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One of the mainstays of treatment for locally advanced head and neck squamous cell carcinoma is surgery. However, for post-operative patients with high-risk factors for recurrence, surgery alone is insufficient and improving survival requires adjuvant treatment after surgery. Unlike with most other malignancies, the standard adjuvant treatment for post-operative head and neck cancer patients with high-risk factors for recurrence is radiotherapy concurrent with chemotherapy. This review article focuses on the history and future perspectives of adjuvant treatment for post-operative head and neck squamous cell carcinoma., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Head and neck squamous cell carcinoma (HNSCC) accounts for around 6% of all cancers in the USA. Few of the greatest obstacles in HNSCC include development of secondary primary tumor, resistance and toxicity associated with the conventional treatments, together decreasing the overall 5-year survival rate in HNSCC patients to ≤50%. Radiation and chemotherapy are the conventional treatment options available for HNSCC patients at both early and late stage of this cancer type malignancy. Unfortunately, patients response poorly to these therapies leading to relapsed cases, which further, emphasizes the need of additional strategies for the prevention/intervention of both primary and the secondary primary tumors post-HNSCC therapy. In recent years, growing interest has focused on the use of natural products or their analogs to reduce the incidence and mortality of cancer, leading to encouraging results. Resveratrol, a component from grape skin, is one of the well-studied agents with a potential role in cancer chemoprevention and other health benefits. As an anticancer agent, resveratrol suppresses metabolic activation of pro-carcinogens to carcinogens by modulating the metabolic enzymes responsible for their activation, and induces phase II enzymes, thus, further detoxifying the effect of pro-carcinogens. Resveratrol also inhibits cell growth and induces cell death in cancer cells by targeting cell survival and cell death regulatory pathways. Growing evidence also suggest that resveratrol directly binds to DNA and RNA, activates antioxidant enzymes, prevents inflammation, and stimulates DNA damage checkpoint kinases affecting genomic integrity more specifically in malignant cells.

Purpose: A complete economic evaluation requires accurate data concerning the resources used, outcomes, and utilities (patient's preferences) to properly value the cost utility of human papillomavirus (HPV) vaccination strategies. This study was designed to measure the utility loss in health states affected by a broad range of HPV-induced pathologies in both sexes in Italy. As a secondary objective, risk factors influencing the viral transmission and development of HPV infections were also investigated., Methods: Patients with a diagnosis of several HPV-induced pathologies including atypical squamous cells of undetermined significance (ASC-US), cervical intraepithelial neoplasia (CIN), cervical and anal-colorectal cancer, head and neck squamous cell carcinoma (HNSCC) and anogenital warts (AWs) were evaluated. Utilities, quality of life, and risk factors were elicited using a standardized and computer-guided administration of time trade-off, European Quality of Life 5 Dimensions (EQ-5D), 3 levels, and risk factor questionnaires. Utilities were measured at 6 clinical research centers across Italy. A group of healthy subjects was used as a control. A mean number of 20 healthy subjects was used as a control for each pathology group., Findings: Overall, 600 respondents were eligible for analysis: 465 patients (mean [SD] age, 44.0 [16.3] years) and 135 controls (mean [SD] age, 44.0 [13.2] years). With the exception of anal and HNSCC cancer, no statistically significant differences were observed between case and control groups, in terms of either age or quality of life at the time of interview. The patients' perception of their health condition at baseline was equal to an EQ-5D score of 0.87 (0.22). The mean (SD) value of utilities associated with the HPV-induced pathologies corresponded to 0.83 (0.24), 0.78 (0.27), 0.83 (0.22), 0.81 (0.27), 0.58 (0.31), 0.51 (0.26), and 0.69 (0.30) for ASC-US, AWs, CIN 1 (mild), CIN 2-3 (moderate to severe), cervical cancer, anal cancer and HNSCC, respectively. Utility lost due to AWs was significantly higher in females compared with males (0.71 [0.29] vs 0.83 [0.25]; P = 0.018). Having >5 sexual partners increased the risk of acquiring HPV-induced infections as much as 2.52-fold (P = 0.004), whereas for smoking or the age at start of sexual activity younger than 18 years, the risk increased by ~1.62-fold (P = 0.034). High levels of education were associated with a statistically significant protective effect (P < 0.001)., Implications: Risk factors and utilities elicited in this study can be used as part of future economic assessments of other HPV vaccination strategies, including an immunization program for preadolescents of both sexes in Italy., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

550,000 new cases of cancer of the oral cavity and pharynx and 160,000 of larynx are diagnosed each year worldwide. It is estimated that each year because of head and neck cancer 400,000 of patients will die. Head and neck neoplasms are the tumors which, because of their location, secretly develop and produce uncharacteristic symptoms identical to those that accompany the banal infections of the upper respiratory tract. Results of treatment of patients with head and neck cancer in Poland are highly unsatisfactory. This is due to significant advancement of tumor at the moment of diagnosis. Therefore, raising awareness and improving knowledge of health care workers on head and neck cancers by creating access to prevention research is a priority that will ensure improvement in treatment outcomes in this group of tumors in Poland and abroad.

HPV-positive oropharyngeal squamous cell carcinoma (HPV-OSCC) is associated with oral sexual behaviors. The sharp rise in incidence of HPV-OSCC in the USA has been attributed to changes in sexual norms over the past five decades, with lower age at sexual debut and higher numbers of sexual partners per individual. In addition, variations in HPV-OSCC prevalence by race, age cohort and gender may be attributable to differences in oral sexual behaviors among these groups. Oral HPV infection is the putative precursor to HPV-OSCC. Risk factors for oral HPV incidence, prevalence, clearance and persistence are crucial to understanding how, and in whom, oral HPV infection progresses to malignancy. Future investigation should focus on elucidating the natural history of oral HPV infection persistence and malignant transformation, developing effective screening tools and exploring opportunities for prevention such as vaccination and public health education.

Introduction: Squamous-cell carcinoma of the head and neck (SCCHN) remains a challenging clinical problem, due to the persistent high rate of local and distant failures and the occurrence of secondary primaries. For locally advanced SCCHN, a combination of chemotherapy (CT), radiation or surgery is often used, but there are limitations, which may reduce compliance. Molecular targeted therapies, namely anti-EGFR treatments, are in development with the aim of improving clinical outcomes and mitigating treatment-related toxicities., Areas Covered: This review provides an overview of early investigational drugs that target EGFR for the treatment of SCCHN and discusses the ongoing trials in this domain., Expert Opinion: Targeted therapies are increasingly used in oncology, especially in SCCHN. Cetuximab has demonstrated a significant improvement in the treatment outcome, both as a curative treatment in combination with radiation therapy and as a palliative treatment in combination with CT; however, it failed to show any benefit in combination with concomitant chemoradiotherapy. Presently, there are many new agents, including monoclonal antibodies and small-molecule tyrosine kinase inhibitors, which are either currently under investigation for or which warrant further investigation for treating SCCHN. The discovery of predictive factors that help to identify patients most likely to respond to EGFR inhibitors as well as patient-customized therapies would help to improve patient outcomes in the future.

The epidermal growth factor receptor (EGFR) has been implicated in head and neck squamous cell carcinoma (HNSCC) carcinogenesis. It is currently the only molecular target in head and neck cancers for which there are pharmacologic therapeutic interventions approved by regulatory agencies worldwide to treat advanced disease. Oral pre-malignant lesions have increased EGFR protein expression and increased egfr gene copy number compared to normal mucosa. Oral pre-malignant lesions with overexpression of EGFR or egfr gene copy number gain are at higher risk for malignant transformation. Inhibition of EGFR in pre-clinical models of oral pre-malignancies validates this approach as an effective way to reduce the incidence of oral cancer, and supports investigation of this strategy in the clinic. Clinical trials with EGFR targeted agents, including cetuximab, erlotinib, and vandetanib, are currently under way, some with promising preliminary results. If ultimately shown to reduce the risk of oral cancer, chemoprevention with EGFR inhibitors may significantly reduce morbidity and possibly mortality from HNSCC., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Head and neck cancer is frequently associated with alcohol and tobacco consumption but there is an increasing incidence of oropharyngeal carcinoma associated with oncogenic type-16 human papillomavirus (HPV). The clinical profile of these patients is distinct from that of other patients, with an earlier onset, 1/1 male to female sex ratio, cystic cervical nodes. Detection of intratumoral viral DNA is essential to confirm the role of HPV. According to several reports, the prognosis in terms of survival and locoregional control is better in HPV-positive oropharyngeal carcinoma than in HPV-negative oropharyngeal carcinoma or associated with tobacco consumption. The future lies in vaccination of women against cervical cancer but vaccination of boys will be certainly necessary., (Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Head and neck cancer is a major source of morbidity and mortality worldwide. Intervention during the early phases of carcinogenesis represents a promising new strategy for curbing the devastating effects of this disease and its primary treatment modalities, surgery and radiation with or without concomitant chemotherapy. This review focuses on the peroxisome proliferator-activated receptor gamma (PPARγ) as a target for chemoprevention of oral cancer. Accumulating data suggest that ligands of PPARγ, which include the thiazolidinedione class of agents approved for the treatment of diabetes, inhibit cancer cell growth in vitro and in animal carcinogenesis models, providing the rationale for testing this approach in populations at risk for head and neck cancer., (Published by Elsevier Ltd.)

Background: Although existing literature provides surgical recommendations for treating occult disease (cN0) in early-stage oral cavity squamous cell carcinoma (SCC), a focus on late-stage oral cavity SCC is less pervasive., Methods: The medical records of 162 patients with late-stage oral cavity SCC pN0 who underwent primary neck dissections were reviewed. Lymph node yield as a prognosticator was examined., Results: Despite being staged pN0, patients that had a higher lymph node yield had an improved regional/distant control rates, disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). Lymph node yield consistently outperformed all other standard variables as being the single best prognostic factor with a tight risk ratio range (RR = 0.95-0.98) even when correcting for the number of lymph nodes examined., Conclusion: The results of this study showed that lower regional recurrence rates and improved survival outcomes were seen as lymph node yield increased for advanced T classification oral cavity SCC pN0. This suggests that increasing lymph node yield with an extended cervical lymphadenectomy may result in lower recurrence rates and improved survival outcomes for this advanced stage group., (© 2014 Wiley Periodicals, Inc.)

Nuclear factor-kappa B (NF-κB) transcription factors regulate cellular processes such as inflammation and cell survival. The NF-κB pathway is often activated with development and progression of head and neck squamous cell carcinoma (HNSCC). As such, NF-κB represents an attractive target for chemoprevention. HNSCC involves progression of lesions from premalignant to malignant, providing a window of opportunity for intervention with chemopreventive agents. Appropriate chemopreventive agents should be inexpensive, nontoxic, and target important pathways involved in the development of HNSCC. Several such agents that inhibit the NF-κB pathway have been investigated in HNSCC. Retinoids have been studied most extensively but have shown limited potential in human trials. Epidermal growth factor receptor inhibitors and PI3K-mTOR inhibitors may benefit a subset of patients. Other agents such as green tea extract and curcumin are appealing because they are generally regarded as safe. In contrast, there is evidence that Vitamin E supplementation may actually increase mortality of cancer patients. Repurposed drugs such as cyclooxygenase (COX) inhibitors and antidiabetic drugs are an emerging area of interest. Future research to develop agents with lower toxicity and higher specificity for the NF-κB pathway, and to target these therapies to individual patient genetic signatures should help to increase the utility of chemoprevention in HSNCC., (Published by Elsevier Ltd.)

Purpose: How tumors evade or suppress immune surveillance is a key question in cancer research, and overcoming immune escape is a major goal for lengthening remission after cancer treatment. Here, we used the papillomavirus-associated rabbit auricular VX2 carcinoma, a model for studying human head and neck cancer, to reveal the mechanisms underlying the antitumorigenic effects of intraperitoneal oxidative stress following O3/O2-pneumoperitoneum (O3/O2-PP) treatment., Experimental Design: Solid auricular VX2 tumors were induced in immune-competent adult New Zealand White Rabbits. Animals were O3/O2-PP- or sham-treated, after which they underwent tumor ablation upon reaching no-go criteria. CD3(+) tumor-infiltrating lymphocytes (TIL) were evaluated by immunohistochemistry, and expression levels of 84 immune response genes were measured by quantitative real-time PCR. Adoptive transfer of peripheral blood leukocytes (PBL)-derived from animals with tumor regression-into control animals with progressing tumors was implemented to assess acquired tumor resistance functionally., Results: Auricular VX2 tumors regressing after O3/O2-PP treatment exhibited increased levels of CD3(+) TILs; they also exhibited enhanced expression of genes that encode receptors involved in pattern recognition, molecules that are required for antigen presentation and T cell activation, and inflammatory mediators. Adoptive cell transfer of PBLs from donor rabbits with regressing tumors to recipient rabbits with newly implanted VX2 carcinoma resulted in acquired tumor resistance of the host and tumor regression., Conclusion: Intraperitoneal oxidative stress effectively converts the immune response against the papillomavirus-associated rabbit VX2 carcinoma from tumor permissive to tumoricidal and leads to a sustainable, adoptively transferable oncolytic immune response., (©2014 American Association for Cancer Research.)

Background: Oral human papillomavirus (HPV) is associated with a rising incidence of certain head and neck cancers, and oral sex has been associated with oral HPV. This study sought to identify more specific patterns of oral sexual activity, including self-inoculation, that are associated with oral HPV infections in young women., Methods: A total of 1010 women attending a large university completed a computer-based questionnaire and provided oral specimens that were tested for any oral HPV using a Linear Array assay that detects any HPV as well as 37 HPV genotypes. Twenty-seven women provided additional samples up to 12 months after enrollment. Bivariable and multivariable analyses were conducted to identify oral sexual patterns and other risk factors associated with prevalent oral HPV., Results: Nineteen women had prevalent oral HPV (1.9%), with 10 women (1%) having a type-specific infection. Oral HPV was significantly associated with lifetime coital sex partnership numbers (P = 0.03), lifetime and yearly oral sex partnership numbers (P < 0.01), and hand and/or sex toy transfer from genitals to mouth (P < 0.001). Oral HPV was also associated with greater use of alcohol, cigarettes, marijuana, and sharing of smoking devices, lipstick, or toothbrushes (P < 0.05 for each), with an apparent dose-response for alcohol use and smoking behavior, stratified by number of sexual partners. Of 7 women with prevalent HPV who provided follow-up samples, none had evidence of a persistent type-specific infection., Conclusions: These data provide additional evidence of transmission of oral HPV from oral sexual activity and also suggest possible transmission from self-inoculation or sharing of oral products.

Recent data demonstrate that human papilloma virus (HPV) plays a role in pathologies other than ano-genital cancers, specifically head and neck malignancies, and non-cancerous conditions such as recurrent respiratory papillomatosis (RRP). High-risk HPV16 and 18, and low risk HPV6 and 11 play the main role in HPV-related pathologies. As more and more information about the role of HPV infection in non-cervical diseases is amassed, additional questions about whether prophylactic HPV vaccines will effectively prevent these conditions are raised. HPV vaccination programs for the cervical pathology are being implemented worldwide. In the United States, the US Food and Drug Administration (FDA) approved the quadrivalent HPV vaccine for girls in 2006 and for boys in 2011. These vaccination programs were aimed at the genital, HPV-related lesions, and there was not much recognition at that time of how HPV vaccination programs might affect oral HPV infection, which is a risk factor for the development of HPV-related head and neck cancers. Vaccination has proved to be a successful policy, and an extant recommendation is aimed at preventing HPV and associated cervical and other anogenital cancers with the routine use of HPV vaccines for males and females. However, HPV vaccines are presently not recommended for preventing oropharyngeal cancer (OPC), although they have been shown to be highly effective against the HPV strains that are most commonly found in the oropharynx. This review is aimed at presenting the evidence-based knowledge concerning HPV vaccination and highlighting the trials and strategies for vaccine administration in HPV-dependent head and neck pathologies., (Copyright © 2014 Polish Otorhinolaryngology - Head and Neck Surgery Society. Published by Elsevier Urban & Partner Sp. z.o.o. All rights reserved.)

Background: The current study evaluated the association between tea consumption and head and neck cancer (HNC) in Taiwan, where tea is a major agricultural product and a popular beverage., Methods: Interviews regarding tea consumption (frequency, duration, and types) were conducted with 396 HNC cases and 413 controls. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with tea drinking, adjusted for sex, age, education, cigarette smoking, betel quid chewing, and alcohol drinking., Results: A reduced HNC risk associated with tea drinking (OR for every cup per day = 0.96, 95% CI: 0.93-0.99; OR for ≧5 cups per day = 0.60, 95% CI: 0.39-0.94) was observed. The association was especially significant for pharyngeal cancer (OR for every cup per day = 0.93, 95% CI: 0.88-0.98; OR for ≧5 cups per day = 0.32, 95% CI: 0.16-0.66). A significant inverse association between HNC and tea consumption was observed particularly for green tea., Conclusions: This study suggests that tea drinking may reduce the risk of HNC. The anticancer property of tea, if proven, may offer a natural chemopreventive measure to reduce the occurrence of HNC.

Background: Little is known about the medium- and long-term outcomes of thyroid ablation with 1.1 GBq (30 mCi) ¹³¹I in patients with papillary thyroid carcinoma who have a tumor >4 cm or accompanied by extrathyroid invasion or clinically detected lymph node metastases (cN1). The objective of this study was to evaluate the efficacy of ablation with 30 mCi ¹³¹I in this subgroup of patients and to report the medium-term outcomes., Methods: We studied 152 patients with papillary thyroid carcinoma submitted to total thyroidectomy with apparently complete tumor resection, who had a tumor >4 cm or 2-4 cm accompanied by extrathyroid invasion or lymph node metastases, or ≤2 cm accompanied by both extrathyroid invasion and lymph node metastases. Patients with extensive extrathyroid invasion by the primary tumor were excluded. Lymph node involvement was detected by ultrasonography or palpation (cN1)., Results: Forty-two patients were prepared by administration of recombinant human thyrotropin and 110 by levothyroxine withdrawal. Posttherapy whole-body scanning revealed unequivocal ectopic uptake in three patients. When evaluated 9-12 months after ablation, 123 patients had achieved complete ablation (stimulated thyroglobulin [Tg] <1 ng/mL, negative anti-Tg antibodies, and neck ultrasonography); a new posttherapy whole-body scanning revealed persistent disease in 2 patients whose initial posttherapy whole-body scanning (obtained at the time of ablation) had already shown ectopic uptake; 12 patients presented with a Tg >1 ng/mL and 14 had positive anti-Tg antibodies without apparent metastases; 1 patient had metastases not detected at the time of ablation. Recurrence was observed in an additional 6 patients during follow-up (median 76 months). There was no case of death related to the disease. Therefore, an activity of 30 mCi failed in only 9 (6%) patients with persistent disease or recurrence after ablation. None of the variables analyzed (sex, age, tumor size, multicentricity, extrathyroid invasion, lymph node metastases, preparation [recombinant human thyrotropin or levothyroxine withdrawal]) was a predictor of ablation failure., Conclusions: An activity of 30 mCi ¹³¹I is effective in thyroid ablation in patients with stage T3 and/or N1 papillary thyroid carcinoma.

Background: Epigenetic events play a major role in the carcinogenesis of tobacco-related cancers. The authors conducted a retrospective cohort study to evaluate the effects of exposure to the anticonvulsant agent valproic acid (VPA), a histone deacetylase inhibitor, on the risk of developing cancers of the lung, head and neck, prostate, bladder, and colon., Methods: The study was based on the 2002 through 2008 National Veterans Affairs (VA) medical SAS data set linked to the VA Central Cancer Registry. The cohort was defined as subjects aged>40 years who were followed in the VA system for at least 1 year for 1 of 4 diagnoses for which a VPA indication exists (bipolar disorder, posttraumatic stress disorder, migraines, and seizures). Multivariable Cox proportional hazards models were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) reflecting the association between use of VPA and cancer incidence., Results: VPA use was associated with a significant reduction in the risk of cancers of the head and neck (HR, 0.66; 95% CI, 0.48-0.92). Additional associations were noted with the duration of treatment and median VPA drug levels. No significant differences in cancer incidence were observed for cancers of the lung (HR, 1.00; 95% CI, 0.84-1.19), bladder (HR, 0.86; 95% CI, 0.64-1.15), colon (HR, 0.95; 95% CI, 0.74-1.22), and prostate (HR, 0.96; 95% CI, 0.88-1.12)., Conclusions: Use of VPA is associated with a lower risk of developing head and neck cancers., (© 2013 American Cancer Society.)

Background: It is unclear whether differentiated thyroid cancer (DTC) patients classified as intermediate risk based on the presence of microscopic extrathyroidal extension (ETE) should be treated with low or high doses of radioiodine (RAI) after surgery. We evaluated success rates and long-term clinical outcomes of patients with DTC of small tumor size, microscopic ETE, and no cervical lymph node (LN) metastasis treated either with a low (1.1 GBq) or high RAI dose (5.5 GBq)., Methods: This is a retrospective analysis of a historical cohort from 2000 to 2010 in a tertiary referral hospital. A total of 176 patients with small (≤2 cm) DTC, microscopic ETE, and no cervical LN metastasis were included. Ninety-six patients were treated with 1.1 GBq (LO group) and 80 patients with 5.5 GBq (HI group). Successful RAI therapy was defined as (i) negative stimulated thyroglobulin (Tg) in the absence of Tg antibodies, and (ii) absence of remnant thyroid tissue and of abnormal cervical LNs on ultrasonography. Clinical recurrence was defined as the reappearance of disease after ablation, which was confirmed by cytologically or pathologically proven malignant tissue or of distant metastatic lesions., Results: There was no significant difference in the rate of successful RAI therapy between the LO and HI groups (p=0.75). In a subgroup analysis based on tumor size, success rates were not different between the LO group (34/35, 97%) and the HI group (50/56, 89%) in patients with a tumor size of 1-2 cm (p=0.24). In patients with smaller tumor size (≤1 cm), there was no significant difference in success rates between the LO (59/61, 97%) and HI groups (22/24, 92%; p=0.30). No patient had clinical recurrences in either group during the median 7.2 years of follow-up., Conclusions: Low-dose RAI therapy is sufficient to treat DTC patients classified as intermediate risk just by the presence of microscopic ETE.

The prospects for chemoprevention to reduce the incidence of squamous cell carcinoma of the head and neck (SCCHN) are great. The tissue at risk for harboring disease is relatively accessible for examination and biopsy. Patients appropriate for study can be easily identified by their risk factors and the presence of premalignant lesions. Our understanding of the pathogenesis of SCCHN is ever increasing, and offers new opportunities to explore strategies for prevention therapies. In this issue of Cancer Prevention Research, Saba and colleagues report on a phase Ib trial of celecoxib plus erlotinib to prevent progression to higher-grade dysplasia or invasive carcinoma in patients with oral premalignant lesions. The overall response rate was 57%, though by the time of last analysis, 85% of patients relapsed. In this commentary, challenges to the success of chemoprevention clinical trials for SCCHN, such as pitfalls in using surrogate biomarkers and reversal of histologic premalignant changes as study endpoints, are discussed. In addition, strategies to help ensure further development in the field of head and neck cancer prevention are reviewed. These include focusing efforts on tobacco cessation and human papillomavirus vaccination, targeting key molecular drivers of head and neck carcinogenesis, and focusing on combination strategies that have the potential to eradicate premalignant clones, even if some toxicity is encountered.

Background: Head and neck cancer (HNC) is the seventh most common cancer worldwide. Although diet has been proposed to play an important role in HNC, few associations with diet have been convincing other than alcohol intake. Studies of dietary patterns that examine overall diets may provide broader insight than studies of individual foods. Little is known about the association between dietary patterns and risk of HNC., Objective: We prospectively evaluated the association between 2 index-based dietary patterns [ie, the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet Score (aMED)] and risk of head and neck squamous cell carcinoma., Design: We included 494,967 participants from the NIH-AARP Diet and Health study (1995-2006). HRs (95% CIs) were estimated by using Cox regression. Scores for the HEI-2005 and aMED were calculated on the basis of diet assessed by using a baseline food-frequency questionnaire. Higher scores reflected adherence to dietary recommendations for healthy eating. Our main outcome was the incidence of HNC, including cancer of the larynx, oral cavity, and orohypopharynx., Results: A total of 1868 HNC cases were identified during follow-up. Higher HEI-2005 scores were associated with reduced risk of HNC in men [HR: 0.74 (95% CI: 0.61, 0.89) for highest compared with lowest quintiles; P-trend = 0.0008] and women [HR: 0.48; 95% CI: 0.33, 0.70; P-trend < 0.0001]. High aMED scores were also associated with lower HNC risk in men (HR: 0.80; 95% CI: 0.64, 1.01; P-trend = 0.002) and women (HR: 0.42; 95% CI: 0.24, 0.74; P-trend < 0.0001). Associations were similar among subsites. We did not find significant interactions between smoking and alcohol intake and each index on HNC risk., Conclusions: HEI-2005 and aMED scores were associated inversely with risk of HNC. Large interventional studies are required to assess the causality before conveying definite public health messages.

Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.

The EUROGIN 2012 roadmap is focused on the comparative epidemiology of human papillomavirus (HPV) associated head and neck squamous cell cancers (HNSCC) and cervical cancers. Discussed are the similarities and differences between the two cancers with regard to global disease burden, HPV prevalence and type distribution, disease cofactors, molecular pathogenesis, treatment approaches, prognostic factors and primary and secondary prevention. The global incidence of HNSCC and cervical cancer is similar; however, a minority of HNSCC in comparison to virtually all cervical cancers is caused by HPV. HPV infection prevalence is considerably lower in the oral than genital regions for reasons that are as yet unclear. Infection at both sites is strongly associated with sexual behavior, but this association does not appear to explain the male predominance of oral HPV infection. Studies of the molecular pathogenesis of HPV-associated HNSCC (predominantly oropharyngeal cancers) are hampered by the lack of a readily detectable intermediate clinical endpoint analogous to cervix intraepithelial neoplasia. Nevertheless, similarities in chromosomal aberrations, gene expression, methylation and microRNA profiles between HPV-positive HNSCC and cervical cancer argue for shared carcinogenic pathways. Treatment approaches to oropharyngeal and cervical cancers are remarkably similar, with the development of HPV-targeted therapies as the ultimate treatment goal. Key research challenges include understanding oral HPV transmission and male predominance, clarifying the role of cofactors, and developing new screening and treatment methods for HPV-associated HNSCC., (© 2013 UICC.)

Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest because of the broad safety window of these compounds. However, many of these compounds are hydrophobic and poorly soluble in water. They frequently display low bioavailability, poor systemic delivery, and low efficacy. To circumvent this problem, we explored a novel approach toward chemoprevention using nanotechnology to deliver luteolin, a natural compound present in green vegetables. We formulated water-soluble polymer-encapsulated Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, like luteolin, Nano-Luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50 value of Nano-Luteolin was 4.13 μmol/L, and that of luteolin was 6.96 μmol/L. In H292 cells, the IC50 of luteolin was 15.56 μmol/L, and Nano-Luteolin was 14.96 μmol/L. In vivo studies using a tumor xenograft mouse model demonstrated that Nano-Luteolin has a significant inhibitory effect on the tumor growth of SCCHN in comparison to luteolin. Our results suggest that nanoparticle delivery of naturally occurring dietary agents like luteolin has many advantages and may have potential application in chemoprevention in clinical settings., (©2013 AACR.)

Background: There is a considerable number of studies on the efficacy HPV (human papillomavirus) vaccination against different cancers but relevant information is scattered in diverse journals. This paper is a review summarizing current knowledge of the potential of HPV vaccination against all HPV related cancers., Aim: HPV infection is probably the most frequent sexually transmitted disease. At least 13 HPV genotypes are classified as carcinogenic or probably carcinogenic in respect to cervical cancer. Almost 100% of cervical cancers are linked to HPV infection. HPV 16 and HPV 18 are the most frequently involved genotypes and account together for approximately 70% of cervical cancer in the world. Persistent high risk HPV infection is responsible for a significant proportion of vulvar, vaginal, anal and penile carcinomas. The virus has also been implicated in oncogenesis of head and neck cancers, including oropharyngeal cancers. HPV infection can play an important role in cancerogenesis of lung, esophagus, breast, and colon and rectum. On the contrary, published results indicate that HPV infection is not associated with prostate oncogenesis. Strong predominance of HPV 16 has been reported for all HPV associated cancer sites. Generally, it is estimated that approximately 5.2% of all cancers are associated with oncogenic HPV infection. Currently, there are two vaccines on the market; quadrivalent Silgard® (Gardasil®) and bivalent CervarixTM. Large trials for both vaccines have shown efficacy against HPV related infection and disease. Efficacy has been very high in HPV naive subjects to vaccine related types. While HPV vaccination is currently approved for the prevention of cervical cancer, it also has the potential in the prevention of all HPV associated malignancies. The Czech republic belongs to countries that cover HPV vaccination of girls at the age of 13- 14 years by general health insurance. Overall impact of this vaccination remains to be evaluated. The new issues of the role of HPV in oncogenesis, as well as the potential effect of HPV vaccination against HPV related nongenital cancers are discussed., Conclusion: Approximately 5.2% of all human cancers are associated with oncogenic human papillomavirus infection. HPV vaccination against the most risky HPV oncotypes may cause a significant reduction of these cancers mainly in the HPV naive population.

Human papillomavirus (HPV) infections are estimated to be the most common sexually transmitted infections worldwide. Meanwhile, it is well established that infection by high-risk HPVs is considered the major cause of cervical cancer since more than 96% of these cancers are positive for high-risk HPVs, especially types 16 and 18. Moreover, during the last 2 decades, numerous studies pointed-out the possible involvement of high-risk HPV in several human carcinomas including head and neck, colorectal and breast cancers. The association between high-risk HPVs and cervical cancer and potentially other human malignancies would necessitate the introduction of vaccines which were generated against the 2 most frequent high-risk HPVs (types 16 and 18) worldwide, including the Middle East (ME) as well as North African countries. The presence of high-risk HPVs in the pathogenesis of human cancers in the ME, which is essential in order to evaluate the importance of vaccination against HPVs, has not been fully investigated yet. In this review, we present an overview of the existing epidemiological evidence regarding the presence of HPV in human cancers in the ME and the potential impact of vaccination against HPV infections and its outcome on human health in this region.

Eighteen percent of incident malignancies in the United States are a second (or subsequent) cancer. Second primary neoplasms (SPNs), particularly solid tumors, are a major cause of mortality and serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer survivor subsequently being diagnosed with an SPN, including radiotherapy for the first cancer, unhealthy lifestyle behaviors, genetic factors, aging, or an interaction between any of these factors. In this article, we discuss these factors and synthesize this information for use in clinical practice, including preventive strategies and screening recommendations for SPNs., (© 2013 Elsevier Inc. All rights reserved.)

Background and Objectives: Sparing internal jugular vein (IJV) in neck dissection for head and neck cancer is controversial. We aimed at evaluating the prognostic impact of IJV preservation., Methods: We examined 206 files of head and neck cancer patients who underwent radical or modified radical neck dissection at the Otolaryngology University of Florence. The site of primary tumor was larynx and hypopharynx in 44.66%, oropharynx in 25.24%, oral cavity in 23.3%, unknown in 4.85%, salivary glands and rhinopharynx in 0.97%. In 60.19% the IJV was resected, in 39.81% preserved. Prognostic impact of IJV preservation was assessed by Kaplan-Meier and multivariate analysis., Results: Neck recurrence occurred in 25.2%: the IJV was resected in 42.31%, in 57.69% preserved (P = 0.02). At multivariate analysis, neck recurrence resulted significantly associated to extracapsular spread (ECS) (P = 0.009), IJV preservation (P = 0.01), positive margins (P = 0.02). In ECS positive patients, a higher risk of neck recurrence was documented for IJV preservation (P = 0.012). A worse prognosis was observed for patients with IJV spared (P = 0.06)., Conclusions: IJV preservation is associated with an increased risk of neck failure and a worse outcome, mainly in patients with ECS of nodes., (© 2013 Wiley Periodicals, Inc.)

Overexpression of epidermal growth factor receptor (EGFR), Her2, and uroporphyrinogen decarboxylase (UROD) occurs in a variety of malignant tumor tissues. UROD has potential to modulate tumor response of radiotherapy for head and neck cancer, and EGFR and Her2 are common drug targets for the treatment of head and neck cancer. This study attempts to find a possible lead compound backbone from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) for EGFR, Her2, and UROD proteins against head and neck cancer using computational techniques. Possible traditional Chinese medicine (TCM) lead compounds had potential binding affinities with EGFR, Her2, and UROD proteins. The candidates formed stable interactions with residues Arg803, Thr854 in EGFR, residues Thr862, Asp863 in Her2 protein, and residues Arg37, Arg41 in UROD protein, which are key residues in the binding or catalytic domain of EGFR, Her2, and UROD proteins. Thus, the TCM candidates indicated a possible molecule backbone for evolving potential inhibitors for three drug target proteins against head and neck cancer.

The chemokine receptor CXCR7, belonging to the membrane-bound G protein-coupled receptor superfamily, is expressed in several tumor types. Inhibition of CXCR7 with either small molecules or small interference (si)RNA has shown promising therapeutic benefits in several tumor models. With the increased interest and effectiveness of biologicals inhibiting membrane-bound receptors we made use of the "Nanobody platform" to target CXCR7. Previously we showed that Nanobodies, i.e. immunoglobulin single variable domains derived from naturally occurring heavy chain-only camelids antibodies, represent new biological tools to efficiently tackle difficult drug targets such as G protein-coupled receptors. In this study we developed and characterized highly selective and potent Nanobodies against CXCR7. Interestingly, the CXCR7-targeting Nanobodies displayed antagonistic properties in contrast with previously reported CXCR7-targeting agents. Several high affinity CXCR7-specific Nanobodies potently inhibited CXCL12-induced β-arrestin2 recruitment in vitro. A wide variety of tumor biopsies was profiled, showing for the first time high expression of CXCR7 in head and neck cancer. Using a patient-derived CXCR7-expressing head and neck cancer xenograft model in nude mice, tumor growth was inhibited by CXCR7-targeting Nanobody therapy. Mechanistically, CXCR7-targeting Nanobodies did not inhibit cell cycle progression but instead reduced secretion of the angiogenic chemokine CXCL1 from head and neck cancer cells in vitro, thus acting here as inverse agonists, and subsequent angiogenesis in vivo. Hence, with this novel class of CXCR7 inhibitors, we further substantiate the therapeutic relevance of targeting CXCR7 in head and neck cancer.

Importance: Understanding head and neck surgeons' current knowledge, practices, and opinions regarding human papillomavirus (HPV) education and prevention will enable efforts to assist surgeons in this important endeavor., Objective: To assess knowledge, attitudes, and beliefs of head and neck surgeons regarding HPV education and vaccination., Design, Setting, and Participants: Online survey of members of the American Head and Neck Society (AHNS) in late 2011 and early 2012., Main Outcomes and Measures: Knowledge, attitudes, and current practices regarding HPV education and vaccination., Results: All 1081 members of the AHNS were approached via e-mail, and 297 members completed the survey, for an overall response rate of 27.5%. Most respondents were male (86.2%) fellowship-trained head and neck surgeons (80.4%), and most practice in an academic setting (77.1%) in the United States (78.1%). More than 90% of respondents discuss risk factors for head and neck cancer and HPV as a specific risk factor with their patients. However, only 49.1% discuss the importance of vaccinating preadolescents for HPV, most commonly citing that they do not do so because their patients are adults (38.7%). Of those respondents with daughters, 68.9% reported that their daughters had received or they intend their daughters to receive the HPV vaccine. Of those respondents with sons, only 55.8% reported that their sons had been vaccinated or they intend for them to be. Respondents reported divergent attitudes toward HPV vaccination safety and efficacy. However, respondents were overwhelmingly supportive of possible future ANHS activities to educate clinicians, increase public awareness, educate patients, and advocate for health policy related to HPV., Conclusions and Relevance: Head and neck surgeons are knowledgeable about HPV and show generally positive attitudes and beliefs about HPV education and vaccination. They endorse AHNS actions to improve public and patient education, as well as health policy on HPV. These findings support AHNS developing a strategic plan and actions to improve knowledge and reduce HPV infection among the American public.

Constitutive activation of proinflammatory transcription factors such as STAT3 and NF-κB plays a pivotal role in the proliferation and survival of squamous cell carcinoma of the head and neck (HNSCC). Thus, the agents that can modulate deregulated STAT3 and NF-κB activation have a great potential both for the prevention and treatment of HNSCC. In the present report, we investigated the potential effects of garcinol, an active component of Garcinia indica on various inflammatory mediators involved in HNSCC progression using cell lines and xenograft mouse model. We found that garcinol inhibited constitutively activated STAT3 in HNSCC cells in a time- and dose-dependent manner, which correlated with the suppression of the upstream kinases (c-Src, JAK1, and JAK2) in HNSCC cells. Also, we noticed that the generation of reactive oxygen species is involved in STAT3 inhibitory effect of garcinol. Furthermore, garcinol exhibited an inhibitory effect on the constitutive NF-κB activation, mediated through the suppression of TGF-β-activated kinase 1 (TAK1) and inhibitor of IκB kinase (IKK) activation in HNSCC cells. Garcinol also downregulated the expression of various gene products involved in proliferation, survival, and angiogenesis that led to the reduction of cell viability and induction of apoptosis in HNSCC cells. When administered intraperitoneally, garcinol inhibited the growth of human HNSCC xenograft tumors in male athymic nu/nu mice. Overall, our results suggest for the first time that garcinol mediates its antitumor effects in HNSCC cells and mouse model through the suppression of multiple proinflammatory cascades.

Background: Use of tobacco products, excessive alcohol consumption, and high-risk sexual behaviors increase the risk of developing head and neck cancer and impacts treatment effectiveness after diagnosis. This study examined smoking and engagement in other modifiable behavioral risk factors and human papillomavirus (HPV) status in patients with head and neck cancer in order to facilitate identification and foster development of targeted interventions in high-risk patients., Methods: Participants were 102 patients with head and neck cancer at a large urban cancer center who completed a self-report background and health questionnaire and provided a saliva sample for determination of the long-acting nicotine metabolite cotinine., Results: Compared with former and never-smokers, current smokers were less educated, less likely to be married or living with a partner, and consumed more alcohol. Cotinine analysis indicated that 4 of 16 (25%) patients who denied past-month cigarette use misrepresented their true smoking status. Of patients with oropharyngeal cancer, 74% were confirmed as HPV-positive, and compared with HPV-negative patients, they were younger, more likely to be married/partnered and of Caucasian race, and reported more past vaginal and oral sexual partners. Only one-third of HPV-positive patients were aware of their HPV disease status., Conclusions: Cigarette smoking is associated with engagement in other modifiable risk factors in patients with head and neck cancer. Self-report measures of smoking may not accurately depict true smoking status. HPV-positive cancer patients were more likely to endorse a history of multiple sexual partners. Regular screening and targeted interventions for these distinct risk factors are warranted., (Copyright © 2013 American Cancer Society.)

In order to improve the prognosis for patients with head and neck squamous cell cancer (HNSCC) the introduction of new therapeutic strategies is necessary. The concept of immunotherapy has been applied and improved for several years and recent studies have used tumor-specific antigens which facilitates targeted oncologic therapy. However, immunotherapy is hampered by the fact that immunosuppressive mechanisms are pronounced and relevant effector cells are suppressed, especially in patients with HNSCC. Successful immunotherapy could induce an antitumor immune response by restitution of these cell populations. Current anti-tumor immunotherapy includes unspecific immune stimulation, genetic modification of tumor and immune cells, the use of monoclonal antibodies, e.g. cetuximab, adoptive cell transfer and tumor vaccination. In the future, these biologic therapies alone or in combination with conventional therapeutic regimens could present a valuable therapeutic option for HNSCC patients.

Human papillomavirus (HPV) is the most common viral cause of cancer, and is responsible for 5% of cancers worldwide. Following demonstration of the causative link between HPV and cervical cancer, HPV has been shown to be associated with several anogenital malignancies and with oral pharyngeal cancers. HPV-related anal and oral pharyngeal disease is rising in incidence and includes anal warts and neoplasia, recurrent respiratory papillomatosis, and oral pharyngeal neoplasia. This article presents an overview of the epidemiology, clinical manifestations, diagnosis, and treatment of nongenital HPV-related disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Despite continuous improvement of treatment regimes, the mortality rates for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) remain disappointingly high and novel anticancer agents are urgently awaited., Experimental Design: We combined the data from genome-wide siRNA screens on tumor cell lethality in a lung and a head and neck cancer cell line., Results: We identified 71 target genes that seem essential for the survival of both cancer types. We identified a cluster of 20 genes that play an important role during G2-M phase transition, underlining the importance of this cell-cycle checkpoint for tumor cell survival. Five genes from this cluster (CKAP5, KPNB1, RAN, TPX2, and KIF11) were evaluated in more detail and have been shown to be essential for tumor cell survival in both tumor types, but most particularly in HNSCC. Phenotypes that were observed following siRNA-mediated knockdown of KIF11 (kinesin family member 11) were reproduced by inhibition of KIF11 using the small-molecule inhibitor ispinesib (SB-715992). We showed that ispinesib induces a G2 arrest, causes aberrant chromosome segregation, and induces cell death in HNSCC in vitro, whereas primary keratinocytes are less sensitive. Furthermore, growth of HNSCC cells engrafted in immunodeficient mice was significantly inhibited after ispinesib treatment., Conclusion: This study identified a wide array of druggable genes for both lung and head and neck cancer. In particular, multiple genes involved in the G2-M checkpoint were shown to be essential for tumor cell survival, indicating their potential as anticancer targets.

Background: Fear of recurrence (FoR) following head and neck cancer (HNC) treatment is a major patient concern but is infrequently discussed in outpatient settings and may cause significant detrimental effect on patient psychological well-being., Aim: The aim of this paper is to determine longitudinal trends and predictors of significant FoR., Method: Prospective data collection was obtained in 189 post-treatment HNC patients with 456 clinic attendances from October 2008 to January 2011. All patients completed Patient Concerns Inventory (PCI), University of Washington Quality of Life Questionnaire version 4 and the FoR questionnaires using a combination of paper and touch-screen technology., Results: The prevalence of significant FoR was 35%, which was stable longitudinally. Logistic regression-delineated predictors of significant FoR were young age (<65 years), anxiety/mood and patient-reported FoR. Conventional prognostic factors including standard clinicopathological factors, treatment modality and length of follow-up did not predict significant FoR. Over time, 20% of patients reported significant FoR intermittently, whereas 30% experienced it consistently. The remaining 50% did not experience significant FoR., Discussion: Patient-related characteristics were more important than clinicopathological prognostic factors in predicting significant FoR, potentially creating a mismatch between the doctors' perception of patient's experience of FoR with what patients may experience. In the long term, FoR is expressed across a spectrum extending from 'normal' FoR to persistent significant FoR with an intermediate category of intermittent significant FoR. Those patients experiencing intermittent and consistent levels of significant FoR may benefit from psychological support. This study confirmed that self-reported screening FoR using the PCI is a valuable tool in identifying significant FoR., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: The causal link between cervical cancer and human papilloma virus (HPV) is well known. It is now becoming clear that some types of squamous-cell carcinoma of the head and neck, particularly oropharyngeal carcinoma (OPC), are also linked to HPV infection. The development of vaccines against certain HPV genotypes has changed the management strategy for HPV-associated diseases of the uterine cervix. An analogous approach is now being considered for the prevention of HPV-associated diseases of the head and neck., Method: We review pertinent articles retrieved by a selective search of the literature for phase II and III trials providing evidence about a possible effect of HPV status on the survival rates of patients with OPC. Seven trials fulfilled our search criteria: four phase III trials with retrospective HPV analysis and three phase II trials with retrospective and prospective HPV analysis., Results: Patients with HPV-positive OPC survive significantly longer than those with HPV-negative OPC. Tobacco smoking has been identified as a negative prognostic factor in patients with either HPV-negative or HPV-positive disease., Conclusion: The established treatment strategy for OPC in patients with and without the traditional risk factors (tobacco and alcohol consumption) is now being reconsidered in the light of what we have learned about the role of HPV infection. Ongoing and projected clinical trials with risk-factor stratification may soon lead to changes in treatment. Further study is needed to answer the question whether HPV infection in the head and neck region is carcinogenic.

While there are 35,000 diagnosed oral cancers per year and 7,500 deaths, there are 30 times this amount when it comes to cases of skin cancer, the majority of which are found on the head and neck. Because many patients see their dentist more frequently than their medical doctor, dentistry is in an advantageous position to reduce the mortality/morbidity of this most common malignancy. This article discusses various types of head and neck skin cancer and how dental practitioners can perform clinical examinations to provide early detection for patients.