Management Of Head And Neck Squamous Cell Carcinoma Research Articles

Proinflammatory cytokine profile in head and neck squamous cell carcinoma patients: Preliminary report

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant neoplasms globally. Tobacco and alcohol use are predominant risk factors. Inflammation plays a major role in the etiopathogenesis of cancers and cytokines influence activation, growth, and differentiation of several target cells. This study aimed at profiling head and neck cancer patients with regards to the serum level of proinflammatory cytokines and disease stage. Materials and Methods: This study involved thirty newly diagnosed cases of HNSCC and thirty apparently healthy comparable group. Five milliliter of venous blood was collected from the antecubital vein of each individual. The blood samples dispensed in plain bottles were allowed to clot and retract; serum was stored at −20°C until analysis. Cytokine assay was carried out by enzyme-linked immunosorbent assay technique using a commercial kit. Results: The study group was made up of 19 (63.3%) males and 11 (36.7%) females. The ages ranged from 19 to 92 years with a mean of 59.1 ± 19.1 years. The comparative group was made up of 14 (46.7%) males and 16 (53.3%) females with a mean age of 63.2 ± 7.5 years. The oral cavity was the most common site of SCC [6 (20.0%)]. The cases were mostly advanced in 28 (93.3%, Stages III and IV). Serum interleukin-1 IL-1 (β), IL-6, IL-8, TNF – α, and IFN – γ were elevated in the test cases relative to the controls. This however, was only statistically significantly so with IL-6 and IL-8. The mean values for both cytokines for all tumor sites were exceeded in nasopharyngeal carcinoma. Conclusion: Serum IL-6 and IL-8 appear to be significant in the pathology of head and neck cancer and could be explored for possible roles in the management of HNSCC.

Long non-coding RNA LOC541471: A novel prognostic biomarker for head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer. Early detection and management of HNSCC may prevent progression of the disease. Long non-coding RNAs (lncRNAs) may serve as prognostic biomarkers for various cancer types. The current study downloaded an RNA-Seq dataset containing 43 tumor-normal pairs. An independent t-test identified that the expression level of lncRNA LOC541471 was significantly increased in tumor tissues compared with healthy tissues. Additionally, the current study demonstrated that high lncRNA LOC541471 expression was significantly associated with increasing lymph node metastasis classification and perineural invasion. A multivariate Cox regression analysis revealed that high lncRNA LOC541471 expression levels were an independent predictor for reduced overall survival (n=487) and relapse-free survival (n=355). According to the anatomic neoplasm subdivision, HNSCC samples were classified as oropharyngeal carcinoma (n=297), oral carcinoma (n=80), laryngeal carcinoma and hypopharyngeal carcinoma (n=123). A negative association was revealed between lncRNA LOC541471 expression and overall survival in all subtypes of HNSCC. Therefore, lncRNA LOC541471 is significantly negatively associated with overall survival and relapse-free survival of patients with HNSCC and may be considered a potential prognostic factor for HNSCC.

Intérêt complémentaire de la TEP/TDM au FDG et de l’imagerie conventionnelle dans le bilan initial et le suivi post-thérapeutique des cancers des VADS : recommandations et perspectives

Functional imaging by 18fluorodesoxyglucose (FDG) positron emission tomography (PET) and morphological imaging by computed tomography (CT) and magnetic resonance imaging (MRI) hold an important and complementary role in characterization of head and neck squamous cell carcinoma (HNSCC). Based on an exhaustive literature, the recommendations and perspectives of their use in the initial assessment and the post-therapeutic management of HNSCC are presented.

Immune Checkpoint Inhibition in Head and Neck Cancer.

Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common cancer globally and commonly presents with locally advanced disease, which has a recurrence rate of around 50% despite aggressive multi-modality treatment involving surgery, radiotherapy and chemotherapy or EGFR inhibition where appropriate. As understanding of the underlying cancer biology and the complex interactions within the tumor microenvironment improves, there is gathering interest in and evidence for the role of immunomodulating agents in the management of HNSCC. Immune checkpoint inhibitors, which aim to hinder the inhibitory interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1, have demonstrated durable improvements in patient outcomes in advanced / metastatic HNSCC, with both pembrolizumab and nivolumab being granted FDA approval in 2016. There are numerous ongoing clinical trials exploring the role of checkpoint inhibitors both as single agents and in combination, administered with established treatment modalities such as chemotherapy and radiotherapy, as well as alongside other novel immune modulators. These trials are not limited to advanced / metastatic HNSCC, but also to the neo-adjuvant or adjuvant settings. As studies complete and more results become available, the role immunotherapy agents will have within the treatment strategies for HNSCC may change, with increasing biomarker selection resulting in personalized therapy aiming to further improve patient outcomes.

Systematic review and meta-analyses of intensity-modulated radiation therapy versus conventional two-dimensional and/or or three-dimensional radiotherapy in curative-intent management of head and neck squamous cell carcinoma.

IntroductionTechnological advancements in treatment planning and delivery have propelled the use of intensity-modulated radiation therapy (IMRT) in head and neck squamous cell carcinoma (HNSCC). This review compares IMRT with conventional two-dimensional (2D) and/or three-dimensional (3D) radiotherapy (RT) in curative-intent management of HNSCC.MethodsOnly randomized controlled trials (RCTs) offering curative-intent RT in patients with non-metastatic HNSCC were included. Outcome data was extracted independently by two reviewers, pooled using the Cochrane methodology, and expressed as risk ratio (RR) or hazard ratio (HR) as appropriate with 95% confidence intervals (CIs). Xerostomia was the primary outcome of interest whereas loco-regional control, overall survival and quality-of-life (QOL) were secondary endpoints.ResultsSeven RCTs involving 1155 patients directly comparing IMRT with 2D/3D-RT in HNSCC were included. The primary objective in five of seven index RCTs was reduction in xerostomia, with only one trial each using loco-regional control and overall survival as primary endpoints for sample size calculation. The use of IMRT was associated with a 36% relative risk reduction in ≥grade 2 acute xerostomia (RR = 0.64, 95%CI = 0.49–0.84; p = 0.001) compared to 2D/3D-RT. More importantly, IMRT significantly reduced the risk of ≥grade 2 late xerostomia (RR = 0.44, 95%CI = 0.34–0.57; p = 0.00001) compared to non-IMRT techniques at all time-points. Within the limitations of inadequate sample size and low statistical power, IMRT also resulted in 24% relative reduction in the risk of loco-regional relapse (HR = 0.76, 0.57–1.01; p = 0.06) and 30% relative reduction in risk of death (HR = 0.70, 95%CI = 0.57–0.88; p = 0.002) compared to 2D/3D-RT. However, this benefit of IMRT for loco-regional control and overall survival was limited to nasopharyngeal cancer patients alone, with no significant difference in efficacy between the two techniques in patients with cancers of the laryngo-pharynx in this analysis, highlighting the inconsistency in results of subgroup analyses stratified by primary site. Inadequate reporting of data precluded statistically pooling of results for QOL outcomes.ConclusionsThere is consistent moderate-quality evidence that IMRT significantly reduces the risk of moderate to severe acute and late xerostomia compared to 2D/3D-RT in curative-intent radiotherapeutic management of HNSCC. However, the quality of evidence regarding the superiority of IMRT over conventional techniques for disease-related endpoints is rather low due to relative lack of power and inconsistency of results precluding robust conclusions.

PO-140 MAPKAPK2 regulates the transcript stability of TNF-α, VEGF, P27 and MKP-1 in the progression of head and neck squamous cell carcinoma

IntroductionGlobally, head and neck squamous cell carcinoma (HNSCC) having an estimated annual burden of 6 33 000 new cases with 3 55 000 deaths is the sixth most common cancer. 90% of head and neck cancers are HNSCCs with environmental and lifestyle risk factors including sustained tobacco exposure and alcohol consumption as the primary causes. The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in a variety of pathological conditions including inflammation and metastasis. Post-transcriptional regulation of genes harbouring adenine/uridine-rich elements (AREs) in their 3’-untranslated region (3’-UTR) is controlled by MAPK-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of the p38 MAPK. In response to diverse extracellular stimuli, MK2 influences crucial signalling events, regulates inflammatory cytokine release, mRNA stability and cellular processes including cell cycle regulation, angiogenesis, proliferation, metastasis and cell death. Till date, the biological significance of MK2 pathway in cancer progression is not well elucidated.Material and methodsHuman clinical samples were processed for histopathological, immunohistochemical, western blotting and quantitative real time-polymerase chain reaction analysis. The findings were validated in vitro in HNSCC cell lines. Transcript levels of susceptible genes harbouring RNA-binding sites in their 3’-UTRs were evaluated along with their post-transcriptional stability in MK2-knockdown (MK2KD) cells in both normoxic and hypoxic conditions.Results and discussionsIn the present study, we have reported that MK2 is reproducibly overexpressed in HNSCC and plays a crucial role in its pathogenesis by altering the translational landscape. The increased stability of cyclin-dependent kinase inhibitor 1B (p27) and mitogen-activated protein kinase phosphatase-1 (MKP-1) transcripts and the decreased half-life of tumour necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) transcripts in MK2KD cells suggested that MK2 regulates their mRNA turnover.ConclusionTaken together, our results portray a critical role of MK2 in modulating HNSCC pathogenesis and implicate MK2 as a prominent tumour marker. Majority of p38 inhibitors have already failed in the clinical trials, hence, we have tried to unveil MK2 as a potential novel anticancer therapeutic target in the management of HNSCC.

Drug Targeting and Biomarkers in Head and Neck Cancers: Insights from Systems Biology Analyses.

The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but robust biomarkers and diagnostics are still not available. This study provides in-depth insights from systems biology analyses to identify molecular biomarker signatures to inform systematic drug targeting in HNSCC. Gene expression profiles from tumors and normal tissues of 22 patients with histological confirmation of nonmetastatic HNSCC were subjected to integrative analyses with genome-scale biomolecular networks (i.e., protein-protein interaction and transcriptional and post-transcriptional regulatory networks). We aimed to discover molecular signatures at RNA and protein levels, which could serve as potential drug targets for therapeutic innovation in the future. Eleven proteins, 5 transcription factors, and 20 microRNAs (miRNAs) came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq datasets, and risk discrimination performance of the reporter biomolecules, BLNK, CCL2, E4F1, FOSL1, ISG15, MMP9, MYCN, MYH11, miR-1252, miR-29b, miR-29c, miR-3610, miR-431, and miR-523, was also evaluated. Using the transcriptome guided drug repositioning tool, geneXpharma, several candidate drugs were repurposed, including antineoplastic agents (e.g., gemcitabine and irinotecan), antidiabetics (e.g., rosiglitazone), dermatological agents (e.g., clocortolone and acitretin), and antipsychotics (e.g., risperidone), and binding affinities of the drugs to their potential targets were assessed using molecular docking analyses. The molecular signatures and repurposed drugs presented in this study warrant further attention for experimental studies since they offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of HNSCC.

Role of Genetic Variations in Determining Treatment Outcome in Head and Neck Cancer

Worldwide, head and neck squamous cell carcinoma (HNSCC) is responsible for >550,000 diagnoses and 380,000 deaths annually. It originates in the upper aerodigestive tract and has a multifactorial origin involving both genetic and lifestyle risk factors. The clinical management of HNSCC involves surgery, radiotherapy, and chemotherapy. Several studies point to the role of genetic variations in predicting drug efficacy and toxicity. Cancer pharmacogenomics has fast emerged as a new and promising field for the early identification of genetic markers that can predict drug response or toxicity, with the number of studies of genetic polymorphisms as prognostic factors of HNSCC treatment outcomes growing. The number of studies evaluating the association of candidate polymorphisms in drug-metabolising Phase I and II enzymes with treatment outcome far exceed the studies involving other candidate genes, such as those involved in drug metabolism, DNA repair, and cell cycle regulation. This review focusses on the relevance of genetic variations in genes, where the corresponding gene products play an important role in drug metabolism (TPMT, DPD), DNA repair (X-ray repair cross complementing 1), cell cycle (tumour protein P53), and carcinogenesis (matrix metalloproteinase 3 and 7), thereby contributing to the treatment outcome for HNSCC. This could greatly help clinicians in identifying genetic markers useful for the selection of optimal drugs, dose, and treatment duration on an individual basis, resulting in improved drug efficacy and decreased toxicity. However, further studies are needed in well characterised and larger HNSCC populations with proper validation of pharmacogenetic markers in experimental settings before application in clinical routine diagnostics.

Tumor DNA: an emerging biomarker in head and neck cancer.

Head and neck cancer (HNC) includes a diverse range of malignancies arising commonly from mucosal epithelia of the upper aerodigestive tract. Head and neck squamous cell carcinoma (HNSCC), the most common form of HNC, develops in the oral cavity, pharynx, and larynx and is associated with tobacco exposure, alcohol abuse, and infection with oncogenic viruses. Despite global advances in cancer care, HNSCC often presents with advanced disease and is associated with poor 5-year survival of ~50%. Genotyping tumor tissue to guide clinical decision-making is becoming commonplace in modern oncology, but in the management of HNSCC, tissue biopsies with cytopathology or histopathology remain the mainstay for diagnosis. Furthermore, conventional biopsies are temporally and spatially limited, often providing a brief snapshot of a single region of a heterogeneous tumor. In the absence of a useful biomarker, both primary and recurrent HNSCCs are diagnosed with conventional imaging and clinical examination. As a result, many patients are diagnosed with advanced disease. Tumor DNA is an emerging biomarker in HNSCC. DNA fragments are constantly being shed from tumors and metastatic lesions, and can therefore be detected in blood and other bodily fluids. Utilizing next-generation sequencing techniques, these tumor DNA can be characterized and quantified. This can serve as a minimally invasive liquid biopsy allowing for specific tumor profiling, dynamic tumor burden monitoring, and active surveillance for disease recurrences. In HNSCC, analysis of tumor DNA has the potential to enhance tumor profiling, aid in determining patient prognosis, and guide treatment decisions.

Abstract 4176: Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC

Abstract Radiation, cisplatin, and cetuximab are clinical therapeutics used in the treatment of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of HNSCC. Thus, identifying and targeting molecules driving this drug resistance is essential for improving efficacy of treatment approaches. Recent studies have identified a role for the TAM family of receptor tyrosine kinases (Tyro, Axl, and Mer) in tumor biology, especially the Axl receptor in promoting tumor growth and metastasis. Previously, we identified Axl as a logical molecular target in HNSCC and indicated that it may play a pivotal role in resistance to radiation, cisplatin, and cetuximab. In the current study, we advanced these early findings into pre-clinical models using patient-derived xenografts (PDXs). We have shown that small molecules targeting Axl can enhance therapy in PDXs that express high levels of Axl and have been identified as resistant to radiation, cisplatin, and cetuximab. Current studies are focusing on antibody-based targeting of Axl using PDXs and genetically-modified models of resistance. Furthermore, studies focused on co-targeting of Axl and Mer in vitro and in vivo have shown striking results and denote the importance of establishing logical approaches to target TAMs in the management of HNSCC. Finally, investigations into the molecular mechanisms of how Axl signaling can lead to resistance have underscored the importance of tyrosine 821 (Y821) of Axl. Overexpression of Axl rendered cetuximab sensitive lines resistant, but cell lines overexpressing Axl-Y821F retained their sensitivity to cetuximab. Advancing this line of study in vivo indicated that tumors expressing Axl were resistant to cetuximab whereas tumors harboring the Y821 mutation were sensitive demonstrating that signals emanating from Y821 may be critical for cetuximab resistant pathways. Collectively, the studies presented herein identify the TAM family of receptors as key players in radiation, cisplatin, and cetuximab resistance. These results provide rationale for the clinical targeting of TAM receptors to enhance the therapeutic modalities used in treating HNSCC. Citation Format: Nellie K. Black, Mari Iida, Tamara S. Rodems, Toni M. Brand, Randall J. Kimple, Deric L. Wheeler. Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4176. doi:10.1158/1538-7445.AM2017-4176

Abstract 5761: C-Fos drives non-tumorigenic head and neck squamous cell carcinoma cells to tumorigenic by promoting cancer stem cells like properties

Abstract Purposes of the study: Head and neck squamous cell carcinoma (HNSCC) is the sixth most widespread cancer and leading cause of cancer related death world widely. Regardless of the advancement in treatment processes the overall survival rate of patients having this cancer has not substantially improved in the past few decades. Development of tumor and its progression exclusively resides in a small population of cancer cells, termed as cancer stem cells (CSCs). This population of cells can self-renew and re-form the ordered organization of tumors. CSCs contribute to HNSCC and may offer prominent therapeutic strategy for the management of HNSCC. We previously observed that c-Fos was highly up-regulated in the HNSCC sphere forming cells. In the present study, we explored the role of c-Fos in the tumor initiation in relation with cancer stemness and EMT. Experimental procedures: We examined whether overexpression of c-Fos has an effect on tumorigenicity and stemness. For this, c-Fos was overexpressed in non-tumorigenic HNSCC cell lines and tumor growth was investigated. We also examined the expression of different CSC marker genes expression by Western blot analysis. Summary: Our results demonstrated that exogenous expression of c-Fos in non-tumorigenic MDA1386Tu cells makes the cells tumorigenic in nude mice. Mechanistic investigations showed that c-Fos overexpression in MDA1386Tu cells enhanced epithelial-mesenchymal transition (EMT)/CSC properties and increased numbers of oralspheres when grown in ultra-low binding plate. Conclusions: Collectively, our data strongly demonstrate that c-Fos plays a critical role in the modulation of EMT and cancer stem cell reprogramming in HNSCC cells and enhance tumor growth. Note: This abstract was not presented at the meeting. Citation Format: Naoshad Muhammad, Sourav Bhattacharya, Robert Steele, Nancy Phillips, Ratna B. Ray. C-Fos drives non-tumorigenic head and neck squamous cell carcinoma cells to tumorigenic by promoting cancer stem cells like properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5761. doi:10.1158/1538-7445.AM2017-5761

Multimodal Imaging of Head and Neck Squamous Cell Carcinoma.

The role of imaging in the staging, treatment planning, and ongoing surveillance of patients with head and neck squamous cell carcinoma (HNSCC) continues to evolve. Changes in patient demographics, treatment paradigms, and technology present opportunities and challenges for the management of HNSCC. The general indications and usage of standard and multimodal cross-sectional imaging in the evaluation and management of HNSCC are reviewed, with an emphasis on incorporating them into treatment pathways. Emerging imaging technologies and methods with a potential near-term impact on HNSCC are discussed. In general, the complex, multidisciplinary approach to the treatment of advanced HNSCC requires multimodal imaging for adequate treatment planning and follow up. Early-stage disease can often be managed with clinical and endoscopic examinations and a single, cross-sectional imaging modality (eg, computed tomography, magnetic resonance imaging). Although generalized treatment pathways and guidelines do exist, the literature is rapidly advancing and new radiotracers and evaluation methods are expected to alter both imaging and treatment recommendations in the years to come.

PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.

BackgroundThe robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer. Moreover, the high recurrence rate and poor clinical response to chemotherapy and radiation treatment further underscores that the non-cancerous cells of the microenvironment, such as mesenchymal stromal cells (MSCs), cancer associated fibroblasts (CAFs), and pericytes, may be important in the pathophysiology of HNSCC.MethodsConfocal microscopy and immunohistomchemistry approaches were used to identify MSCs tumor microenvironment from patients with oral cavity and oral pharyngeal squamous cell carcinoma (SCC). In vitro Boyden chamber assays and multiplex magnetic bead assays were used to measure MSC chemotaxis and to identify the chemokines secreted by JHU-011, -012, -019, three cells lines derived from patients with oral pharyngeal SCC.ResultsWe show here that MSCs reside in the tumor microenvironment of patients with oral cavity and oral pharyngeal SCC and are recruited via paracrine mediated tumor cell secretion of (platelet derived growth factor) PDGF-AA. The MSC markers CD90+, CD105+, and gremlin-1+ were found to co-localize on cells within the tumor microenvironment in oral cavity SCC specimens distinct from α-smooth muscle actin staining CAFs. The conditioned media from JHU-011, -012, and -019 caused a significant increase in MSC migration (>60%) and invasion (>50%; p < 0.0001) compared to oral keratinocyte (OKT) controls. Tumor cell induced MSC chemotaxis appears to be mediated through paracrine secretion of PDGF-AA as inhibition of the PDGF-AA receptor, PDGFR-α but not PDGFR-β, resulted in near arrest of MSC chemotaxis (p < 0.0001).ConclusionsTumor microenvironment expression of PDGFR-α has been shown to correlate with a worse prognosis in patients with prostate, breast, ovarian, non-small cell lung cancer and osteosarcoma. This is the first evidence that a similar signaling paradigm may be present in HNSCC. PDGFR-α inhibitors have not been studied as adjunctive treatment options in the management of HNSCC and may prove to be an important driver of the malignant phenotype in this setting.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1091-6) contains supplementary material, which is available to authorized users.

Abstract C169: ER maleate is a novel anticancer agent in oral cancer cells: Implications for cancer therapy

Abstract ER maleate was investigated as a novel anticancer agent for oral squamous cell carcinoma (OSCC), the most common head and neck squamous cell carcinoma (HNSCC). We identified its putative molecular targets, demonstrated their clinical relevance, and showed its chemosensitization potential for platinum drugs to aid in HNSCC management. Biologic effects of ER maleate were determined on cell proliferation, spheroid/colony formation, caspase activity, cell migration and invasion in vitro and using oral tumor xenografts in vivo. mRNA profiling, real time PCR and western blot suggested ER maleate modulated the expression of polo-like kinase 1 (PLK1) and spleen tyrosine kinase (Syk). Their clinical significance was determined in oral SCC patients by immunohistochemistry and correlated with prognosis by Kaplan-Meier survival analysis. ER maleate induced cell apoptosis, inhibited proliferation, colony formation, migration and invasion in oral cancer cells. Imagestream analysis revealed cell cycle arrest in G2/M phase and increased polyploidy, unravelling deregulation of cell division and cell death. Mechanistically, ER maleate decreased expression of PLK1 and Syk, induced cleavage of PARP, caspase 9 and caspase 3 and increased chemosensitivity to carboplatin; significantly suppressed tumor growth and increased antitumor activity of carboplatin in tumor xenografts. ER maleate treated tumor xenografts showed reduced PLK1 and Syk expression; clinical investigations revealed overexpression of PLK1 and Syk in oral SCC patients that correlated with disease prognosis. In conclusion, our in vitro and in vivo findings provide a strong rationale for pre-clinical efficacy of ER maleate as a novel anti-cancer agent and chemosensitizer of platinum drugs for OSCC. Citation Format: Guodong Fu, Sr.. ER maleate is a novel anticancer agent in oral cancer cells: Implications for cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C169.

Decision management in transoral robotic surgery: Indications, individual patient selection, and role in the multidisciplinary treatment for head and neck cancer from a European perspective.

Transoral robotic surgery (TORS) has become an accepted first-line treatment for T1 and T2 head and neck squamous cell carcinoma (HNSCC). The growing popularity of this procedure is the result of mounting skepticism as to the survival and quality of life (QOL) benefits of primary chemoradiation over definitive surgery, the rising incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) in progressively younger patients, and the advantages of TORS over transoral laser microsurgery (TOLM) and open surgery. The authors use their experience and data gained from the TORS-based management of >100 patients to establish a systematic approach to the use of TORS in HNSCC. This approach is constructed on a framework which goal is to select the primary treatment option that is most likely to reduce morbidity while preserving function and maintaining oncologic safety. A consensus regarding the indications of TORS and its role in the multidisciplinary management of HNSCC is to be established. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2190-E2196, 2016.

Abstract B29: The role of MYD88-dependent signaling in the anti-tumor efficacy of the EGFR inhibitor erlotinib in head and neck cancer cells

Abstract Epidermal growth factor receptor (EGFR) is upregulated in the majority of head and neck squamous cell carcinomas (HNSCC). Unfortunately, the incorporation of EGFR inhibitors (EGFRIs) into the management of HNSCC has not improved long-term survival rates in patients with advanced stage HNSCC tumors. Therefore, the identification and understanding of strategies that will improve the efficacy of EGFRIs may potentially improve patient treatment and survival. Using microarray analysis, our laboratory has observed a profound increase in genes involved in MYD88-dependent pro-inflammatory pathways in EGFRI-treated HNSCC cell lines compared to their respective vehicle-treated cell lines. Additionally, we have previously shown that EGFRIs induce production of the inflammatory cytokine interleukin-6 (IL-6), leading to the reduced efficacy and acquired resistance to EGFRIs in HNSCC cells. Since MYD88-dependent signaling may lead to IL-6 production and secretion, the purpose of these studies is to determine if MYD88-dependent pathways such as Toll-like receptor (TLR), interleukin-1 receptor (IL-1R) and interleukin-18 receptor (IL-18R) pathways are responsible for the IL-6 production induced by EGFRIs. We found that knockdown of MYD88 (using siRNA and shRNA) significantly inhibited IL-6 secretion induced by the EGFRI erlotinib in Cal-27 and SQ20B HNSCC cells in vitro, increased the anti-tumor activity of erlotinib in vitro and enhanced the anti-tumor efficacy of erlotinib in a HNSCC xenograft mouse model. These results suggested that MYD88-dependent signaling was involved in IL-6 production and in the reduced efficacy of erlotinib. In order to elucidate which MYD88-dependent pathway was involved in erlotinib-induced IL-6 production, we investigated the involvement of TLR, IL-1R or IL-18R-mediated signaling. Although TLRs and the IL-18R were expressed and active on our HNSCC cells, we found little to no evidence of their involvement in erlotinib-induced IL-6 production. However, inhibition of the IL-1R through pharmacologic (anakinra) or genetic (siRNA and shRNA transfection) methods significantly reduced erlotinib-induced IL-6 production and increased HNSCC cell sensitivity to erlotinib in vitro. These observations point to the IL-1R/MYD88 pathway being involved in IL-6 production and in the reduced efficacy of erlotinib. We observed a time-dependent increase of IL-1 alpha (IL-1α) but not IL-1 beta (IL-1β) in response to erlotinib treatment implicating IL-1α as the damage associated molecular pattern (DAMP) responsible for activating the IL-1R. Furthermore, suppression of cell death with a pan-caspase inhibitor reduced erlotinib-induced IL-1α secretion. Finally, human HNSCC tumors were found to have higher IL-1α mRNA levels than matched normal tissue, and comparison of high and low IL-1α expressing HNSCC tumors (from the TCGA PANCAN databank) showed IL-1α to be negatively correlated with survival. Altogether, erlotinib-induced cell death may result in the release of IL-1α which activates IL-1R on adjacent surviving cells resulting in MYD88-mediated IL-6 secretion and the development of acquired resistance to erlotinib. In summary, the IL-1α/IL-1R/MYD88/IL-6 pathway may be responsible for the reduced anti-tumor efficacy of erlotinib and other EGFRIs; and blockade of the IL-1 pathway may improve the efficacy of EGFRIs in the treatment of HNSCC. This work was supported by the grants NIH K01CA134941 and ACS IRG7700434. Citation Format: Andrean L. Simons, Adam T. Koch, Laurie Love-Homan, Aditya Stanam. The role of MYD88-dependent signaling in the anti-tumor efficacy of the EGFR inhibitor erlotinib in head and neck cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B29.

PET imaging biomarkers in head and neck cancer.

In locally advanced head and neck squamous cell carcinoma (HNSCC), the role of imaging becomes more and more critical in the management process. In this framework, molecular imaging techniques such as PET allow noninvasive assessment of a range of tumour biomarkers such as metabolism, hypoxia and proliferation, which can serve different purposes. First, in a pretreatment setting they can influence therapy selection strategies and target delineation for radiation therapy. Second, their predictive and/or prognostic value could help enhance the therapeutic ratio in the management of HNSCC. Third, treatment modification can be performed through the generation of a molecular-based heterogeneous dose distribution with dose escalation to the most resistant parts of the tumour, a concept known as dose painting. Fourth, they are increasingly becoming a tool for monitoring response to therapy. In this review, PET imaging biomarkers used in the routine management of HNSCC or under investigation are discussed.

Role of (18)F-FDG PET/CT in pre and post treatment evaluation in head and neck carcinoma.

Head and neck cancer (HNC) ranks as the 6(th) most common cancer worldwide, with the vast majority being head and neck squamous cell carcinoma (HNSCC). The majority of patients present with complicated locally advanced disease (typically stage III and IV) requiring multidisciplinary treatment plans with combinations of surgery, radiation therapy and chemotherapy. Tumor staging is critical to decide therapeutic planning. Multiple challenges include accurate tumor localization with precise delineation of tumor volume, cervical lymph node staging, detection of distant metastasis as well as ruling out synchronous second primary tumors. Some patients present with cervical lymph node metastasis without obvious primary tumors on clinical examination or conventional cross sectional imaging. Treatment planning includes surgery, radiation, chemotherapy or combinations that could significantly alter the anatomy and physiology of this complex head and neck region, making assessment of treatment response and detection of residual/ recurrent tumor very difficult by clinical evaluation and computed tomography (CT) or magnetic resonance imaging (MRI). (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography/CT ((18)F-FDG PET/CT) has been widely used to assess HNC for more than a decade with high diagnostic accuracy especially in detection of initial distant metastasis and evaluation of treatment response. There are some limitations that are unique to PET/CT including artifacts, lower soft tissue contrast and resolution as compared to MRI, false positivity in post-treatment phase due to inflammation and granulation tissues, etc. The aim of this article is to review the roles of PET/CT in both pre and post treatment management of HNSCC including its limitations that radiologists must know. Accurate PET/CT interpretation is the crucial initial step that leads to appropriate tumor staging and treatment planning.

Hemochromatosis Enhances Tumor Progression via Upregulation of Intracellular Iron in Head and Neck Cancer

IntroductionDespite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC.Experimental DesignExpression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS), clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry.ResultsIn a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP) expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX), significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression.ConclusionsOur data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management.

Wnt Signaling Pathway Inhibition Enhances Efficacy of Cetuximab

Objectives: 1) Investigate whether Wnt pathway inhibition via a small molecule inhibitor, ICG-001, enhances cetuximab efficacy in head and neck squamous cell carcinoma (HNSCC). 2) Elucidate the mechanism of cetuximab sensitization and increased cell death that results from ICG-001/cetuximab cotreatment. Methods: HNSCC cell line SCC-15 was grown for 24 hours then incubated with: ICG-001, cetuximab, or both for 48-72 hrs. Cells grown in media alone served as control. Cell proliferation was analyzed using WST-1 and clonogenic assays. The mechanism of ICG-001/cetuximab interaction was investigated using reverse transcription polymerase chain reaction (RT-PCR), Western blot, immunohistochemistry, and TUNEL staining. Results: SCC-15 cells treated with ICG-001/cetuximab demonstrated significantly decreased viability (19.9%) as determined by WST-1 assay compared to control (100%), cetuximab (90.3%), or ICG-001 (35.1%) treatment ( P &lt; 0.05). Additionally, clonogenic assay demonstrated that combination ICG-001/cetuximab treatment led to significantly decreased cell proliferation (2.6%) compared to control (100%) or monotherapy (cetuximab 94.3%; ICG-001 20.2%; P &lt; 0.05). ICG-001 treatment resulted in increased epidermal growth factor receptor (EGFR) expression, as demonstrated by Western blot, RT-PCR, and immunohistochemistry. TUNEL-positive cells were shown to be significantly increased in both ICG-001 and ICG-001/cetuximab treatment groups. Additionally, combination therapy increased levels of cleaved caspase-3, a marker of apoptosis. Conclusions: ICG-001/cetuximab cotreatment results in cetuximab sensitization and increased cell death in HNSCC in vitro. Increased EGFR expression and pathway dependence leading to cetuximab vulnerability, along with increased apoptosis, play a major role in this observed effect. ICG-001/cetuximab cotreatment represents a potential novel therapy in HNSCC management which may offer superior outcomes with fewer side effects compared to existing first-line treatment.