Publications by authors named "Stefan Hartmann"

57 Publications

Mammary analogue secretory carcinoma of a salivary gland of the hard palate with contralateral cervical lymph node metastases: A case report.

Mol Clin Oncol 2021 Nov 6;15(5):226. Epub 2021 Sep 6.

Department of Maxillofacial and Plastic Surgery of The University of Wuerzburg, D-97070 Wuerzburg, Germany.

Mammary analogue secretory carcinoma (MASC) is a rare malignant tumour of the salivary glands, with only few cases reported in the literature to date. Initial preoperative staging is crucial for all patients with an oral malignancy to visualize the tumour, detect lymph node or distant metastases and plan therapeutic interventions. In the case presented herein, radiological imaging revealed a tumour of the right hard palate with suspected positive contralateral lymph nodes. Therefore, local tumour resection comprising hemimaxillectomy and bilateral neck dissection was performed. The diagnosis of MASC was finally based on characteristic histopathological and immunohistochemical findings, such as S100 protein and mammaglobin positivity. The diagnosis of MASC may be challenging, as such findings lack specificity. To confirm the diagnosis, molecular genetic examinations may be performed to detect a highly specific ETV6-NTRK3 fusion gene. Depending on the results of these examinations, surgery, alone or combined with adjuvant radiation or chemoradiation, is the recommended approach. In summary, MASC should be treated similarly to other low-grade salivary gland tumours, such as acinic cell carcinoma, as they exhibit biological and histopathological similarities.
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http://dx.doi.org/10.3892/mco.2021.2389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506652PMC
November 2021

The Building Blocks of Child Bilingual Code-Mixing: A Cross-Corpus Traceback Approach.

Front Psychol 2021 27;12:682838. Epub 2021 Jul 27.

Faculty of Arts and Humanities, German Department, University of Düsseldorf, Düsseldorf, Germany.

This paper offers an inductive, exploratory study on the role of input and individual differences in the early code-mixing of bilingual children. Drawing on data from two German-English bilingual children, aged 2-4, we use the traceback method to check whether their code-mixed utterances can be accounted for with the help of constructional patterns that can be found in their monolingual data and/or in their caregivers' input. In addition, we apply the traceback method to check whether the patterns used by one child can also be found in the input of the other child. Results show that patterns found in the code-mixed utterances could be traced back to the input the children receive, suggesting that children extract lexical knowledge from their environment. Additionally, tracing back patterns within each child was more successful than tracing back to the other child's corpus, indicating that each child has their own set of patterns which depends very much on their individual input. As such, these findings can shed new light on the interplay of the two developing grammars in bilingual children and their individual differences.
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http://dx.doi.org/10.3389/fpsyg.2021.682838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353255PMC
July 2021

Validation of the German-language version of the Liverpool Oral Rehabilitation Questionnaire version 3 and evaluation of oral-health-related quality of life among patients with squamous cell carcinoma of the head and neck.

J Craniomaxillofac Surg 2021 Nov 18;49(11):1081-1087. Epub 2021 Jun 18.

Department of Psychology (Biological Psychology, Clinical Psychology and Psychotherapy), University of Würzburg, Marcusstraße 9-11, 97070, Würzburg, Germany. Electronic address:

The aim of this study was to translate the Liverpool Oral Rehabilitation Questionnaire version 3 (LORQv3) into German and validate this version in order to assess oral-health-related quality of life (OHRQoL) among head and neck cancer patients. This study was conducted at a German university clinic among patients who had completed therapy for squamous cell carcinoma of the head and neck (HNSCC). The original English-language LORQv3 was translated into German according to the forward-backward approach. Validity and reliability were evaluated using further questionnaires related to OHRQoL and psychological impairments. Subgroups were built with reference to oral rehabilitation status and type of cancer therapy. Furthermore, OHRQoL was evaluated. Test-retest reliability was assessed by weighted kappa with a 10-14 day interval. Data were analysed by using Spearman's correlation and the following tests: Shapiro-Wilk, Kruskal-Wallis, Mann-Whitney U and Cronbach's alpha. The level of significance was set at α = 0.05. Analysis of the LORQv3 evaluations revealed excellent Cronbach's alpha and high test-retest reliability. Construct validity were supported by the data. LORQv3 summary score and domains were significantly affected by status of oral rehabilitation (p = 0.003, p = 0.008, p = 0.024) and treatment approach (p < 0.001, p = 0.025, p = 0.035). The German version of the LORQv3 showed high reliability and validity and an impaired OHRQoL of HNSCC patients. It can therefore be recommended for the assessment of OHRQoL.
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http://dx.doi.org/10.1016/j.jcms.2021.06.007DOI Listing
November 2021

Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity - initial experience and comparison to [F]FDG PET/CT and MRI.

Eur J Nucl Med Mol Imaging 2021 11 29;48(12):3951-3960. Epub 2021 May 29.

Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany.

Purpose: While [F]-fluorodeoxyglucose ([F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT.

Methods: Ten consecutive, treatment-naïve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [F]FDG and [Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUV) and peak (SUV) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference.

Results: [F]FDG and FAP-directed PET/CT detected all primary tumors with a SUV of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUV of 16.1 ± 10.3 ([F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3% vs. 87.5%; P = 0.32) and specificity (93.3% vs. 81.3%; P = 0.16) to [F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples.

Conclusion: FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.
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http://dx.doi.org/10.1007/s00259-021-05422-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484183PMC
November 2021

Accuracy of 18-F Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Imaging in Primary Staging of Squamous Cell Carcinoma of the Oral Cavity.

JAMA Netw Open 2021 04 1;4(4):e217083. Epub 2021 Apr 1.

Department of Nuclear Medicine, University Hospital of Würzburg, Würzburg, Germany.

Importance: Squamous cell carcinoma (SCC) of the oral cavity is one of the most common tumor entities worldwide. Precise initial staging is necessary to determine a diagnosis, treatment, and prognosis.

Objective: To examine the diagnostic accuracy of preoperative 18-F fluorodeoxyglucose (FDG) positron emission tomographic/computed tomographic (PET/CT) imaging in detecting cervical lymph node metastases.

Design, Setting, And Participants: This prospective diagnostic study was performed at a single tertiary reference center between June 1, 2013, and January 31, 2016. Data were analyzed from April 7, 2018, through May 31, 2019. Observers of the FDG PET/CT imaging were blinded to patients' tumor stage. A total of 150 treatment-naive patients with clinical suspicion of SCC of the oral cavity were enrolled.

Exposures: All patients underwent FDG PET/CT imaging before local tumor resection with selective or complete neck dissection.

Main Outcomes And Measures: The accuracy of FDG PET/CT in localizing primary tumor, lymph node, and distant metastases was tested. Histopathologic characteristics of the tissue samples served as the standard of reference.

Results: Of the 150 patients enrolled, 135 patients (74 [54.8%] men) with a median age of 63 years (range, 23-88 years) met the inclusion criteria (histopathologically confirmed primary SCC of the oral cavity/level-based histopathologic assessment of the resected lymph nodes). Thirty-six patients (26.7%) in the study cohort had neck metastases. Use of FDG PET/CT detected cervical lymph node metastasis with 83.3% sensitivity (95% CI, 71.2%-95.5%) and 84.8% specificity (95% CI, 77.8%-91.9%) and had a negative predictive value of 93.3% (95% CI, 88.2%-98.5%). The specificity was higher than for contrast-enhanced cervical CT imaging (67.0%; 95% CI, 57.4%-76.7%; P < .01) and cervical magnetic resonance imaging (62.6%; 95% CI, 52.7%-72.6%; P < .001). Ipsilateral lymph node metastasis in left- or right-sided primary tumor sites was detected with 78.6% sensitivity (95% CI, 63.4%-93.8%) and 83.1% specificity (95% CI, 75.1%-91.2%), and contralateral metastatic involvement was detected with 66.7% sensitivity (95% CI, 28.9%-100.0%) and 98.6% specificity (95% CI, 95.9%-100.0%). No distant metastases were observed.

Conclusions And Relevance: In this study, FDG PET/CT imaging had a high negative predictive value in detecting cervical lymph node metastasis in patients with newly diagnosed, treatment-naive SCC of the oral cavity. Routine clinical use of FDG PET/CT might lead to a substantial reduction of treatment-related morbidity in most patients.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.7083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060833PMC
April 2021

Constructing a protolanguage: reconstructing prehistoric languages in a usage-based construction grammar framework.

Philos Trans R Soc Lond B Biol Sci 2021 05 22;376(1824):20200200. Epub 2021 Mar 22.

Centre for Language Evolution Studies, Nicolaus Copernicus University in Toruń, ul. Gagarina 11, 87-100 Toruń, Poland.

Construction grammar is an approach to language that posits that units and structures in language can be exhaustively described as pairings between form and meaning. These pairings are called constructions and can have different degrees of abstraction, i.e. they span the entire range from very concrete () to very abstract constructions such as the ditransitive construction (). This approach has been applied to a wide variety of different areas of research in linguistics, such as how new constructions emerge and change historically. It has also been applied to investigate the evolutionary emergence of modern fully fledged language, i.e. the question of how systems of constructions can arise out of prelinguistic communication. In this paper, we review the contribution of usage-based construction grammar approaches to language change and language evolution to the questions of (i) the structure and nature of prehistoric languages and (ii) how constructions in prehistoric languages emerged out of non-linguistic or protolinguistic communication. In particular, we discuss the possibilities of using constructions as the main unit of analysis both in reconstructing predecessors of existing languages (protolanguages) and in formulating theories of how a potential predecessor of human language in general (protolanguage) must have looked like. This article is part of the theme issue 'Reconstructing prehistoric languages'.
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http://dx.doi.org/10.1098/rstb.2020.0200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059648PMC
May 2021

HGF-Induced PD-L1 Expression in Head and Neck Cancer: Preclinical and Clinical Findings.

Int J Mol Sci 2020 Nov 20;21(22). Epub 2020 Nov 20.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.

Head and neck squamous cell carcinoma (HNSCC) is a widespread disease with a low survival rate and a high risk of recurrence. Nowadays, immune checkpoint inhibitor (ICI) treatment is approved for HNSCC as a first-line treatment in recurrent and metastatic disease. ICI treatment yields a clear survival benefit, but overall response rates are still unsatisfactory. As shown in different cancer models, hepatocyte growth factor/mesenchymal-epithelial transition (HGF/Met) signaling contributes to an immunosuppressive microenvironment. Therefore, we investigated the relationship between HGF and programmed cell death protein 1 (PD-L1) expression in HNSCC cell lines. The preclinical data show a robust PD-L1 induction upon HGF stimulation. Further analysis revealed that the HGF-mediated upregulation of PD-L1 is MAP kinase-dependent. We then hypothesized that serum levels of HGF and soluble programmed cell death protein 1 (sPD-L1) could be potential markers of ICI treatment failure. Thus, we determined serum levels of these proteins in 20 HNSCC patients before ICI treatment and correlated them with treatment outcomes. Importantly, the clinical data showed a positive correlation of both serum proteins (HGF and sPD-L1) in HNSCC patient's sera. Moreover, the serum concentration of sPD-L1 was significantly higher in ICI non-responsive patients. Our findings indicate a potential role for sPD-L1 as a prognostic marker for ICI treatment in HNSCC.
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http://dx.doi.org/10.3390/ijms21228770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699574PMC
November 2020

Sensitization of head and neck squamous cell carcinoma to apoptosis by combinational SMAC mimetic and Fas ligand-Fc treatment in vitro.

J Craniomaxillofac Surg 2020 Jul 2;48(7):685-693. Epub 2020 Jun 2.

Department of Oral and Maxillofacial Plastic Surgery (Head: A.C. Kübler), University Hospital of Würzburg, Pleicherwall 2, 97070, Würzburg, Germany.

This study aimed to investigate the in vitro efficacy of three different SMAC mimetics for pro-apoptotic sensitization of HNSCC cells. We evaluated BV-6 in comparison to Birinapant and LCL161, for which pro-apoptotic sensitization effects have been demonstrated. Concentration-dependent response was measured for BV-6 in each cell line with an average IC value 8-fold lower than of aforementioned SMAC mimetics. Combination treatment of FasL (log2) and BV-6 (IC) showed highly significant cell count reductions even in the lowest applied concentration in five cell lines (PCI-1: p = 0.0002, PCI-13: p = 0.0002, Detroit 562: p: p < 0.0001, FaDu: p < 0.0001, SCC-25: p = 0.0047). Synergistic effects (y < 1) were evident in eight out of 10 cell lines (PCI-1, PCI-9, PCI-13, PCI-68, Detroit 562, FaDu, SCC-25 and HaCaT). Annexin V assays revealed in nine cell lines very highly significant (p < 0.001) pro-apoptotic effects of BV-6. Western blots showed a heterogeneous IAP expression following SMAC mimetic treatment. Except for two cell lines, at least the cellular inhibitor of apoptosis protein 1 (cIAP1) was degraded in response to BV-6. For prospective targeted HNSCC therapy, this study identifies SMAC mimetics, particularly BV-6 as the compound with the highest pro-apoptotic potency, as promising antitumor agents.
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http://dx.doi.org/10.1016/j.jcms.2020.05.007DOI Listing
July 2020

The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma.

Int J Mol Sci 2020 Jan 11;21(2). Epub 2020 Jan 11.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.

Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Met-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC.
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http://dx.doi.org/10.3390/ijms21020471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013520PMC
January 2020

Constructing a Consensus on Language Evolution? Convergences and Differences Between Biolinguistic and Usage-Based Approaches.

Front Psychol 2019 14;10:2537. Epub 2019 Nov 14.

German Department, Chair of German Linguistics, University of Bamberg, Bamberg, Germany.

Two of the main theoretical approaches to the evolution of language are biolinguistics and usage-based approaches. Both are often conceptualized as belonging to seemingly irreconcilable "camps." Biolinguistic approaches assume that the ability to acquire language is based on a language-specific genetic foundation. Usage-based approaches, on the other hand, stress the importance of domain-general cognitive capacities, social cognition, and interaction. However, there have been a number of recent developments in both paradigms which suggest that biolinguistic and usage-based approaches are actually moving closer together. For example, theoretical advancements such as evo-devo and complex adaptive system theory have gained traction in the language sciences, leading to changed conceptions of issues like the relative influence of "nature" and "nurture." In this paper, we outline points of convergence between current minimalist biolinguistic and usage-based approaches regarding four contentious issues: (1) modularity and domain specificity; (2) innateness and development; (3) cultural and biological evolution; and (4) knowledge of language and its description. We show that across both paradigms, researchers have come to increasingly embrace more complex views of these issues. They also have come to appreciate the view that biological and cultural evolution are closely intertwined, which lead to an increased amount of common ground between minimalist biolinguistics and usage-based approaches.
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http://dx.doi.org/10.3389/fpsyg.2019.02537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868443PMC
November 2019

Multi-kinase inhibitors and cisplatin for head and neck cancer treatment .

Oncol Lett 2019 Sep 28;18(3):2220-2231. Epub 2019 Jun 28.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.

Multidrug resistance (MDR) remains one of the major causes of suboptimal outcome following therapy in head and neck squamous cell carcinoma (HNSCC). ATP-binding cassette (ABC) transporters are overexpressed in HNSCC, which contributes to the limited effect of chemotherapeutic treatment. In addition to their named function, tyrosine kinase inhibitors (TKIs) have been revealed to impact on ABC transporter activity and expression. Therefore, the present study aimed to investigate the effects of combination therapy using different TKIs combined with cisplatin. Reverse transcription-quantitative PCR was used to characterize ABC transporter and receptor expression in 5 HNSCC cell lines treated with 3 different TKIs (pazopanib, dovitinib, nintedanib) and cisplatin. Treatment efficacy was analyzed using a crystal violet staining assay. Analysis of ABC transporter (ABCB1, ABCC1 and ABCG2) genetic alterations was performed using The Cancer Genome Atlas. Statistical analysis was conducted to evaluate the effects of mono- and combination treatment. With the exception of ABCB1, all of the investigated ABC transporters were expressed in each cell line. The additive effects of TKI + cisplatin combination treatment were observed for pazopanib in three cell lines, nintedanib in four cell lines, and were not observed for dovitinib in any of the cell lines investigated. The combination of multi-kinase inhibitors and conventional chemotherapy in HNSCC may strengthen the use of current therapeutic strategies; nintedanib appears to be the most suitable TKI for combination therapy. Further efforts are required to classify TKI efficacy with regard to cisplatin resistance.
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http://dx.doi.org/10.3892/ol.2019.10541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676536PMC
September 2019

Targeting inhibitors of apoptosis in oral squamous cell carcinoma in vitro.

J Craniomaxillofac Surg 2019 Oct 19;47(10):1589-1599. Epub 2019 Jul 19.

Department of Oral and Maxillofacial Plastic Surgery (Head: A. C. Kübler), University Hospital Würzburg, Pleicherwall 2, 97070 Würzburg, Germany; Comprehensive Cancer Center Mainfranken (CCC MF) (Head: R. C. Bargou), Josef-Schneider-Str. 6, 97080 Würzburg, Germany.

Head and neck cancer, which predominantly arises from the oral mucosa, represents the sixth most common malignancy worldwide. These cancer cells can be resistant to programmed cell death triggered by extrinsic stimuli due to innate overexpression of inhibitor of apoptosis proteins (IAPs). The cellular protein second mitochondria-derived activator of caspases (SMAC) can antagonize IAP-induced caspase inhibition and thus trigger apoptosis. Here, we investigate the cell death-sensitizing effects of the SMAC mimetic LCL161 alone and in combination with Fas ligand (FasL) using a panel of six cell lines. Fas receptor (FasR) expression was analyzed by flow cytometry. Cells were treated with FasL and LCL161 alone or in combination, and cytotoxicity was measured using crystal violet assays. Annexin V and cell viability assays using zVAD-fmk and Necrostatin-1 (Nec-1) were carried out to assess the type of programmed cell death induced by LCL161. To demonstrate the sensitizing effects of LCL161, we employed the t-test to compare the effects of FasL alone and in combination with LCL161. Linear regression analysis was performed to determine initial and half maximal inhibitory concentrations (IC and IC, respectively). Distinct FasR expression was detected in each cell line. Four of six cell lines were significantly sensitized to FasL by LCL161 (p < 0.05), and synergistic effects were observed (y < 1). Moreover, the initially resistant cell line SCC-25 was effectively sensitized to FasL by LCL161. Annexin V FACS analysis demonstrated apoptosis-sensitizing and apoptosis-inducing effects of LCL161 across all cell lines. Using specific cell death inhibitors (zVAD-fmk and Nec-1), we demonstrated that LCL161-initiated apoptosis could not be prevented, highlighting the proapoptotic potential of this mimetic in these cells. Our findings show the effectiveness of apoptotic sensitization of OSCC cells by LCL161 in combination with FasL, thus confirming the importance of an IAP-targeting therapeutic approach for oral squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.jcms.2019.07.022DOI Listing
October 2019

The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy.

Int J Mol Sci 2019 Mar 15;20(6). Epub 2019 Mar 15.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.

Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.
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http://dx.doi.org/10.3390/ijms20061306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471923PMC
March 2019

A new multilayered membrane for tissue engineering of oral hard- and soft tissue by means of melt electrospinning writing and film casting - An in vitro study.

J Craniomaxillofac Surg 2019 Apr 4;47(4):695-703. Epub 2019 Feb 4.

Department of Oral and Maxillofacial Plastic Surgery, (Head: Prof. Dr. Dr. Alexander C. Kübler), University Hospital Würzburg, Pleicherwall 2, 97080 Würzburg, Germany; Interdisciplinary Center for Clinical Research, University Hospital Würzburg, Josef-Schneider-Straße 2, 97070 Würzburg, Germany.

Membranes that form a mechanical barrier not only for cells but also for the bacterial flora of the oral cavity may be helpful in infection-free wound healing for guided tissue regeneration (GTR) applications in the field of oral- and maxillofacial surgery. Controlled wound healing without interference from bacterial contamination appears to be achievable in combination with surface scaffolds for bone- and soft tissue regeneration. As this has not yet been realized, we developed multilayered membranes in this study consisting of specific surface scaffolds for bone- and mucosal regeneration as well as bacteria-tight core membranes. These membranes were evaluated in terms of cell growth of osteoblast- (MG63), keratinocyte- (HaCaT), and fibroblast (L929) cell lines. Scaffolds were fabricated via melt electrospinning writing (MEW), while the core membrane was produced via film casting. All constructs were made of medical-grade poly(ε-caprolactone) (PCL). The bacteria-tightness was tested via a bacterial transmigration-assay. PCL scaffolds and core membranes alone demonstrated good cytocompatibility for all cell lines, which was even enhanced by fusing both components together. The core membrane displayed complete bacteria-tightness over two weeks. These bacteria-tight, individually-designed membranes from medical-grade PCL represent a high-potential, clinically oriented method of GTR in the field of oral- and maxillofacial surgery.
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http://dx.doi.org/10.1016/j.jcms.2019.01.043DOI Listing
April 2019

MicroRNA expression correlates with disease recurrence and overall survival in oral squamous cell carcinoma.

J Craniomaxillofac Surg 2019 Mar 17;47(3):523-529. Epub 2019 Jan 17.

University of Würzburg, Department of Oral and Maxillofacial Plastic Surgery, Pleicherwall 2, D-97070, Würzburg, Germany.

Objectives: Locoregional disease recurrence and metastatic events are the leading causes of death and the most important prognostic factors in patients with head and neck squamous cell carcinoma (HNSCC). A major goal of oncology is the identification of clinical and molecular parameters to evaluate the individual risk of recurrence. MicroRNAs (miRNAs) have been shown to correlate well with tumor size and differentiation. Therefore, they are candidate biomarkers for estimating clinical outcomes.

Materials And Methods: In this study, the expression levels of distinct miRNAs extracted from formalin-fixed, paraffin-embedded (FFPE) samples of oral squamous cell carcinoma were compared.

Results: Statistical analysis revealed significant correlations between distinct miRNAs and disease recurrence (miR-99*, miR-194*; p < 0.05) and overall survival (miR-99*; p < 0.05). The results were then validated via data from The Cancer Genome Atlas (TCGA).

Conclusions: Our data show that miR-99* and miR-194* can possibly serve as biomarkers for clinical outcome in HNSCC. These findings may help to identify high-risk patients, who could profit from a more individualized treatment and follow-up.
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http://dx.doi.org/10.1016/j.jcms.2019.01.015DOI Listing
March 2019

MAGE-A9 in head and neck cancer: Prognostic value and preclinical findings in the context of irradiation.

Mol Clin Oncol 2018 Mar 19;8(3):513-519. Epub 2018 Jan 19.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital of Würzburg, D-97070 Würzburg, Germany.

Radiotherapy alone, or as an addition to surgery is important for the treatment of head and neck squamous cell carcinoma (HNSCC). In addition to their expression in germ cells, melanoma associated antigens-A (MAGE-A) are only expressed in malignant tissue. Notably, there is a known correlation between MAGE-A9 expression and poor prognosis in HNSCC patients. However, current knowledge regarding the function of MAGE-A9 expression, particularly in the context of irradiation, is limited. MAGE-A9 expression in 37 oral squamous cell carcinoma patents was immunohistochemically determined and analyzed for overall survival by the Kaplan-Meier log-rank test. Next, the expression of MAGE-A9 was determined by reverse transcription-quantitative polymerase chain reaction in HNSCC cell lines prior to and following irradiation with 2 Gray. The radiosensitivity of each cell line was determined using a clonogenic survival assay. There was a significantly (P=0.0468) longer overall survival in patients with a low level of MAGE-A9 expression. The median overall survival in patients with high MAGE-A9 expression was 47% compared to 73% in the group with low MAGE-A9 expression. The cell lines revealed a distinct expression pattern of MAGE-A9. Following irradiation of the cell lines, a significant enhancement of MAGE-A9 mRNA expression levels was observed. The most prominent alteration in MAGE-A9 expression was observed in the most radioresistant cell line. A high MAGE-A9 expression level correlates significantly with lower overall survival in HNSCC patients. Additionally, irradiation increased the MAGE-A9 mRNA levels in all five HNSCC cell lines, and the most resistant cell line demonstrated the greatest increase in MAGE-A9 expression following irradiation.
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http://dx.doi.org/10.3892/mco.2018.1558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844004PMC
March 2018

Apoptosis-sensitizing activity of birinapant in head and neck squamous cell carcinoma cell lines.

Oncol Lett 2018 Mar 12;15(3):4010-4016. Epub 2018 Jan 12.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.

Inhibitor of apoptosis proteins, which are overexpressed in head and neck squamous cell carcinoma (HNSCC), may cause therapeutic resistance. Using SMAC mimetic compounds, including birinapant, to degrade and/or inhibit these proteins and sensitize apoptosis may enhance therapies in HNSCC. Fas expression was analyzed in nine HNSCC cell lines and one keratinocyte cell line via flow cytometry. These cell lines were treated with Fas ligand-Fc (FasL) and birinapant, a bivalent SMAC mimetic, in mono and combination therapies. Cytotoxicity was measured using a crystal violet assay. Annexin V assay was performed for detection of apoptosis. The treatment efficacy of mono and combination therapies was statistically analyzed. Nonlinear regression analysis was performed to determine the inhibitory concentration (IC) of birinapant. Fas expression was detected in each cell line tested. Mono treatment with FasL revealed minor to no apoptotic effects in the majority of the cell lines. Crystal violet and Annexin V staining revealed increased apoptosis rates for all cell lines following incubation with birinapant in mono treatment. Combination treatment with FasL and birinapant (IC) revealed additional and synergistic effects in eight out of the ten cell lines. To the best of our knowledge, the present study provided the first evidence of the apoptosis-sensitizing activity of combination treatment with FasL and birinapant in HNSCC cell lines.
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http://dx.doi.org/10.3892/ol.2018.7783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796371PMC
March 2018

Squamous cell carcinoma of the maxilla: Analysis of clinicopathological predictors for disease recurrence and metastatic behavior.

J Craniomaxillofac Surg 2018 Apr 2;46(4):611-616. Epub 2018 Feb 2.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital of Würzburg, Würzburg, Germany (Chair: Alexander Kuebler, MD, DDS, PhD).

Introduction: Squamous cell carcinoma of the maxilla only constitutes a small fraction of Head and Neck Cancers. There is thereby a lack of information about frequent tumor staging and localization and their effect on patients' outcome. The main factors that influence longterm survival in HNSCC are the extent of the primary disease and recurrence rate, including local neck metastases.

Patients And Methods: In this study, clinical outcome and rates of disease recurrence in 68 surgically treated patients with maxillary SCC were evaluated in terms of primary tumor staging and localization.

Results: It could be demonstrated that maxillary cancer is mostly located in the posterior region of the upper jaw (70%). The rate of neck node metastasis was 35.3%, which is equivalent to the rest of the oral cavity and supports the role of elective neck dissection for patients with clinically negative neck node status. Staging, tumor differentiation, and infiltration of lymphatic structures correlated significantly with the development of local neck node metastases (r = 0.321, p = 0.01; r = 0.348, p < 0.01; r = 0.64; p < 0.01).

Conclusion: Maxillary carcinomas exhibit similar rates of locoregional disease recurrence as the rest of the oral cavity. The existence of cervical metastases even in patients with T1 tumors supports the concept of elective neck dissection in early tumors with clinically negative neck status.
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http://dx.doi.org/10.1016/j.jcms.2018.01.002DOI Listing
April 2018

Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer.

Cancer Res 2018 05 12;78(9):2383-2395. Epub 2018 Feb 12.

Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.

Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors. These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537867PMC
May 2018

Melanoma-associated antigen A11 reduces erlotinib and afatinib efficacy in head and neck cancer.

J Craniomaxillofac Surg 2018 Mar 24;46(3):492-497. Epub 2017 Dec 24.

Department of Oral and Maxillofacial Plastic Surgery, Head: Alexander C. Kübler, University Hospital Würzburg, Pleicherwall 2, 97070, Würzburg, Germany.

Melanoma-associated antigen A (MAGE-A) proteins are members of the cancer/testis antigens (CTA), and the expression of these proteins is almost exclusively limited to malignant cells, making them an attractive treatment target. MAGE-A expression is correlated with poor overall survival in several cancers, including head and neck squamous cell carcinoma (HNSCC). Among others, MAGE-A11 was found to be associated with resistance to different antineoplastic and targeted compounds, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We searched The Cancer Genome Atlas (TCGA) database with a focus on MAGE-A and found that MAGE-A overexpression is a common event in HNSCC (27.5%). Furthermore, MAGE-A overexpression was correlated with significantly reduced overall survival (35.45 months vs. 64.78 months, P = 0.0173). In particular, MAGE-A11 overexpression was found in 9% of specimens. We then examined MAGE-A11 expression, the efficacy of EGFR and the EGFR mutational status and the effects of the pan-HER (human EGFR) TKIs erlotinib and afatinib in HNSCC cell lines. Next, we used a model of stable MAGE-A11 overexpression to demonstrate that MAGE-A11 impaired the efficacy of erlotinib and afatinib. In summary, our study provides evidence that MAGE-A11 contributes to erlotinib and afatinib resistance in head and neck cancer cell lines.
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http://dx.doi.org/10.1016/j.jcms.2017.12.014DOI Listing
March 2018

MAGE-A11 expression contributes to cisplatin resistance in head and neck cancer.

Clin Oral Investig 2018 Apr 15;22(3):1477-1486. Epub 2017 Oct 15.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Pleicherwall 2, 97070, Würzburg, Germany.

Objective: The objective of this study is to investigate the roles of melanoma-associated antigens (MAGEs) in the cisplatin treatment of head and neck cancer.

Materials And Methods: We assessed the efficacy of cisplatin in a set of four head and neck cancer cell lines using a crystal violet assay. The MAGE-A expression in all cell lines was measured with RT-qPCR. The correlation between MAGE-A expression and cisplatin efficacy was investigated using Spearman's correlation analysis. Furthermore, we established a cell line with stable overexpression of MAGE-A11 and determined influence on proliferation, cisplatin efficacy and cell apoptosis. In this cell line, the effects of cisplatin were assessed using either crystal violet assays or flow cytometry (Annexin V).

Results: For MAGE-A11, we observed the highest correlation (r = 1.000, p = 0.0417) with low cisplatin efficacy. Stable overexpression of MAGE-A11 resulted in no changes in proliferation, but in lower cisplatin cytotoxicity and lower rates of apoptosis. Also, mouse double minute 2 homolog (MDM2) expression was induced by MAGE-A11 overexpression.

Conclusion: We provide evidence that MAGE-A11 expression contributes to cisplatin resistance in head and neck cancer.

Clinical Relevance: Our study underscores the negative predictive role of MAGE-A11 expression in head and neck cancer.
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http://dx.doi.org/10.1007/s00784-017-2242-8DOI Listing
April 2018

Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.

Ann Surg Oncol 2017 Oct 31;24(11):3430-3437. Epub 2017 Jul 31.

Department of Oral and Maxillofacial Plastic Surgery, Würzburg University Hospital, Würzburg, Germany.

Background: Merkel cell carcinoma (MCC) is a rare, aggressive tumor that often occurs in the head and neck region. Because of these features, the classifications and diagnostic and treatment regimens are frequently modified. Especially in the anatomically complex head and neck region, it is crucial to be aware of the current recommendations for diagnostics and treatment of MCC to ensure appropriate treatment. This overview aims to summarize the currently available literature.

Methods: The authors reviewed the relevant literature and international guidelines for MCC from 2012 to 2017 with respect to epidemiology and prognosis, diagnostic procedures and imaging, surgery, radiation, systemic treatment, and aftercare. These results were compared with existing guidelines, some of them current, and recommendations were derived.

Results: Marked developments in imaging have resulted in an increased use of functional imaging. The surgical concepts have changed regarding safety margins and the use of sentinel node biopsies. In systemic treatment, a move from conventional agents toward immuno-oncology can be observed.

Conclusions: For staging, it is important to be as exact as possible using functional imaging (e.g., positron emission tomography/computed tomography scan), especially in the head and neck area with its complex lymph drainage. This often plays an especially important role in early stages of the tumor, when the resection margin can be reduced to preserve the organ. Aftercare also should include functional imaging. In an advanced, metastatic stage, immuno-oncology (PD-1, PD-L1, CTLA-4) is superior to the previous methods of systemic treatment.
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http://dx.doi.org/10.1245/s10434-017-5993-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596053PMC
October 2017

Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro.

Oncol Rep 2017 Sep 10;38(3):1877-1885. Epub 2017 Jul 10.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by a tumor microenvironment (TME) that overexpresses vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which can lead to neovascularization, tumor growth and metastasis. Therapeutic strategies inhibiting these signaling pathways might lead to innovative HNSCC treatments. Five HNSCC cell lines were characterized based on VEGFR1-3 and FGFR1-4 expression by sqRT-PCR and treated with three different tyrosine kinase inhibitors (TKIs) (nintedanib, dovitinib and pazopanib), all of which are effective against VEGFR and FGFR family members. Crystal violet assays were performed to analyze the effect of the treatments on cell growth (viability). Additionally, VEGFR1-3 and FGFR1-4 expression data were retrieved from The Cancer Genome Atlas (TCGA), and statistical analyses were performed to investigate the receptor expression level in the different cell lines and the efficacy of the single-agent treatments. A correlation analysis was performed to quantify the degree of relationship between receptor expression and drug efficacy. With the exception of VEGFR2, the targeted receptors were expressed at different levels in all of the cell lines. The cell lines exhibited concentration-dependent responses with cell line-specific differences toward two of the three TKIs (nintedanib and dovitinib). Notably, all of the cell lines were resistant to pazopanib. TKIs have potential as therapeutic agents for HNSCC. Cell line-specific differences were observed in our in vitro experiments. The observed pazopanib resistance could be explained by receptor expression. Further investigation is required to determine TKI efficacy in HNSCC.
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http://dx.doi.org/10.3892/or.2017.5801DOI Listing
September 2017

Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV Patients.

Clin Cancer Res 2017 Jun 16;23(12):3072-3083. Epub 2016 Dec 16.

Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.

Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV versus HPV tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV HNSCC. HER3 was investigated as a molecular target in HPV HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV and HPV HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379. HER3 was overexpressed in HPV HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV cell lines and PDXs. This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV patients. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474133PMC
June 2017

Contrary melanoma-associated antigen-A expression at the tumor front and center: A comparative analysis of stage I and IV head and neck squamous cell carcinoma.

Oncol Lett 2016 Oct 3;12(4):2942-2947. Epub 2016 Aug 3.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.

There is a growing body of evidence indicating that several melanoma-associated antigen-A (MAGE-A) subgroups contribute to the malignancy of head and neck cancer. The present study retrospectively analyzed the expression of all known MAGE-A subgroups in the tumor front and center of 38 head and neck cancer patients (Union for International Cancer Control stage I or IV) by immunohistochemistry. MAGE-A1, -A6, -A8, -A9 and -A11 were expressed at significantly higher levels at the tumor front of stage IV specimens compared with the tumor front of stage I specimens. In stage I cancer, the tumor center and front ratio (C/F ratio) for each subgroup was >1.0. In stage IV cancer, the C/F ratio was <1.0 in 9/11 subgroups. The most significant change in the expression pattern was observed for MAGE-A11. These results indicated that there is a marked alteration and shift to the invasive front of almost all MAGE-A subgroups, but particularly MAGE-A11, during the progression of head and neck squamous cell carcinoma.
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http://dx.doi.org/10.3892/ol.2016.4945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038879PMC
October 2016

Mandibular intraosseous pseudocarcinomatous hyperplasia: a case report.

J Med Case Rep 2016 Sep 29;10(1):268. Epub 2016 Sep 29.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Pleicherwall 2, 97070, Würzburg, Germany.

Background: Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases.

Case Presentation: The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved.

Conclusions: Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041521PMC
http://dx.doi.org/10.1186/s13256-016-1052-yDOI Listing
September 2016

Treatment of head and neck cancer in the elderly.

Expert Opin Pharmacother 2016 Oct 16;17(14):1903-21. Epub 2016 Aug 16.

a Department of Otolaryngology , University of California San Francisco , San Francisco , CA , USA.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and the majority of patients present with advanced stage disease. Chemotherapy is an important component of head and neck cancer treatment regimens and has shown beneficial effects in locally advanced and recurrent/metastatic stages of disease. Approximately 25% of HNSCC patients are aged 70 and older, often associated with co-morbid medical conditions. Most clinical trials exclude patients of advanced chronological age such that valid information about the efficacy and safety of drugs and treatment regimens in elderly patients is not available.

Areas Covered: Surgery, radiotherapy and particularly chemotherapy with the six FDA-approved chemotherapeutic agents for head and neck cancer treatment are discussed with a focus on age, performance status, comorbidities. New targeted therapies and the field of immune checkpoint inhibitors are evaluated in the context of elderly populations.

Expert Opinion: Surgery, radiotherapy and administration of cytotoxic chemotherapeutic agents are largely safe and effective in elderly patients. Targeted therapies are mostly well tolerated. Clinical studies should be designed to include elderly patients (>70 years). Immune checkpoint inhibitor therapies may exert age-related effects, since substantial functional changes in T cell responses increase during the aging process.
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http://dx.doi.org/10.1080/14656566.2016.1220540DOI Listing
October 2016

The prognostic value of GLUT-1 staining in the detection of malignant transformation in oral mucosa.

Clin Oral Investig 2017 Jun 8;21(5):1631-1637. Epub 2016 Sep 8.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Pleicherwall 2, 97070, Würzburg, Germany.

Background: Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most common tumor entity worldwide. Unfortunately, the multimodal treatment consisting of surgery, radiation, and chemotherapy does not show the desired efficacy. The intent of this study was to evaluate the sensitivity and specificity of an oral brush biopsy in combination with glucose transporter (GLUT)-1 staining in identifying premalignant and malignant lesions.

Methods: A total of 72 patients were included in the study, divided into four diagnostic subgroups (24 healthy, 15 carcinoma, 18 leukoplakia, 15 oral lichen planus). Oral brush biopsies were taken and analyzed for GLUT-1 expression by immunocytologic staining. Incisional biopsy served as the gold standard.

Results: Twelve (80 %) of the 15 carcinomas, nine (50 %) of the 18 leukoplakia, nine (60 %) of the 15 oral lichen planus, and none of the healthy specimens stained positive for GLUT-1. This resulted in a sensitivity rate of 80 % and a specificity rate of 68.42 %. Diagnostic accuracy was 70.83 % based on the correct diagnoses in 51 of 72 patients.

Conclusion: An oral brush biopsy can easily be performed throughout the entire oral cavity, is noninvasive, and shows high sensitivity and specificity rates with conventional cytology or computer-assisted analysis.

Clinical Relevance: The significance of GLUT-1-specific staining with an oral brush biopsy is more limited than expected but could be used as an additional tool in detecting malignant transformation in the oral cavity.
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http://dx.doi.org/10.1007/s00784-016-1954-5DOI Listing
June 2017

HGF/Met Signaling in Head and Neck Cancer: Impact on the Tumor Microenvironment.

Clin Cancer Res 2016 Aug 1;22(16):4005-13. Epub 2016 Jul 1.

Department of Otolaryngology, University of California San Francisco, San Francisco, California.

Studies to date have revealed several major molecular alterations that contribute to head and neck squamous cell carcinoma (HNSCC) initiation, progression, metastatic spread, and therapeutic failure. The EGFR is the only FDA-approved therapeutic target, yet responses to cetuximab have been limited. Activation and cross-talk of cellular receptors and consequent activation of different signaling pathways contribute to limited activity of blockade of a single pathway. The hepatocyte growth factor (HGF) receptor, Met, has been implicated in HNSCC tumorigenesis and EGFR inhibitor resistance. HGF, the sole ligand of Met, is overexpressed in the tumor microenvironment. The role of HGF/Met signaling in proliferation, metastasis, and angiogenesis has been investigated in HNSCC, leading to clinical trials with various Met inhibitors and HGF antibodies. However, the role of the HGF/Met signaling axis in mediating the tumor microenvironment has been relatively understudied in HNSCC. In this review, we discuss the functional roles of Met and HGF in HNSCC with a focus on the tumor microenvironment and the immune system. Clin Cancer Res; 22(16); 4005-13. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820346PMC
August 2016
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