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1.  Obesity and the Risk of Papillary Thyroid Cancer: A Pooled Analysis of Three Case–Control Studies 
Thyroid  2014;24(6):966-974.
Background: There is a correlation between temporal trends of obesity prevalence and papillary thyroid cancer (PTC) incidence in the United States. Obesity is a well-recognized risk factor for many cancers, but there are few studies on the association between obesity and PTC risk. We investigated the association between anthropometric measurements and PTC risk using pooled individual data from three case–control populations.
Methods: Height and weight information were obtained from three independent case–control studies, including 1917 patients with PTC (1360 women and 557 men) and 2127 cancer-free controls from the United States, Italy, and Germany. Body mass index (BMI), body fat percentage, and body surface area (BSA) were calculated. An unconditional logistic regression model was used to calculate odds ratios (ORs) and confidence intervals (CIs) with respect to risk of PTC, adjusted by age, sex, race/ethnicity, and study site.
Results: In the pooled population, for both men and women, an increased risk of PTC was found to be associated with greater weight, BMI, body fat percentage, and BSA, whereas a reduced risk of PTC was associated with greater height, in the pooled population for both men and women. Compared with normal-weight subjects (BMI 18.5–24.9 kg/m2), the ORs for overweight (BMI 25–29.9 kg/m2) and obese (BMI≥30 kg/m2) subjects were 1.72 [CI 1.48–2.00] and 4.17 [CI 3.41–5.10] respectively. Compared with the lowest quartile of body fat percentage, the ORs for the highest quartile were 3.83 [CI 2.85–5.15] in women and 4.05 [CI 2.67–6.15] in men.
Conclusion: Anthropometric factors, especially BMI and body fat percentage, were significantly associated with increased risk of PTC. Future studies of anthropometric factors and PTC that incorporate intermediate factors, including adiposity and hormone biomarkers, are essential to help clarify potential mechanisms of the relationship.
doi:10.1089/thy.2013.0566
PMCID: PMC4046192  PMID: 24555500
2.  Human Papillomavirus and WHO Type I Nasopharyngeal Carcinoma 
The Laryngoscope  2010;120(10):1990-1997.
Objectives
Nasopharyngeal carcinoma (NPC) is a rare cancer in the United States. An association between NPC and Epstein-Barr virus (EBV) is well-established for World Health Organization (WHO) types II and III (WHO-II/III) NPC but less well-established for WHO type I (WHO-I) NPC. Given the rise in oropharyngeal tumors positive for high-risk human papillomavirus (HPV) and the unique biology of WHO-I NPC, we examined the relationship between HPV and WHO-I NPC.
Study Design
Retrospective case-comparison study.
Methods
A search of a large multidisciplinary cancer center tumor registry identified 183 patients seen from January 1999 to December 2008 with incident NPC and no prior cancer. Available paraffin-embedded tumor specimens (N=30) were analyzed for oncogenic HPV status by in-situ hybridization (ISH) and polymerase chain reaction (PCR) for HPV-16 and HPV-18; EBV status by ISH; and p16 expression by immunohistochemistry. Demographic parameters, including race and smoking, were obtained from the medical records.
Results
Among the 18 WHO-I NPC patients, 66% (N=12) were smokers and 17% (N=3) Asian; among the 165 WHO-II/III NPC patients, 44% (N=73) were smokers and 24% (N=39) Asian. Eight WHO-I NPC patients had available paraffin blocks; 5 of 6 were HPV-16-positive by PCR and 4 of 8 were HPV-positive by ISH; only 2 of 8 (25%) were EBV-positive. Twenty-two WHO-II/III NPC patients had available paraffin blocks; only 1 was HPV-positive by ISH, and 13 of 22 (60%) were EBV-positive.
Conclusions
These results suggest that WHO-I NPC is associated with oncogenic HPV, though larger studies are needed to verify these findings.
doi:10.1002/lary.21089
PMCID: PMC4212520  PMID: 20824783
Human papillomavirus; Nasopharyngeal Carcinoma; WHO Type; In-situ hybridization; Polymerase chain reaction
3.  Incidence and Pattern of Second Primary Malignancies in Patients with Index Oropharyngeal Cancers versus Index Non-oropharyngeal Head and Neck Cancers 
Cancer  2013;119(14):2593-2601.
Background
A recent review of the SEER registry suggested that patients with index squamous cell carcinoma (SCC) of the oropharynx (SCCOP) are less likely to develop second primary malignancies (SPM) than patients with index SCC of non-oropharyngeal sites (oral cavity, larynx, hypopharynx). The purpose of this study was to determine the impact of index primary tumor site on SPM risk and explore factors potentially affecting this risk within a large prospectively accrued cohort of patients with index SCC of the head and neck (SCCHN).
Methods
A cohort of 2230 patients with incident SCCHN was reviewed for development of SPM. Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards models were used to detect the impact of various factors, including index tumor site, on SPM risk.
Results
The SPM rate was lower for patients with index SCCOP than for patients with index non-oropharyngeal cancer (P<.001). Among SCCOP patients, former-smokers had a 50% greater risk of SPM and current-smokers had a 100% greater risk of SPM than never-smokers (Ptrend=.008). Among SCCOP patients, those with classic SCCHN phenotype had SPM risk similar to that of patients with index non-oropharyngeal cancers; those with typical HPV phenotype had very low SPM risk. SPM most commonly occurred at non-tobacco-related sites in patients with index SCCOP and at tobacco-related sites in patients with index non-oropharyngeal cancers.
Conclusion
In patients with SCCHN, index cancer site and smoking status affect the risk and distribution of SPM.
doi:10.1002/cncr.28107
PMCID: PMC3909962  PMID: 23605777
Head and neck neoplasms; second primary malignancy; smoking; oropharyngeal cancer; oral cancer; laryngeal cancer; human papillomavirus
4.  Low risk of second primary malignancies among never smokers with human papillomavirus-associated index oropharyngeal cancers 
Head & neck  2012;35(6):794-799.
Background
Among index oropharyngeal cancer patients, second primary malignancies (SPMs) may be less common in human papillomavirus (HPV)-associated tumors than HPV-negative tumors. Further modification of these SPM risks by smoking has not been reported.
Methods
SPM outcomes of 356 incident oropharyngeal cancer patients were analyzed using Cox proportional hazards and Kaplan-Meier models. SPM risk and SPM-free survival were compared in HPV-seronegative patients, HPV-seropositive never smokers, and HPV-seropositive ever smokers.
Results
HPV-seropositive patients had a lower 5-year SPM rate than HPV-seronegative patients (5.6% vs. 14.6%, p=0.051). Compared to HPV-seronegative patients, HPV-seropositive never smokers had a 73% reduced SPM risk, and HPV-seropositive ever smokers had a 27% reduced SPM risk (trend p=0.028). While HPV-seronegative patients had SPMs in traditional locations, 70% of SPMs among HPV-seropositive patients were outside typical tobacco-related sites.
Conclusions
HPV serologic status and smoking may stratify patients with index oropharyngeal cancers in terms of risk and location of SPMs.
doi:10.1002/hed.23033
PMCID: PMC3459137  PMID: 22711172
Head and neck neoplasms; second primary; smoking; oropharyngeal cancer; human papillomavirus
5.  Phase II Trial of Induction Chemotherapy Followed by Surgery for Squamous Cell Carcinoma of the Oral Tongue in Young Adults 
Head & neck  2011;34(9):1255-1262.
Background
We conducted a phase II clinical trial of induction chemotherapy followed by surgery ± radiotherapy for squamous cell carcinoma of the oral tongue (SCCOT) in young adults.
Methods
From September 2001 to October 2004, 23 patients aged 18–49 years with clinical T2-3N0-2M0 SCCOT and no prior radiotherapy, chemotherapy, or neck dissection underwent induction chemotherapy (paclitaxel, ifosfamide, and carboplatin) followed by glossectomy and neck dissection ± radiotherapy and chemotherapy.
Results
On final surgical pathology, 9 (39%) patients had a complete/major (2 complete) histologic response at the primary tumor site; 8 (35%) had no response or progression. Similarly, 9 (39%) patients had a complete response in the neck or remained node negative; 6 (26%) had an increase in nodal category. No treatment-associated deaths occurred, and toxicity was modest. At a median follow-up from the end of treatment of 52 months (minimum, 23 months), 10 (43%) patients developed recurrence, and all 10 died of cancer. Crude recurrence/cancer death rates were associated with ≤ a partial response at the tongue (P = .029), poor histologic differentiation (P = .012), and multiple adverse features on final surgical pathology (P = .040).
Conclusions
Response rates and overall survival with this induction chemotherapy regimen were limited, but complete/major response at the tongue was associated with excellent prognosis. Additionally, improved patient selection and predictive tumor biomarkers will be needed for induction chemotherapy to be routinely incorporated into the treatment of oral tongue cancer in young adults.
doi:10.1002/hed.21906
PMCID: PMC3893095  PMID: 22009800
Oral tongue cancer; Young adults; Induction chemotherapy
6.  An evolution in demographics, treatment, and outcomes of oropharyngeal cancer at a major cancer center: A staging system in need of repair 
Cancer  2012;119(1):81-89.
Background
This retrospective review examines demographic/clinical characteristics and overall survival of patients with squamous cell carcinoma of the oropharynx (SCCOP) at a tertiary cancer center and reports the characteristics influencing any observed survival trends over time.
Methods
The study included 3891 newly diagnosed, previously untreated patients presenting to our institution between 1955 and 2004.
Results
Over time, patients presented at younger ages and were more likely to have base of tongue or tonsil tumors and to be never or former smokers. Patients diagnosed in 1995–2004 were almost half as likely to die as those diagnosed before 1995 (HR,0.6; 95% CI,0.6–0.8). In both multivariable and recursive partitioning survival analyses, the TNM staging system predicted survival of patients treated before 1995 but not of patients treated in 1995–2004.
Conclusion
Survival among patients with SCCOP improved substantially over the past 50 years. The main contributing factors were changes in clinical characteristics, in particular surrogates for HPV positivity. The current TNM staging system for SCCOP is inadequate. Incorporation of HPV status and perhaps smoking status is encouraged.
doi:10.1002/cncr.27727
PMCID: PMC3469778  PMID: 22736261
head and neck cancer; head and neck neoplasms; human papillomavirus; oropharyngeal cancer; neoplasm staging
7.  Impact of Enhanced Detection on the Increase in Thyroid Cancer Incidence in the United States: Review of Incidence Trends by Socioeconomic Status Within the Surveillance, Epidemiology, and End Results Registry, 1980–2008 
Thyroid  2013;23(1):103-110.
Background
In the past 3 decades, the incidence of thyroid cancer in the United States has been increasing. There has been debate on whether the increase is real or an artifact of improved diagnostic scrutiny. Our hypothesis is that both improved detection and a real increase have contributed to the increase.
Methods
Because socioeconomic status (SES) may be a surrogate for access to diagnostic technology, we compared thyroid cancer incidence trends between high- and low-SES counties within the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries. The incidence trends were assessed using joinpoint regression analysis.
Results
In high-SES counties, thyroid cancer incidence increased moderately (annual percentage change 1 [APC1]=2.5, p<0.05) before the late 1990s and more pronounced (APC2=6.3, p<0.05) after the late 1990s. In low-SES counties, incidence increased steadily with an APC of 3.5 (p<0.05) during the entire study period (1980–2008). For tumors ≤4.0 cm, incidence was higher in high-SES counties, and APC was higher for high- than low-SES counties after the late 1990s. For tumors >4.0 cm, high- and low-SES counties had similar increasing incidence trends. Similarly, for tumors ≤2.0 cm, the incidence trends differed between counties that are in or adjacent to metropolitan areas and counties that are in rural areas, whereas for tumors >2.0 cm, all counties regardless of area of residence had similar increasing trends.
Conclusions
Enhanced detection likely contributed to the increased thyroid cancer incidence in the past decades, but cannot fully explain the increase, suggesting that a true increase exists. Efforts should be made to identify the cause of this true increase.
doi:10.1089/thy.2012.0392
PMCID: PMC3539256  PMID: 23043274
8.  Functional Single-Nucleotide Polymorphisms in the BRCA1 Gene and Risk of Salivary Gland Carcinoma 
Oral oncology  2012;48(9):842-847.
Objectives
Polymorphic BRCA1 is a vital tumor suppressor gene within the DNA double-strand break repair pathways, but its association with salivary gland carcinoma (SGC) has yet to be investigated.
Materials and Methods
In a case-control study of 156 SGC patients and 511 controls, we used unconditional logistical regression analyses to investigate the association between SGC risk and seven common functional single-nucleotide polymorphisms (A1988G, A31875G, C33420T, A33921G, A34356G, T43893C and A55298G) in BRCA1.
Results
T43893C TC/CC genotype was associated with a reduction of SGC risk (adjusted odds ratio =0.55, 95% CI: 0.38–0.80, Bonferroni-adjusted p=0.011), which was more pronounced in women, non-Hispanic whites, and individuals with a family history of cancer in first-degree relatives. The interaction between T43893C and family history of cancer was significant (p=0.009). The GATGGCG and AACAACA haplotypes, both of which carry the T43893C minor allele, were also associated with reduced SGC risk.
Conclusion
Our results suggest that polymorphic BRCA1, particularly T43893C polymorphism, may protect against SGC.
doi:10.1016/j.oraloncology.2012.03.012
PMCID: PMC3408797  PMID: 22503699
BRCA1 polymorphism; salivary gland carcinoma; genetic susceptibility; DNA repair; case-control study
9.  A Comparison of the Demographics, Clinical Features, and Survival of Patients with Adenoid Cystic Carcinoma of Major and Minor Salivary Glands Versus Less Common Sites within the SEER Registry 
Cancer  2011;118(16):3945-3953.
Objectives
The scientific literature to date lacks population-based studies on the demographics, clinical features, and survival of patients with adenoid cystic carcinoma (ACC) of different anatomic sites.
Methods
We identified 5349 ACC cases in major salivary glands (N=1850), minor salivary glands (N=2077), breast (N=696), skin (N=291), lung and bronchus (N=203), female genital system (N=132), and eye and orbit (N=100) from the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in demographics, clinical features, and survival of patients were assessed.
Results
ACC of the eye and orbit was associated with younger age at presentation (mean=49.9 years). ACC of the skin or breast tended to present with less aggressive prognostic features, while ACC of the lung and bronchus or eye and orbit tended to present with more aggressive prognostic features. In multivariate survival analysis of patients presenting with localized disease, patients with ACC of breast (HR=0.40) or skin (HR=0.40) had a significantly lower risk death than patients with ACC of major salivary glands, while patients with ACC of lung and bronchus (HR=3.72) or eye and orbit (HR=3.67) had a significantly higher risk. For patients presenting with regional disease, the only clear prognostic difference in multivariate analysis was that patients with ACC of skin did significantly better.
Conclusions
The demographics and clinical features of ACC differ by disease site. Site may be an important predictor of survival for patients presenting with localized disease but is less important for patients presenting with regional disease.
doi:10.1002/cncr.26740
PMCID: PMC3412946  PMID: 22179977
Adenoid Cystic Carcinoma; SEER; Epidemiology; Site; Survival
10.  Family History of Cancer and Risk of Sporadic Differentiated Thyroid Carcinoma 
Cancer  2011;118(5):1228-1235.
BACKGROUND
Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since 1980s. While the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid cancer (DTC). Therefore, we explored the association between sporadic DTC and family history of cancer.
METHODS
In a retrospective hospital-based case-control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first-degree family history of cancer.
RESULTS
The study included 288 patients with sporadic DTC and 591 cancer-free controls. Family history of thyroid cancer in first-degree relatives was associated with increased DTC risk (adjusted OR = 4.1, 95% CI: 1.7–9.9). All DTC cases in patients with a first-degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR = 4.6, 95 CI%: 1.9–11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR = 7.4, 95% CI: 1.8–30.4). In addition, multifocal primary tumor was more common among PTC patients with first-degree family history of thyroid cancer than among PTC patients with no first-degree family history of thyroid cancer (68.8% vs. 35.5%, p = 0.01).
CONCLUSIONS
Our study suggests that family history of thyroid cancer in first-degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC.
doi:10.1002/cncr.26398
PMCID: PMC3208119  PMID: 21800288
Differentiated thyroid carcinoma; papillary thyroid carcinoma; benign thyroid disease; multifocal; family history of cancer
11.  Association of BRCA1 Functional Single Nucleotide Polymorphisms with Risk of Differentiated Thyroid Carcinoma 
Thyroid  2012;22(1):35-43.
Background
Breast cancer 1, early onset (BRCA1) is a vital DNA repair gene, and the single nucleotide polymorphisms (SNPs) of this gene have been studied in diverse cancer types. In this study, we investigated the association between eight common BRCA1 functional SNPs and the risk of differentiated thyroid carcinoma (DTC).
Methods
This cancer center-based case–control study included 303 DTC cases and 511 controls. A polymerase chain reaction-based restriction fragment length polymorphism assay was performed for genotyping. Unconditional logistical regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) in single-SNP analysis and haplotype analysis.
Results
A decreased risk of DTC was found for the A1988G heterozygous AG genotype (adjusted OR=0.63, 95% CI: 0.45–0.87, Bonferroni-adjusted p-value=0.036). AATAATA and ATAA haplotypes that carry C33420T variant allele were associated with reduced papillary thyroid cancer risk (adjusted OR=0.52, 95% CI: 0.33–0.84; adjusted OR=0.62, 95% CI: 0.40–0.95, respectively). Also, having a combination of ≥3 favorable genotypes was associated with a DTC risk reduction (adjusted OR=0.69, 95% CI: 0.50–0.95). The A31875G AG/GG genotype was associated with a 69% reduced risk of multifocal primary tumor in DTC patients (adjusted OR=0.31, 95% CI: 0.12–0.81).
Conclusion
BRCA1 genetic polymorphisms may play a role in DTC risk, while the possible associations warrant confirmation in independent studies.
doi:10.1089/thy.2011.0117
PMCID: PMC3263304  PMID: 22136207
12.  Differences in history of sexual behavior between patients with oropharyngeal squamous cell carcinoma and patients with squamous cell carcinoma at other head and neck sites 
Head & neck  2010;33(6):847-855.
Background
An emerging epidemic of human papillomavirus (HPV)-associated oropharyngeal cancer has been proposed. We compared the sexual behaviors of patients with squamous cell carcinoma of the oropharynx (SCCOP) and patients with squamous cell carcinoma of non-oropharyngeal head and neck sites (SCCNOP) to expand our understanding of sexual behavior as a risk factor for HPV-associated head and neck cancer.
Methods
The sexual history of 165 SCCOP patients and 87 SCCNOP patients was determined in a hospital-based case-case comparison study.
Results
SCCOP patients were significantly more likely than SCCNOP patients to have had >9 lifetime sex partners (odds ratio [OR]=39.2; 95% confidence interval [CI]=8.2–187.3), to have engaged in oral-genital sex (OR=3.5; 95% CI=1.1–11.1), and to have had > 4 oral-genital sex partners (OR=8.6; 95% CI=2.2–33.4).
Conclusions
The findings of this study suggest that some risk factors are site specific and provide further evidence that certain sexual behaviors increase the risk of HPV-associated SCCOP.
doi:10.1002/hed.21550
PMCID: PMC2994955  PMID: 20737488
head and neck neoplasms; human papillomavirus; sexual behavior; oropharynx; HPV16
13.  No Evidence of Sex-Related Survival Disparities among Head and Neck Cancer Patients Receiving Similar Multidisciplinary Care: A Matched-Pair Analysis 
Purpose
It is unknown whether there are survival disparities between men and women with squamous cell carcinoma of the head and neck (SCCHN), though some data suggest that men have worse outcomes. We conducted a matched-pair study that controlled for several potentially confounding prognostic variables to assess whether a survival advantage exists for female compared with male SCCHN patients receiving similar care.
Experimental Design
We selected 286 female patients and 286 matched male patients from within a prospective epidemiologic study of 1654 patients with incident SCCHN evaluated and treated at a single large multidisciplinary cancer center. Matching variables included age (± 10 years), race/ethnicity, smoking status (never versus ever), tumor site (oral cavity versus oropharynx versus larynx versus hypopharynx), tumor classification (T1–2 versus T3–4), nodal status (negative versus positive), and treatment (surgery, radiation therapy, surgery and radiation therapy, surgery and chemotherapy, chemoradiotherapy, or surgery and chemoradiotherapy).
Results
Matched-pair and log-rank analyses showed no significant differences between women and men in recurrence-free, disease-specific, or overall survival. When the analysis was restricted to individual sites (oral cavity, oropharynx, or larynx/hypopharynx), there was also no evidence of a disparity in survival associated with sex.
Conclusions
We conclude that there is no evidence to suggest that a survival advantage exists for women as compared to men with SCCHN receiving similar multidisciplinary directed care at a tertiary cancer center.
doi:10.1158/1078-0432.CCR-10-0755
PMCID: PMC2956614  PMID: 20943762
Survival disparity; Head and neck cancer; Gender-related disparity; Matched pair study; Gender-related prognosis
14.  Matched Pair Analysis of Race or Ethnicity in Outcomes of Head and Neck Cancer Patients Receiving Similar Multidisciplinary Care 
It is unknown whether population-level racial or ethnic disparities in mortality from squamous cell carcinoma of the head and neck (SCCHN) also occur in the setting of standardized multidisciplinary-team directed care. Therefore, we conducted a matched-pair study that controlled for several potentially confounding prognostic variables to assess whether a difference in survival exists for African-American or Hispanic-American compared with non-Hispanic white American SCCHN patients receiving similar care. Matched pairs were 81 African-American case and 81 non-Hispanic white control patients and 100 Hispanic-American cases and 100 matched non-Hispanic white controls selected from 1833 patients of a prospective epidemiologic study of incident SCCHN within a single, large multidisciplinary cancer center. Matching variables included age (± 10 years), sex, smoking status (never versus ever), site, tumor stage (T1–2 versus T3–4), nodal status (negative versus positive), and treatment. Cases and controls were not significantly different in proportions of comorbidity score, alcohol use, subsite distribution, overall stage, or tumor grade. Matched-pair and log-rank analyses showed no significant differences between cases and controls in recurrence-free, disease-specific, or overall survival. Site-specific analyses suggested that more-aggressive oropharyngeal cancers occurred more frequently in minority than non-Hispanic white patients. We conclude that minority and non-Hispanic white SCCHN patients receiving similar multidisciplinary-team directed care at a tertiary cancer center have similar survival results overall. These results encourage reducing health disparities in SCCHN through public-health efforts to improve access to multidisciplinary oncologic care (and to preventive measures) and through individual clinician efforts to make the best multidisciplinary cancer treatment choices available for their minority patients. The subgroup finding suggests a biologically based racial/ethnic disparity among oropharyngeal patients and that prevention and treatment strategies should be tailored to different populations of these patients.
doi:10.1158/1940-6207.CAPR-09-0154
PMCID: PMC2774765  PMID: 19737985
15.  Genetic Variants in DNA Double-Strand Break Repair Genes and Risk of Salivary Gland Carcinoma: A Case-Control Study 
PLoS ONE  2015;10(6):e0128753.
DNA double strand break (DSB) repair is the primary defense mechanism against ionizing radiation-induced DNA damage. Ionizing radiation is the only established risk factor for salivary gland carcinoma (SGC). We hypothesized that genetic variants in DSB repair genes contribute to individual variation in susceptibility to SGC. To test this hypothesis, we conducted a case-control study in which we analyzed 415 single nucleotide polymorphisms (SNPs) in 45 DSB repair genes in 352 SGC cases and 598 controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Rs3748522 in RAD52 and rs13180356 in XRCC4 were significantly associated with SGC after Bonferroni adjustment; ORs (95% CIs) for the variant alleles of these SNPs were 1.71 (1.40-2.09, P=1.70 × 10-7) and 0.58 (0.45-0.74, P=2.00 × 10-5) respectively. The genetic effects were modulated by histological subtype. The association of RAD52-rs3748522 with SGC was strongest for mucoepidermoid carcinoma (OR=2.21, 95% CI: 1.55-3.15, P=1.25 × 10-5, n=74), and the association of XRCC4-rs13180356 with SGC was strongest for adenoid cystic carcinoma (OR=0.60, 95% CI: 0.42-0.87, P=6.91 × 10-3, n=123). Gene-level association analysis revealed one gene, PRKDC, with a marginally significant association with SGC risk in non-Hispanic whites. To our knowledge, this study is the first to comprehensively evaluate the genetic effect of DSB repair genes on SGC risk. Our results indicate that genetic variants in the DSB repair pathways contribute to inter-individual differences in susceptibility to SGC and show that the impact of genetic variants differs by histological subtype. Independent studies are warranted to confirm these findings.
doi:10.1371/journal.pone.0128753
PMCID: PMC4452711  PMID: 26035306
16.  Epidemiology of HPV-associated oropharyngeal cancer 
Oral oncology  2014;50(5):380-386.
Squamous cell carcinoma of the oropharynx is increasing in incidence in epidemic proportion. This site specific increase in incidence is due to an increase in human papillomavirus (HPV)-related squamous cell carcinoma, while the incidence of tobacco related squamous cell carcinoma is decreasing. In particular, the incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is increased among middle aged white men, and sexual behavior is a risk factor. HPV-related oropharyngeal squamous cell carcinoma represents a growing etiologically distinct subset of head and neck cancers with unique epidemiological, clinical, and molecular characteristics that differ from those of HPV-unassociated cancers. In this review, we discuss the epidemiology of HPV-related OPSCC, the prevalence of oral/oropharyngeal HPV infection, and efforts aimed at reducing the incidence of HPV-related OPSCC.
doi:10.1016/j.oraloncology.2013.12.019
PMCID: PMC4444216  PMID: 24461628
human papillomavirus; oropharyngeal cancer; epidemiology
17.  Genetic variants in TNF-α promoter are predictors of recurrence in patients with squamous cell carcinoma of oropharynx after definitive radiotherapy 
The promoter variants of TNF-α, a major regulator of immune and inflammation responses, have been implicated in cancer development and prognosis. Thus, we investigated associations between four TNF-α promoter variants and risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated associations of four TNF-α polymorphisms with risk of recurrence in a cohort of 846 patients with SCCOP. Log-rank test and multivariable Cox models were used to evaluate associations. Compared with patients with variant genotypes of the TNF-α −308 and TNF-α −863 polymorphisms, patients with common homozygous genotypes had worse disease-free survival (log-rank P = 0.0002 and P < 0.0001, respectively) and increased risk of SCCOP recurrence (HR, 1.9, 95% CI, 1.3–2.8 and HR, 1.9, 95% CI, 1.3–2.7, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of the TNF-α −308 and −863 polymorphisms had worse disease-free survival (log-rank P = 0.005 and P = 0.007, respectively) and higher recurrence risk than patients with variant genotypes of these polymorphisms (HR, 5.1, 95% CI, 1.4–18.4 and HR, 3.7, 95% CI, 1.5–9.1, respectively), while no such significant associations were found for TNF-α −857 or −1031 polymorphisms. Our findings suggest that TNF-α −308 and −863 polymorphisms may modulate the risk of SCCOP recurrence in patients with HPV16-positive tumors. However, larger studies are needed to validate these results.
doi:10.1002/ijc.28512
PMCID: PMC3947426  PMID: 24122460
TNF-α variant; recurrence; genetic polymorphisms; biomarkers; human papillomavirus; head and neck cancer; oropharyngeal cancer
18.  Trends in Thyroid Cancer Incidence in Texas from 1995 to 2008 by Socioeconomic Status and Race/Ethnicity 
Thyroid  2014;24(3):556-567.
Background: Thyroid cancer incidence is increasing, potentially due to enhanced diagnostic practices. However, access to healthcare may be dependent on socioeconomic status (SES) and race/ethnicity. Consequently, certain segments of the population may experience thyroid cancer overdiagnosis as a result of greater access to and use of enhanced diagnostic technology. The current study examined trends by SES in thyroid cancer incidence at the census tract level from 1995 to 2008 for the population of Texas, as well as by racial/ethnic subgroup.
Methods: Joinpoint regressions were used to examine incidence trends over time by SES for the study population, and for the non-Hispanic white, non-Hispanic black, and Hispanic subgroups separately. Other race/ethnicities were not adequately represented for subgroup analyses.
Results: There were 22,390 incident thyroid cancer cases (65.0% white, 6.7% black, 24.3% Hispanic, 4.1% Asian/other races; 85.9% papillary histology). The low SES group experienced a steady increase in incidence since 1995 (6.7% per year, p<0.05), whereas incidence among the high SES group has increased at a rate of 8.6% per year since 1999 (p<0.05). The joinpoint projected incidence trends for the low and high SES groups were significantly different (p=0.047). Whites experienced a steady increase in incidence over time among both high and low SES groups (7.6% per year p<0.05), whereas blacks and Hispanics of higher SES had a much more pronounced increase in incidence over time relative to their lower SES counterparts (blacks=12.8% vs. 4.1%; Hispanics=11.2% vs. 8.3%, p<0.05). For blacks and Hispanics, joinpoint projected incidence trends for the low and high SES groups were significantly different from one another (p<0.001–0.004).
Conclusions: These results identify groups experiencing the greatest problem of increasing thyroid cancer incidence, and raise concern that greater access to healthcare may be accompanied by thyroid cancer overdiagnosis. A dual focus on delineating and preventing disease-related causal factors and focusing clinical attention on avoiding overdiagnosis among certain populations (e.g., high SES) may be advisable to address thyroid cancer in Texas. Clinicians are encouraged to adhere to ATA/NCCN guidelines when choosing patients for thyroid ultrasound, selecting which nodules to examine, and deciding which patients should proceed to biopsy.
doi:10.1089/thy.2013.0284
PMCID: PMC3949437  PMID: 24063701
19.  Prospective Imaging Biomarker Assessment of Mortality Risk in Patients Treated with Head and Neck Radiotherapy 
Purpose
The optimal roles for imaging-based biomarkers in the management of head and neck cancer remain undefined. Unresolved questions include whether functional or anatomic imaging biomarkers might improve mortality risk assessment for this disease. We addressed these issues in a prospective institutional trial.
Methods and Materials
Ninety-eight patients with locally advanced pharyngolaryngeal squamous cell cancer were enrolled. Each underwent pre-and post-chemoradiotherapy contrast-enhanced CT and FDG-PET/CT imaging. Imaging parameters were correlated with survival outcomes.
Results
Low post-radiation primary tumor FDG avidity correlated with improved survival on multivariate analysis; so too did complete primary tumor response by CT alone. Although both imaging modalities lacked sensitivity, each had high specificity and negative predictive value for disease-specific mortality risk assessment. Kaplan-Meier estimates confirmed that both CT and FDG-PET/CT stratify patients into distinct high- and low-probability survivorship groups on the basis of primary tumor response to radiotherapy. Subset analyses demonstrated that the prognostic value for each biomarker was primarily derived from patients at high risk for local treatment failure (HPV-negative disease, non-oropharyngeal primary disease, or tobacco use).
Conclusions
CT- and FDG-PET/CT-based biomarkers are useful clinical tools in head and neck cancer-specific mortality risk assessment following radiotherapy, particularly for high-risk HPV-unrelated disease. Focus should be placed on further refinement and corroboration of imaging-based biomarkers in future studies.
doi:10.1016/j.ijrobp.2009.08.063
PMCID: PMC3072063  PMID: 20171802
Radiotherapy; head and neck cancer; PET; CT; survival
20.  Potentially functional variants of p14 ARF are associated with HPV-positive oropharyngeal cancer patients and survival after definitive chemoradiotherapy 
Carcinogenesis  2013;35(1):62-68.
Since p14 ARF and human papillomavirus (HPV) 16 E6/E7 oncoproteins are important regulators participating in the p53/Rb pathways, genetic variations of p14 ARF may modify tumor HPV16 status and survival of HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) patients. We determined tumor HPV16 status and expression of p14/p53 and genotyped p14 ARF-rs3731217 and -rs3088440 polymorphisms in 552 incident SCCOP patients. We found that patients having variant genotypes for each p14 ARF polymorphism were approximately two or three times as likely to have HPV16-positive tumors compared with patients with corresponding common homozygous genotype, and such an association was particularly pronounced in patients with variant genotypes of both polymorphisms. After definitive chemoradiotherapy, patients having p14 ARF rs3731217 TG/GG variant genotypes had significantly better overall, disease-specific and disease-free survival than those having TT genotype, respectively. Multivariable analysis found that patients with p14 ARF-rs3731217 TT genotype had an ~7-, 11- and 3-fold increased risk for death overall, death due to SCCOP and recurrence than those with TG/GG variant genotypes, respectively. Furthermore, such significantly prognostic effect was also found when survival analysis was limited to HPV16-positive patients. Additionally, potentially functional relevance of the two variants was characterized to explore the genotype–phenotype correlation. Our findings indicate p14 ARF variants may predict tumor HPV16-positive SCCOP patients and survival.
doi:10.1093/carcin/bgt336
PMCID: PMC3871940  PMID: 24104554
21.  Association of marijuana smoking with oropharyngeal and oral tongue cancers: Pooled analysis from the INHANCE Consortium 
Background
The incidence of oropharyngeal and oral tongue cancers have increased over the last twenty years which parallels increased use of marijuana among individuals born after 1950.
Methods
Pooled analysis of individual-level data from nine case-control studies from the U.S. and Latin America in the INHANCE consortium. Self-reported information on marijuana smoking, demographic, and behavioral factors was obtained from 1,921 oropharyngeal cases, 356 oral tongue cases, and 7,639 controls.
Results
Compared with never marijuana smokers, ever marijuana smokers had an elevated risk of oropharyngeal (adjusted odds ratio [aOR]: 1.24; 95% confidence interval [CI]: 1.06, 1.47) and a reduced risk of oral tongue cancer (aOR: 0.47; 95% CI: 0.29, 0.75). The risk of oropharyngeal cancer remained elevated among never tobacco and alcohol users. The risk of oral tongue cancer decreased with increasing frequency (ptrend=0.005), duration (ptrend=0.002), and joint-years of marijuana use (ptrend=0.004), and was reduced among never users tobacco and alcohol users. Sensitivity analysis adjusting for potential confounding by HPV exposure attenuated the association of marijuana use with oropharyngeal cancer (aOR: 0.99; 95% CI: 0.71, 1.25), but had no effect on the oral tongue cancer association.
Conclusions
These results suggest that the association of marijuana use with Head and Neck Carcinoma may differ by tumor site.
Impact
The associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with both possible pro- and anti-carcinogenic effects of cannabinoids. Additional work is needed to rule out various sources of bias, including residual confounding by HPV infection and misclassification of marijuana exposure.
doi:10.1158/1055-9965.EPI-13-0181
PMCID: PMC3947141  PMID: 24351902
marijuana; oropharynx; oral tongue; INHANCE; human papillomavirus
22.  Telomere length in peripheral blood lymphocytes contributes to the development of HPV-associated oropharyngeal carcinoma 
Cancer research  2013;73(19):5996-6003.
Sexual transmission of human papillomavirus, particularly HPV16, has been associated with an increasing incidence of oropharyngeal squamous cell carcinoma (OPC). Telomere shortening results in chromosomal instability, subsequently leading to cancer development. Given that HPV16 can affect telomerase activity and telomere length (TL), we conjectured that TL in peripheral blood lymphocytes (PBLs) may affect the risk of HPV16-associated OPC and tumor HPV16 status in patients. TL in PBLs and HPV16 serological status were measured in peripheral blood samples in 188 patients with OPC, 137 patients with oral cavity cancer (OCC) and 335 controls of non-Hispanic whites. Tumor HPV status was determined in 349 OPC cases. Odds ratios and 95% confidence intervals were calculated in univariate and multivariable logistic regression models. Overall, compared with long TL, short TL was associated significantly with a moderately increased risk of OPC but no increased risk of OCC. When we stratified the data by HPV16 serological status, using long TL and HPV16 seronegativity as the reference group, we found that the risk associated with HPV16 seropositivity was higher among OPC patients with short TL. Notably, such risk was particularly pronounced in never smokers, never drinkers and those >50 years of age. Furthermore, short TL was also associated significantly with tumor HPV-positive OPC. Together, our findings suggest that TL in PBLs may be associated with higher risk of HPV16-associated OPC and tumor HPV16 status, particularly in certain patient subgroups. Larger studies are needed to validate these findings.
doi:10.1158/0008-5472.CAN-13-0881
PMCID: PMC3790860  PMID: 23928994
telomere length; HPV; molecular epidemiology; oropharyngeal cancer
23.  Differences in Imaging Characteristics of HPV-Positive and HPV-Negative Oropharyngeal Cancers: A Blinded Matched-Pair Analysis 
BACKGROUND AND PURPOSE
Human papillomavirus–positive oropharyngeal cancers typically have younger age of onset, limited tobacco exposure, and more favorable prognosis than HPV-negative oropharyngeal cancers. We assessed whether HPV-positive and HPV-negative oropharyngeal cancers have consistent differences in pretreatment imaging characteristics.
MATERIALS AND METHODS
A retrospective review of 136 pretreatment CT examinations of paired HPV-positive and HPV-negative oropharyngeal cancers matched for T stage, tumor subsite, and smoking status was performed with the reviewing radiologist blinded to HPV status and clinical stage. Demographic/clinical characteristics and imaging characteristics of primary lesions and metastatic nodal disease were compared by use of Fisher exact testing. The McNemar χ2 test was used for the matched-pair analysis.
RESULTS
By imaging, HPV-negative tumors were more likely to demonstrate invasion of adjacent muscle (26% versus 6%, P = .013). HPV-positive primary tumors were more likely to be enhancing and exophytic with well-defined borders, whereas HPV-negative primary tumors were more likely to be isoattenuated and demonstrate ill-defined borders, though these results were not statistically significant. HPV-positive tumors were more likely to demonstrate cystic nodal metastases than HPV-negative tumors (36% versus 9%, P = .002).
CONCLUSIONS
In this matched and blinded analysis of the imaging differences between HPV-positive and HPV-negative oropharyngeal cancers, HPV-positive carcinomas often had primary lesions with well-defined borders and cystic nodal metastases, whereas HPV-negative primaries more often had poorly defined borders and invasion of adjacent muscle.
doi:10.3174/ajnr.A3524
PMCID: PMC3951375  PMID: 23660291
24.  Cigarette, Cigar, and Pipe Smoking and the Risk of Head and Neck Cancers: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium 
American Journal of Epidemiology  2013;178(5):679-690.
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.
doi:10.1093/aje/kwt029
PMCID: PMC3755640  PMID: 23817919
head and neck neoplasms; smoking
25.  The Impact of Radiographic Retropharyngeal Adenopathy in Oropharyngeal Cancer 
Cancer  2013;119(17):3162-3169.
Background
We carried out this study to define the incidence of radiographic retropharyngeal lymph node (RPLN) involvement in oropharyngeal cancer (OPC) and its impact on clinical outcomes, which have not been well established to date.
Methods
Our departmental database was queried for patients irradiated for OPC from 2001–2007. Analyzable patients were those with imaging data available for review to determine radiographic RPLN status. Demographic, clinical, and outcomes data were retrieved and analyzed.
Results
The cohort consisted of 981 patients. Median follow up was 69 months. The base of tongue (47%) and tonsil (46%) were the most common primary sites. The majority of patients had T1-2 primaries (64%) and 94% stage 3-4B disease. IMRT was used in 77%, and systemic therapy was delivered to 58%. The incidence of radiographic RPLN involvement was 10% and highest for pharyngeal wall (23%) and lowest for base of tongue tumors (6%). RPLN adenopathy correlated with a number of patient and tumor factors. RPLN involvement was associated with poorer 5-year outcomes on univariate analysis (p <.001 for all): local control (79% vs. 92%), nodal control (80% vs. 93%), recurrence-free (51% vs. 81%), distant metastases-free (66% vs. 89%), and overall survival (52% vs. 82%), and maintained significance for local control (p=.023), recurrence-free (p=.001), distant metastases-free (p=.003), and overall survival (p=.001) on multivariate analysis.
Conclusions
In this cohort of nearly 1000 patients investigating radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends a negative influence on disease recurrence, distant relapse, and survival.
doi:10.1002/cncr.28195
PMCID: PMC3775996  PMID: 23733178
Oropharyngeal cancer; retropharyngeal lymph nodes; incidence; radiation therapy; survival

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