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The authors have obtained rotationally resolved vacuum ultraviolet pulsed field ionization-photoelectron (vuv-PFI-PE) spectrum of HD in the photon energy range of 15.29–18.11 eV, covering the ionization transitions HD+(X 2Σg+,v+=0–21,N+)←HD(X 1Σg+,v″=0,J″). The assignment of rotational transitions resolved in the vuv-PFI-PE vibrational bands for HD+(X 2Σg+,v+=0–20) and their simulation using the Buckingham-Orr-Sichel (BOS) model are presented. Rotational branches corresponding to the ΔN=N+-J″=0, ±1, ±2, ±3, and ±4 transitions are observed in the vuv-PFI-PE spectrum of HD. The BOS simulation shows that the perturbation of vuv-PFI-PE rotational line intensities due to near resonance autoionization is very minor at v+>=5 and decreases as v+ is increased. Thus, the rotationally resolved PFI-PE bands for HD+(v+>=5) presented here provide reliable estimates of state-to-state cross sections for direct photoionization of HD, while the rotationally resolved PFI-PE bands for HD+(v+<5) are useful data for fundamental understanding of the near resonance autoionizing mechanism. On the basis of the rovibrational assignment of the vuv-PFI-PE bands, the ionization energies for the formation of HD+(X 2Σg+,v+=0–20,N+) from HD(X 1Σg+,v″=0,J″) and the vibrational constants (ωe, ωeχe, ωeye, and ωeze), the rotational constants (Be and αe), the vibrational energy spacings, and the dissociation energy for HD+(X 2Σg+) are determined. As expected, these values are found to be in excellent agreement with high level theoretical predictions. [ABSTRACT FROM AUTHOR]

Reports on the acquisition of rotationally resolved pulsed field ionization photoelectron spectra of oxygen covering the ionization transitions of O[sup +][sub 2](B [sup 2]Sigma[sup -][sub g], v[sup +]=0-7,N[sup +]...O[sub 2](X [sup 3]Sigma[sup -][sub g], v''=0,N''). Pulsed field ionization photoelectron measurements; Measurements of lifetimes for high-n Rydberg states.

Examines the pulsed field ionization photoelectron spectrum (PFI-PE) of oxygen gas. Observation on the rotational branches; Estimation of the rotational linewidths; Determination of the predissociation lifetimes; Calculation of equilibrium bond distances; Measurement of nominal lifetimes for Rydberg states.

Examines the collision-induced dissociation (CID) reaction of chloro compounds. Measurement of the absolute total cross sections produced by the CID reaction in the center-of-mass collision energy; Validity of the energy randomization of chloro compounds; Promotion of couplings or energy flow among the vibrational modes.

Presents a theoretical study of the vacuum ultraviolet pulsed field ionization photoelectron band for carbonyl sulphide. Correlation between the experimental and theoretical Renner-Teller calculations of the vibronic states; Factors attributing the symmetry of geometry-dependent electronic transition dipole operator components.

Improves a newly developed experimental scheme for high resolution pulsed field ionization photoelectron (PFI-PE) studies of oxygen using the high resolution monochromatized multibunch undulator synchroton of the chemical dynamics beamline at the advanced light source. Advantage of the scheme for PFI-PE measurements to have no contamination by background electrons.

The vacuum ultraviolet pulsed field ionization-photoelectron (PFI-PE) spectra for CO[sub 2] have been measured in the energy range of 13.6-14.7 eV, revealing complex vibronic structures for the ground CO[sub 2][sup +](X [sup 2]Π[sub g]) state. Many vibronic bands for CO[sub 2][sup +](X [sup 2]Π[sub g]), which were not resolved in previous photoelectron studies, are identified in the present measurement based on comparison with available optical data and theoretical predictions. As observed in the HeI photoelectron spectrum of CO[sub 2], the PFI-PE spectrum is dominated by the symmetry allowed ν[sub 1][sup +] (symmetric stretch) vibrational progression for CO[sub 2][sup +](X [sup 2]Π[sub g]). However, PFI-PE vibronic bands due to excitation of the symmetry disallowed ν[sub 2][sup +] (bending) and ν[sub 3][sup +] (asymmetric stretch) modes with both odd quanta, together with the symmetry allowed even quanta excitations, are clearly discernible. The simulation of rotational contours resolved in PFI-PE vibronic bands associated with excitation to the (ν[sub 1][sup +]=0-1, ν[sub 2][sup +]=0-2, ν[sub 3][sup +]=0) vibrational levels has yielded accurate ionization energies for the formation of these vibronic states from CO[sub 2](X [sup 1]Σ[sub g][sup +]). © 2000 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Objective: We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries., Subjects and Methods: The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared., Results: The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites., Conclusion: These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer., (© 2022 Wiley Periodicals LLC.)

The American Cancer Society predicted more than 52 000 new cases of thyroid cancer in 2020, making it the most prevalent endocrine malignancy. Due to the approximately threefold higher incidence of thyroid cancer in women, we hypothesize that androgens and/or androgen receptors play a protective role and that thyroid cancer in men represents an escape from androgen-mediated cell regulation. The analysis of androgen receptor (AR) expression in patient tissue samples identified a 2.7-fold reduction in AR expression (p < 0.005) in papillary thyroid cancer compared with matched, normal tissue. An in vitro cell model was developed by stably transfecting AR into 8505C undifferentiated thyroid cancer cells (resulting in clone 84E7). The addition of DHT to the clone 84E7 resulted in AR translocation into the nucleus and a 70% reduction in proliferation, with a shift in the cell cycle toward G1 arrest. RNASeq analysis revealed significant changes in mRNA levels associated with proliferation, cell cycle, and cell cycle regulation. Furthermore, androgen significantly decreased the levels of the G1-associated cell cycle progression proteins cdc25a CDK6 CDK4 and CDK2 as well as increased the levels of the cell cycle inhibitors, p27 and p21. The data strongly suggest that DHT induces a G1 arrest in androgen-responsive thyroid cancer cells. Together, these data support our hypothesis that AR/androgen may play a protective, antiproliferative role and are consistent with younger men having a lower incidence of thyroid cancer than women., (© 2021 Wiley Periodicals LLC.)

Background: Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk., Methods: Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking., Results: For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx)., Conclusions: Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.

Head and neck cancer (HNC) risk prediction models based on risk factor profiles have not yet been developed. We took advantage of the large database of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, including 14 US studies from 1981-2010, to develop HNC risk prediction models. Seventy percent of the data were used to develop the risk prediction models; the remaining 30% were used to validate the models. We used competing-risk models to calculate absolute risks. The predictors included age, sex, education, race/ethnicity, alcohol drinking intensity, cigarette smoking duration and intensity, and/or family history of HNC. The 20-year absolute risk of HNC was 7.61% for a 60-year-old woman who smoked more than 20 cigarettes per day for over 20 years, consumed 3 or more alcoholic drinks per day, was a high school graduate, had a family history of HNC, and was non-Hispanic white. The 20-year risk for men with a similar profile was 6.85%. The absolute risks of oropharyngeal and hypopharyngeal cancers were generally lower than those of oral cavity and laryngeal cancers. Statistics for the area under the receiver operating characteristic curve (AUC) were 0.70 or higher, except for oropharyngeal cancer in men. This HNC risk prediction model may be useful in promoting healthier behaviors such as smoking cessation or in aiding persons with a family history of HNC to evaluate their risks., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

High dietary glycaemic index (GI) and glycaemic load (GL) may increase cancer risk. However, limited information was available on GI and/or GL and head and neck cancer (HNC) risk. We conducted a pooled analysis on 8 case-control studies (4081 HNC cases; 7407 controls) from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of HNC, and its subsites, from fixed- or mixed-effects logistic models including centre-specific quartiles of GI or GL. GI, but not GL, had a weak positive association with HNC (OR Q4 vs. Q1  = 1.16; 95% CI = 1.02-1.31). In subsites, we found a positive association between GI and laryngeal cancer (OR Q4 vs. Q1  = 1.60; 95% CI = 1.30-1.96) and an inverse association between GL and oropharyngeal cancer (OR Q4 vs. Q1  = 0.78; 95% CI = 0.63-0.97). This pooled analysis indicates a modest positive association between GI and HNC, mainly driven by laryngeal cancer.

Background: Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk., Methods: We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models., Results: Without adjusting for tobacco packyears, we observed that younger age at starting tobacco use was associated with an increased HNC risk for ever smokers (OR <10 years vs. ≥30 years : 1.64, 95% CI: 1.35, 1.97). However, the observed association between age at starting tobacco use and HNC risk became null after adjusting for tobacco packyears (OR <10 years vs. ≥30 years : 0.97, 95% CI: 0.80, 1.19). In the stratified analyses on HNC subsites by tobacco packyears or years since quitting, no difference in the association between age at start and HNC risk was observed., Conclusions: Results from this pooled analysis suggest that increased HNC risks observed with earlier age at starting tobacco smoking are largely due to longer duration and higher cumulative tobacco exposures., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures., Materials and Methods: We pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework., Results: For oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30  years. In former smokers who quit ≥10  years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers., Conclusion: Referring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Thyroid cancer is the most common endocrine malignancy worldwide, with the predominant form papillary thyroid carcinoma (PTC) representing approximately 80% of cases., Objective: This study was addressed to identify potential genes and pathways involved in the pathogenesis of PTC and potential novel biomarkers for this disease., Methods: Gene expression profiling was carried out by DNA microarray technology. Validation of microarray data by qRT-PCR, western blot, and enzyme linked immunosorbent assay was also performed in a selected set of genes and gene products, with the potential to be used as diagnostic or prognostic biomarkers, such as those associated with cell adhesion, extracellular matrix (ECM) remodeling and immune/inflammatory response., Results: In this study we found that upregulation of extracellular activities, such as proteoglycans, ECM-receptor interaction, and cell adhesion molecules, were the most prominent feature of PTC. Significantly over-expressed genes included SDC1 (syndecan 1), SDC4 (syndecan 4), KLK7 (kallikrein-related peptidase 7), KLK10 (kallikrein-related peptidase 10), SLPI (secretory leukocyte peptidase inhibitor), GDF15 (growth/differentiation factor-15), ALOX5 (arachidonate 5-lipoxygenase), SFRP2 (secreted Frizzled-related protein 2), among others. Further, elevated KLK10 levels were detected in patients with PTC. Many of these genes belong to KEGG pathway "Proteoglycans in cancer"., Conclusions: Using DNA microarray analysis allowed the identification of genes and pathways with known important roles in malignant transformation, and also the discovery of novel genes that may be potential biomarkers for PTC.

There have been few published studies on differences between Blacks and Whites in the estimated effects of alcohol and tobacco use on the incidence of head and neck cancer (HNC) in the United States. Previous studies have been limited by small numbers of Blacks. Using pooled data from 13 US case-control studies of oral, pharyngeal, and laryngeal cancers in the International Head and Neck Cancer Epidemiology Consortium, this study comprised a large number of Black HNC cases (n = 975). Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for several tobacco and alcohol consumption characteristics. Blacks were found to have consistently stronger associations than Whites for the majority of tobacco consumption variables. For example, compared to never smokers, Blacks who smoked cigarettes for > 30 years had an OR 4.53 (95% CI 3.22-6.39), which was larger than that observed in Whites (OR 3.01, 95% CI 2.73-3.33; p interaction  < 0.0001). The ORs for alcohol use were also larger among Blacks compared to Whites. Exclusion of oropharyngeal cases attenuated the racial differences in tobacco use associations but not alcohol use associations. These findings suggest modest racial differences exist in the association of HNC risk with tobacco and alcohol consumption.

The first Rhinology Future Debates was held in Brussels in December 2016, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases). The purpose of these debates is to bring novel developments in the field of Rhinology to the attention of the medical, paramedical and patient community, in a highly credible and balanced context. For the first time in Rhinology, a peer to peer scientific exchange with key experts in the field of rhinology and key medical colleagues from leading industries let to a brainstorming and discussion event on a number of hot issues in Rhinology. Novel developments are presented by key experts from industry and/or key thought leaders in Rhinology, and then followed by a lively debate on the potential positioning of new developments in care pathways, the strengths and weaknesses of the novel development(s), and comparisons with existing and/or competing products, devices, and/or molecules. As all debates are recorded and distributed on-line with limited editing (www.rhinology-future.com), EUFOREA aims at maximizing the education of the target groups on novel developments, allowing a critical appraisal of the future and a more rapid implementation of promising novel tools, techniques and/or molecules in clinical practise in Europe. The next Rhinology Future debate will be held in Brussels in December 2017.

The possible role of dietary fiber in the etiology of head neck cancers (HNCs) is unclear. We used individual-level pooled data from ten case-control studies (5959 cases and 12,248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium, to examine the association between fiber intake and cancer of the oral cavity/pharynx and larynx. Odds Ratios (ORs) and their 95% Confidence Intervals (CIs) were estimated using unconditional multiple logistic regression applied to quintile categories of non-alcohol energy-adjusted fiber intake and adjusted for tobacco and alcohol use and other known or putative confounders. Fiber intake was inversely associated with oral and pharyngeal cancer combined (OR for 5th vs. 1st quintile category = 0.49, 95% CI: 0.40-0.59; p for trend <0.001) and with laryngeal cancer (OR = 0.66, 95% CI: 0.54-0.82, p for trend <0.001). There was, however, appreciable heterogeneity of the estimated effect across studies for oral and pharyngeal cancer combined. Nonetheless, inverse associations were consistently observed for the subsites of oral and pharyngeal cancers and within most strata of the considered covariates, for both cancer sites. Our findings from a multicenter large-scale pooled analysis suggest that, although in the presence of between-study heterogeneity, a greater intake of fiber may lower HNC risk., (© 2017 UICC.)

The objective of this report is to summarize the symptoms, diagnostic workup, necessary imaging, and management of Eagle syndrome. A comprehensive literature review was conducted on peer-reviewed publications of Eagle syndrome across multiple disciplines in order to gain a thorough understanding of the presentation, diagnosis, and management of this disorder. Diagnoses of Eagle Syndrome have increased, in part due to the awareness of physicians to patient symptomatology. While cervical pain and dysphagia are among the typical symptoms, patients can present with a wide spectrum of benign and dangerous symptoms. CT scan is the gold standard for diagnosis and can be aided by both 3D reconstructive imaging and Angiography. Treatment strategies include medical management (analgesics, corticosteroids, antidepressants, and anticonvulsants) and varied surgical approaches (extraoral, transoral, endoscopic assisted). Increased understanding by providers treating patients with Eagle Syndrome allows for a more comprehensive treatment plan. With a variety of medical regimens and more definitive surgical approaches, Eagle Syndrome can be treated safely and effectively., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Previous studies on smokeless tobacco use and head and neck cancer (HNC) have found inconsistent and often imprecise estimates, with limited control for cigarette smoking. Using pooled data from 11 US case-control studies (1981-2006) of oral, pharyngeal, and laryngeal cancers (6,772 cases and 8,375 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, we applied hierarchical logistic regression to estimate odds ratios and 95% confidence intervals for ever use, frequency of use, and duration of use of snuff and chewing tobacco separately for never and ever cigarette smokers. Ever use (versus never use) of snuff was strongly associated with HNC among never cigarette smokers (odds ratio (OR) = 1.71, 95% confidence interval (CI): 1.08, 2.70), particularly for oral cavity cancers (OR = 3.01, 95% CI: 1.63, 5.55). Although ever (versus never) tobacco chewing was weakly associated with HNC among never cigarette smokers (OR = 1.20, 95% CI: 0.81, 1.77), analyses restricted to cancers of the oral cavity showed a stronger association (OR = 1.81, 95% CI: 1.04, 3.17). Few or no associations between each type of smokeless tobacco and HNC were observed among ever cigarette smokers, possibly reflecting residual confounding by smoking. Smokeless tobacco use appears to be associated with HNC, especially oral cancers, with snuff being more strongly associated than chewing tobacco.

Most mouthwashes contain alcohol, a known cause of head and neck cancer (oral cavity, pharynx, larynx), likely through the carcinogenic activity of acetaldehyde, formed in the oral cavity from alcohol. We carried out a pooled analysis of 8981 cases of head and neck cancer and 10 090 controls from 12 case-control studies with comparable information on mouthwash use in the International Head and Neck Cancer Epidemiology Consortium. Logistic regression was used to assess the association of mouthwash use with cancers of the oral cavity, oropharynx, hypopharynx, and larynx, adjusting for study, age, sex, pack-years of tobacco smoking, number of alcoholic drinks/day, and education. Compared with never users of mouthwash, the odds ratio (OR) of all head and neck cancers was 1.01 [95% confidence interval (CI): 0.94-1.08] for ever users, based on 12 studies. The corresponding ORs of cancer of the oral cavity and oropharynx were 1.11 (95% CI: 1.00-1.23) and 1.28 (95% CI: 1.06-1.56), respectively. OR for all head and neck cancer was 1.15 (95% CI: 1.01-1.30) for use for more than 35 years, based on seven studies (P for linear trend=0.01), and OR 1.31 (95% CI: 1.09-1.58) for use more than one per day, based on five studies (P for linear trend <0.001). Although limited by the retrospective nature of the study and the limited ability to assess risks of mouthwash use in nonusers of tobacco and alcohol, this large investigation shows potential risks for head and neck cancer subsites and in long-term and frequent users of mouthwash. This pooled analysis provides the most precise estimate of the association between mouthwash use and head and neck cancer.

Food and nutrition play an important role in head and neck cancer (HNC) etiology; however, the role of carotenoids remains largely undefined. We explored the relation of HNC risk with the intake of carotenoids within the International Head and Neck Cancer Epidemiology Consortium. We pooled individual-level data from 10 case-control studies conducted in Europe, North America, and Japan. The analysis included 18,207 subjects (4414 with oral and pharyngeal cancer, 1545 with laryngeal cancer, and 12,248 controls), categorized by quintiles of carotenoid intake from natural sources. Comparing the highest with the lowest quintile, the risk reduction associated with total carotenoid intake was 39 % (95 % CI 29-47 %) for oral/pharyngeal cancer and 39 % (95 % CI 24-50 %) for laryngeal cancer. Intakes of β-carotene equivalents, β-cryptoxanthin, lycopene, and lutein plus zeaxanthin were associated with at least 18 % reduction in the rate of oral and pharyngeal cancer (95 % CI 6-29 %) and 17 % reduction in the rate of laryngeal cancer (95 % CI 0-32 %). The overall protective effect of carotenoids on HNC was stronger for subjects reporting greater alcohol consumption (p < 0.05). The odds ratio for the combined effect of low carotenoid intake and high alcohol or tobacco consumption versus high carotenoid intake and low alcohol or tobacco consumption ranged from 7 (95 % CI 5-9) to 33 (95 % CI 23-49). A diet rich in carotenoids may protect against HNC. Persons with both low carotenoid intake and high tobacco or alcohol are at substantially higher risk of HNC.

Pediatric neck masses represent a variety of differential diagnoses. A common pathology in pediatric cystic neck tumors include ranulas, mucus retention cysts due to salivary gland obstruction. Epidermoid cysts are lesions infrequently encountered in the pediatric population and may appear similarly to ranulas on computed tomography imaging. MRI more easily differentiates these masses, and should therefore be the preferred imaging modality. Due to their distinct intraoperative management, ranulas and epidermoid cysts should be distinguished preoperatively through proper workup., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Evidence of associations between single nutrients and head and neck cancer (HNC) is still more limited and less consistent than that for fruit and vegetables. However, clarification of the protective mechanisms of fruit and vegetables is important to our understanding of HNC etiology. We investigated the association between vitamin C intake from natural sources and cancer of the oral cavity/pharynx and larynx using individual-level pooled data from ten case-control studies (5,959 cases and 12,248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. After harmonization of study-specific exposure information via the residual method, adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using unconditional multiple logistic regression models on quintile categories of 'non-alcohol energy-adjusted' vitamin C intake. In the presence of heterogeneity of the estimated ORs among studies, we derived those estimates from generalized linear mixed models. Higher intakes of vitamin C were inversely related to oral and pharyngeal (OR = 0.54, 95% CI: 0.45-0.65, for the fifth quintile category versus the first one, p for trend<0.001) and laryngeal cancers (OR = 0.52, 95% CI: 0.40-0.68, p for trend = 0.006), although in the presence of heterogeneity among studies for both sites. Inverse associations were consistently observed for the anatomical subsites of oral and pharyngeal cancer, and across strata of age, sex, education, body mass index, tobacco, and alcohol, for both cancer sites. The inverse association of vitamin C intake from foods with HNC may reflect a protective effect on these cancers; however, we cannot rule out other explanations., (© 2014 UICC.)

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 - 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 - 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels., (© 2014 UICC.)

There are suggestions of an inverse association between folate intake and serum folate levels and the risk of oral cavity and pharyngeal cancers (OPCs), but most studies are limited in sample size, with only few reporting information on the source of dietary folate. Our study aims to investigate the association between folate intake and the risk of OPC within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. We analyzed pooled individual-level data from ten case-control studies participating in the INHANCE consortium, including 5,127 cases and 13,249 controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated for the associations between total folate intake (natural, fortification and supplementation) and natural folate only, and OPC risk. We found an inverse association between total folate intake and overall OPC risk (the adjusted OR for the highest vs. the lowest quintile was 0.65, 95% CI: 0.43-0.99), with a stronger association for oral cavity (OR = 0.57, 95% CI: 0.43-0.75). A similar inverse association, though somewhat weaker, was observed for folate intake from natural sources only in oral cavity cancer (OR = 0.64, 95% CI: 0.45-0.91). The highest OPC risk was observed in heavy alcohol drinkers with low folate intake as compared to never/light drinkers with high folate (OR = 4.05, 95% CI: 3.43-4.79); the attributable proportion (AP) owing to interaction was 11.1% (95% CI: 1.4-20.8%). Lastly, we reported an OR of 2.73 (95% CI:2.34-3.19) for those ever tobacco users with low folate intake, compared with nevere tobacco users and high folate intake (AP of interaction =10.6%, 95% CI: 0.41-20.8%). Our project of a large pool of case-control studies supports a protective effect of total folate intake on OPC risk., (© 2014 UICC.)

Background: Increasing incidence of head and neck cancer (HNC) in young adults has been reported. We aimed to compare the role of major risk factors and family history of cancer in HNC in young adults and older patients., Methods: We pooled data from 25 case-control studies and conducted separate analyses for adults ≤ 45 years old ('young adults', 2010 cases and 4042 controls) and >45 years old ('older adults', 17700 cases and 22 704 controls). Using logistic regression with studies treated as random effects, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs)., Results: The young group of cases had a higher proportion of oral tongue cancer (16.0% in women; 11.0% in men) and unspecified oral cavity / oropharynx cancer (16.2%; 11.1%) and a lower proportion of larynx cancer (12.1%; 16.6%) than older adult cases. The proportions of never smokers or never drinkers among female cases were higher than among male cases in both age groups. Positive associations with HNC and duration or pack-years of smoking and drinking were similar across age groups. However, the attributable fractions (AFs) for smoking and drinking were lower in young when compared with older adults (AFs for smoking in young women, older women, young men and older men, respectively, = 19.9% (95% CI=9.8%, 27.9%), 48.9% (46.6%, 50.8%), 46.2% (38.5%, 52.5%), 64.3% (62.2%, 66.4%); AFs for drinking=5.3% (-11.2%, 18.0%), 20.0% (14.5%, 25.0%), 21.5% (5.0%, 34.9%) and 50.4% (46.1%, 54.3%). A family history of early-onset cancer was associated with HNC risk in the young [OR=2.27 (95% CI=1.26, 4.10)], but not in the older adults [OR=1.10 (0.91, 1.31)]. The attributable fraction for family history of early-onset cancer was 23.2% (8.60% to 31.4%) in young compared with 2.20% (-2.41%, 5.80%) in older adults., Conclusions: Differences in HNC aetiology according to age group may exist. The lower AF of cigarette smoking and alcohol drinking in young adults may be due to the reduced length of exposure due to the lower age. Other characteristics, such as those that are inherited, may play a more important role in HNC in young adults compared with older adults., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Aim: To evaluate the locoregional control and treatment toxicity of patients with pleomorphic adenoma after resection with close or positive margins followed by postoperative radiation therapy (PORT)., Patients and Methods: Between 2002 and 2011, twenty-one patients underwent PORT at the Mount Sinai Beth Israel Medical Center for pleomorphic adenoma of the parotid with close or positive margins. Four out of the 21 patients (19%) had recurrent lesions. The median dose was 57.6 Gy (range 55.8-69.96) delivered at 1.8-2.12 Gy/fraction. Treatment and follow-up data were retrospectively analyzed for locoregional control as well as acute- and late-treatment toxicities. Actuarial survival analysis was also performed., Results: Twelve women and 9 men with a median age of 46 (26-65) at PORT were included in this study. Eighty-one percent of the cohort had positive resection margins while 19% had close margins. At a median follow-up of 92 months, 19/21 patients (90%) had locoregional control. Two patients who failed had primary lesions which recurred locally, and initially had positive margins. The two recurrences occurred at 8 months and 12 months. Acute Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicities were experienced by 11 (52%) and 4 (19%) patients, respectively, while 2 (10%) experienced late RTOG grade 1 toxicities. No patients experienced any grade 2-4 late toxicities. Actuarial survival was 100%., Conclusion: PORT for patients with pleomorphic adenoma of the parotid gland after resection with close or positive margins results in excellent locoregional control and low treatment-related morbidity., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: To retrospectively review our single institution experience of patients with tonsillar squamous cell carcinoma., Material and Methods: Between 1999 and 2005, a total of 79 patients were identified. Stage distribution was as follows: stages I-II, III, IVA, and IVB were in 6, 14, 43, and 16 patients, respectively. Sixty-three patients (80%) were male. Median age was 55.5 years. Treatment generally consisted of external beam radiation therapy (RT) (median dose, 70 Gy), concomitant chemotherapy (CCRT) (cisplatin 100 mg/m on days 1, 22, and 43), and neck dissection (ND), and was administered as follows: stages I/II, 6 patients received RT alone; stages III/IVA, 20, 5, and 32 patients received RT alone, CCRT, and CCRT followed by ND, respectively; stage IVB, 9 and 7 patients received CCRT and CCRT plus ND, respectively., Results: After a median follow-up of 56 months (range, 12 to 122 mo), the 5-year local control (LC), regional control (RC), distant control (DC), and overall survival (OS) by stage were as follows: stage I-II 100%, 100%, 100%, 100%; stage III-IVA 98%, 96%, 95%, and 88%; stage IVB 100%, 100%, 69%, and 66%, respectively. Among stage IVB patients, DC was significantly lower (P=0.01) and a trend toward lower OS was noted (P=0.08). Long-term percutaneous endoscopic gastrostomy dependence was noted in 3% of them who had received CCRT. The effect of both chemotherapy and ND on treatment outcomes was analyzed; in stage III/IVA patients treated with or without chemotherapy, LC was 97% and 100% (P=0.43); RC was 92% and 100%(P=0.27); and DC was 91% and 94% (P=0.92), respectively. In stage III/IVA, patients treated with CCRT with or without ND, RC was 100% and 88%, respectively (P=0.087)., Conclusions: Primary radiotherapy with or without CCRT followed by ND provides excellent tumor control with acceptable toxicity in treating squamous cell carcinoma of the tonsil.

Several epidemiological studies have shown a positive association between adult height and cancer incidence. The only study conducted among women on mouth and pharynx cancer risk, however, reported an inverse association. This study aims to investigate the association between height and the risk of head and neck cancer (HNC) within a large international consortium of HNC. We analyzed pooled individual-level data from 24 case-control studies participating in the International Head and Neck Cancer Epidemiology Consortium. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated separately for men and women for associations between height and HNC risk. Educational level, tobacco smoking, and alcohol consumption were included in all regression models. Stratified analyses by HNC subsites were performed. This project included 17,666 cases and 28,198 controls. We found an inverse association between height and HNC (adjusted OR per 10 cm height = 0.91, 95% CI 0.86-0.95 for men; adjusted OR = 0.86, 95% CI 0.79-0.93 for women). In men, the estimated OR did vary by educational level, smoking status, geographic area, and control source. No differences by subsites were detected. Adult height is inversely associated with HNC risk. As height can be considered a marker of childhood illness and low energy intake, the inverse association is consistent with prior studies showing that HNC occur more frequently among deprived individuals. Further studies designed to elucidate the mechanism of such association would be warranted.

Aim: Metastasis of unknown primary (MUP) is commonly treated with radiation therapy (RT) to the entire mucosal surfaces and bilateral neck nodes (LN). We report outcomes of oropharynx-targeted RT, retropharyngeal nodes (RPN) and bilateral LN in this context., Patients and Methods: Single-Institution retrospective study of 68 patients. Forty percent were treated with intensity-modulated radiation therapy (IMRT). Fifty-six percent received concurrent chemoradiotherapy (CCRT). The median age was 58 years, 82% were Caucasian, and 75% males. Stage III disease was present in 9%, stage IVA in 75% and IVB in 16%., Results: At a median follow-up of 3.5 years, the actuarial locoregional control was 95.5%. The emergence of primary developed in 1patient (1.5%) and 2patients (3%) failed in the neck. The median time-to-locoregional failure (LRF) was 18 months. Actuarial long-term RT toxicity was grade 1 xerostomia (68%), dysphagia (35%), neck stiffness (15%) and trismus (6%)., Conclusion: RT to the oropharynx, RPN, and bilateral neck provides excellent oncological and functional outcomes in MUP in non-Asian patients. Sparing the mucosal surfaces of the nasopharynx, hypopharynx, and larynx seems reasonable without impacting on survival and locoregional control.

Aim: To report the outcome of radiation therapy (RT) +/- chemotherapy in HIV-seropositive patients with Head and Neck Squamous Cell Carcinoma (HNSCC)., Patients and Methods: This is the largest single-Institution retrospective study to date, consisting of 73 HIV patients with HNSCC treated from January 1997-2010. The median age at RT, HIV diagnosis and the duration of patients being HIV seropositive were 51, 34, and 11 years, respectively. Seventy patients had SCC and one had submandibular salivary duct carcinoma. Stages I-II, III and IVA/B were: 22%, 27% and 51%, respectively. Primary cancer sites comprised the larynx (37%), oropharynx (32%), oral cavity (13%), hypopharynx (7%), nasopharynx (4%), unknown primary (MUP) (4%), nasal cavity (3%), and submandibular salivary duct (1%). All patients had an ECOG performance scale of ≤1 and were treated with RT +/- chemotherapy. Fifty patients (70%) were on highly active anti-retroviral therapy (HAART) during treatment, and the median CD4 count was 290 (range: 203-1142). Median dose of 70, 63, and 54 Gy were delivered to the gross disease, high-risk neck, and low-risk neck respectively. Median duration of treatment was 52 (range: 49-64) days. Twelve patients (17%) underwent neck dissection for N3 disease., Results: After a median follow-up of 47 months (range: 7-140), the 4-year locoregional control (LRC) and overall survival (OS) were 69% and 55% respectively. Seven patients (10%) developed second primary sites within the first 5 years of completing RT (2 anal SCCs and 5 HNSCCs). The LRC for Stages III/IV larynx and oropharynx SCC (which represent the majority of the cohort) were 76% and 70%, respectively. Chemo/RT-related late toxicities were dysphagia of grade≤2, 3, and 4 found in 74%, 15% and 11% of patients, respectively. Hoarseness (grade 1) was reported in 10% of patients; no patient experienced grade ≥2. Xerostomia grade ≤2, and 3 was found in 77% and 23% of patients, respectively. A Chi-square test and univariate analysis showed statistically significant relationships between LRC and duration of RT (p<0.001), as well as positive trends for weight loss (<10%) and absence of second malignancy., Conclusion: Definitive RT +/- chemotherapy for HIV-seropositive patients with HNSCC appears to be less effective compared to the observed rates of LRC and OS of other HNSCC without HIV. Due to advances in the HAART which prolongs HIV patients' survival, it is extremely important to establish better treatment strategies to improve therapeutic ratio in this growing patient population.

Objective: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive malignancy with optimal management remains unclear. We performed a review of the impact of trimodality approach on SNUC outcome., Methods: This is a single-institution retrospective study of 18 patients, who were managed between 1997 and 2009. The median age at presentation was 52 years (28 to 82). Nine patients (50%) were female. Three patients had stage II disease and underwent surgery alone, 12 had stages III and IVa and underwent surgery combined with chemoradiation, and 3 had stage IVb and underwent definitive chemoradiation. Patients who underwent preoperative, postoperative, and definitive chemoradiation received 60, 66, and 70 Gy of radiation, respectively. In all patients receiving concurrent chemoradiation, cisplatin was used, at a dose of 100 mg/m every 3 weeks for 3 cycles. Neoadjuvant chemotherapy included docetaxel, cisplatin, and 5-fluorouracil (TPF) every 3 weeks for 2 to 3 cycles., Results: After a median follow-up of 26 months (16 to 120), a total of 8 patients (44%) have experienced the following: 1 persistent disease (5.5%), 4 local failure (22%), and 3 distant metastases (DM, 16.5%). Five of the 8 patients had preexisting cranial nerve deficits or gross cranial invasion. The 2-, 3-, and 4-year local control (LC), disease-free survival (DFS), and overall survival (OS) were 78%, 72%, and 56%; 75%, 65%, and 52%; and 75%, 50%, and 48%, respectively. Trimodality approach provided 83% LC and 92% DM-free survival, whereas other modalities provided 50% LC and 33% DM-free survival. The causes of death for the entire cohort were DM and local invasion. Acute chemoradiotherapy toxicity was 100% grades 1 and 2 dermatitis, mucositis, and fatigue, 55% developed grades 1 and 2 dysphagia, and 6% had grade 3 mucositis. Long-term toxicity was 28% grade 1 xerostomia, 11% retinopathy and optic neuropathy, and 6% orbital exenteration and grade 3 peripheral neuropathy., Conclusions: SNUC is an aggressive neoplasm that frequently presents at an advanced stage. Our data show that trimodality approach in the form of surgery combined with chemoradiation seems to offer better LC and lower DM compared with other modalities.

Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ≤ 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.

Background: The purpose of this article was to present the Beth Israel Medical Center experience using high-dose-rate intraoperative radiotherapy (HDR-IORT) in the management of recurrent head and neck cancer., Methods: We conducted a retrospective review of all patients with locally or regionally recurrent head and neck cancer who underwent HDR-IORT at our institution between 2001 and 2010., Results: Seventy-six patients were identified who underwent treatment to a total of 87 sites after gross-total resection. The 2-year estimate of in-field tumor control was found to be 62%. Median overall survival was 19 months with 42% of the patients surviving at least 2 years. Significantly longer survival was found for patients achieving in-field control versus infield progression (33 months vs 17 months, respectively; p = .01)., Conclusion: HDR-IORT is well tolerated and associated with encouraging in-field disease control. In-field control is associated with improved survival. Further study is warranted to more fully investigate HDR-IORT in the salvage setting., (Copyright © 2012 Wiley Periodicals, Inc.)

To investigate the potential role of vitamin or mineral supplementation on the risk of head and neck cancer (HNC), we analyzed individual-level pooled data from 12 case-control studies (7,002 HNC cases and 8,383 controls) participating in the International Head and Neck Cancer Epidemiology consortium. There were a total of 2,028 oral cavity cancer, 2,465 pharyngeal cancer, 874 unspecified oral/pharynx cancer, 1,329 laryngeal cancer and 306 overlapping HNC cases. Odds ratios (OR) and 95% confidence intervals (CIs) for self reported ever use of any vitamins, multivitamins, vitamin A, vitamin C, vitamin E, and calcium, beta-carotene, iron, selenium and zinc supplements were assessed. We further examined frequency, duration and cumulative exposure of each vitamin or mineral when possible and stratified by smoking and drinking status. All ORs were adjusted for age, sex, race/ethnicity, study center, education level, pack-years of smoking, frequency of alcohol drinking and fruit/vegetable intake. A decreased risk of HNC was observed with ever use of vitamin C (OR = 0.76, 95% CI = 0.59-0.96) and with ever use of calcium supplement (OR = 0.64, 95% CI = 0.42-0.97). The inverse association with HNC risk was also observed for 10 or more years of vitamin C use (OR = 0.72, 95% CI = 0.54-0.97) and more than 365 tablets of cumulative calcium intake (OR = 0.36, 95% CI = 0.16-0.83), but linear trends were not observed for the frequency or duration of any supplement intake. We did not observe any strong associations between vitamin or mineral supplement intake and the risk of HNC., (Copyright © 2011 UICC.)

Arachidonate 5-lipoxygenase (ALOX5) expression and activity has been implicated in tumor pathogenesis, yet its role in papillary thyroid carcinoma (PTC) has not been characterized. ALOX5 protein and mRNA were upregulated in PTC compared to matched, normal thyroid tissue, and ALOX5 expression correlated with invasive tumor histopathology. Evidence suggests that PTC invasion is mediated through the induction of matrix metalloproteinases (MMPs) that can degrade and remodel the extracellular matrix (ECM). A correlation between MMP-9 and ALOX5 protein expression was established by immunohistochemical analysis of PTC and normal thyroid tissues using a tissue array. Transfection of ALOX5 into a PTC cell line (BCPAP) increased MMP-9 secretion and cell invasion across an ECM barrier. The ALOX5 product, 5(S)-hydroxyeicosatetraenoic acid also increased MMP-9 protein expression by BCPAP in a dose-dependent manner. Inhibitors of MMP-9 and ALOX5 reversed ALOX5-enhanced invasion. Here we describe a new role for ALOX5 as a mediator of invasion via MMP-9 induction; this ALOX5/MMP9 pathway represents a new avenue in the search for functional biomarkers and/or potential therapeutic targets for aggressive PTC., (Copyright © 2012 Wiley Periodicals, Inc.)

We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p (trend) = 0.13) and processed meat (OR = 1.37, 95% CI = 1.14-1.65, p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97).

Objectives: To explore the induction of a proangiogenic phenotype in endothelial cells in the thyroid tumor microenvironment by estrogen-treated thyroid cancer cells and to define the role of vascular endothelial growth factor (VEGF) in this interaction., Design: Cell-based in vitro systems analysis., Subjects: Thyroid tumor cell lines (BCPAP [papillary thyroid cancer] and ML-1 [follicular thyroid cancer]) were cultured with estradiol with and without an estrogen receptor (ER) inhibitor (fulvestrant or ICI) and used to treat human umbilical vein endothelial cells (HUVECs)., Interventions: Immunofluorescence was used to confirm the presence of ERα and ERβ in BCPAP cells. Conditioned medium was then used to evaluate the induction of HUVEC tubulogenesis and migration. Secretion of VEGF in this medium was evaluated by Western blot analysis. The expression of phosphoinositide 3-kinase (PI3K), the initiator of a proangiogenic pathway, was evaluated with Western blot analysis of HUVEC lysates. The subsequent effects of an ER inhibitor (fulvestrant/ICI) and a neutralizing VEGF antibody were also observed., Results: Estrogen receptor α and ERβ are expressed in thyroid cancer cells. Estrogen-stimulated ML-1 cells secreted an increased amount of VEGF likely as a result of ER signaling. In contact with this environment, HUVECs demonstrate enhanced tubulogenesis and migration. Western blot analysis documented estrogen-mediated upregulation of PI3K in HUVECs. These effects were mitigated by an ER inhibitor (fulvestrant/ICI) and a neutralizing VEGF antibody., Conclusions: Our data provide evidence that estrogen can induce a proangiogenic endothelial cell phenotype in the thyroid tumor microenvironment through ER and VEGF signaling. Our findings suggest that the effect of antiestrogenic therapy targeting tumor angiogenesis can be enhanced through VEGF inhibition.

Papillary thyroid carcinoma (PTC) is the most common endocrine and thyroid malignancy.  The urokinase plasminogen activator receptor (uPAR) plays an important role in cancer pathogenesis, including breakdown of the extracellular matrix, invasion, and metastasis.  Additionally, there is increasing evidence that uPAR also promotes tumorigenesis via the modulation of multiple signaling pathways.  BRAFV600E, the most common initial genetic mutation in PTC, leads to ERK1/2 hyperphosphorylation, which has been shown in numerous cancers to induce uPAR.  Treatment of the BRAFV600E-positive PTC cell line, BCPAP, with the MEK/ERK inhibitor U0126 reduced uPAR RNA levels by 90%.  siRNA-mediated down-regulation of uPAR in BCPAP cells resulted in greatly decreased activity in the focal adhesion kinase (FAK)/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.  This phenomenon was concurrent with drastically reduced proliferation rates and decreased clonigenic survival, as well as demonstrated senescence-associated nuclear morphology and induction of b-galactosidase activity. uPAR-knockdown BCPAP cells also displayed greatly reduced migration and invasion rates, as well as a complete loss of the cells' ability to augment their invasiveness following plasminogen supplementation. Taken together, these data provide new evidence of a novel role for uPAR induction (as a consequence of constitutive ERK1/2 activation) as a central component in PTC pathogenesis, and highlight the potential of uPAR as a therapeutic target.