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Background: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed.Methods: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined.Results: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 × 10−6), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 × 10−4). DNA methylation profiles did not differ by recurrence status for the other genes.Conclusions: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence.Impact: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence. Cancer Epidemiol Biomarkers Prev; 23(7); 1331–9. ©2014 AACR.

Background: The matrix metalloproteinases (MMP) cause degradation of the extracellular matrix and basement membranes, and thus may play a key role in cancer development.Methods: In our search for biomarkers for oral squamous cell carcinomas (OSCC), we compared primary OSCC, oral dysplasia and control subjects with respect to: (i) expression of MMP1, MMP3, MMP10, and MMP12 in oral epithelial tissue using Affymetrix U133 2.0 Plus GeneChip arrays, followed by quantitative reverse transcription-PCR (qRT-PCR) for MMP1, and (ii) determination of MMP1 and MMP3 concentrations in saliva.Results:MMP1 expression in primary OSCC (n = 119) was >200-fold higher (P = 7.16 × 10−40) compared with expression levels in nonneoplastic oral epithelium from controls (n = 35). qRT-PCR results on 30 cases and 22 controls confirmed this substantial differential expression. The exceptional discriminatory power to separate OSCC from controls was validated in two independent testing sets (AUC% = 100; 95% CI: 100–100 and AUC% = 98.4; 95% CI: 95.6–100). Salivary concentrations of MMP1 and MMP3 in OSCC patients (33 stage I/II, 26 stage III/IV) were 6.2 times (95% CI: 3.32–11.73) and 14.8 times (95% CI: 6.75–32.56) higher, respectively, than in controls, and displayed an increasing trend with higher stage disease.Conclusion: Tumor and salivary MMPs are robust diagnostic biomarkers of OSCC.Impact: The capacity of MMP gene expression to identify OSCC provides support for further investigation into MMPs as potential markers for OSCC development. Detection of MMP proteins in saliva in particular may provide a promising means to detect and monitor OSCC noninvasively. Cancer Epidemiol Biomarkers Prev; 20(12); 2628–36. ©2011 AACR.

PDF file - 57K, Genes with over 50% of the 5' region CpG sites having higher methylation in tumor tissue from prostate cancer patients with recurrence versus no recurrence.

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Background: A history of diabetes is associated with an increased risk of several types of cancers. Whether diabetes is a risk factor for head and neck cancer (HNC) has received little attention.Methods: We pooled data from 12 case–control studies including 6,448 cases and 13,747 controls, and estimated OR and 95% CI for the associations between diabetes and HNC, adjusted for age, education level, sex, race/ethnicity, study center, cigarette smoking, alcohol use, and body mass index.Results: We observed a weak association between diabetes and the incidence of HNC overall (OR, 1.09; 95% CI: 0.95–1.24). However, we observed a modest association among never smokers (OR, 1.59; 95% CI: 1.22–2.07), and no association among ever smokers (OR, 0.96; 95% CI: 0.83–1.11); likelihood ratio test for interaction P = 0.001.Conclusion: A history of diabetes was weakly associated with HNC overall, but we observed evidence of effect modification by smoking status, with a positive association among those who never smoked cigarettes.Impact: This study suggests that glucose metabolism abnormalities may be a HNC risk factor in subgroups of the population. Prospective studies incorporating biomarkers are needed to improve our understanding of the relationship between diabetes and HNC risk, possibly providing new strategies in the prevention of HNC. Cancer Epidemiol Biomarkers Prev; 21(2); 294–304. ©2011 AACR.

Background: Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified.Methods: To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case–control study (n = 1,155 incident prostate cancer cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry.Results: The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7; 95% CI, 1.27–5.87; P = 0.010; rs28362675: OR, 2.5; 95% CI, 1.16–5.46; P = 0.019).Conclusions: Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer.Impact: Results implicate BTNL2 as a novel prostate cancer susceptibility gene. Cancer Epidemiol Biomarkers Prev; 22(9); 1520–8. ©2013 AACR.

PDF - 59K, Legend for Supplementary Figure 1.

PDF - 51K, Summary of the whole-exome sequencing statistics for the 91 members of 19 hereditary prostate cancer families.

PDF - 61K, Information on the 22 insertion/deletions identified by whole-exome sequencing.

PDF - 109K, Information on the 174 single nucleotide variants identified by whole-exome sequencing.

PDF - 53K, Flow diagram of results from family- and bioinformatics-based filtering of whole-exome sequencing data and confirmation steps.

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Author(s): Stott-Miller, Marni; Mullerova, Hana; Miller, Bruce; Tabberer, Maggie; El Baou, Celine; Keeley, Tom; Martinez, Fernando J; Han, Meilan; Dransfield, Mark; Hansel, Nadia N; Cooper, Christopher B; Woodruff, Prescott; Ortega, Victor E; Comellas, Alejandro P; Paine Iii, Robert; Kanner, Richard E; Anderson, Wayne; Drummond, M Bradley; Kim, Victor; Tal-Singer, Ruth; Lazaar, Aili L | Abstract: BackgroundChronic cough and phlegm are frequently reported chronic obstructive pulmonary disease (COPD) symptoms. Prior research classified chronic mucus hypersecretion (CMH) based on the presence of these symptoms for ≥3 months, called chronic bronchitis (CB) if respiratory infection symptoms were present for 1-2 years (Medical Research Council [MRC] definition). We explored whether the COPD Assessment Test (CAT), a simple measure developed for routine clinical use, captures CMH populations and outcomes similarly to MRC and St. George's Respiratory Questionnaire (SGRQ) definitions.MethodsWe identified CMH in the SPIROMICS COPD cohort using (a) MRC definitions, (b) SGRQ questions for cough and phlegm (both as most/several days a week), and (c) CAT cough and phlegm questions. We determined optimal cut-points for CAT items and described exacerbation frequencies for different CMH definitions. Moderate exacerbations required a new prescription for antibiotics/oral corticosteroids or emergency department visit; severe exacerbations required hospitalization. Results were stratified by smoking status.ResultsIn a population of 1431 participants (57% male; mean FEV1% predicted 61%), 47% and 49% of evaluable participants had SGRQ- or CAT-defined CMH, respectively. A cut-point of ≥2 for cough and phlegm items defined CMH in CAT. Among SGRQ-CMH+ participants, 80% were also defined as CMH+ by the CAT. CMH+ participants were more likely to be current smokers. A higher exacerbation frequency was observed for presence of CMH+ versus CMH- in the year prior to baseline for all CMH definitions; this trend continued across 3 years of follow-up, regardless of smoking status.ConclusionItems from the CAT identified SGRQ-defined CMH, a frequent COPD trait that correlated with exacerbation frequency. The CAT is a short, simple questionnaire and a potentially valuable tool for telemedicine or real-world trials. CAT-based CMH is a novel approach for identifying clinically important characteristics in COPD that can be ascertained in these settings.

Even modest improvements in the probability of success of selecting drug targets which are ultimately approved can substantially reduce the costs of research and development. Drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. A key enabler of identifying and validating these genetically validated targets is access to association results from genome-wide genotyping, whole-exome sequencing, and whole-genome sequencing studies with observable traits (often diseases) across large numbers of individuals. Today, linkage between genotype and real-world data (RWD) provides significant opportunities to not only increase the statistical power of genome-wide association studies by ascertaining additional cases for diseases of interest, but also to improve diversity and coverage of association studies across the disease phenome. As RWD-genetics linked resources continue to grow in diversity of participants, breadth of data captured, length of observation, and number of participants, there is a greater need to leverage the experience of RWD experts, clinicians, and highly experienced geneticists together to understand which lessons and frameworks from general research using RWD sources are relevant to improve genetics-driven drug discovery and development. This paper describes new challenges and opportunities for phenotypes enabled by diverse RWD sources, considerations in the use of RWD phenotypes for disease gene identification across the disease phenome, and challenges and opportunities in leveraging RWD phenotypes in target validation. The paper concludes with views on the future directions for phenotype development using RWD, and key questions requiring further research and development to advance this nascent field.

Previous research suggests that weight loss is associated with decreases in health care costs among individuals with type 2 diabetes mellitus (T2DM) and that weight change can affect clinical measures, including hemoglobin A1c (A1c), low-density lipoprotein cholesterol (LDLC), and blood pressure. Previous research has also demonstrated more pronounced impact of weight change among patients with T2DM who are obese and have no evidence of cardiovascular disease (CVD).To (a) examine the association between weight change and all-cause and diabetes-related health care costs among patients with T2DM; (b) examine the association between weight change and select clinical measures among patients with T2DM; and (c) analyze a subgroup of obese patients with no previous CVD.This retrospective, observational cohort study used U.S. insurance claims linked to laboratory and electronic medical records. This study included patients with T2DM aged 18 years or older who added or switched to a nonmetformin antidiabetes medication after metformin monotherapy between January 1, 2007, and June 30, 2012 (date of add/switch was the index date). The primary predictor was percentage weight change (PWC) between a weight measurement at index and a follow-up measurement 6 months later; PWC ranged from negative (weight loss) to positive (weight gain). Outcomes, measured in the 12-month period beginning at the time of follow-up weight measurement, included all-cause and diabetes-related health care costs and achievement of thresholds for A1c, blood pressure, and LDL-C. Multivariable models quantified the association between PWC (linear effect) and study outcomes.A total of 1,520 patients (mean age 55 years; 47% female) were included, with 780 patients (mean age 53 years; 51% female) in the subgroup sample. Mean (SD) index weight and PWC were 224.6 (52.8) lbs and +0.2% (4.7%) in the primary analysis, and 241.3 (47.3) lbs and -0.2% (4.6%) in the subgroup sample. In adjusted analyses, decreasing PWC was associated with decreasing diabetes-specific pharmacy costs (P0.001) in the primary analysis sample and with decreasing all-cause pharmacy costs (P = 0.018), diabetes-specific total costs (P = 0.039), diabetes-specific medical costs (P = 0.002), and diabetes-specific pharmacy costs (P0.001) in the subgroup sample. PWC was not associated with all-cause total health care costs or all-cause medical costs in either sample. In adjusted analyses, decreasing PWC was also associated with increasing odds of attaining the A1c goals of6.5% (P0.001) and7.0% (P0.001) in the primary analysis sample and increasing odds of attaining the A1c goals of6.5% (P0.001),7.0% (P0.001), and8.0% (P = 0.010) in the subgroup sample. PWC was not associated with any of the other clinical measures in either of the study samples.This real-world study suggests that among patients with T2DM, weight loss over a short-term (6-month) period is associated with positive impact on attainment of A1c goals and decreased diabetes-specific pharmacy costs over the subsequent 12 months. In the subset of patients who were obese and had no previus CVD, weight loss over the 6-month period was also associated with decreased all-cause pharmacy costs, diabetes-specific medical costs, and diabetes-specific total health care costs. Future research is warranted to examine whether these associations change over longer-term periods of follow-up.This study was sponsored by AstraZeneca and Bristol-Myers Squibb. Truven Health Analytics received funding from Bristol-Myers Squibb and AstraZeneca to conduct this study. Mukherjee is an employee of Bristol-Myers Squibb. Bell and Sternhufvud are employees of AstraZeneca. Johnston, Stott-Miller, and McMorrow are employees of Truven Health Analytics. Nancy Smith is a consultant to Bristol-Myers Squibb and is employed by GreenKey Resources. Study concept was created by Mukherjee, Sternhufvud, Bell, and Johnston. Stott-Miller and McMorrow took the lead in data collection, along with Johnston, with data interpretation performed by Mukherjee, Sternhufvud, Smith, Stott-Miller, and Johnston. The manuscript was written by Mukherjee, Johnston, and Stott-Miller, along with Sternhufvud and Smith, and revised by Mukherjee, Smith, and Johnston, along with Sternhufvud and Stott-Miller.

ObjectiveTo examine the effects of belimumab initiation on healthcare resource utilisation (HCRU) and costs in SLE.MethodsThis retrospective observational cohort study used healthcare administrative claims data from the IBM MarketScan Commercial Claims and Encounters Database to identify patients with SLE billing codes who received ≥1 intravenous belimumab infusion between March 2011 and December 2015. The first belimumab administration was the ‘index date’. During the 6-month postindex period, nine belimumab infusions were recommended: three during the initiation period and six during the maintenance period. HCRU and cost data for inpatient admissions, emergency department visits, physician office visits, hospital-based outpatient visits, laboratory services, other outpatient services and outpatient pharmacy prescriptions were compared in the 6-month pre/postindex periods.ResultsOf the 1879 patients with SLE included, 43% received ≥3 intravenous initiation administrations. An average of 5.3 (SD: 2.4) of the nine recommended belimumab administrations were received within 6 months. In the 6-month preindex versus postindex periods, significant reductions were noted for inpatient hospitalisations (18% vs 9%, pConclusionsIn this study of real-world intravenous belimumab for SLE, adherence to recommended infusion schedules was low. Outpatient healthcare and associated costs were higher in the 6 months after belimumab was initiated, although inpatient costs were lower. Reasons for non-adherence with belimumab and implications should be investigated.

Objective.Oral glucocorticoid (OGC) use for rheumatoid arthritis (RA) is debated because of the adverse event (AE) profile of OGC. We evaluated the associations between cumulative doses of OGC and potential OGC-related AE, and quantified the associated healthcare expenditures.Methods.Using the MarketScan databases, patients ≥ 18 years old who have RA with continuous enrollment from January 1 to December 31, 2012 (baseline), and from January 1 to December 31, 2013 (evaluation period), were identified. Cumulative OGC dose was measured using prescription claims during the baseline period. Potential OGC-related AE (osteoporosis, fracture, aseptic necrosis of the bone, type 2 diabetes, ulcer/gastrointestinal bleeding, cataract, hospitalization for opportunistic infection, myocardial infarction, or stroke) and AE-related expenditures (2013 US$) were gathered during the evaluation period. Multivariable regression models were fitted to estimate OR of AE and incremental costs for patients with AE.Results.There were 84,357 patients analyzed, of whom 48% used OGC during the baseline period and 26% had an AE during the evaluation period. A cumulative OGC dose > 1800 mg was associated with an increased risk of any AE compared with no OGC exposure (OR 1.19, 99.65% CI 1.09–1.30). Incremental costs per patient with any AE were significantly greater for cumulative OGC dose > 1800 mg compared with no OGC exposure (incremental cost = $3528, 99.65% CI $2402–$4793).Conclusion.Chronic exposure to low to medium doses of OGC was associated with significantly increased risk of potential OGC-related AE in patients with RA, and greater cumulative OGC dose was associated with substantially higher AE-related healthcare expenditures among patients with AE.

Background: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed. Methods: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined. Results: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 × 10−6), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 × 10−4). DNA methylation profiles did not differ by recurrence status for the other genes. Conclusions: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence. Impact: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence. Cancer Epidemiol Biomarkers Prev; 23(7); 1331–9. ©2014 AACR.

Background: Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified. Methods: To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case–control study (n = 1,155 incident prostate cancer cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry. Results: The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7; 95% CI, 1.27–5.87; P = 0.010; rs28362675: OR, 2.5; 95% CI, 1.16–5.46; P = 0.019). Conclusions: Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer. Impact: Results implicate BTNL2 as a novel prostate cancer susceptibility gene. Cancer Epidemiol Biomarkers Prev; 22(9); 1520–8. ©2013 AACR.

BACKGROUND Recently, a genetic variant (rs10993994) in the MSMB gene associated with prostate cancer (PCa) risk was shown to correlate with reduced prostate secretory protein of 94 amino acids (PSP94) levels. Although the biological activity of PSP94 is unclear, one of its hypothesized functions is to protect prostatic cells from pathogens. Number of sexual partners and a history of sexually transmitted infections (STIs) have been positively associated with PCa risk, and these associations may be related to pathogen-induced chronic prostatic inflammation. Based on these observations, we investigated whether MSMB genotype modifies the PCa-sexual history association. METHODS We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the association between number of sexual partners and PCa by fitting logistic regression models, stratified by MSMB genotype, and adjusted for age, family history of PCa, and PCa screening history among 1,239 incident cases and 1,232 controls. RESULTS Compared with 1–4 female sexual partners, men with ≥15 such partners who carried the variant T allele of rs10993994 were at increased risk for PCa (OR = 1.32; 95% CI, 1.03–1.71); no association was observed in men with the CC genotype (OR = 1.03; 95% CI, 0.73–1.46; P = 0.05 for interaction). Similar estimates were observed for total sexual partners (any T allele OR = 1.37; 95% CI, 1.07–1.77; CC genotype OR = 1.11; 95% CI, 0.79–1.55; P = 0.06 for interaction). CONCLUSIONS The rs10993994 genotype in the MSMB gene modifies the association between number of sexual partners and PCa risk. These findings support a hypothesized biological mechanism whereby prostatic infection/inflammation may enhance risk of PCa. Prostate 73:1803–1809, 2013. © 2013 Wiley Periodicals, Inc.

Background Diabetes and metabolic syndrome have been found to increase the risk of various cancers. Previous studies indicated that diabetes may increase the risk of head and neck squamous cell carcinoma (HNSCC). Metabolic syndrome has not been investigated as a risk factor. We tested whether type II diabetes or metabolic syndrome were associated with HNSCC using a very large database of medical administrative records, providing the ability to investigate relatively weak effects and stratify by subgroups. Methods We identified persons diagnosed with HNSCC between 1994 and 2007 in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. We selected controls from a 5% sample of Medicare beneficiaries and frequency matched to cases on sex and duration of enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between type II diabetes/metabolic syndrome and HNSCC, adjusted for potential confounders, among 14,022 cases and 42,066 controls. Results We observed a very weak inverse association between type II diabetes and HNSCC (OR = 0.92; 95% CI, 0.88–0.96) and a moderate inverse association for metabolic syndrome (OR = 0.81; 95% CI, 0.78–0.85). Associations were modified by tobacco use, with null results for type II diabetes among never users (OR = 1.00; 95% CI, 0.95–1.06) and inverse associations among ever users (OR = 0.80; 95% CI, 0.75–0.86). Conclusions We observed moderate inverse associations between metabolic syndrome and HNSCC and weak inverse associations between type II diabetes and HNSCC, which was contrary to the evidence to date. Inadequate control for confounding factors, such as overweight/obesity, may have influenced results.

BACKGROUND Evidence suggests that high-heat cooking methods may increase the risk of prostate cancer (PCa). The addition of oil/fat, as in deep-frying, may be of particular concern, and has not specifically been investigated in relation to PCa. Potential mechanisms include the formation of potentially carcinogenic agents such as aldehydes, acrolein, heterocyclic amines, polycyclic aromatic hydrocarbons, and acrylamide. METHODS We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between tertiles of intake of deep-fried foods from a food frequency questionnaire (French fries, fried chicken, fried fish, doughnuts and snack chips) and PCa risk, adjusted for potential confounders, among 1,549 cases and 1,492 controls. We additionally examined associations with more aggressive PCa (defined as regional/distant stage, elevated Gleason score or prostate-specific antigen level). RESULTS Compared with

BACKGROUND Prostate cancer (PC) is the most frequently diagnosed non-skin malignancy in men in the Western world, yet few disease-associated mutations have been found. Recently, a low frequency recurring mutation in the HOXB13 gene was reported among both hereditary PC families and men from the general population.

A history of allergies is associated with a decreased risk of several types of cancers. Potential mechanisms include enhanced immune surveillance against tumor cells early in disease development and/or carcinogenic infectious agents. We tested whether allergies are inversely associated with oral squamous cell carcinoma (OSCC), accounting for factors that may modify the association, such as tumor site, stage, and HPV infection.We estimated odds ratios (OR) and 95 % confidence intervals (CI) for the association between allergy history (including different types of allergies) and OSCC, adjusted for potential confounders, among 400 cases and 613 controls. Analyses were also stratified by site, stage, and measures of HPV infection.We observed a weak inverse association between history of any allergy and OSCC (OR = 0.81, 95 % CI 0.61-1.08). This association was present only for allergies to airborne allergens (dust/pollen/mold) (OR = 0.67; 95 % CI 0.48-0.93). The inverse associations with airborne allergies were slightly stronger for oropharyngeal SCC (OR = 0.56; 95 % CI 0.35-0.90) than for oral cavity SCC (OR = 0.71; 95 % CI 0.49-1.05) and present only for later-stage cancers (OR = 0.42; 95 % CI 0.26-0.66) as opposed to earlier-stage cancers (OR = 0.98; 95 % CI 0.66-1.46). Inverse associations were not particularly present or stronger among HPV-16-seropositive individuals or for HPV DNA-positive OSCC.There is an inverse association between history of allergies to dust, pollen, or mold and OSCC. Whether the inverse association involves heightened immune surveillance, increased immune response to HPV or other antigen, or other carcinogenic mechanism remains to be determined in more definitive studies.

Purpose Treatment options for patients with ulcerative colitis (UC) or Crohn disease (CD) have increased considerably in recent years with the advent of new biologics, but little is known about treatment pathways in clinical practice. We aimed to characterize treatment patterns and sequences in patients with UC or CD newly initiated on a biologic or an immunosuppressant (IMS). Methods This retrospective cohort study used US health insurance claims data dated from January 1, 2009, to December 31, 2013, from patients with UC or CD newly initiated on a biologic or an IMS. Treatment patterns and sequences were described during a 24-month follow-up period. Findings Among 5543 patients with UC and 7561 patients with CD, 2403 and 4677 patients, respectively, were initiated on a biologic; 3140 and 2884 patients were initiated on an IMS. In patients initiated on a biologic, monotherapy was chosen in 71% for UC (primarily infliximab [68%]) and in 79% for CD (primarily adalimumab [52%]). Approximately one third of patients remained on the first-line biologic during the follow-up period; 69% (UC) and 70% (CD) of patients were initiated on a second-line therapy, among whom 25% (UC) and 39% (CD) received a different biologic monotherapy, suggesting intolerance, inadequate response, or loss of response to first-line therapy. In patients initiated on an IMS, 58% (UC) and 66% (CD) were initiated on monotherapy; combination therapy with a corticosteroid was prescribed in 41% (UC) and 30% (CD) of patients; and second-line therapy was initiated in 72% (UC) and 75% (CD) of patients. Implications While current treatment options seem effective in a proportion of patients with UC and CD, others require multiple lines of therapy, suggesting an unmet need for alternative treatments in UC and CD to achieve disease control.

Our objective was to evaluate whether infants born to obese or diabetic women are at higher risk of non-syndromic orofacial clefting. We conducted a population-based case–control study using Washington State birth certificate and hospitalisation data for the years 1987–2005. Cases were infants born with orofacial clefts (n = 2153) and controls infants without orofacial clefts (n = 18 070). The primary exposures were maternal obesity (body mass index ≥30) and diabetes (either pre-existing or gestational). We estimated adjusted odds ratios (ORs) to compare, for mothers of cases and controls, the proportions of obese vs. normal-weight women and diabetic vs. non-diabetic women. We additionally performed Monte Carlo-based simulation analysis to explore possible influences of biases. Obese women had a small increased risk of isolated orofacial clefts in their offspring compared with normal-body mass index women [adjusted OR 1.26; 95% confidence interval 1.03, 1.55]. Results were similar regardless of type of cleft. Bias analyses suggest that estimates may represent underlying ORs of stronger magnitude. Results for diabetic women were highly imprecise and inconsistent. We and others have observed weak associations of similar magnitude between maternal obesity and risk of nonsyndromic orofacial clefts. These results could be due to bias or residual confounding. However, it is also possible that these results represent a stronger underlying association. More precise exposure measurement could help distinguish between these two possibilities.

Bioactive compounds found in coffee and tea may delay the progression of prostate cancer. We investigated associations of pre-diagnostic coffee and tea consumption with risk of prostate cancer recurrence/progression. Study participants were men diagnosed with prostate cancer in 2002-2005 in King County, Washington, USA. We assessed the usual pattern of coffee and tea consumption two years before diagnosis date. Prostate cancer-specific outcome events were identified using a detailed follow-up survey. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). The analysis of coffee intake in relation to prostate cancer recurrence/progression included 630 patients with a median follow-up of 6.4 years, during which 140 prostate cancer recurrence/progression events were recorded. Approximately 61 % of patients consumed at least one cup of coffee per day. Coffee consumption was associated with a reduced risk of prostate cancer recurrence/progression; the adjusted HR for a parts per thousand yen4 cups/day versus a parts per thousand currency sign1 cup/week was 0.41 (95 % CI: 0.20, 0.81; p for trend = 0.01). Approximately 14 % of patients consumed one or more cups of tea per day, and tea consumption was unrelated to prostate cancer recurrence/progression. Results indicate that higher pre-diagnostic coffee consumption is associated with a lower risk of prostate cancer recurrence/progression. This finding will require replication in larger studies.

Recently, a genetic variant (rs10993994) in the MSMB gene associated with prostate cancer (PCa) risk was shown to correlate with reduced prostate secretory protein of 94 amino acids (PSP94) levels. Although the biological activity of PSP94 is unclear, one of its hypothesized functions is to protect prostatic cells from pathogens. Number of sexual partners and a history of sexually transmitted infections (STIs) have been positively associated with PCa risk, and these associations may be related to pathogen-induced chronic prostatic inflammation. Based on these observations, we investigated whether MSMB genotype modifies the PCa-sexual history association.We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the association between number of sexual partners and PCa by fitting logistic regression models, stratified by MSMB genotype, and adjusted for age, family history of PCa, and PCa screening history among 1,239 incident cases and 1,232 controls.Compared with 1-4 female sexual partners, men with ≥ 15 such partners who carried the variant T allele of rs10993994 were at increased risk for PCa (OR = 1.32; 95% CI, 1.03-1.71); no association was observed in men with the CC genotype (OR = 1.03; 95% CI, 0.73-1.46; P = 0.05 for interaction). Similar estimates were observed for total sexual partners (any T allele OR = 1.37; 95% CI, 1.07-1.77; CC genotype OR = 1.11; 95% CI, 0.79-1.55; P = 0.06 for interaction).The rs10993994 genotype in the MSMB gene modifies the association between number of sexual partners and PCa risk. These findings support a hypothesized biological mechanism whereby prostatic infection/inflammation may enhance risk of PCa.

Prostate cancer (PC) is the most frequently diagnosed non-skin malignancy in men in the Western world, yet few disease-associated mutations have been found. Recently, a low frequency recurring mutation in the HOXB13 gene was reported among both hereditary PC families and men from the general population.We determined the distribution and frequency of the G84E HOXB13 variant in 1,310 incipient PC cases and 1,259 age-mated controls from a population-based, case-control study of PC.The G84E mutation was more frequent in cases than controls (1.3% vs. 0.4%, respectively), and men with the HOXB13 G84E variant had a 3.3-fold higher relative risk of PC compared with noncarriers (95% CI, 1.21-8.96). There was a stronger association between the G84E variant and PC among men with no first-degree relative with PC (OR, 4.04; 95% CI, 1.12-14.51) compared to men with a family history of PC (OR, 1.49; 95% CI, 0.30-7.50; P = 0.36 for interaction). We observed some evidence of higher risk estimates associated with the variant for men with higher versus lower Gleason score (OR, 4.13; 95% CI, 1.38-12.38 vs. OR, 2.71; 95% CI, 0.88-8.30), and advanced versus local stage (OR, 4.47; 95% CI, 1.28-15.57 vs. OR, 2.98; 95% CI, 1.04-8.49), however these differences were not statistically different.These results confirm the association of a rare HOXB13 mutation with PC in the general population and suggest that this variant may be associated with features of more aggressive disease.

Background: A history of diabetes is associated with an increased risk of several types of cancers. Whether diabetes is a risk factor for head and neck cancer (HNC) has received little attention. Methods: We pooled data from 12 case–control studies including 6,448 cases and 13,747 controls, and estimated OR and 95% CI for the associations between diabetes and HNC, adjusted for age, education level, sex, race/ethnicity, study center, cigarette smoking, alcohol use, and body mass index. Results: We observed a weak association between diabetes and the incidence of HNC overall (OR, 1.09; 95% CI: 0.95–1.24). However, we observed a modest association among never smokers (OR, 1.59; 95% CI: 1.22–2.07), and no association among ever smokers (OR, 0.96; 95% CI: 0.83–1.11); likelihood ratio test for interaction P = 0.001. Conclusion: A history of diabetes was weakly associated with HNC overall, but we observed evidence of effect modification by smoking status, with a positive association among those who never smoked cigarettes. Impact: This study suggests that glucose metabolism abnormalities may be a HNC risk factor in subgroups of the population. Prospective studies incorporating biomarkers are needed to improve our understanding of the relationship between diabetes and HNC risk, possibly providing new strategies in the prevention of HNC. Cancer Epidemiol Biomarkers Prev; 21(2); 294–304. ©2011 AACR.

Background: Treatment of MM has undergone dramatic changes in the past decade. However, few studies have focused on treatment patterns among elderly patients. The present study sought to describe contemporary FL treatment patterns among elderly MM patients in a community practice setting. Methods: A retrospective cohort study of patients (≥65 years old) with newly diagnosed MM between 7/1/2011 and 5/31/2014 who had ≥1 oncologist visit within 90 days after diagnosis and ≥90 days of follow-up was conducted. Patients were selected from the Truven MarketScan Oncology Electronic Medical Records (EMR) database and followed until last visit in the EMR database or 8/31/2014, whichever occurred first. Baseline demographics and clinical characteristics were compared between treated patients and patients who did not receive anti-MM treatment in the EMR network (untreated). FL treatment included all anti-MM agents received from first anti-MM prescription/administration after initial diagnosis until the initiation of second-line treatment, which was defined as the first day of any gap in treatment >90 days or initiation of a new regimen. FL treatment patterns were characterized based on descriptive analyses of the EMR data. Time from diagnosis to FL therapy initiation and duration of FL treatment were analyzed using Kaplan-Meier (K-M) methods. Results: A total of 3,768 patients met eligibility criteria: 2,896 (77%) initiated systemic FL therapy (median age 75 years, 56% male) and 872 (23%) were untreated (median age 76 years, 49% male; Table 1). The K-M estimate of treatment rate at 12 months from MM diagnosis was 76% (Table 2). With a median follow-up of 13.2 months, 55% of patients had discontinued FL, while 34% remained on FL. Treated patients were younger (mean age 75.4 years versus 76.4 years, P Of the 2,896 treated patients, 13% received a stem cell transplant at any time. Median time from diagnosis to FL therapy initiation was 28 days (95% CI 25-31; Table 2). The most common FL therapy was bortezomib +/- steroids (44%), followed by steroids only (14%), lenalidomide +/- steroids (13%), bortezomib + lenalidomide +/- steroids (10%), bortezomib + cyclophosphamide +/- steroids (8%), carfilzomib- or pomalidomide-containing regimens (4%), and conventional chemotherapy (4%). During FL therapy, 14% switched therapies. 17% of those who were treated with bortezomib + lenalidomide +/- steroids and 10% of those treated with bortezomib + cyclophosphamide +/- steroids received maintenance therapy. Median duration of FL treatment was 196 days (95% CI 180-208; Table 2). Conclusions: Results suggest that almost one-quarter of elderly patients newly diagnosed with MM remain untreated. In addition, about 20% of those treated in FL received suboptimal therapy (i.e., chemotherapy or steroids). Despite the advances in the treatment of MM with the availability of proteasome inhibitors/immunomodulatory agents, there still seems to be an unmet need in this patient population for novel therapies in the FL setting, especially for elderly patients who are at higher risk of comorbidities and clinical complications. Table 1. Demographics and baseline clinical characteristics of newly diagnosed MM patients Treated Patients n=2,896 Untreated Patients n=872 P Age at diagnosis, years (mean, SD) 75.4 6.9 76.4 7.3 Table 2. K-M estimates of time from diagnosis to FL initiation and FL duration of treatment K-M Estimate 95% CI Median time to therapy initiation, days 28 25-31 % patients treated at 3 months 65% 63-66% % patients treated at 6 months 70% 69-72% % patients treated at 9 months 73% 71-74% % patients treated at 12 months 76% 74-77% Median duration of FL treatment, days 196 180-208 Still on treatment at 3 months 74% 72-75% Still on treatment at 6 months 52% 50-54% Still on treatment at 9 months 41% 39-43% Still on treatment at 12 months 35% 33-37% Disclosures Farr: Truven Health Analytics: Employment, Other: I am employed by Truven Health Analytics which received funding from Bristol-Myers Squibb to conduct this analysis.. Stott-Miller:Truven Health Analytics: Employment, Other: I am an employee of Truven Health Analytics which received funding from Bristol-Myers Squibb to conduct this analysis.. Varker:Truven Health Analytics: Employment, Other: I am an employee of Truven Health Analytics which received funding from Bristol-Myers Squibb to conduct this analysis.. Spencer:Truven Health Analytics: Employment, Other: I am an employee of Truven Health Analytics which received funding from Bristol-Myers Squibb to conduct this analysis.. Shah:Bristol-Myers Squibb: Employment, Other: Stocks. Chen:Bristol-Myers Squibb: Employment.

Background: With more targeted agents in development, the treatment of relapsed/refractory MM has become more complicated and, as a consequence, has resulted in great heterogeneity in treatment patterns. Little is known about treatment sequences in the US community practice setting for elderly patients. The goal of this study was to describe treatment sequencing patterns in elderly MM patients. Methods: A retrospective cohort study of patients (≥65 years old) with newly diagnosed MM between 7/1/2011 and 5/31/2014 who had ≥2 oncologist visits within 90 days after diagnosis and ≥90 days of follow-up was conducted. Patients were selected from the Truven MarketScan Oncology Electronic Medical Records (EMR) database and followed until last visit in the EMR database or 8/31/2014, whichever occurred first. First-line (1L) treatment included treatment that a patient received since first anti-MM prescription/administration. For any given line of therapy, the end of treatment was defined as the first day of any gap in treatment >90 days or initiation of a new regimen. Treatment patterns for 1L, second-line (2L), and third-line (3L) treatment were described. Duration of treatment and treatment-free intervals were analyzed using Kaplan-Meier (K-M) methods. Results: 2,896 MM patients met the selection criteria and initiated anti-MM therapy in the study period. Of these, 1,032 (36%) patients (median age 75 years, 55% male) received 2L treatment and 352 (12%) received 3L treatment. The median patient follow-up for those who received 2L treatment was 19.2 months. Of the 1,032 patients with 2L treatment, 715 (69%) received a proteasome inhibitor (PI=bortezomib, carfilzomib) or an immunomodulatory drug (IMiD=lenalidomide, pomalidomide, thalidomide) and 317 (31%) received conventional chemotherapy (CT) or steroid (S) only (Table 1). 16% received a stem cell transplant at any time. Of the 352 patients with 3L treatment, 227 (64%) received a PI or IMiD, and 125 (36%) received CT or S only (Table 1). The use of carfilzomib and pomalidomide increased slightly from 1L to 3L (Table 2). Of the 374 patients who received 2L IMiD, over 80% received a PI or IMiD in 1L treatment (PI: 45%, IMiD: 22%, both: 15%); of those who received an IMiD in both 1L and 2L, 86% repeated the IMiD received in 1L and 9% switched to pomalidomide. Of the 307 patients who received 2L PI, >80% received a PI or IMiD in 1L treatment (PI: 57%, IMiD: 22%, both: 5%); of those who received a PI in both 1L and 2L, 72% repeated the PI received in 1L and 26% switched to carfilzomib. Similarly, of the 124 patients who received 3L IMiD, most received a PI or IMiD in 2L (PI: 13%, IMiD: 47%, both: 3%). The same was true of the 92 patients who received 3L PI (PI: 28%, IMiD: 45%, both: 3% in 2L treatment). Of the 352 patients with 1L-3L treatment, 93% received a PI or IMiD in 1L, 2L, or 3L; 32% had a PI or IMiD in all 3 lines. Median duration of 1L, 2L, and 3L treatment was 196, 148, and 124 days, respectively (Table 3). Median treatment-free interval from end of 1L to initiation of 2L, and from end of 2L to initiation of 3L, was 175 and 137 days, respectively (Table 3). Conclusions: The data suggest that elderly MM patients run out of treatment options when they fail 1L/2L treatment; therefore, duration of treatment as well as treatment-free interval decreases as disease progresses. These findings highlight the unmet needs for newer therapies in elderly MM patients who fail prior anti-MM treatment. Table 1. 2L and 3L treatment for first- and second-relapsed elderly MM patients PI or IMiD, n (%) CT, n (%) S, n (%) n All PI only IMiD only Both 2L 1,032 715 (69) 307 (30) 374 (36) 34 (3) 78 (8) 239 (23) 3L 352 227 (64) 92 (26) 124 (35) 11 (3) 26 (7) 99 (28) Table 2. Use of carfilzomib and pomalidomide among the 1,032 patients in 1L, 2L and 3L treatment Treatment n Carfilzomib, n (%) Pomalidomide, n (%) 1L 2,896 99 (3) 15 (1) 2L 1,032 72 (7) 41 (4) 3L 352 32 (9) 23 (7) Table 1. K-M estimates of duration of treatment and treatment-free interval for 1L, 2L, and 3L treatment in elderly patients with MM K-M Estimate 95% CI Treatment duration, days 1L (n=2,896) 196 180-208 2L (n=1,032) 148 127-165 3L (n=352) 124 100-194 Treatment-free interval, days 1L to 2L (n=1,596) 175 164-191 2L to 3L (n=507) 137 127-157 Disclosures Farr: Truven Health Analytics: Employment, Other: I am employed by Truven Health Analytics which received funding from Bristol-Myers Squibb to conduct this analysis. Stott-Miller:Truven Health Analytics: Employment, Other: I am an employee of Truven Health Analytics which received funding from Bristol-Myers Squibb to conduct this analysis. Varker:Truven Health Analytics: Employment, Other: I am an employee of Truven Health Analytics which received funding from Bristol-Myers Squibb to conduct this analysis. Spencer:Truven Health Analytics: Employment, Other: I am an employee of Truven Health Analytics which received funding from Bristol-Myers Squibb to conduct this analysis. Shah:Bristol-Myers Squibb: Employment, Other: Stocks. Chen:Bristol-Myers Squibb: Employment.

OBJECTIVE To assess the hypothesis that retinopathies are indicative of systemic microvascular injury. RESEARCH DESIGN AND METHODS The only U.S. national survey assessing microvascular hemorrhaging at two distinct anatomical sites was the National Health and Nutrition Examination Survey (1988–1994). The systemic microvascular injury hypothesis was assessed by modeling the association of retinal and gingival hemorrhaging and the factors that explain this association. RESULTS Individuals in whom one or more in five gingival sites was hemorrhaging had a 57% increased odds for retinal hemorrhaging (95% CI: 1.26–1.94). This association between retinal and gingival hemorrhaging was 51% explained by A1C concentrations. Retinal and gingival hemorrhaging exhibited the signature J-shaped prevalence patterns when plotted as a function of A1C concentrations. CONCLUSIONS Gingival hemorrhaging reflected on retinal hemorrhaging, and both shared chronic hyperglycemia as an explanatory marker. These epidemiological findings support the hypothesis that retinopathies are reflective of systemic microvascular injury.

Our objective was to evaluate whether infants born to obese or diabetic women are at higher risk of non-syndromic orofacial clefting. We conducted a population-based case-control study using Washington State birth certificate and hospitalisation data for the years 1987-2005. Cases were infants born with orofacial clefts (n = 2153) and controls infants without orofacial clefts (n = 18 070). The primary exposures were maternal obesity (body mass indexor =30) and diabetes (either pre-existing or gestational). We estimated adjusted odds ratios (ORs) to compare, for mothers of cases and controls, the proportions of obese vs. normal-weight women and diabetic vs. non-diabetic women. We additionally performed Monte Carlo-based simulation analysis to explore possible influences of biases. Obese women had a small increased risk of isolated orofacial clefts in their offspring compared with normal-body mass index women [adjusted OR 1.26; 95% confidence interval 1.03, 1.55]. Results were similar regardless of type of cleft. Bias analyses suggest that estimates may represent underlying ORs of stronger magnitude. Results for diabetic women were highly imprecise and inconsistent. We and others have observed weak associations of similar magnitude between maternal obesity and risk of non-syndromic orofacial clefts. These results could be due to bias or residual confounding. However, it is also possible that these results represent a stronger underlying association. More precise exposure measurement could help distinguish between these two possibilities.

OBJECTIVE: We assessed the neurodevelopment of infants with and without deformational plagiocephaly (DP), at an average age of 6 months. METHODS: The Bayley Scales of Infant Development III (BSID-III) were administered to 235 case subjects and 237 demographically similar, control participants. Three-dimensional head photographs were randomized and rated for severity of deformation by 2 craniofacial dysmorphologists who were blinded to case status. RESULTS: We excluded 2 case subjects with no photographic evidence of DP and 70 control subjects who were judged to have some degree of DP. With control for age, gender, and socioeconomic status, case subjects performed worse than control subjects on all BSID-III scales and subscales. Case subjects' average scores on the motor composite scale were ∼10 points lower than control subjects' average scores (P < .001). Differences for the cognitive and language composite scales were ∼5 points, on average (P < .001 for both scales). In subscale analyses, case subjects' gross-motor deficits were greater than their fine-motor deficits. Among case subjects, there was no association between BSID-III performance and the presence of torticollis or infant age at diagnosis. CONCLUSIONS: DP seems to be associated with early neurodevelopmental disadvantage, which is most evident in motor functions. After follow-up evaluations of this cohort at 18 and 36 months, we will assess the stability of this finding. These data do not necessarily imply that DP causes neurodevelopmental delay; they indicate only that DP is a marker of elevated risk for delays. Pediatricians should monitor closely the development of infants with this condition.

Objective To examine reading and related skills in children with and without orofacial clefts. Methods Forty-two children with orofacial clefts were recruited from an urban craniofacial center. A demographically similar sample of 43 children without clefts was recruited using community advertisements and a research registry. Participants completed assessments of basic reading, phonological awareness, phonological memory, reading fluency, and rapid naming. Parents completed a semi-structured interview regarding educational and medical history. Results Children with clefts scored significantly lower than controls on measures of basic reading, phonological memory, and reading fluency. Conclusions This is one of the first studies of reading in children with orofacial clefts to include a control sample. The findings suggest that children with clefts are less adept readers than demographically matched peers without clefts, supporting the need to monitor academic achievement in this population.

History of any type of allergy is associated with a decreased risk of multiple types of cancers, including colorectal, cervical, esophageal, pancreatic, stomach, leukemia and glioma. It is proposed that having a history of allergies may prevent cancer by enhancing immune surveillance against tumor cells early in disease development and/or against carcinogenic infectious agents. While a few prior studies suggest an inverse relationship between history of allergies and oral squamous cell carcinoma (OSCC); they did not distinguish between oropharyngeal cancer and oral cavity cancers, and did not account for HPV infection. We compared 400 OSCC cases newly diagnosed between 1985-1995 with 613 general population controls from the Seattle-Puget Sound metropolitan areas with respect to self-reported history of allergy to each of the following: dust, pollen, mold, dogs, cats, bee stings, drugs and food. We estimated odds ratios (OR) and 95% confidence intervals (CI), adjusted for age, education level, sex, race, pack years of cigarette smoking, and lifetime average alcoholic drinks per week. We observed a small inverse association between history of any allergy and OSCC (OR=0.81, 95% CI, 0.61-1.08). This inverse association was present only for dust (OR=0.70; 95% CI,0.43-1.13), pollen (OR=0.72; 95% CI,0.51-1.02) and mold (OR=0.34; 95% CI,0.14-0.83). Additional adjustment for HPV-16 seropositivity did not materially affect the estimates. In exploratory analyses, we examined associations with dust, pollen or mold more closely, and observed stronger associations with oropharyngeal cancer (OR=0.56; 95% CI, 0.35-0.90) than with oral cavity cancer (OR=0.71; 95% CI, 0.49-1.05); although a polytomous regression model did not suggest heterogeneity by site (p=0.5). There was no effect modification by sex, cigarette smoking, alcohol consumption, HPV-16 seropositivity (for all sites or oropharynx alone), or herpes simplex virus 1 seropositivity. The inverse association with dust/pollen/mold was near null for 30 cases of oncogenic HPV DNA-positive oropharyngeal cancer (OR=0.86; 95% CI, 0.38-1.94) and stronger for 46 cases of oncogenic HPV DNA-negative oropharyngeal cancer (OR=0.53; 95% CI, 0.24-1.19). These results suggest that a history of allergies to dust, pollen or mold may confer some protection against OSCC. That the inverse association was particularly apparent for oropharyngeal SCC would be consistent with heightened immune surveillance, due to the substantial amount of lymphatic tissue in this organ. Whether the inverse association involves an immune response to HPV or other antigen, or other carcinogenic mechanism, remains to be determined in more definitive studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5491. doi:1538-7445.AM2012-5491

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The matrix metalloproteinase genes have frequently been identified as important in cancer development and progression, including in oral squamous cell carcinoma (OSCC). These proteases are believed to cause degradation of the extracellular matrix and basement membranes and therefore to play a key role in tumor metastasis, cell migration, cancer cell growth, and angiogenesis. We compared MMP1 expression levels in primary OSCC (n=119) with expression levels in normal oral epithelium from control subjects (n=35), as measured by Affymetrix U133 2.0 Plus GeneChip arrays, adjusting for age and sex. MMP1 was expressed more than 200-fold higher in OSCC compared with normal control epithelium. qRT-PCR results on 30 of the cases and 22 of the controls confirmed the substantial differential expression of MMP1, with a difference in mean threshold cycle (Ct) value for cases versus controls of 9.85 (95% CI, 8.74-10.97, p

MicroRNAs (miRNAs), a group of small non-coding RNAs, regulate post transcriptional gene expression by binding to their target messenger RNAs resulting in their degradation or reduced translation. Evidence suggests that miRNAs are involved in the pathogenesis of cancer and could potentially be used as diagnostic or prognostic markers. MicroRNAs have been studied extensively in solid tumors such as breast, lung and colon cancers; however, there are few studies of miRNA in oral squamous cell carcinoma (OSCC). The purpose of this study was to investigate the potential role of miRNA in OSCC. We selected tumors from 40 patients with OSCC (10 HPV-positive oral cavity tumors, 10 HPV-negative oral cavity tumors, 10 HPV-positive oropharyngeal tumors, and 10 HPV-negative oropharyngeal tumors) and normal oral tissues from 10 patients without cancer (all HPV-negative) who were treated at three University of Washington affiliated medical centers between December 2003 and April 2007 and were enrolled in the study with informed consent. The tissues were obtained at the time of surgery and DNA and RNA were simultaneously extracted using TRIzol method (Invitrogen, Carlsbad, CA). RNA was tested using miRCURY LNATM microRNA v.11.0 (Exiqon, Vedbaek, Denmark). This array covers 1,282 mature human miRNAs and 80 viral miRNAs. Using TIGR software and significance analysis of microarrays (SAM) and a cut point of 2-fold change, we found 30 miRNAs (12 up-regulated and 18 down-regulated) differentially expressed between OSCC and controls. We found no difference in miRNA expression between HPV-positive and HPV-negative tumors, both overall and among oropharyngeal tumors. To confirm the Exiqon array results, we conducted qRT-PCR of miRNAs that had >4-fold change (miR-223: 6.2-fold; miR-21: 4.5-fold); the correlation between miRNA expression as measured by Exiqon array and qRT-PCR was 0.63 (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3052.

Background: This retrospective cohort study aimed to describe and quantify healthcare resource utilization and costs for patients with ulcerative colitis (UC) and Crohn’s disease (CD) following initiation of biologic therapy. Methods: Resource utilization and costs were analyzed at baseline and 1- and 2-years after initiating a biologic. Data were extracted from a US administrative health insurance claims database for adults ≥18 years. Eligible patients were continuously enrolled in a health plan with medical and pharmacy benefits for ≥12 months prior to, and 12 months (primary analysis) or 24 months (secondary analysis) after index date (biologic initiation). Results: In total, 4864 and 2692 patients with UC, and 8910 and 5227 patients with CD were identified in the 1- and 2-year follow-up cohorts, respectively. Of 1-year follow-up cohort patients, 45% received the same biologic initiated at index for ≥1 year. Infliximab and adalimumab were the most commonly initiated biologics in patients with UC or CD. The highest proportion of patients who continued with the same biologic after 1-and 2-years had initiated therapy with infliximab for both indications (although at the 1-year follow-up for CD, the highest proportion continued to use natalizumab, but this was a small sample [n=15]). Generally, the proportion of patients having inpatient admissions and emergency department (ED) visits decreased after receiving the same biologic for 1 year compared with baseline, although the proportion having outpatient visits did not change. Mean per patient all-cause costs for inpatient hospitalizations, ED visits and outpatient visits decreased for patients with UC or CD who received the same biologic for 1 year, while mean pharmacy costs per patient increased. Conclusions; This descriptive analysis shows that although biologics effectively reduced inpatient and ED resource utilization and corresponding costs in patients with UC and CD, total management costs increased, driven by increased pharmacy costs.