Genetic sequence variants and the development of secondary primary cancers in patients with head and neck cancers.

BACKGROUND: Secondary primary cancers (SPCs), a major cause of morbidity and mortality in head and neck cancers (HNCs), are commonly associated with field cancerization. We comprehensively evaluated 23 germline sequence variants (from published literature) in 17 genes from 7 biological pathways associated with the HNC survival. Because cancer prognosis correlates with disease aggressiveness, the factors that determine aggressive disease may influence field cancerization process to favor SPC development. We thus hypothesized that the same sequence variants associated with HNC survival can also be associated with SPC. METHODS: Germline DNA from 531 stage I-II radiation-treated HNC patients (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention clinical trial) were genotyped, and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: The majority of SPCs were of lung and HNCs. Median follow-up time was 5 years. SPCs were diagnosed in 21% of patients. The 5-year SPC-free survival was 79%. All but 1 evaluated sequence variant were not associated with SPC. There was a strong association of the DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) sequence variant, DNMT3B:C149T (rs2424913) with SPC: the adjusted hazard ratio (aHR) for TT versus CC was 2.23 (1.32-3.78; P = .003), whereas each variant T allele was associated with an aHR of 1.49 (1.15-1.95; P = .003). CONCLUSIONS: A functional sequence variant in DNMT3B is associated with the development of SPCs in HNC early stage patients treated with radiation. Aberrant DNA methylation may be an important modulator of SPC development in at-risk individuals with HNCs.

Eye care utilization by older adults in low, middle, and high income countries.

BACKGROUND: The risk of visual impairment increases dramatically with age and therefore older adults should have their eyes examined at least every 1 to 2 years. Using a world-wide, population-based dataset, we sought to determine the frequency that older people had their eyes examined. We also examined factors associated with having a recent eye exam. METHODS: The World Health Surveys were conducted in 70 countries throughout the world in 2002-2003 using a random, multi-stage, stratified, cluster sampling design. Participants 60 years and older from 52 countries (n = 35,839) were asked "When was the last time you had your eyes examined by a medical professional?". The income status of countries was estimated using gross national income per capita data from 2003 from the World Bank website. Prevalence estimates were adjusted to account for the complex sample design. RESULTS: Overall, only 18% (95% CI 17, 19) of older adults had an eye exam in the last year. The rate of an eye exam in the last year in low, lower middle, upper middle, and high income countries was 10%, 24%, 22%, and 37% respectively. Factors associated with having an eye exam in the last year included older age, female gender, more education, urban residence, greater wealth, worse self-reported health, having diabetes, and wearing glasses or contact lenses (p < 0.05). CONCLUSIONS: Given that older adults often suffer from age-related but treatable conditions, they should be seen on a regular basis to prevent visual impairment and its disabling consequences.

The gender gap in mobility: a global cross-sectional study.

BACKGROUND: Several studies have demonstrated that women have greater mobility disability than men. The goals of this research were: 1) to assess the gender gap in mobility difficulty in 70 countries; 2) to determine whether the gender gap is explained by sociodemographic and health factors; 3) to determine whether the gender gap differs across 6 regions of the world with different degrees of gender equality according to United Nations data. METHODS: Population-based data were used from the World Health Survey (WHS) conducted in 70 countries throughout the world. 276,647 adults aged 18 years and over were recruited from 6 world regions. Mobility was measured by asking the level of difficulty people had moving around in the last 30 days and then creating a dichotomous measure (no difficulty, difficulty). The human development index and the gender-related development index for each country were obtained from the United Nations Development Program website. Poisson regression with Taylor series linearized variance estimation was used. RESULTS: Women were more likely than men to report mobility difficulty (38% versus 27%, P < 0.0001). The age-adjusted prevalence rate ratio for female gender was 1.35 (95% CI 1.31-1.38). The addition of education, marital status, and urban versus rural setting reduced the prevalence rate ratio to 1.30 (95% CI 1.26-1.33). The addition of the presence of back pain, arthritis, angina, depressive symptoms, and cognitive difficulties further reduced the prevalence rate ratio to 1.12 (95% CI 1.09-1.15). There was statistical interaction on the multiplicative scale between female gender and region (P < 0.01). The Eastern Mediterranean region, which had the greatest loss of human development due to gender inequality, showed the largest gender gap in mobility difficulty, while the Western Pacific region, with the smallest loss of human development due to gender inequality, had the smallest gender gap in mobility difficulty. CONCLUSIONS: These are the first world-wide data to examine the gender gap in mobility. Differences in chronic diseases are the main reasons for this gender gap. The gender gap seems to be greater in regions with the largest loss of human development due to gender inequality.

Dietary vitamin D intake and serum 25-hydroxyvitamin D level in relation to disease outcomes in head and neck cancer patients.

Low pretreatment vitamin D status has been associated with worsened disease outcomes in patients with cancer at various sites. Its prognostic significance in head and neck cancer (HNC) patients has not been studied. Patients with HNC who participated in a randomized trial were evaluated for: (i) total intake of vitamin D from diet and supplements using a validated food frequency questionnaire (all trial participants, n = 540) and (ii) pretreatment serum 25-hydroxyvitamin D through a radioimmunoassay (n = 522). The association of dietary/serum measures of vitamin D status with HNC recurrence, second primary cancer (SPC) incidence, and overall mortality was evaluated using multivariate Cox proportional hazard models. There was no significant association between dietary or serum vitamin D measures and the three HNC outcomes. The hazard ratios (HRs) comparing the highest with the lowest quartile of dietary/supplemental vitamin D intake were 1.10 (95% confidence interval (CI): 0.66-1.84) for recurrence, 1.05 (95% CI: 0.63-1.74) for SPC, and 1.27 (95% CI: 0.87-1.84) for overall mortality. HRs comparing the uppermost to the lowest quartile of serum 25-hydroxyvitamin D levels were 1.12 (95% CI: 0.65-1.93) for recurrence, 0.72 (95% CI: 0.40-1.30) for SPC, and 0.85 (95% CI: 0.57-1.28) for overall mortality. There was no effect modification by cancer stage, season of initial treatment, or trial arm. Among patients with HNC, vitamin D status before treatment does not influence disease outcomes. Our results contrast with those from most published studies, which suggest prognostic significance of vitamin D status in cancer patients at least in subgroups.

The global burden of visual difficulty in low, middle, and high income countries.

PURPOSE: Using a world-wide, population-based dataset of adults, we sought to determine the frequency of far visual difficulty and its associated risk factors. METHODS: The World Health Survey (WHS) was conducted in 70 countries throughout the world in 2003 using a random, multi-stage, stratified, cluster sampling design of adults ages 18 years and older. Far vision was assessed by asking "In the last 30 days, how much difficulty did you have in seeing and recognizing a person you know across the road (i.e. from a distance of about 20 meters)?". Responses included none, mild, moderate, severe, or extreme/unable. The income status of countries was estimated using gross national income per capita data from 2003 from the World Bank. Prevalence and regression estimates were adjusted to account for the complex sample design. RESULTS: 21% of adults reported any visual difficulty. The rate varied by the income status of the country with the percentage who had any visual difficulty being 24%, 23%, and 13% in low, middle, and high income countries, respectively. Five percent of people reported severe or extreme visual difficulty with rates in low, middle, and high income countries of 6%, 5%, and 2% respectively. Risk factors for visual difficulty included older age, female sex, poorer socioeconomic status, little to no formal education, and diabetes (P<0.05). CONCLUSIONS: One out of five adults in the WHS reported some degree of far visual difficulty. Given the importance of vision to living an independent life, better access to quality eye care services and life course factors affecting vision health (e.g. repeated eye infections, diet lacking vitamin A) must receive adequate attention and resources, especially in low and middle income countries.

Validation of genetic sequence variants as prognostic factors in early-stage head and neck squamous cell cancer survival.

PURPOSE: From the published literature, we identified 23 germ line sequence variants in 17 genes from hypothesis-generating studies that were associated with prognosis of head and neck cancer, including sequence variants of DNA repair (ERCC1, ERCC4, ERCC5, MSH2, XPA, ERCC2, XRCC1, XRCC3), DNA methylation (DNMT3B), cell cycle and proliferation (CCND1, TP53), xenobiotic metabolism (GSTM1, GSTT1, CYP2D6), metastatic -potential (MMP3), immunologic (CTLA4), and growth factor pathways (FGFR4). The purpose of this study was to validate the role of these 23 sequence variants for overall (OS) and disease-free survival (DFS) in a large, comprehensive, well-annotated data set of patients with head and neck cancer. EXPERIMENTAL DESIGN: We genotyped these sequence variants in 531 patients with stage I and II radiation-treated head and neck cancer (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention study), and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: Two OS associations were statistically significant for each variant allele when compared with the wild-type: CTLA4: A49G [rs231775; adjusted HR (aHR), 1.32 (1.1-1.6); P = 0.01] and XRCC1: Arg339Gln [rs25487; aHR, 1.28 (1.05-1.57); P = 0.02]. Both of these sequence variants had significant results in the opposite direction as prior published literature. Two DFS associations were of borderline significance in the same direction as prior literature: ERCC2: Lys751Gln [rs13181; aHR, 0.80 (0.6-1.0); P = 0.05] and TP53: Arg72Pro [rs1042522; aHR, 1.28 (1.0-1.6); P = 0.03], comparing number of variant alleles with reference of zero variants. CONCLUSIONS: None of the prognostic sequence variants previously published was validated for OS in our patients with early-stage radiation-treated head and neck cancer, though rs1381and rs1042522 had borderline significant association with DFS.

Serum prognostic markers in head and neck cancer.

PURPOSE: Recognized prognostic factors do not adequately predict outcomes of head and neck cancer (HNC) patients after their initial treatment. We identified from the literature nine potential serum prognostic markers and assessed whether they improve outcome prediction. EXPERIMENTAL DESIGN: A pretreatment serum sample was obtained from 527 of the 540 HNC patients who participated in a randomized controlled trial. During follow-up, 115 had a HNC recurrence, 110 had a second primary cancer (SPC), and 216 died. We measured nine potential serum prognostic markers: prolactin, soluble interleukin-2 (IL-2) receptor-alpha, vascular endothelial growth factor, IL-6, squamous cell carcinoma antigen, free beta-human choriogonadotropin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and soluble epidermal growth factor receptor. Cox regression was used to identify a reference predictive model for (a) HNC recurrence, (b) SPC incidence, and (c) overall mortality. Each serum marker was added in turn to these reference models to determine by the likelihood ratio test whether it significantly improved outcome prediction. We controlled for the false discovery rate that results from multiple testing. RESULTS: IL-6 was the only serum marker that significantly improved outcome prediction. Higher levels of IL-6 were associated with a higher SPC incidence. The hazard ratio comparing the uppermost quartile to the lowest quartile of IL-6 was 2.68 (95% confidence interval, 1.49-4.08). IL-6 was also associated with SPC-specific mortality but not with mortality due to other causes. No marker improved outcome prediction for cancer recurrence or overall mortality. CONCLUSIONS: IL-6 significantly improves outcome prediction for SPC in HNC patients.

Predictors of weight loss during radiotherapy in patients with stage I or II head and neck cancer.

BACKGROUND: The purpose of the study was to identify predictors of weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer. METHODS: This study was conducted as part of a phase 3 chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Their baseline characteristics, including lifestyle habits, diet, and quality of life, were assessed as potential predictors. Predictors were identified using multiple linear regressions. The reliability of the model was assessed by bootstrap resampling. A receiver operating characteristics curve was generated to estimate the model's accuracy in predicting critical weight loss (>or=5%). RESULTS: The mean weight loss was 2.2 kg (standard deviation, 3.4). Five factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P<.001), higher pre-RT body weight (P<.001), stage II disease (P = .002), dysphagia and/or odynophagia before RT (P = .001), and a lower Karnofsky performance score (P = .028). There was no association with pre-RT lifestyle habits, diet, or quality of life. The bootstrapping method confirmed the reliability of this predictive model. The area under the curve was 71.3% (95% confidence interval, 65.8-76.9), which represents an acceptable ability of the model to predict critical weight loss. CONCLUSIONS: These results could be useful to clinicians for screening patients with early stage HN cancer treated by RT who require special nutritional attention.