Photodynamic Therapy with 5-Aminolevulinic acid (ALA) Impairs Tumor Initiating and Chemo-Resistance Property in Head and Neck Cancer-Derived Cancer Stem Cells

Background

Head and neck cancer (HNC) ranks the fourth leading malignancy and cancer death in male population in Taiwan. Despite recent therapeutic advances, the prognosis for HNC patients is still dismal. New strategies are urgently needed to improve the chemosensitization to conventional chemotherapeutic drugs and clinical responses of HNC patients. Studies have demonstrated that topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is being used in the treatment of various human premalignant and malignant lesions with some encouraging clinical outcomes. However, the molecular mechanisms of ALA-PDT in the therapeutic effect in HNC tumorigenesis and whether ALA-PDT as chemosensitizer for HNC treatment remain unclear. Accumulating data support cancer stem cells (CSCs) contributes chemo-resistance in HNC. Based on the previous studies, the purpose of the study is to investigate the effect of ALA-PDT on CSCs and chemosensitization property in HNC.

Methodology/Principal Finding

CSCs marker ALDH1 activity of HNC cells with ALA-PDT treatment as assessed by the Aldefluor assay flow cytometry analysis. Secondary Sphere-forming self-renewal, stemness markers expression, and invasiveness of HNC-CSCs with ALA-PDT treatment were presented. We observed that the treatment of ALA-PDT significantly down-regulated the ALDH1 activity and CD44 positivity of HNC-CSCs. Moreover, ALA-PDT reduced self-renewal property and stemness signatures expression (Oct4 and Nanog) in sphere-forming HNC-CSCs. ALA-PDT sensitized highly tumorigenic HNC-CSCs to conventional chemotherapies. Lastly, synergistic effect of ALA-PDT and Cisplatin treatment attenuated invasiveness/colongenicity property in HNC-CSCs.

Conclusion/Significance

Our results provide insights into the clinical prospect of ALA-PDT as a potential chemo-adjuvant therapy against head and neck cancer through eliminating CSCs property.     

Infectious Complications in Head and Neck Cancer Patients Treated with Cetuximab: Propensity Score and Instrumental Variable Analysis

Background

To compare the infection rates between cetuximab-treated patients with head and neck cancers (HNC) and untreated patients.

Methodology

A national cohort of 1083 HNC patients identified in 2010 from the Taiwan National Health Insurance Research Database was established. After patients were followed for one year, propensity score analysis and instrumental variable analysis were performed to assess the association between cetuximab therapy and the infection rates.

Results

HNC patients receiving cetuximab (n = 158) were older, had lower SES, and resided more frequently in rural areas as compared to those without cetuximab therapy. 125 patients, 32 (20.3%) in the group using cetuximab and 93 (10.1%) in the group not using it presented infections. The propensity score analysis revealed a 2.3-fold (adjusted odds ratio [OR] = 2.27; 95% CI, 1.46–3.54; P = 0.001) increased risk for infection in HNC patients treated with cetuximab. However, using IVA, the average treatment effect of cetuximab was not statistically associated with increased risk of infection (OR, 0.87; 95% CI, 0.61–1.14).

Conclusions

Cetuximab therapy was not statistically associated with infection rate in HNC patients. However, older HNC patients using cetuximab may incur up to 33% infection rate during one year. Particular attention should be given to older HNC patients treated with cetuximab.     

Periodontal Disease and Risk of Head and Neck Cancer: A Meta-Analysis of Observational Studies

Background

Many epidemiological studies have found a positive association of periodontal disease (PD) with risk of head and neck cancer (HNC), but the findings are varied or even contradictory. In this work, we performed a meta-analysis to ascertain the relationship between PD and HNC risk.

Methods

We searched the PubMed, Embase, and Cochrane Library databases for relevant observational studies on the association between PD and HNC risk published up to March 23, 2013. Data from the included studies were extracted and analyzed independently by two authors. Meta-analysis was performed using RevMan 5.2 software.

Results

We obtained seven observational studies involving two cohort and six case-control studies. Random-effects meta-analysis indicated a significant association between PD and HNC risk (odds ratio = 2.63, 95% confidence interval = 1.1.68 - 4.14; p < 0.001), with sensitivity analysis showing that the result was robust. Subgroup analyses based on adjustment for covariates, study design, PD assessment, tumor site, and ethnicity also revealed a significant association.

Conclusions

Based on currently evidence, PD is probably a significant and independent risk factor of HNC.     

DNA Repair Biomarkers XPF and Phospho-MAPKAP Kinase 2 Correlate with Clinical Outcome in Advanced Head and Neck Cancer

Background

Induction chemotherapy is a common therapeutic option for patients with locoregionally-advanced head and neck cancer (HNC), but it remains unclear which patients will benefit. In this study, we searched for biomarkers predicting the response of patients with locoregionally-advanced HNC to induction chemotherapy by evaluating the expression pattern of DNA repair proteins.

Methods

Expression of a panel of DNA-repair proteins in formalin-fixed paraffin embedded specimens from a cohort of 37 HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation were analyzed using quantitative immunohistochemistry.

Results

We found that XPF (an ERCC1 binding partner) and phospho-MAPKAP Kinase 2 (pMK2) are novel biomarkers for HNSCC patients undergoing platinum-based induction chemotherapy. Low XPF expression in HNSCC patients is associated with better response to induction chemoradiotherapy, while high XPF expression correlates with a worse response (p = 0.02). Furthermore, low pMK2 expression was found to correlate significantly with overall survival after induction plus chemoradiation therapy (p = 0.01), suggesting that pMK2 may relate to chemoradiation therapy.

Conclusions

We identified XPF and pMK2 as novel DNA-repair biomarkers for locoregionally-advanced HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation. Our study provides insights for the use of DNA repair biomarkers in personalized diagnostics strategies. Further validation in a larger cohort is indicated.     

Investigation of urinary volatomic alterations in head and neck cancer: a non-invasive approach towards diagnosis and prognosis

Introduction

Head and neck cancer (HNC), like many other forms of cancer, is usually detected in advanced stages, causing poor survival outcomes. Lack of specific and sensitive screening markers for early detection of HNC has worsened the scenario for the patients as well as the clinicians. Therefore, identification of efficient, noninvasive and affordable screening marker/methodology with high specificity and sensitivity is imminent need of situation.

Objectives

This study aims to identify and characterize urinary volatomic alterations specific to HNC.

Methods

Volatomic analysis of urine samples collected from HNC patients (n?=?29) and healthy controls (n?=?31) was performed using headspace solid phase microextraction coupled to gas chromatography mass spectrometry (GC–MS). Both univariate and multivariate statistical approaches were used to investigate HNC specific volatomic alterations.

Results

Statistical analysis revealed a total of 28 metabolites with highest contribution towards discrimination of HNC patients from healthy controls (VIP >1, p?<?0.05, Log₂ FC ≥0.58/≤?0.57). The discrimination efficiency and accuracy of urinary VOCs was ascertained by ROC curve analysis that allowed the identification of four metabolites viz. 2,6-dimethyl-7-octen-2-ol, 1-butanol, p-xylene and 4-methyl-2-heptanone with highest sensitivity and specificity to discriminate HNC patients from healthy controls. Further, the metabolic pathway analysis identified several dysregulated pathways in HNC patients and their detailed investigations could unravel novel mechanistic insights into the disease pathophysiology.

Conclusion

Overall, this study provides valuable fingerprint of the volatile profile of HNC patients, which in turn, might help in improving the current understanding of this form of cancer and lead to the development of non-invasive approaches for HNC diagnosis.

     

Tea Consumption and Risk of Head and Neck Cancer

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.     

Examining the incidence of human papillomavirus-associated head and neck cancers by race and ethnicity in the U.S., 1995-2005

Background

Head and neck cancer (HNC) incidence, mortality and survival rates vary by sex and race, with men and African Americans disproportionately affected. Risk factors for HNC include tobacco and alcohol exposure, with a recent implication of human papillomavirus (HPV) in the pathogenesis of HNC. This study describes the epidemiology of HNC in the United States, examining variation of rates by age, sex, race/ethnicity and potential HPV-association.

Methods

We used the North American Association of Central Cancer Registries (NAACCR) Cancer in North America (CINA) Deluxe Analytic Data to analyze HNC incidence for 1995–2005 from forty population-based cancer registries. We calculated age-adjusted incidence rates and incidence trends using annual percent change by age, sex, race/ethnicity and HPV-association.

Results

Males and Non-Hispanic Blacks experienced greater HNC incidence compared to women and other race/ethnicity groupings. A significant overall increase in HNC incidence was observed among HPV-associated sites during 1995–2005, while non HPV-associated sites experienced a significant decline in HNC incidence. Overall, younger age groups, Non-Hispanic Whites and Hispanics experienced greater increases in incidence for HPV-associated sites, while HNC incidence declined for Non-Hispanic Blacks independent of HPV-association. In particular, for HPV-associated sites, HNC incidence for Non-Hispanic White males aged 45–54 increased at the greatest rate, with an APC of 6.28% (p<0.05). Among non HPV-associated sites, Non-Hispanic Black males aged 0–44 years experienced the greatest reduction in incidence (APC, −8.17%, p<0.05), while a greater decline among the older, 55–64 year age group (APC, −5.44%, p<0.05) occurred in females.

Conclusions

This study provides evidence that HPV-associated tumors are disproportionately affecting certain age, sex and race/ethnicity groups, representing a different disease process for HPV-associated tumors compared to non HPV-associated tumors. Our study suggests that HPV tumor status should be incorporated into treatment decisions for HNC patients to improve prognosis and survival.     

Meta-Analysis of MMP2, MMP3, and MMP9 Promoter Polymorphisms and Head and Neck Cancer Risk

Background

The 1306 C>T, 1171 5A>6A, and 1562C>T polymorphisms of matrix metalloproteinase (MMP) 2, MMP3, and MMP9 genes, respectively, have been found to be functional and may contribute to head and neck carcinogenesis. However, the results of case-control studies examining associations between MMP polymorphisms and head and neck cancer (HNC) risk remain inconclusive. Therefore, we performed a meta-analysis to further evaluate the role of these polymorphisms in HNC development.

Methods

We searched PubMed, ISI Web of Knowledge, MEDLINE, Embase, and Google Scholar to identify all published case-control studies of MMP2-1306 C>T, MMP3-1171 5A>6A, and MMP9-1562 C>T polymorphisms and HNC risk in the meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between these polymorphisms and HNC risk.

Results

Thirteen studies were included in this meta-analysis. For MMP2-1306 C>T polymorphism, significant associations were observed under three genetic models both in overall comparison and in a hospital-based subgroup, and in oral cavity cancer and nasopharyngeal cancer under dominant model as well. For MMP3-1171 5A>6A and MMP9-1562 C>T polymorphisms, no association was found in overall comparison; however, in subgroup analyses based on ethnicity and tumor site, significant associations were detected between the MMP3-1171 5A>6A polymorphism and HNC risk in a European population and pharyngeal/laryngeal cancer under two genetic contrasts.

Conclusion

This meta-analysis suggests that the MMP2-1306 C>T polymorphism is associated with HNC risk, as is the MMP3-1171 5A>6A polymorphism specifically in some subgroups. Further studies with larger sample sizes are warranted.     

Association of GSTP1 Ile105Val Polymorphism and Risk of Head and Neck Cancers: A Meta-Analysis of 28 Case-Control Studies

Background and Aims

The Glutathione S-transferase P1 (GSTP1) polymorphism have been considered a risk modifier for developing head and neck cancer (HNC) in many studies; however, the results of such studies are inconsistent. The aim of this study was to evaluate the possible association between the GSTP1 Ile105Val polymorphism and risk of HNC.

Method

We performed a search in the relevant electronic database and a meta-analysis based on 28 published case–control studies that included 6,404 cases and 6,523 controls. To take into account the possibility of heterogeneity across the studies, a Chi-square based I²-statistic test was performed. Crude pooled odds ratios (ORs) with 95% confidence intervals (CIs) were assessed using both fixed-effects and random-effects models.

Results

The results of this meta-analysis showed that the GSTP1 Ile105Val polymorphism was not significantly associated with risk of HNC in the overall study population (pooled OR 1.00, 95% CI 0.92–1.09) or in subgroup analyses stratified by ethnicity, sample size, tumor site or publication year. Moreover, substantial evidence of heterogeneity among the studies was observed. Publication year was identified as the main cause of heterogeneity.

Conclusion

This meta-analysis does not support a significant association between the GSTP1 Ile105Val polymorphism and risk of HNC.     

Association of X-Ray Repair Cross-Complementing Group 1 Arg194Trp,Arg399Gln and Arg280His Polymorphisms with Head and Neck Cancer Susceptibility: A Meta-Analysis

Background

Previous studies on the association of X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg399Gln, and Arg280His polymorphisms with head and neck cancer (HNC) have produced inconsistent results. The aim of the present study was to evaluate the effects of these three polymorphic variants on HNC risk.

Methods

The PubMed and EMBASE databases were searched for genetic association studies on the XRCC1 Arg194Trp, Arg399Gln, and Arg280His polymorphisms and HNC risk. (The most recent search was conducted on 20 August, 2013.) Twenty-six studies were identified and meta-analysis was performed to evaluate the association between the polymorphism and HNC by calculating combined odds ratios and 95% confidence intervals.

Results

No significant association was found under the allelic, homozygous, heterozygote, and dominant genetic models in the overall comparison. Further, no significant association between the XRCC1 Arg399Gln and Arg280His polymorphisms and HNC risk was detected under the four genetic models in subgroup analyses based on ethnicity, cancer site, and whether or not the studies had been adjusted for cigarette smoking and alcohol. However, in stratified analyses based on cancer site, a significant association was found between the XRCC1 Arg194Trp polymorphism and oral cancer under the allelic, heterozygote, and dominant models. The XRCC1 Arg194Trp polymorphism was significantly associated with HNC risk in studies that were adjusted for smoking and alcohol under the homozygous and heterozygote models.

Conclusion

The meta-analysis results suggest that the XRCC1 Arg399Gln and Arg280His polymorphisms are probably not associated with the risk of HNC, but the XRCC1 Arg194Trp polymorphism was associated with increased risk of HNC in the subgroup analysis of studies adjusted for smoking and alcohol and with increased risk of oral cancer in the stratified analyses based on cancer site. Further studies with larger samples are needed to confirm these findings.     

Systematic Review and Meta-Analysis of the Relationship between EPHX1 Polymorphisms and the Risk of Head and Neck Cancer

Aim

To evaluate the association between the EPHX1 Tyr113His and His139Arg polymorphisms in the EPHX1 gene and the risk of head and neck cancer.

Materials and Methods

Studies on the association of EPHX1 Tyr113His and His139Arg polymorphisms with HNC performed up until June 1st, 2014, were identified using a predefined search strategy. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of these associations.

Results

In this meta-analysis, 10 case-control studies, which included 9 studies of Tyr113His (1890 cases and 1894 controls) and 10 studies of His139Arg polymorphisms (1982 cases and 2024 controls), were considered eligible for inclusion. Overall, the pooled results indicated that the EPHX1 Tyr113His polymorphism was significantly associated with increased HNC risk (Tyr/His vs. Tyr/Tyr, OR = 1.26, 95%1.02–1.57;His/His+ Tyr/His vs. Tyr/Tyr, OR = 1.29, 95% I = 1.03–1.61). However, no significant association was found between the His139Arg polymorphism and HNC risk. In the subgroup analysis, a statistically significant association between the EPHX1 Tyr113His polymorphism and HNC was observed in population-based case-control studies (PCC), which involved less than 500 participants and genotype frequencies in HWE. This association showed minimal heterogeneity after excluding studies that were determined to contribute to heterogeneity. After categorizing the studies by publication time, a sensitivity analysis and cumulative meta-analysis of the two associations were conducted, and the results of the two analyses were consistent.

Conclusion

Our meta-analysis suggests that EPHX1 Tyr113His polymorphism may be a risk factor for HNC, while the EPHX1 His139Arg polymorphism has no association with HNC risk.     

The Impact of Second Primary Malignancies on Head and Neck Cancer Survivors: A Nationwide Cohort Study

Background

Head and neck cancer (HNC) is associated with a high rate of developing second primary malignancies(SPMs). But the impact on survival remains poorly understood before. Therefore, we want to estimate the impact of SPMs on HNC survivors.

Methods and Findings

Between 1986 and 2008, a total of 9,996 SPMs were recorded for 93,891 patients with an initial diagnosis of HNC by the Taiwan Cancer Registry. Patients were followed with national death registry database to 2011.Using the Kaplan–Meier method, a time-dependent covariate was employed to compare the survival rates between patients with and without SPMs. A Cox proportional hazards model that treated age and sex as confounders was used to examine the hazard ratios of SPMs. The relative survival rates were calculated using age- and sex-specific life tables for the population. Parametric mixture cure fraction models were then employed to estimate the percentage of cancer survivors who would be cured. Use of the Kaplan–Meier method showed that the crude survival rates differed significantly for patients with and patients without SPMs (log-rank test <0.01). For the results of Cox proportional hazards regression analysis, SPMs had a significant influence on survival rates with univariate (HR 2.59,95% CI 2.53to 2.65) and multivariate analysis (HR 2.34, 2.28 to 2.40). Patients with SPMs of nasopharyngeal carcinoma (NPC) had the highest cure rate at 39%, where as esophageal and lung cancer had the worst prognosis, with a cure rate of 11%.

Conclusions

A worse prognosis was found for second primary cancer such as esophageal or lung cancer. Patients and healthcare providers must strongly consider and have a high clinical suspicion of these SPMs.     

Development and Validation of a Prediction Model for Tube Feeding Dependence after Curative (Chemo-) Radiation in Head and Neck Cancer

Background

Curative radiotherapy or chemoradiation for head and neck cancer (HNC) may result in severe acute and late side effects, including tube feeding dependence.The purpose of this prospective cohort study was to develop a prediction model for tube feeding dependence 6 months (TUBE_M6) after curative (chemo-) radiotherapy in HNC patients.

Patients and Methods

Tube feeding dependence was scored prospectively. To develop the multivariable model, a group LASSO analysis was carried out, with TUBE_M6 as the primary endpoint (n = 427). The model was then validated in a test cohort (n = 183). The training cohort was divided into three groups based on the risk of TUBE_M6 to test whether the model could be extrapolated to later time points (12, 18 and 24 months).

Results

Most important predictors for TUBE_M6 were weight loss prior to treatment, advanced T-stage, positive N-stage, bilateral neck irradiation, accelerated radiotherapy and chemoradiation. Model performance was good, with an Area under the Curve of 0.86 in the training cohort and 0.82 in the test cohort. The TUBE_M6-based risk groups were significantly associated with tube feeding dependence at later time points (p<0.001).

Conclusion

We established an externally validated predictive model for tube feeding dependence after curative radiotherapy or chemoradiation, which can be used to predict TUBE_M6.     

GSTM3 A/B Polymorphism and Risk for Head and Neck Cancer: A Meta-Analysis

Background

Glutathione S-transferase M3 (GSTM3) is an important member of the GSTs that plays a critical role in the development of head and neck cancer (HNC). Several studies have investigated between the GSTM3 A/B polymorphism and risk of HNC, however, the results remain controversial. The aim of this meta-analysis is to evaluate the association between the GSTM3 A/B polymorphism and the risk of HNC.

Methods

All eligible case-control studies published up to July 2013 were identified by searching PubMed and Web of Science. The HNC risk associated with the GSTM3 A/B polymorphism was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively.

Results

Fourteen studies from ten publications with 2110 patients and 2259 controls were included. Overall, the GSTM3 A/B polymorphism was associated with a decreased risk of HNC using the dominant model, homozygote comparison model and heterozygote comparison model (OR = 0.82, 95%CI: 0.71–0.94; OR = 0.67, 95%CI: 0.49–0.94; and OR = 0.84, 95%CI: 0.73–0.97, respectively); besides, in stratification analyses by ethnicity, similar results were observed in Caucasian populations. Stratification by tumor site indicated that the GSTM3 polymorphism was associated with a decreased risk of laryngeal cancer under recessive model and homozygote comparison (OR = 0.52, 95%CI: 0.30–0.89; and OR = 0.50, 95%CI: 0.29–0.87, respectively); By stratifying source of control, decreased cancer risk was observed in hospital-based population under all genetic models (OR = 0.67, 95%CI: 0.56–0.81 for the dominant model; OR = 0.66, 95%CI: 0.46–0.95 for the recessive model; OR = 0.55, 95%CI: 0.37–0.83 for the homozygote comparison model, and OR = 0.70, 95%CI: 0.58–0.84 for the heterozygote comparison model).

Conclusions

This meta-analysis suggests that the GSTM3 A/B polymorphism may be an important protective factor for HNC, especially of laryngeal cancer and Caucasian populations.     

TLR8 stimulation enhances cetuximab-mediated natural killer cell lysis of head and neck cancer cells and dendritic cell cross-priming of EGFR-specific CD8+ T cells

Background

Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that prolongs survival in the treatment for head and neck cancer (HNC), but only in 10–20 % of patients. An immunological mechanism of action such as natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC) has been suggested. We investigated the effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcγR-bearing cells.

Objective

To determine the capability of TLR8-stimulation to enhance the activation and function of NK cells and dendritic cells (DC) in the presence of cetuximab-coated HNC cells.

Methods

Peripheral blood mononuclear cells (PBMC), NK, DC, and CD8⁺ T cells were isolated and analyzed using ⁵¹Cr release ADCC, flow cytometry analysis, cytokine ELISA, and EGFR_853-861 tetramer staining.

Results

TLR8 stimulation of unfractionated PBMC led to enhanced cetuximab-mediated ADCC in healthy donors (p < 0.01) and HNC patients (p < 0.001), which was dependent on NK cells. Secretion of Th1 cytokines TNFα (p < 0.0001), IFNγ (p < 0.0001), and IL-12p40 (p < 0.005) was increased. TLR8 stimulation of PBMC augmented cetuximab-enhanced NK cell degranulation (p < 0.001). TLR8-stimulated NK cells enhanced DC maturation markers CD80, CD83, and CD86 in co-culture with cetuximab-treated HNC cells. TLR8 stimulation of NK-DC co-cultures significantly increased DC priming of EGFR-specific CD8⁺ T cells in the presence of cetuximab.

Discussion

VTX-2337 and cetuximab combination therapy can activate innate and adaptive anti-cancer immune responses. Further investigation in human trials will be important for determining the clinical benefit of this combination and for determining biomarkers of response.     

Brain-Sparing Methods for IMRT of Head and Neck Cancer

Purpose

Radical radiotherapy for head and neck cancer (HNC) may deliver significant doses to brain structures. There is evidence that this may cause a decline in neurocognitive function (NCF). Radiation dose to the medial temporal lobes, and particularly to the hippocampi, seems to be critical in determining NCF outcomes. We evaluated the feasibility of two alternative intensity-modulated radiotherapy (IMRT) techniques to generate hippocampus- and brain-sparing HNC treatment plans to preserve NCF.

Methods and Materials

A planning study was undertaken for ten patients with HNC whose planning target volume (PTV) included the nasopharynx. Patients had been previously treated using standard (chemo)-IMRT techniques. Bilateral hippocampi were delineated according to the RTOG atlas, on T1w MRI co-registered to the RT planning CT. Hippocampus-sparing plans (HSRT), and whole-brain/hippocampus-sparing fixed-field non-coplanar IMRT (BSRT) plans, were generated. DVHs and dose difference maps were used to compare plans. NTCP calculations for NCF impairment, based on hippocampal dosimetry, were performed for all plans.

Results

Significant reductions in hippocampal doses relative to standard plans were achieved in eight of ten cases for both HSRT and BSRT. EQD2 D40% to bilateral hippocampi was significantly reduced from a mean of 23.5 Gy (range 14.5–35.0) in the standard plans to a mean of 8.6 Gy (4.2–24.7) for HSRT (p = 0.001) and a mean of 9.0 Gy (4.3–17.3) for BSRT (p < 0.001). Both HSRT and BSRT resulted in a significant reduction in doses to the whole brain, brain stem, and cerebellum.

Conclusion

We demonstrate that IMRT plans for HNC involving the nasopharynx can be successfully optimised to significantly reduce dose to the bilateral hippocampi and whole brain. The magnitude of the achievable dose reductions results in significant reductions in the probability of radiation-induced NCF decline. These results could readily be translated into a future clinical trial.     

Paucity of HPV-Related Head and Neck Cancers (HNC) in Nigeria

IntroductionThe burden of HPV-related Head and Neck Cancers (HNC) has been rising in the U.S. and other developed countries but this trend has not been reported in Africa. Objective of study was to evaluate the prevalence of HPV infection in HNC cancer cases seen between 1990 and 2011 at the tertiary health care institutions in Nigeria.MethodsWe retrieved 149 head and neck cancer formalin fixed, paraffin embedded tumor specimens diagnosed between 1990 and 2011 from four teaching hospitals in Nigeria. One hundred and twenty-three blocks (83%) contained appropriate HNC for analysis while DNA extraction was successful in 60% (90/149). PCR amplification was successful in 33% (49/149) and Linear Array genotyping for HPV was successful in 11% (17/149) of these cases. These were in tumors from the larynx (6), cervical lymph nodes (3), nasal cavity (2), parotid (1), palate (1), maxillary sinus (1) and mandible (1). Two cases were non-specific and none were from the oropharynx. Histologically, 41% (7/17) of the successfully genotyped blocks were squamous cell carcinomas (larynx 6, maxillary sinus 1).

Results and Conclusion

We were unable to detect HPV in any of the HNC samples in our study. Our result may suggest that there is a low prevalence of HPV-related HNC among the adult population in Nigeria. Our results provide a benchmark to compare future incidence of HPV -related HNC in this community in future. We had significant analytical challenges from possible poor tissue processing and urge that future studies should prospectively collect samples and ensure high quality sample processing.     

Association between MMP1 -1607 1G>2G Polymorphism and Head and Neck Cancer Risk: A Meta-Analysis

Background

MMP1 is an important member of the MMP endopeptidase family that plays a critical role in the development of head and neck cancer (HNC). Several studies have investigated the association between the MMP1 -1607 1G>2G polymorphism and risk of HNC, but their results have been inconsistent. Here, we conducted a meta-analysis to further explore the role of the MMP1 -1607 1G>2G polymorphism in HNC development.

Methods

We identified all eligible studies in the electronic databases of PubMed, ISI Web of Knowledge, MEDLINE, Embase, and Google Scholar (from January 2000 to June 2012). A meta-analysis was performed to evaluate the association between the MMP1 -1607 1G>2G polymorphism and risk of HNC by calculating odds ratios (OR) and 95% confidence interval (CIs).

Results

Twelve studies were included in this meta-analysis. In overall comparison, significant associations were found using the recessive and allelic contrast models (OR, 1.38; 95% CI, 1.07–1.79 and OR, 1.27; 95% CI, 1.05–1.53, respectively), but no association was detected using the dominant model. In the stratified analyses by several variables, significant associations were observed using the recessive, dominant, and allelic contrast models in the Asian population (OR, 1.64; 95% CI, 1.29–2.08; OR, 1.39; 95% CI, 1.06–1.82; and OR, 1.41; 95% CI, 1.21–1.65, respectively), European population (OR, 0.58; 95% CI, 0.40–0.84; OR, 0.64; 95% CI, 0.44–0.92; and OR, 0.68; 95% CI, 0.54–0.85, respectively), and population-based subgroup (OR, 1.24; 95% CI,1.05–1.47; OR,1.48; 95% CI,1.04–2.12; and OR, 1.22; 95% CI, 1.07–1.38, respectively). Furthermore, significant associations were detected in oral cavity cancer and nasopharyngeal cancer under the recessive model.

Conclusion

Our results suggest that the MMP1 -1607 1G>2G polymorphism is associated with risk of HNC and that it plays different roles in Asian and European populations. Further studies with large sample size are needed to validate our findings.     

Robust Intensity Modulated Proton Therapy (IMPT) Increases Estimated Clinical Benefit in Head and Neck Cancer Patients

Purpose

To compare the clinical benefit of robust optimized Intensity Modulated Proton Therapy (minimax IMPT) with current photon Intensity Modulated Radiation Therapy (IMRT) and PTV-based IMPT for head and neck cancer (HNC) patients. The clinical benefit is quantified in terms of both Normal Tissue Complication Probability (NTCP) and target coverage in the case of setup and range errors.

Methods and Materials

For 10 HNC patients, PTV-based IMRT (7 fields), minimax and PTV-based IMPT (2, 3, 4, 5 and 7 fields) plans were tested on robustness. Robust optimized plans differed from PTV-based plans in that they target the CTV and penalize possible error scenarios, instead of using the static isotropic CTV-PTV margin. Perturbed dose distributions of all plans were acquired by simulating in total 8060 setup (±3.5 mm) and range error (±3%) combinations. NTCP models for xerostomia and dysphagia were used to predict the clinical benefit of IMPT versus IMRT.

Results

The robustness criterion was met in the IMRT and minimax IMPT plans in all error scenarios, but this was only the case in 1 of 40 PTV-based IMPT plans. Seven (out of 10) patients had relatively large NTCP reductions in minimax IMPT plans compared to IMRT. For these patients, xerostomia and dysphagia NTCP values were reduced by 17.0% (95% CI; 13.0–21.1) and 8.1% (95% CI; 4.9–11.2) on average with minimax IMPT. Increasing the number of fields did not contribute to plan robustness, but improved organ sparing.

Conclusions

The estimated clinical benefit in terms of NTCP of robust optimized (minimax) IMPT is greater than that of IMRT and PTV-based IMPT in HNC patients. Furthermore, the target coverage of minimax IMPT plans in the presence of errors was comparable to IMRT plans.     

Tooth Loss and Head and Neck Cancer: A Meta-Analysis of Observational Studies

Backgroud

Epidemiological studies have shown that tooth loss is associated with risk of head and neck cancer (HNC); however, the results were inconsistent. Therefore, we conducted a meta-analysis to ascertain the relationship between tooth loss and HNC.

Methods

We searched for relevant observational studies that tested the association between tooth loss and risk of HNC from PubMed and were conducted up to January 30, 2013. Data from the eligible studies were independently extracted by two authors. The meta-analysis was performed using the Comprehensive Meta-Analysis 2.2 software. Sensitivity and subgroup analyses were conducted to evaluate the influence of various inclusions. Publication bias was also detected.

Results

Ten articles involving one cohort and ten case-control studies were yielded. Based on random-effects meta-analysis, an association between tooth loss and HNC risk was identified [increased risk of 29% for 1 to 6 teeth loss (OR = 1.29, 95% CI = 0.52–3.20, p = 0.59), 58% for 6 to 15 teeth loss (OR = 1.58, 95% CI = 1.08–2.32, p = 0.02), 63% for 11+ teeth loss (OR = 1.63, 95% CI = 1.23–2.14, p<0.001), 72% for 15+ teeth loss (OR = 1.72, 95% CI = 1.26–2.36, p<0.001), and 89% for 20+ teeth loss (OR = 1.89, 95% CI = 1.27–2.80, p<0.001)]. The sensitivity analysis shows that the result was robust, and publication bias was not detected.

Conclusions

Based on the current evidence, tooth loss is probably a significant and dependent risk factor of HNC, which may have a dose-response effect. People who lost six or more teeth should pay attention to symptoms of HNC, and losing 11 teeth or 15 teeth may be the threshold.