worldwide. Next to imaging technologies, molecular methods for early detection and for monitoring of the course of disease are of increasing interest. Thus, over the past years numerous studies have focused on the identification of biomarkers for cancer diagnosis, prognosis and response to therapy. The study of biomarkers seems to pose a high degree of complexity because many different types of molecules may, in principle, serve as potential biomarkers. In addition, these molecules can be produced either by the tumor or by the tumor-host in response to the presence of cancer. In this review the authors will address several major topics encompassed by the field of biomarker research. They will discuss the primary sources from which biomarker candidates can be 'mined' as well as the technological or methodological challenges associated with identification of biomarkers. Furthermore, the review will focus on current biomarker candidates for head and neck squamous cell carcinoma (HNSCC), with particular interest on several molecules yielding potential relevance for detection and prognosis of this type of cancer. Finally, several biomarker candidates with predictive potential for the response to therapy of HNSCC patients will be discussed, since identifying such molecules is crucial for developing individually-tailored and improved therapeutic strategies., (© Georg Thieme Verlag KG Stuttgart · New York.)

Traditional diagnostic methods such as clinical assessment, histopathological examination and imaging techniques are limited in their capacity to provide information on prognosis and treatment choice of head and neck cancer. In recent years, molecular techniques have been developed that enabled us to get more insight into the molecular biological cellular pathways underlying tumor progression and metastasis. Correlation of these molecular changes with clinical events has been explored. However, consistently useful markers have not been identified yet, although many promising developments are in progress. It may be expected that in the near future, molecular markers will be useful for clinical purposes. In this paper, an overview will be given of the several molecular techniques that may have potential to be introduced in clinical practice in the management of head and neck squamous cell carcinoma.

Conclusions: Survivin expression should be studied as a potential hallmark of higher risk oral, oropharyngeal and laryngeal squamous cell carcinomas (SCCs) to develop loco-regional recurrences. These outcomes could have a significant impact on both the treatment modalities and the intensity of post-treatment follow-up. Further investigation is necessary before considering elective neck dissection in patients with laryngeal SCC with high survivin expression., Objectives: Functioning simultaneously at cell division and apoptosis inhibition, survivin, a member of the inhibitor of apoptosis proteins family, plays a pivotal role in determining cell survival. Significant over-expression of survivin has been demonstrated in most human malignancies and correlated with more aggressive forms. This review focuses on the attempts to translate survivin biologic properties toward both a diagnostic/prognostic tool and a novel therapeutic target in head and neck SCC (HNSCC)., Materials and Methods: An exhaustive review of literature was performed to investigate available evidence about survivin expression, biological role and therapeutic potential in HNSCC., Results: Multiple evidence indicates that, in HNSCC cell lines, survivin inhibition by gene therapy and by small molecule inhibitors significantly increases the anti-tumour activity of several cytotoxic and other targeted therapies.

Objectives: To examine (1) the molecular angiogenic relationship between endothelial and stromal cells of angiofibromas and how this may elucidate the pathogenesis of angiofibromas and (2) the effects of embolization on the expression of angiotrophic factors and proapoptotic and antiapoptotic factors within the tumor., Design: The expression of mesenchymal and endothelial stem/progenitor cell-associated proteins (MECAPs) such as proangiogenic cytokine vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), angiopoietin receptors (Tie-1 and Tie-2), and stem cell subset marker CD133 was assessed by immunohistological staining in 7 embolized angiofibroma specimens. Expression of proapoptotic Bax, antiapoptotic Bcl-2 and Bcl-xL, nuclear proliferation protein MiB-1, and hypoxia-inducible factor 1alpha (Hif-1alpha) in peri-ischemic areas of the embolized angiofibromas was also assessed., Setting: A single pediatric institution., Patients: Seven patients (identified from medical records, January 1, 2001, through December 31, 2005) who were diagnosed as having juvenile angiofibroma and who underwent surgical treatment. Archival tissues were retrieved for immunostaining., Main Outcome Measures: The immunostaining results were evaluated by microscopy and the staining intensities were also recorded., Results: All angiofibroma specimens expressed the stem cell subset marker CD133 and MECAPs except VEGFR3 (a few cases). In the only case tested, we found evidence of VEGF-induced angiogenic signaling as the expression of phosphorylated VEGFR2 (Tyr951). Endothelial cells expressed VEGFR1 and VEGFR2 and angiopoietin receptors Tie-1 and Tie-2 but not VEGF. In contrast, VEGF was expressed within stromal cells. Viable tumor adjacent to the ischemic areas demonstrated increased staining intensities to VEGFR2, Tie-1, Tie-2 (all cases), and VEGFR3 (2 cases) and increased nuclear proliferation (5%-20%). All cases expressed proapoptotic and antiapoptotic factors, and the expression of Hif-1alpha was unaffected by ischemia., Conclusions: Stromal cells appear to be similar to mesenchymal stem cells with endothelial differentiation potential in umbilical cord blood cells. Stromal cells support endothelial growth by providing VEGF as a paracrine factor. Under ischemic stress, the embolized tumor tissues show upregulation of angiogenic receptors, retention of Hif-1alpha, and increased nuclear proliferation rates. Specific angiogenesis blockers may represent a novel treatment strategy for angiofibromas.

Background: In recent years, a number of molecular markers have been tested for their potential to predict the outcome after radiotherapy or radiochemotherapy in patients with advanced head and neck squamous cell carcinomas (HNSCC). These studies have produced controversial results., Patients and Methods: The expression patterns of the proteins p53, pRb, cyclinD1, cdk4, p21(CIP1/WAF1), p16(INK4a), bcl-2, and mib-1/ki-67 were analyzed in pretreatment tumor biopsies of 53 patients with advanced nonresectable head and neck squamous cell carcinomas (mainly UICC IV). The patterns obtained were compared with clinical outcome after accelerated radiochemotherapy with carboplatin and 5-fluorouracil or accelerated fractionated radiotherapy alone, respectively., Results: The expression patterns of the proteins examined did not correlate with response to therapy or with further clinical course., Conclusion: In patients with advanced head and neck squamous cell carcinomas, the prognostic relevance of pretreatment expression patterns of the proteins investigated in this study, particularly p53, cyclinD1, and cdk4, has to be questioned.

Lung as well as head and neck cancer represent an important public health problem worldwide, with lung cancer being the leading cause of cancer death in western countries. Although early stage disease is often curable with surgery or radiotherapy, the majority of patients present with advanced disease in which despite advances in combined modality therapy the outcomes have not dramatically improved. Furthermore, patients cured of their initial early stage lung or head and neck carcinoma are at high risk for development of second primary tumors, which pose the main threat to their survival. An alternative approach in reducing the incidence and thus mortality of these cancers is chemoprevention, the use of agents to reverse, halt or delay carcinogenesis. The carcinogenesis process in lung and head and neck cancer results from a dysregulation of cellular proliferation, differentiation and cell death resulting from field-wide exposure of the upper and lower airway track to tobacco smoking. This review article presents main data regarding the actual understanding of lung and head and neck carcinogenesis, as well as results of major chemoprevention trials in this field.

Background: Scientific research work of the last decade has been performed in order to investigate biological parameters of prognostic significance for head and neck squamous cell carcinoma. In contrast to other cancer types, like colon carcinoma, where tumour progression is accompanied by an almost defined sequel of gene activations and inactivations, cells of squamous cell carcinoma behave more heterogenously., Methods: Publications concerning the most important immunohistochemical, molecular biological and cytogenetic prognostic markers in head and neck cancer have been analyzed., Results: The prognostic markers discussed in this publication have been classified into the following areas: Apoptosis, cell cycle regulation, viral infections, cytokines and growth factors/growth factor receptors, angiogenesis and hypoxia, proteinases, cell-cell contacts and cell-matrix contacts, cytokeratin fragments, chromosomal rearrangements and genetically inherited susceptibility to toxic reagents., Conclusions: Significant prognostic markers are important for the clinical follow-up of patients and the choice of therapeutical approach. However, none of the factors analyzed can be used as an individual and universal prognostic marker at present.

In individual patients with head and neck squamous cell carcinomas (HNSCC), established prognostic factors do not satisfactorily predict clinical outcome. For the first time we investigated a total of 100 HNSCC by Comparative Genomic Hybridization (CGH) to define chromosomal alterations that are associated with the patients prognosis. Patients were followed for at latest 4 but at least 2 years after surgery or until death. During this observation period twenty-nine of them died because of cancer disease. The Kaplan-Meier method was used plotting survival curves for every single chromosomal alteration as well as every clinico-pathological parameter. The curves were tested for significance by the log rank as well as the Breslow test. Significance of particular prognostic parameters was then evaluated by the Cox regression model. The overall survival time as well as the recurrence free survival time were significantly lower in patients who's tumors showed amplifications of the chromosomal region 11q13 (p = 0.0008 for LR and p = 0.0024 for B). The survival time of the patients was also lower if the carcinomas carried over-representations of chromosome 3q (p = 0.0299 for LR and p = 0.0546 for B). Multivariate analysis (Cox's proportional hazards model) revealed both alterations as most important independent prognostic factors in HNSCC. None of the conventional clinicopathological parameters (pT-, pN-status, UICC stage, grading) achieved statistical significance in the multivariate model. These results suggest that in HNSCC the occurrence of 11q13 amplification and 3q overrepresentation are highly significant independent prognostic markers and of better value than the established TNM and grading criteria.

Background: Comparative genomic hybridization (CGH) was applied to squamous cell carcinomas of the head and neck to define genetic alterations that are associated with the metastatic phenotype., Methods: CGH is a molecular cytogenetic method allowing the comprehensive analysis of a tumor genome for chromosomal imbalances. In total, 23 primary squamous cell carcinomas without evidence of metastasis formation and 20 lymph node metastases were investigated., Results: Prevalent changes observed in more than 50% of the primary tumors included deletions on chromosomes 3p, 4p/q, 5q, 6q, 9p, 11q, 13q, and 18q, and DNA overrepresentations on chromosomes 1p, 3q, 5p, 8q, 9q, 11q13, 16p, 17q, 19p, 20q, and 22q. To evaluate the differences between both groups we used a histogram representation, calculation of a difference histogram, and statistical analysis. The analysis revealed that the lymph node metastases were frequently characterized by deletions on chromosomes 10, 11, and 14. In particular, DNA loss of the chromosomal bands 5p12, 10p11.2-12, 10q21, 10q22-23, 10q24-26, 11p13-14, 11q24-25, and 14q22-24 were significantly associated with metastases formation. The statistical analysis indicated that particularly the deletions on chromosome 10q were highly significant markers for the incidence of lymph node metastases., Conclusion: Our data indicate that tumor phenotypes are determined by patterns of chromosomal alterations, and that 10q deletions may predict the metastatic phenotype in head and neck squamous cell carcinomas.

Background: Primary radiochemotherapy is gaining increasing importance for the treatment of advanced head and neck squamous cell carcinomas. However, there is a lack of clinical factors concerning prognostic information in relation to treatment. In this pilot study, we examined whether molecular factors can provide such information., Patients and Methods: The expression patterns and their possible prognostic relevance of the cell cycle regulatory proteins p53, p21(WAF/CIP1), Rb, p16(INK4A), CDK4 and Cyclin D1, MIB1 (Ki-67) and BCL-2 were analysed in pretreatment tumor biopsies from 43 patients with advanced carcinomas of the oropharynx (n = 26), hypopharynx (n = 10) and larynx (n = 7) by applying immunohistochemistry to paraffin sections of tumor specimens. All patients were treated by the same method of an accelerated "concomitant boost" radiochemotherapy with carboplatin in a phase II study. Median followup time was 56 months., Results: No correlation was found between any of the markers and the remission rate, T-stage, N-stage, rate of loco-regional recurrences and distant metastases. However, independent of the tumor stage, patients with CDK4/cyclin-D1 overexpressing tumors had a significantly shortened overall survival (P = 0.014 and 0.026, respectively)., Conclusion: The results of this pilot study indicate that CDK4 and cyclin D1 over-expression provide useful prognostic information about clinical outcome after primary radiochemotherapy of head and neck cancer patients.

The concept of field cancerisation assumes that in head and neck cancer patients (HNCP) with multiple malignancies the second primary cancers may arise independently from the entire upper aerodigestive tract as a consequence of massive exposure to common carcinogens. Since mutations and/or overexpression of the p53 tumour suppressor gene represent a genetic alteration frequently occurring in HNCP, we analysed immunocytochemically p53 oncoprotein expression in first primary, second primary cancers and in macroscopically uninvolved normal epithelium from different sites of the upper aerodigestive tract from 12 HNCP with multiple malignancies, in comparison with p53 expression in biopsy specimens of the upper aerodigestive tract from 5 non-neoplastic heavy smokers, as controls. In patients with multiple malignancies 6 cases (50%) showed positive staining of both first and second primaries, whereas 3 (25%) had positive labelling of first primary cancer but not of the subsequent second primary, 2 (17%) patients showed p53 expression only in the second primary cancer, and finally only 1 patient (8%) showed no p53 immunoreactivity in both first and second primary tumours. Moreover, 10 out of 12 (83%) HNCP with multiple cancers showed p53-positive staining in the normal epithelium from different sites of the upper aerodigestive tract, also at a significant distance from the site of first and second primary malignancies. contrast, sporadic p53 immunostaining was observed only in three out of 35 (8.5%) specimens from non-neoplastic controls. In addition, in 4 HNCP with multiple tumours the histological examination of apparently normal epithelium from the upper aerodigestive tract revealed signs of moderate or severe dysplasia, and in 1 case an in situ carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)