Prognostic Factor For Head And Neck Squamous Cell Carcinoma Research Articles

Phosphoglycerate-kinase-1 Is a Potential Prognostic Biomarker in HNSCC and Correlates With Immune Cell Infiltration.

Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide, with a high recurrence rate and a low cure rate. Phosphoglycerate kinase 1 (PGK1), an essential enzyme in the aerobic glycolysis pathway, is a prognostic marker for a variety of cancers. However, it remains unclear whether a PGK1-based immune signature can be used as a prognostic biomarker in HNSCC patients. We explored the potential oncogenic mechanisms of PGK1 by multiple bioinformatics analyses combined with multiple databases, including the correlation between PGK1 and prognosis, and the infiltration of immune cells in HNSCC. Functional enrichment analyses were further performed to investigate the potential role of PGK1 in HNSCC. The expression of PGK1 was significantly higher in HNSCC tissues compared to normal tissues. High expression of PGK1 was associated with poor prognosis in HNSCC, and multivariate cox regression analysis showed that PGK1 could be an independent prognostic factor in HNSCC. Pathway analysis revealed that PGK1 may regulate the pathogenesis of HNSCC through the immune signaling pathway. Moreover, PGK1 expression significantly correlated with the infiltration level of 16 types of immune cells. The current study reports that PGK1 expression was increased in HNSCC and that high PGK1 expression was closely associated with poor prognosis and immune cell infiltration, which could serve as a promising independent prognostic biomarker and potential immunotherapeutic target for HNSCC.

The prognostic value of lymphatic metastatic size in head and neck squamous cell carcinoma.

Lymphatic metastatic size was proved to predict prognosis in different types of carcinomas, except in head and neck squamous cell carcinoma (HNSCC) located in hypopharynx, oropharynx and supraglottic region et al. The aim of this study is to evaluate the prognostic value of lymphatic metastatic size in HNSCC, which may guide clinical decision-making in practice. From 2008 to 2022, 171 patients, who were diagnosed as HNSCC in our center, were included. The demographic data, clinicopathological characteristics and lymphatic metastatic size were recorded and analyzed using the Kaplan-Meier method and Cox regression analysis. Among 171 patients, 107 cases were hypopharyngeal cancer, 38 cases supraglottic cancer and 26 cases oropharyngeal cancer. The median of lymphatic metastatic size was 8mm (range 0-46). According to lymphatic metastatic size, the patients were assigned to three subgroups: Group I (0mm), Group II ( ≤ 10mm) and Group III (> 10mm). Kaplan-Meier analysis with log rank test revealed that Group I and Group II had similar locoregional control rate, distant metastasis free probability, disease-free survival and overall survival (all p > 0.05), whereas Group III had significant worse prognosis. Adjusted for demographic and other clinicopathological characteristics, lymphatic metastatic size was an independent predictor of disease-free survival and overall survival in HNSCC. Lymphatic metastatic size was an independently prognostic factor in HNSCC, which may assist in postoperative adjuvant treatment decisions.

High-risk TP53 mutations predict poor primary treatment response of patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) poses a diagnostic and therapeutic challenge worldwide and is associated with a poor survival rate. Due to the variability in the efficacy of treatments for HNSCC, new predictive biomarkers of therapy outcomes are needed. Recently, we developed an algorithm that employs the mutational profile of TP53 as an independent prognostic factor in HNSCC. In this study, we investigated its role as a predictive biomarker of treatment outcomes in HNSCC patients. We also tested the usefulness of two classification systems for TP53 mutational landscapes. Clinical and genomic data were retrieved from The Cancer Genome Atlas database. We built a multivariate stepwise backward binary regression model to assess the role of TP53 mutations in predicting therapeutic outcomes. Cases harbouring high-risk-of-death mutations reported an odds ratio of 3.301 for stable or progressive disease compared to wild-type cases, while no significant difference in treatment outcomes was found between cases with low-risk-of-death mutations and wild-type TP53. Our analysis found that older patients with a history of alcohol consumption had a higher risk of stable/progressive disease. This study improves current evidence on the role of TP53 mutations in treatment response in HNSCC patients.

The Prognostic Significance of FOXD1 Expression in Head and Neck Squamous Cell Carcinoma

It has been reported that forkhead box D1 (FOXD1) plays an established role in human early embryonic development and is broadly involved in various malignancies. However, there is limited information regarding FOXD1 expression in head and neck squamous cell carcinoma (HNSCC). This present study aimed to explore the clinical significance of FOXD1 in patients with HNSCC. Tissue microarrays of 334 primary HNSCC patients who underwent surgery between 2008 and 2010 at Sun Yat-sen University Cancer Center were investigated by immunohistochemistry regarding FOXD1 expression. χ2 test was used to estimate the relationship of FOXD1 expression with clinicopathologic characteristics. Univariate and multivariate analyses were performed to identify FOXD1 expression as an independent prognostic indicator of overall survival (OS) and disease-free survival (DFS). FOXD1 expression is closely associated with postoperative recurrence. HNSCC patients with high FOXD1 expression have poorer prognoses than the low-expression group (p < 0.05). According to multivariate analysis, FOXD1 was an independent prognostic factor for OS and DFS. The results revealed that FOXD1 could be a prognostic factor for HNSCC and might serve as a potential target for novel therapies.

Evaluation of Cyclin D1 and Human Epidermal Growth Factor Receptor 2 Neu Protein Expression in Head and Neck Squamous Cell Carcinoma.

Background Head and neck cancers are highly aggressive, frequently occurring cancers that are prevalent worldwide. The mainstay of their treatment is surgery, followed by adjuvant therapy. Various studies have documented the usefulness of molecular markers in carcinogenesis and have proven helpful in the diagnosis and treatment of head and neck cancers. Cyclin D1 is a proto‑oncogene, overexpression of which leads to the accelerated entry of cells in the S phase of the cell cycle, causing uncontrolled proliferation of the cells. The dysregulation of human epidermal growth factor receptor 2 (HER2) neu is also related to multiple features of malignancy, including loss of cell cycle control, induction of angiogenesis, and resistance to apoptotic stimuli. This study seeks to identify a subset of patients with a bad prognosis who may require aggressive treatment strategies. Aim This study aims to determine the proportion of the expression of cyclin D1 and HER2 neu in head and neck squamous cell carcinoma (HNSCC) and analyze the association between the expression of cyclin D1 and HER2 neu using histological grading, tumor, node, and metastasis (TNM) staging, and nodal status of the tumor. Furthermore, this study also aims to document clinical outcomes, such as locoregional control, depth of invasion (DOI), and regional metastasis regarding the expression of cyclin D1 and HER2 neu in HNSCC. Setting and design This study is a laboratory-based observational study. Materials and methods Seventy histologically proven cases of HNSCC were studied for various histopathological parameters, and further immunohistochemistry (IHC) was performed for cyclin D1 and HER2 neu. The expression and intensity of cyclin D1 were multiplied, and the total score was derived. The College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guidelines for HER2 neu testing in breast cancer were used for scoring. Result Out of 70 cases, 52 (75%) demonstrated strong and moderate positivity for cyclin D1, and the p-values were 0.017, 0.001, and 0.032 for depth of invasion, TNM stage, and lymph node metastases, respectively,for cyclin D1, which was considered statistically significant. For HER2 neu, five out of 70 cases were positive, and the p-value was significant for depth of invasion (0.008). Conclusion The expression of the above marker cyclin D1 increases with stage, DOI, and positive lymph node status. Hence, cyclin D1 immunoexpression can be helpful in the early assessment of HNSCC behavior and can serve as an independent prognostic marker. Furthermore, it was observed that HER2 neu was significant with an increase in depth of invasion of tumor, which, in the American Joint Committee on Cancer (AJCC) eighth edition, is considered an important factor for determining the stage of the tumor. Further research is needed to examine whether HER2 neu can act as a prognostic factor for HNSCC and if it can be targeted for treatment options.

IGF2BP2 serves as a core m6A regulator in head and neck squamous cell carcinoma.

Methylation of N6 adenosine (m6A) plays a crucial role in the development and progression of cancers. Its modification is regulated by three types of m6A-related regulators (methyltransferases (writers), demethylases (erasers), and RNA-binding proteins (readers)). Till now, the functions and roles of these regulators in head and neck squamous cell carcinoma (HNSC) remain largely unexplored. Therefore, we utilized the open HNSC dataset in The Cancer Genome Atlas (TCGA), four different cell lines, and our HNSC patient samples (n=40) to explore the clinical significance of 19 m6A regulators, and selected the most significant prognosis-related regulator. Authentic analyses based on online websites were also used in the study (Oncomine, UALCAN, Kaplan-Meier plotter, Human Protein Atlas (HPA), cBioPortal, LinkedOmics, String, etc.). From the results, general overexpression of m6A regulators was observed in pan-cancer, especially in HNSC. IGF2BP2 was recognized as the hub m6A regulator, which was an independent, unfavorable prognostic factor in HNSC. Its mRNA and protein expression in HNSC were significantly up-regulated. Gene mutation types of IGF2BP2 in HNSC (32%) were mainly mRNA High or Amplification, which represented the high expression of IGF2BP2. And these mutations were associated with a poor prognosis. In functional analysis, IGF2BP2 was negatively correlated to tumor immune infiltration in HNSC. Finally, HMGA2 might interact with the IGF2BP2 in HNSC. In conclusion, IGF2BP2 serves as a core m6A regulator among all regulators in HNSC, which has a high expression and predicts the poor prognosis of HNSC patients independently. IGF2BP2 might bring a new direction for HNSC treatment in the future.

Comprehensive Analysis of mTORC1 Signaling Pathway–Related Genes in the Prognosis of HNSCC and the Response to Chemotherapy and Immunotherapy

Objective: The mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway has emerged as a crucial player in the oncogenesis and development of head and neck squamous cell carcinoma (HNSCC), however, to date, no relevant gene signature has been identified. Therefore, we aimed to construct a novel gene signature based on the mTORC1 pathway for predicting the outcomes of patients with HNSCC and their response to treatment. Methods: The gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The key prognostic genes associated with the mTORC1 pathway were screened by univariate Cox regression analyses. A prognostic signature was then established based on significant factors identified in the multivariate Cox regression analysis. The performance of the multigene signature was evaluated by the Kaplan–Meier (K–M) survival analysis and receiver operating characteristic (ROC) analysis. Based on the median risk score, patients were categorized into high- and low-risk groups. Subsequently, a hybrid prognostic nomogram was constructed and estimated by a calibration plot and decision curve analysis. Furthermore, immune cell infiltration and therapeutic responses were compared between the two risk groups. Finally, we measured the expression levels of seven genes by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Results: The mTORC1 pathway–based signature was constructed using the seven identified genes (SEC11A, CYB5B, HPRT1, SLC2A3, SC5D, CORO1A, and PIK3R3). Patients in the high-risk group exhibited a lower overall survival (OS) rate than those in the low-risk group in both datasets. Through the univariate and multivariate Cox regression analyses, this gene signature was confirmed to be an independent prognostic risk factor for HNSCC. The constructed nomogram based on age, American Joint Committee on Cancer (AJCC) stage, and the risk score exhibited satisfactory performance in predicting the OS. In addition, immune cell infiltration and chemotherapeutic and immunotherapeutic responses differed significantly between the two risk groups. The expression levels of SEC11A and CYB5B were higher in HNSCC tissues than in normal tissues. Conclusion: Our study established and verified an mTORC1 signaling pathway–related gene signature that could be used as a novel prognostic factor for HNSCC.

Identification of NUTF2 as a Candidate Diagnostic and Prognostic Biomarker Associated with Immune Infiltration in Head and Neck Squamous Cell Carcinoma.

BackgroundHead and neck squamous cell carcinoma (HNSC) is one of the most common tumors worldwide. Nuclear transport factor 2 (NUTF2) plays a key role in cell death and immune processes. However, few reports have studied correlations between NUTF2 gene expression and the occurrence and development of HNSC.MethodsThe expression of NUTF2 was analyzed using publicly available databases, including the Cancer Genome Atlas and Human Protein Atlas and Gene Expression Omnibus (GEO) database, which was validated by RT-PCR. We evaluated the functions of NUTF2 with Kaplan–Meier curve, logistic regression were used to study the relationship between clinicopathological features and the expression of NUTF2. Cox regression analyses were used to identify the effects of NUTF2 expression on survival. Gene Ontology and Gene Set Enrichment Analysis were used to explore relevant biological pathways. The relationship between NUTF2 and tumor-infiltrating immune cells was investigated with on-line bioinformatic tools.ResultsNUTF2 was significantly upregulated in HNSC lesions and is associated with tumor size (P < 0.01). Increased expression of NUTF2 was linked to shorter overall and progress-free survival in HNSC. Cox regression analyses revealed that NUTF2 is an independent prognostic factor in HNSC. GSEA analysis demonstrated that NUTF2 negatively regulates several immune pathways. NUTF2 was correlated with the infiltrating levels of B cells and CD8+ T cells and was negatively correlated with diverse immune marker sets in HNSC.ConclusionNUTF2 is highly expressed in HNSC and correlates with poor prognosis. Correlation with immune functions suggests that NUTF2 may serve as a biomarker and therapeutic target for HNSC.

Hepatitis B X‐interacting protein, involved in increasing proliferation and cell migration, is a prognostic marker in head and neck squamous cell carcinoma

AbstractIntroductionFactors associated with prognosis and molecular mechanisms leading to a malignant phenotype in head and neck squamous cell carcinoma (HNSCC) need to be identified. The focus was on the biological function and clinical impact of hepatitis B X‐interacting protein (HBXIP) in HNSCC.MethodsmRNA expression profiles of HBXIP were compared between tumor and normal tissues in head and neck cancer cases from an online database. The protein expressions of candidate genes were verified by immunohistochemistry (IHC) with tissue microarray blocks designed with 221 cases. Prognostic significance was analyzed using the Kaplan–Meier method and Cox regression analysis. The molecular function of malignant phenotypes was investigated by generating knockdown cell lines of HNSCC with RNA interference.ResultsAnalysis of the online database showed that the mRNA of HBXIP was significantly higher in the HNSCC group than in normal specimens. IHC analysis showed significant differences in the protein expression of HBXIP by clinical stage, T status, and recurrence. Multivariate analysis showed that, in HBXIP IHC‐positive patients, N status, T status, and neural invasion were significantly associated with overall survival. In addition, downregulation of the HBXIP gene in SAS, a tongue squamous cancer cell line, inhibited proliferation and the invasion phenotype.ConclusionsBy increasing the malignant phenotypes of cell proliferation and invasion, upregulation of HBXIP was a prognostic factor in HNSCC.

BP180 Is a Prognostic Factor in Head and Neck Squamous Cell Carcinoma.

Prognosis plays a vital role in head and neck squamous cell carcinoma (HNSCC) patient management and decision-making. This study aimed to identify the role of BP180 as a prognostic factor in HNSCC. Protein expression of bullous pemphigoid antigen II (BP180) was verified by immunohistochemistry (IHC) in a tissue microarray study of 202 cases. IHC analysis revealed that protein expression of BP180 among HNSCC patients differed significantly in the presence and absence of neural invasion, and according to T status in laryngeal and pharyngeal cancer subgroups. Overall survival and multivariate analysis showed that positive BP180-IHC and advanced clinical stage were significant independent positive predictors of mortality in HNSCC patients. In addition, in the oral cancer subgroup, independent positive predictors were positive BP180-IHC, advanced N status and neural invasion. In laryngeal and pharyngeal cancer subgroups, predictors were positive BP180-IHC and advanced clinical stage. BP180 is a prognostic factor in head and neck squamous cell carcinoma.

Prognostic Value of a Ten-Gene Signature in HNSCC Patients Based on Tumor-Associated Macrophages Expression Profiling.

Tumor-associated macrophages (TAMs) are regarded as the most abundantly infiltrating immune cells around the tumor microenvironment (TME) in head and neck squamous cell carcinoma (HNSCC), which plays an essential role in immunosuppression and tumorigenesis. In the TCGA HNSCC cohort, 500 patients with clinical-pathological information and RNA sequence expression were randomly assigned to training for lasso regression and validation for verification, respectively. A TAM-based ten-gene signature (TBGs) was constructed, which divided the patients into high-risk and low-risk groups, could predict overall survival (OS) of HNSCC patients in the training dataset (p = 3.527e–05) and validation dataset (p = 3.785e–02). The result of Cox univariate and multivariate regression analyses showed that the risk score of TBGs could be an independent prognostic factor in HNSCC. ROC curve confirmed that the risk score of TBGs has good sensitivity and specificity for prognosis prediction (AUC = 0.659) and was also verified by the validation dataset (AUC = 0.621). We obtained key risk transcription factors (TFs)—EHF and SNAI2—by correlation analysis with TBGs. Moreover, we ran a gene set enrichment analysis (GSEA) to speculate that TBGs act on interstitial remodeling, tumor killing, metabolic reprogramming, and tumor immune-related pathways. Finally, we combined clinical–pathological features and risk score of TBGs to establish clinical nomograms, and calibration curves verified the accuracy of long-term clinical prognosis in the two datasets (C-index of 5-year OS = 0.721 and 0.716). In general, the TBGs we obtained may accurately predict the prognosis of HNSCC patients to provide personalized treatment.

Computational analysis of TP53 mutational landscape unveils key prognostic signatures and distinct pathobiological pathways in head and neck squamous cell cancer

BackgroundMutations of the tumour-suppressor gene TP53 are the most frequent somatic genomic alterations in head and neck squamous cell carcinoma (HNSCC). However, it is not yet clear whether specific TP53 mutations bear distinct clinical and pathophysiological significance in different HNSCC subgroups.MethodsA systematic bioinformatics appraisal of TP53 mutations was performed on 415 HNSCC cases available on The Cancer Genome Atlas (TCGA). The following features were analysed and correlated with known clinicopathological variables: mutational profile of TP53, location (within secondary structure and predicted domains of p53 protein) and well-known hotspot mutations. Interactome–genome–transcriptome network analysis highlighted different gene networks. An algorithm was generated to develop a new prognostic classification system based on patients’ overall survival.ResultsTP53 mutations in HNSCCs exhibited distinct differences in different anatomical sites. The mutational profile of TP53 was an independent prognostic factor in HNSCC. High risk of death mutations, identified by our novel classification algorithm, was an independent prognostic factor in TCGA HNSCC database. Finally, network analysis suggested that distinct p53 molecular pathways exist in a site- and mutation-specific manner.ConclusionsThe mutational profile of TP53 may serve as an independent prognostic factor in HNSCC patients, and is associated with distinctive site-specific biological networks.

Prognostic value of trafficking of regulatory T cells to tumors in head and neck cancer patients.

104 Background: The prognostic value of regulatory T cells (Tregs) in head and neck squamous cell carcinoma (HNSCC) remains unknown. We analyzed the prognostic effect of Tregs in HNSCC with immune activity scores, which reflect the activity status of the seven-step cancer-immunity cycle. Methods: We correlated the 23 immune activity scores and clinicopathologic features of The Cancer Genome Atlas (TCGA) HNSCC using multivariate Cox regression analyses and Kaplan-Meier survival curves. The processed data of immune activity scores were obtained from TIP online tool and the clinicopathologic data were downloaded from TCGA HNSCC database. Results: Immune activity scores of “trafficking of Tregs to tumors” was significantly associated with overall survival (OS) and progression-free survival (PFS). Low activity scores of “trafficking of Tregs to tumors” resulted in shorter OS and PFS. In multivariate analysis, low scores predicted poor OS (adjusted HR = 1.87, 95% CI 1.34-2.60 ; P &lt; 0.001) and were related with unfavorable PFS (adjusted HR = 2.04, 95% CI 1.45-2.86 ; P &lt; 0.001). Conclusions: Immune activity scores of “trafficking of Tregs to tumors” was independent significant prognostic factor in HNSCC. Therefore, assessment of immune activity scores may be useful tools for predicting prognosis in these patients.

MK2 Pathway Mediates Radiation-Induced Tumor Inflammation and Is a Poor Prognostic Factor in Head and Neck Cancer

Epithelial-to-mesenchymal transition (EMT) pathway is a known mechanism for tumor metastasis, invasion, proliferation and treatment resistance. We have identified the MAP kinase-activated protein kinase 2 (MK2) pathway as a regulator of inflammatory cytokine production and EMT pathway activation. However, no link has been established between radiotherapy (RT) and MK2 pathway, tumor inflammation, EMT and tumor repopulation in head and neck squamous cell carcinoma (HNSCC). We hypothesize that RT can activate MK2 signaling which in turn leads to increased tumor inflammation, EMT, tumor repopulation and high MK2 phosphorylation (pMK2) is a poor prognostic factor in HNSCC. A 180 patient oropharyngeal SCC (OSCC) tissue microarray, with annotated patient characteristics and survival outcomes, was stained for pMK2, p16, and HPV (ISH, RNA-seq). H-score was calculated for all samples and correlated to stage, HPV-p16 status and survival outcomes (OS and DSS) by log-rank analysis. For in vitro studies, HNSCC cell lines (SCC47, SCC90, TU167, HN11) were treated in 1 of 4 arms: control, MK2 inhibitor (MK2i), RT, or both. Intensity of pMK2 was assessed by immunoblot. Cytokine and EMT gene expression was evaluated by RT-qPCR. Cytokine production was assessed using a commercial kit. The siRNA experiments were performed to assess specificity of RT signaling through the MK2 pathway. For in vivo studies, HNSCC patient-derived xenografts (PDX) were treated and analyzed as the groups described above and survival studies performed. Patients bearing tumors with high pMK2 vs low pMK2 were associated with worse cancer-specific survival. This was more pronounced in p16-negative compared to p16-positive OSCC patients (p<0.0002). In vitro, RT increased TNFA (8-15x), IL6 (5-7x), VIM (4.5x), SNAI1 (2-5x) gene expression significantly. This effect was significantly reduced with the addition of MK2i prior to RT. MK2 siRNA successfully knocked down MK2 expression in all cell lines tested (to 7-14% of scramble). Similar to the small molecule inhibitor, MK2 siRNA could substantially reduce inflammatory cytokine production. The in vivo animal studies demonstrate that combined modality therapy was superior to monotherapy alone (p = 0.0123). Tumor PDX volumes captured at day 19 demonstrated the following average tumor sizes: control (994mm3), MK2i (440mm3), RT(479mm3), and RT+MK2i (185mm3). We observe that RT-induced inflammation, EMT and tumor regrowth appears to be regulated by MK2 pathway. OSCC patients who have p16-negative tumors with high pMK2 have a worse prognosis compared to patients with p16-positive tumors with low pMK2. We demonstrate for the first time that RT can induce MK2 phosphorylation in HNSCC leading to increased tumor inflammatory cytokine and EMT gene expression. Inhibition of the MK2 pathway may help to decrease RT resistance and improve HNSCC treatment outcomes.

Integrating pretreatment diffusion weighted MRI into a multivariable prognostic model for head and neck squamous cell carcinoma

IntroductionIn head and neck squamous cell carcinoma (HNSCC) the ability to anticipate an individual patient’s outcome is very valuable. With this study we wanted to assess the prognostic value of pretreatment apparent diffusion coefficient (ADC) in a large patient population and integrate it into a multivariable prognostic model. MethodsFrom 2004 to 2010 175 patients with pathology proven HNSCC were included in this study. All patients underwent a pretreatment MRI with diffusion weighted imaging (DWI) using six b-values. For each tumor, three ADC values were calculated using different b-value combinations: ADClow (b 0–50–100s/mm2), ADChigh (b 500–750–1000s/mm2) and ADCavg (all b-values). The clinical and radiological variables included: tumor and nodal volume, tumor location and age. Disease recurrence was analyzed using competing risk regression. A prognostic model for disease recurrence was developed, and internal validation was performed using bootstrapping and by dividing patients in three equal sized groups based on prognosis. ResultsOne hundred and sixty-one patients were eligible for analysis. Median follow-up was 50months (range 4–86). A total of 67 patients experienced disease recurrence during follow-up (42%). ADChigh was a prognostic factor for disease recurrence (adjusted hazard ratio: 1.14 per 10–4mm2/s, 95% CI 1.04–1.25). Harrell’s c-index of the multivariable prognostic model was 0.62 (95% CI 0.56–0.70) after internal validation. The validated 3-year disease recurrence rates for the groups with worst, intermediate, and best prognosis were 56%, 33% and 31% respectively. ConclusionPretreatment ADC value derived from high b-values is an independent prognostic factor in HNSCC and increases the performance of a multivariable prognostic model in addition to known clinical and radiological variables. Integration of other biomarkers and external validation is necessary to ensure its clinical applicability.

High Expression of Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Predicts Poor Prognosis in Head and Neck Squamous Cell Carcinoma

Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial inner membrane protein and plays an important role in mitochondrial ATP production and biogenesis. High expression levels of LETM1 have been correlated with numerous human malignancies. This study explored the clinicopathological significance of LETM1 expression as a prognostic determinant in head and neck squamous cell carcinoma (HNSCC). HNSCC samples from 176 patients were selected for immunohistochemical staining of LETM1 protein. Correlations between LETM1 overexpression and clinicopathological features of HNSCC were evaluated by Chi-squared tests and Fisher's exact tests, and relationships between prognostic factors and patient survival were analyzed using Cox proportional hazards models. Our results demonstrated that the strongly positive rate of LETM1 protein was 65.3% in HNSCC, which was significantly higher than in either adjacent nontumor tissue (25.0%) or normal squamous epithelia (6.7%). LETM1 overexpression correlated with poor differentiation, presence of lymph node metastasis, advanced stage, absence of chemoradiotherapy, and 5-year disease-free survival and overall survival rates in HNSCC. Further analysis showed that high LETM1 expression, advanced stage, and nonchemoradiotherapy were significant independent risk factors for mortality in HNSCC. In conclusion, LETM1 plays an important role in the progression of HNSCC and is an independent poor prognostic factor for HNSCC.

Role of EGFR as a prognostic factor for survival in head and neck cancer: a meta-analysis

The prognostic role of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC) remains controversial. The goal of this study was to summarize existing evidence regarding whether EGFR overexpression is a prognostic factor in HNSCC. Relevant studies were identified using Pubmed, Ovid, and Web of Science databases. A meta-analysis was conducted on the prognostic value of EGFR expression for overall survival (OS) and disease-free survival (DFS). Thirty-seven studies were included. Primary analysis indicated that EGFR overexpression was associated with reduced OS (hazard ratio [HR]: 1.694, 95% confidence interval [CI]: 1.432–2.004). DFS, on the other hand, was not associated with EGFR expression after adjusting for publication bias (HR: 1.084, 95% CI: 0.910–1.290). Subgroup analysis gave a statistically significant pooled HR for OS in laryngeal carcinoma (HR: 2.519, 95% CI: 1.615–3.928) and in oropharyngeal carcinoma (HR: 2.078, 95% CI: 1.605–2.690). The pooled HR was statistically significant for DFS with respect to oropharyngeal carcinoma (HR: 1.055, 95% CI: 1.020–1.092), but not laryngeal carcinoma (HR: 1.750, 95% CI: 0.911–3.360). When dividing studies based on the immunohistochemistry (IHC) scoring system, only the group that evaluated EGFR expression according to the intensity and extent of staining showed no between-study heterogeneity for both OS and DFS. Overall, EGFR overexpression was associated with shortened OS, but not DFS. Future studies are needed that stratify patients by specific tumor sites. Furthermore, when estimating protein level by the IHC method, it is advisable to consider both intensity and extent of staining.

Prognostic significance of plasma osteopontin in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation on TROG 02.02 phase III trial.

5506 Background: High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in HNSCC, to correlate with tumor hypoxia and to be predictive of benefit from hypoxia targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial. Methods: Patients with previously untreated Stage III or IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). As previously reported there were no significant differences in any outcome parameter by randomization arm. Eligibility criteria for this prospective substudy included availability of plasma samples and absence of major radiation therapy deviations. Plasma OPN was measured by ELISA. OPN concentrations according to tertiles and median were analysed for overall survival (OS), and time to locoregional failure (TTLRF), adjusting for prognostic factors (site, T category, N category, hemoglobin, performance status). An additional analysis was performed in patients with available p16 immunohistochemistry results. Results: 578/853 patients were eligible and had a median OPN level of 544 µg/L (range: 7 - 2640). High OPN levels were not associated with worse overall survival (HR 1.03 for highest tertile and 0.98 for middle tertile, p=0.95) or time to locoregional failure (HR 0.91 for highest and 0.93 for middle, p=0.91). There was no interaction between OPN and treatment arm for OS or TTLRF (p=0.51 for both). For the highest tertile the 2-year OS was 70% on control arm and 71% on TPZ arm (HR=1.11, p=0.67). Similarly for p16 negative patients in the highest tertile, the 2 year OS was 69% on control arm and 73% on TPZ arm (HR=1.13, p=0.82). Conclusions: In contrast to previous reports we found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy. Supported by 1 R01 CA118582 and NHMRC project grant.

Expression of haptoglobin predicts recurrence in head and neck squamous cell carcinoma

Background We determined whether expression of haptoglobin by head and neck squamous cell carcinoma (HNSCC) cells is associated with prognosis. Methods Western blotting was carried out to investigate the expression of haptoglobin in oral cancer cell lines. We study patients with HNSCC without distant metastasis at diagnosis. Correlation between cellular haptoglobin and clinical characteristics of HNSCC was analyzed to assess the prognostic value of cellular haptoglobin level. Kaplan–Meier survival curves and log-rank test were used to evaluate differences in recurrence, distant metastasis, and overall survival rates between patients grouped according to cellular haptoglobin level in cancer tissues. The relationship of haptoglobin expression with survival was assessed using Cox proportional hazard models. Results Western blotting analysis showed that haptoglobin protein was expressed in 4 oral cancer cell lines. The recurrence rate was higher in HNSCC patients with over-expression of haptoglobin (> 50%) ( P = 0.045). Over-expression of haptoglobin was also associated with an increased risk for recurrence (hazard ratio [HR] 3.2; 95% confidence interval [CI], 1.127–8.895; P = 0.029) after adjusting for age, gender, disease site, stage, and treatment modality. Conclusions Altogether, the data presented show that cellular expression of haptoglobin is closely related to recurrence rate in HNSCC patients. The elevated risk of relapse was confirmed in a multivariate analysis. The cellular expression of haptoglobin may be a prognostic factor in HNSCC.