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PURPOSE Impaired neurocognitive function (NCF) is extremely common in patients with higher grade primary brain tumor. We previously reported evidence of genetic variants associated with NCF in glioma patients prior to treatment. However, little is known about the effect of genetic variants on NCF decline after adjuvant therapy. METHODS Patients (N = 102) completed longitudinal NCF assessments that included measures of verbal memory, processing speed, and executive function. Testing was conducted in the postoperative period with an average follow up interval of 1.3 years. We examined polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase). RESULTS Five polymorphisms were associated with longitudinal changes in processing speed and 14 polymorphisms with executive function. Change in processing speed was strongly associated with MCPH1 rs17631450 (P = 2.2 × 10-7) and CCDC26 rs7005206 (P = 9.3 × 10-7) in the telomerase pathway; while change in executive function was more strongly associated with FANCF rs1514084 (P = 2.9 × 10-6) in the DNA repair pathway and DAOA rs12428572 (P = 2.4 × 10-5) in the cognitive pathway. Joint effect analysis found significant genetic-dosage effects for longitudinal changes in processing speed (Ptrend = 1.5 × 10-10) and executive function (Ptrend = 2.1 × 10-11). In multivariable analyses, predictors of NCF decline included progressive disease, lower baseline NCF performance, and more at-risk genetic variants, after adjusting for age, sex, education, tumor location, histology, and disease progression. CONCLUSION Our longitudinal analyses revealed that polymorphisms in telomerase, DNA repair, and cognitive pathways are independent predictors of decline in NCF in glioma patients.

ObjectivesThis study evaluated the comparative effectiveness of a tumour necrosis factor inhibitor (TNFi) versus a non-TNFi (biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs)) as the first-line treatment following conventional synthetic DMARDs, as well as potential modifiers of response, observed in US clinical practice.MethodsData were from a large US healthcare registry (Consortium of Rheumatology Researchers of North America Rheumatoid Arthritis Registry). The analysis included patients (aged ≥18 years) with a documented diagnosis of rheumatoid arthritis (RA), a valid baseline Clinical Disease Activity Index (CDAI) score of >2.8 and no prior bDMARD or tsDMARD use. Outcomes were captured at 1-year postinitiation of a TNFi (adalimumab, etanercept, certolizumab pegol, golimumab or infliximab) or a non-TNFi (abatacept, tocilizumab, rituximab, anakinra or tofacitinib) and included CDAI, 28-Joint Modified Disease Activity Score, patient-reported outcomes (including the Health Assessment Questionnaire Disability Index, EuroQol-5 Dimension score, sleep, anxiety, morning stiffness and fatigue) and rates of anaemia. Groups were propensity score-matched at baseline to account for potential confounding.ResultsThere were no statistically significant differences observed between the TNFi and non-TNFi treatment groups for outcomes assessed, except the incidence rate ratio for anaemia, which slightly favoured the TNFi group (19.04 per 100 person-years) versus the non-TNFi group (24.01 per 100 person-years, p=0.03). No potential effect modifiers were found to be statistically significant.ConclusionsThe findings of no significant differences in outcomes between first-line TNF versus first-line non-TNF groups support RA guidelines, which recommend individualised care based on clinical judgement and consideration of patient preferences.

Background The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good responders and non-responders in rheumatoid arthritis (RA). Methods Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria. A cell type-specific data analysis was conducted to evaluate the involvement of the most common immune cell sub-populations. Findings concordant between the two cohorts were further assessed for reproducibility using selected NCBI-GEO datasets and clinical laboratory measurements available in the CERTAIN database. Results A treatment-related signature suggesting a reduction in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p n = 1962) from the CERTAIN database confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03–1.41, p = 0.02]). Conclusion Differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

This study described treatment patterns in a psoriatic arthritis (PsA) patient registry for new or ongoing tumor necrosis factor inhibitor (TNFi) monotherapy, conventional synthetic disease-modifying antirheumatic drug (csDMARD) monotherapy, or TNFi/csDMARD combination therapy. This retrospective analysis included adults with PsA who enrolled in the Corrona PsA/spondyloarthritis registry between March 21, 2013 (registry initiation), and January 31, 2017, and received an approved TNFi and/or csDMARD as “existing use” starting before registry entry or “initiated use” starting on/after registry entry. Therapy persistence was defined as index therapy use for ≥ 12 months without a treatment gap of ≥ 30 days. Among the evaluable patients with existing TNFi monotherapy (n = 251), csDMARD monotherapy (n = 225), and combination therapy (n = 214), 93, 87, and 87% were persistent for ≥ 12 months, and another 6, 5, and 5%, respectively, had no change with n = 26), csDMARD monotherapy (n = 35), and combination therapy (n = 15), 50, 43, and 53% were persistent for ≥ 12 months, and another 27, 20, and 20%, respectively, had no change with

Introduction Prednisone is frequently administered in combination with other therapies for the treatment of rheumatoid arthritis (RA); however, its chronic use is associated with an increased risk of comorbidities and mortality. The objective of this analysis was to evaluate changes in prednisone use among patients with RA treated with tocilizumab (TCZ) in routine US clinical practice. Methods TCZ-naïve patients in the Corrona RA registry who initiated TCZ were included. The primary outcome was the proportion of patients with changes in prednisone use over 12 months (primary analysis) and 6 months (secondary analysis). Changes in disease activity over 6 and 12 months (± 3 months) were assessed using the Clinical Disease Activity Index (CDAI). Outcomes were assessed in the overall population and separately for patients receiving TCZ monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs. Results Of patients receiving prednisone at baseline (mean [SD] dose: 7.7 [5.2] mg/day), 30.6% discontinued prednisone over 12 months; among patients receiving > 7.5 mg of prednisone at the time of TCZ initiation, 63.0% discontinued prednisone or decreased their dose by ≥ 5 mg over 12 months. In secondary analyses, 29.7% of patients receiving prednisone at baseline had discontinued prednisone over 6 months; among those receiving > 7.5 mg of prednisone at baseline, 51.3% discontinued or decreased their dose by ≥ 5 mg over 6 months. Changes in prednisone use and improvement from baseline in CDAI score over 6 and 12 months were comparable between patients who initiated TCZ monotherapy vs. TCZ combination therapy. Conclusions In this real-world analysis, many patients initiating TCZ monotherapy or combination therapy were able to discontinue or decrease their prednisone dose over 12 months. Similar changes in prednisone dose were observed over 6 months. Trial Registration ClinicalTrials.gov identifier, NCT01402661. Funding Corrona, LLC and Genentech, Inc. Plain Language Summary Plain language summary available for this article., Plain Language Summary Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint damage and disability. The steroid prednisone is a fast-acting and effective treatment for RA and is often prescribed alongside disease-modifying antirheumatic drugs (DMARDs). The health risks associated with the long-term use of prednisone have led to recommendations to minimize prednisone dose and duration of treatment. Few studies have examined the extent to which biologic DMARDs allow rheumatologists to reduce or discontinue the use of prednisone. The objective of this study was to evaluate changes in prednisone dose while receiving tocilizumab (TCZ) in patients with RA seen in routine US clinical practice. Patients who were enrolled in the Corrona RA registry and were beginning treatment with TCZ were included. Changes in prednisone use were evaluated 12 months after starting treatment. Of patients receiving prednisone at study initiation, 30.6% had discontinued prednisone over 12 months; among patients receiving > 7.5 mg of prednisone at the time of TCZ initiation, 63.0% discontinued prednisone or decreased the dose by ≥ 5 mg over 12 months. In secondary analyses, 29.7% of patients receiving prednisone at study initiation had discontinued prednisone over 6 months; among those receiving > 7.5 mg of prednisone at baseline, 51.3% discontinued or decreased the dose by ≥ 5 mg over 6 months. Changes in prednisone use and improvement in disease activity over 6 and 12 months were comparable between patients who initiated TCZ monotherapy or combination therapy with other DMARDs.

We thank Zheng et al 1 for their interest in our study2 and for providing constructive comments. They mention that even though the baseline mean Clinical Disease Activity Index (CDAI) was not statistically different, the proportion of patients with moderate or high disease at baseline was different and this could have been a key effect modifier.1 We used standardised differences to evaluate variables at baseline. Calculation of the standardised difference not only accounts for the means of the two cohorts, but also the SD. We noticed that continuous CDAI was balanced across the two therapy classes (as listed in the manuscript table 1, SD=−0.015)2 and similarly observed for categorical CDAI (low/moderate/high; SD=0.0515; results not shown …

Objective.To characterize skin severity and joint activity outcomes and associated treatment changes in patients with psoriatic arthritis (PsA) through 12 months of follow-up after enrollment in the Corrona Psoriatic Arthritis/Spondyloarthritis (PsA/SpA) Registry.Methods.Patients ≥ 18 years of age with a diagnosis of PsA and a history of psoriasis between March 21, 2013, and September 30, 2016, were enrolled (n = 647). Demographics, clinical features, and treatment characteristics were collected and stratified by skin severity and joint activity. Change in joint and skin from enrollment to the 12-month visit was classified by change in category of Clinical Disease Activity Index (CDAI) or body surface area (BSA). Tests of association evaluated the relationship between changes in therapy and changes in skin severity and joint activity.Results.Patients with improvement in both joint activity and skin severity saw the largest median reduction in both CDAI and BSA, while those who worsened in both had the greatest median increase in both CDAI and BSA. The majority of PsA patients (> 50%) had no change in skin severity regardless if they had reduced therapy (50%), no therapy changes (54%), or increased therapy (56%; P = 0.5875). However, there was a significant association between changes in therapy and changes in joint activity (P < 0.001). Patients who increased therapy were more likely to have improvement in joint activity (32%) compared to patients who reduced therapy (22%) or had no therapy changes (11%).Conclusion.The clinical implication for our findings suggests the assessment and incorporation of both skin and joint components may be advisable.

Objective To develop and evaluate an adjusted score for the multi-biomarker disease activity (MBDA) test to account for the effects of age, sex and adiposity in patients with RA. Methods Two models were developed to adjust MBDA score for age, sex and adiposity, using either serum leptin concentration or BMI as proxies for adiposity. Two cohorts were studied. A cohort of 325 781 RA patients who had undergone commercial MBDA testing and had data for age, sex and serum leptin concentration was used for both models. A cohort of 1411 patients from five studies/registries with BMI data was used only for the BMI-adjusted MBDA score. Univariate and multivariate linear regression analyses evaluated the adjusted MBDA scores and conventional clinical measures as predictors of radiographic progression, assessed in terms of modified total Sharp score (ΔmTSS). Results Two models were developed, based on findings that MBDA score was higher in females than males and increased with age, leptin concentration and BMI. In pairwise regression analyses, the leptin-adjusted (P = 0.00066) and BMI-adjusted (P = 0.0027) MBDA scores were significant independent predictors of ΔmTSS after adjusting for DAS28-CRP, whereas DAS28-CRP was not, after adjusting for leptin-adjusted (P = 0.74) or BMI-adjusted (P = 0.87) MBDA score. Moreover, the leptin-adjusted MBDA score was a significant predictor of ΔmTSS after adjusting for the BMI-adjusted MBDA score (P = 0.025) or the original MBDA score (0.027), whereas the opposite was not true. Conclusion Leptin-adjusted MBDA score significantly adds information to DAS28-CRP and the original MBDA score in predicting radiographic progression. It may offer improved clinical utility for personalized management of RA.

Background: Melanoma and renal-cell carcinoma (RCC) are known to be immunological neoplasms. Previous studies have shown increased risks in patients with melanoma of developing RCC and in those with RCC of developing melanoma. However, data regarding immunocompromised status in these patients are lacking. Methods: We conducted a retrospective review of patients who had a diagnosis of melanoma and/or RCC. Using summary statistics, we calculated total person-years at risk for developing melanoma among patients with RCC and for developing RCC among patients with melanoma, and compared the results with the SEER data. We also assessed medical history related to immune status and the use of immunosuppressive drugs. Results: Among 13,879 patients with melanoma and 7597 patients with RCC, 89 had diagnoses of both melanoma and RCC (0.6% and 1.2% of melanoma and RCC patients, respectively): eight were diagnosed with both cancers concurrently, 54 were diagnosed with melanoma first, and 27 were diagnosed with RCC first. Standardized incidence ratios (SIRs) were 2.87 (95%CI 2.16–3.74) for developing RCC among the melanoma patients and 2.31 (95%CI 1.52–3.37) for developing melanoma among the RCC patients, compared to age-, sex-, race-, and calendar-specific adjusted incidence rates of each cancer in the SEER registry. None of the 81 patients with sequential diagnoses had a history of immunocompromised disease, nor did they receive chronic immunosuppressive drugs. Only two received chemotherapy and/or radiotherapy. Conclusion: We demonstrated a strong association between the diagnoses of melanoma and RCC. These increased risks could not be attributed to either immune status or previous antineoplastic treatment.

To compare disease burden and biologic use among psoriatic arthritis (PsA) or rheumatoid arthritis (RA) patients recruited to the Corrona registry. Retrospective study of patients with PsA or RA enrolled in Corrona between January 2002 and March 2013 and grouped in 2-year intervals. Clinical outcomes and biologic use were assessed. Biologic use increased over time in both cohorts, with 62 and 52% of patients with PsA and RA, respectively, receiving biologics by 2012-2013. However, 25 and 35% of patients with PsA and RA, respectively, continued to experience moderate/high disease activity. Overall, the progressive increase in biologic use accompanied progressive decreases in Clinical Disease Activity Index (from 14.2 to 10.4 for RA, and 12.4 to 8.1 for PsA) and mean Health Assessment Questionnaire score (from 0.36 to 0.34, and 0.3 to 0.24). Mean patient pain, the proportion of patients reporting morning stiffness, and the mean duration of morning stiffness remained similar for both cohorts. PsA and RA treated in the rheumatology setting had a comparable impact on patient quality of life and functional ability. Disease burden improved with increased biologic utilization in both groups; however, moderate/severe disease remains in a significant proportion of PsA and RA patients.

Despite the promising results of the National Lung Screening Trial in reducing lung cancer mortality among high risk smokers, several challenges remain to be addressed. These include the high false positive rates and the large number of smokers screened in order to prevent one lung cancer death. In addition, host genetic susceptibility has not been integrated into selection of who should be screened. These challenges highlight the need to develop robust ways to identify susceptible smokers for appropriate screening.We used the cytokinesis block micronucleus (CBMN) assay to assess smoking induced genetic instability among NLST participants. Blood cultures were prepared at time of entry into the screening study and DNA damage was recorded as the frequency of binucleated nucleoplasmic bridges and micronuclei. Low dose CT (LDCT) and chest X-ray (CXR) image findings were available upon unblinding of the NLST study and imaging data were merged with blood marker data for statistical analysis.A total of 641 participants were included in this study. The frequency of the CBMN endpoints at time of entry into the study was significantly higher among study participants who had a positive finding during the 3-year screening or reported lung cancer at the end of the follow-up period as compared to participants who were negative. Growth curve models were used to compare trajectories of change in CBMN endpoints between entry into the study and end-of-screening period. A statistically significant increase was predicted for CBMN endpoints among the study participants who were positive versus those who remained negative at the end-of-screening period (P

Background The prevalence of chronic obstructive pulmonary disease (COPD) in smokers enrolled as "healthy" controls in studies is 10–50%. The COPD status of ideal smoker populations for lung cancer case-control studies should be checked via spirometry; however, this is often not feasible, because no medical indications exist for asymptomatic smokers to undergo spirometry prior to study enrollment. Therefore, there is an unmet need for robust, cost effective assays for identifying undiagnosed lung disease among asymptomatic smokers. Such assays would help excluding unhealthy smokers from lung cancer case-control studies. Methods We used the cytokinesis-blocked micronucleus (CBMN) assay (a measure of genetic instability) to identify undiagnosed lung disease among asymptomatic smokers. We used a convenience population from an on-going lung cancer case-control study including smokers with lung cancer ( n = 454), smoker controls ( n = 797), and a self-reported COPD ( n = 200) contingent within the smoker controls. Results Significant differences for all CBMN endpoints were observed when comparing lung cancer to All controls (which included COPD) and Healthy controls (with no COPD). The risk ratio (RR) was increased in the COPD group vs. Healthy controls for nuclear buds (RR 1.28, 95% confidence interval 1.01–1.62), and marginally increased for micronuclei (RR 1.06, 0.98–1.89) and nucleoplasmic bridges (RR 1.07, 0.97–1.15). Conclusion These findings highlight the importance of using truly healthy controls in studies geared toward assessment of lung cancer risk. Using genetic instability biomarkers would facilitate the identification of smokers susceptible to tobacco smoke carcinogens and therefore predisposed to either disease.

Objective To characterize psoriatic arthritis (PsA) patients with dactylitis or enthesitis and evaluate the associations of these manifestations with disease activity and patient-reported outcomes. Methods Using the Corrona PsA/Spondyloarthritis Registry, patient characteristics, disease activity, and patient-reported outcomes at registry enrollment were assessed for PsA patients ages ≥18 years with or without dactylitis or enthesitis. Regression models were used to evaluate associations of dactylitis and enthesitis with outcomes, including minimal disease activity, Health Assessment Questionnaire scores, patient-reported pain and fatigue, and work productivity (Work Productivity and Activity Impairment questionnaire). Adjustments were made for age, sex, race, body mass index, disease duration, and history of biologic agent, disease-modifying antirheumatic drug, and prednisone use. Results This analysis included 1,567 PsA patients (420 with enthesitis; 228 with dactylitis). Patients with versus without dactylitis or enthesitis had greater disease activity and were less likely to be in minimal disease activity (P < 0.05). Patients with versus without enthesitis had poorer functional status as assessed by the Health Assessment Questionnaire (adjusted P = 4.15 x 10−5), greater patient-reported pain and fatigue (adjusted P < 0.0001), and greater likelihood of any impairment while working (adjusted odds ratio [OR] 1.57, P = 0.027), overall work impairment (OR 1.85, P = 0.006), and activity impairment (OR 1.77, P = 0.008). Dactylitis was associated with similar numerical trends, but differences versus patients without dactylitis did not reach statistical significance. Conclusion Enthesitis and dactylitis are associated with greater overall disease burden of PsA, underscoring the importance of identifying, assessing, and effectively managing these periarticular manifestations.

Purpose The Imaging and Radiation Oncology Core – Houston (IROC-H) Quality Assurance Center (formerly the Radiological Physics Center) has reported varying levels of compliance from their anthropomorphic phantom auditing program. IROC-H studies have suggested that one source of disagreement between institution submitted calculated doses and measurement is the accuracy of the institution's treatment planning system dose calculations and heterogeneity corrections used. In order to audit this step of the radiation therapy treatment process, an independent dose calculation tool is needed. Methods Monte Carlo multiple source models for Varian Flattening Filter Free (FFF) 6MV and FFF 10MV therapeutic x-ray beams were commissioned based on central axis depth dose data from a 10 x 10 cm2 field size and dose profiles for a 40 x 40 cm2 field size. The models were validated against open field measurements in a water tank for field sizes ranging from 3 x 3 cm2 to 40 x 40 cm2. The models were then benchmarked against IROC-H's anthropomorphic head and neck phantom and lung phantom measurements. Results Validation results, assessed with a ±2%/2mm gamma criterion, showed average agreement of 99.9% and 99.0% for central axis depth dose data for FFF 6MV and FFF 10MV models, respectively. Dose profile agreement using the same evaluation technique averaged 97.8% and 97.9% for the respective models. Phantom benchmarking comparisons were evaluated with a ±3%/2mm gamma criterion, and agreement averaged 90.1% and 90.8% for the respective models. Conclusions Multiple source models for Varian FFF 6MV and FFF 10MV beams have been developed, validated, and benchmarked for inclusion in an independent dose calculation quality assurance tool for use in clinical trial audits. This article is protected by copyright. All rights reserved.

Objective.Psoriatic arthritis (PsA) is commonly comorbid with psoriasis; the extent of skin lesions is a major contributor to psoriatic disease severity/burden. We evaluated whether extent of skin involvement with psoriasis [body surface area (BSA) > 3% vs ≤ 3%] affects overall clinical and patient-reported outcomes (PRO) in patients with PsA.Methods.Using the Corrona PsA/Spondyloarthritis Registry, patient characteristics, disease activity, and PRO at registry enrollment were assessed for patients with PsA aged ≥ 18 years with BSA > 3% versus ≤ 3%. Regression models were used to evaluate associations of BSA level with outcome [modified minimal disease activity (MDA), Health Assessment Questionnaire (HAQ) score, patient-reported pain and fatigue, and the Work Productivity and Activity Impairment questionnaire score]. Adjustments were made for age, sex, race, body mass index, disease duration, and history of biologics, disease-modifying antirheumatic drug, and prednisone use.Results.This analysis included 1240 patients with PsA with known BSA level (n = 451, BSA > 3%; n = 789, BSA ≤ 3%). After adjusting for potential confounding variables, patients with BSA > 3% versus ≤ 3% had greater patient-reported pain and fatigue and higher HAQ scores (p = 2.33 × 10−8, p = 0.002, and p = 1.21 × 10−7, respectively), were 1.7× more likely not to be in modified MDA (95% CI 1.21–2.41, p = 0.002), and were 2.1× more likely to have overall work impairment (1.37–3.21, p = 0.0001).Conclusion.These Corrona Registry data show that substantial skin involvement (BSA > 3%) is associated with greater PsA disease burden, underscoring the importance of assessing and effectively managing psoriasis in patients with PsA because this may be a contributing factor in PsA severity.

Background: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Real-world data (RWD) complement clinical trial data in assessing long-term safety. To our knowledge, this is the first long-term comparative RWD analysis of tofacitinib. Objectives: To compare 5-year adverse event (AE) incidence rates (IRs) in patients (pts) starting tofacitinib vs biological (b)DMARDs using cohorts from the US Corrona RA registry. Methods: This prospective, observational 5-year study embedded in the ongoing US Corrona RA registry routinely collected 9 categories of predefined AEs from participating physicians. Real-world safety event rates of major adverse cardiovascular events (MACE), serious infectious events (SIEs) and herpes zoster (HZ; serious and non-serious) were compared in pts with RA who started tofacitinib or a bDMARD regardless of dose/schedule between 6 Nov 2012 (US FDA approval) and 30 Jun 2017 (follow-up through 31 Dec 2017). Endpoints were selected a priori as having sufficient power to detect a 2-fold difference between cohorts at this datacut; there was insufficient power to assess malignancy. Baseline variables with a standardised difference >│0.10│ between tofacitinib and bDMARD initiators, and a priori selected covariates (gender, age, line of therapy, history of AE of interest) were used to construct propensity scores (PS) to derive a PS-trimmed (primary) population and a PS–matched population for sensitivity analysis (ratio: max. 4 bDMARD:1 tofacitinib; calliper=0.05). Pts were followed from initiation until an AE of interest, discontinuation and/or start of a new therapy +90 days, death or end of follow-up, whichever came first. Crude IRs (events/100 pt–years [PY]) were estimated; multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) comparing rates of first events between cohorts. Results: In total, 1544 tofacitinib (2138.2 PY) and 7083 bDMARD (9904.9 PY) initiators were included. PS–trimming resulted in 1117 tofacitinib and 5542 bDMARD initiators. Rates of MACE and SIEs were similar in both cohorts (Fig 1A); adjusted HRs (95% confidence intervals [CIs]) were: MACE 0.60 (0.30, 1.18); SIEs 0.99 (0.72, 1.36; Fig 1B). HZ IR was higher for tofacitinib vs bDMARDs (Fig 1A); HRs for HZ were significantly increased with tofacitinib vs bDMARDs (adjusted HR 2.12 [1.22, 3.66]; Fig 1B); all HZ events were non-serious with tofacitinib. Similar results were observed in PS-matched populations. Conclusion: This is the first comparative analysis of RWD for tofacitinib and bDMARDs to use PS-trimmed and PS-matched analyses to adjust for channelling/prescribing patterns for newly approved therapies. Pts starting tofacitinib or bDMARDs for RA had similar rates of MACE and SIEs. Tofacitinib initiators had higher HZ IRs vs bDMARD initiators. These results are consistent with long-term clinical trial findings. Acknowledgement: Sponsors: Corrona, LLC. Corrona is supported by contracted subscriptions with multiple companies. This was a Corrona/Pfizer collaboration with Pfizer financial support. Medical writing support provided by Anthony G McCluskey of CMC Connect and funded by Pfizer Inc. Disclosure of Interests: Joel Kremer Grant/research support from: AbbVie, Genentech, Lilly, Novartis, Pfizer, Consultant for: AbbVie, Amgen, BMS, Genentech, Lilly, Regeneron, Sanofi, Pfizer, Clifton Bingham Grant/research support from: BMS, Consultant for: AbbVie, BMS, Eli Lilly, Genentech/Roche, Janssen, Pfizer, Sanofi/Regeneron, Laura Cappelli Grant/research support from: Bristol-Myers Squibb, Consultant for: Regeneron/Sanofi Genzyme, Carol Etzel Shareholder of: Corrona, LLC, Consultant for: Merck, Employee of: Corrona, LLC, Jeffrey Greenberg Shareholder of: Corrona, LLC, Consultant for: Eli Lilly, Genentech, Janssen, Novartis, and Pfizer Inc, Employee of: Corrona, LLC, Jamie Geier Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ann Madsen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Connie Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Alina Onofrei Employee of: Corrona, LLC, Christine Barr Shareholder of: Corrona, LLC, Employee of: Corrona, LLC, Dimitrios A Pappas Grant/research support from: AbbVie, Consultant for: AbbVie, Employee of: Corrona, Heather J. Litman: None declared, Kimberly J Dandreo Employee of: Corrona, LLC, Andrea Shapiro Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Arthur Kavanaugh Grant/research support from: UCB Pharma

Objective.To analyze prophylaxis using the CORRONA (COnsortium of Rheumatology Researchers Of North America) Gout Registry according to the American College of Rheumatology (ACR) guidelines, and to evaluate whether differences in disease characteristics influenced prophylaxis.Methods.All patients with gout in the CORRONA Gout Registry between November 1, 2012, and November 26, 2013, were included. They were divided into 2 groups: “receiving prophylaxis” versus “not receiving prophylaxis” at the time of enrollment. Patients having a flare at time of visit were excluded. Descriptive statistics and multivariable logistic regression models were performed to evaluate the factors associated with prophylaxis.Results.There were 1049 patients with gout available for analysis. There were 441 patients (42%) receiving prophylaxis and 608 (58%) not receiving prophylaxis. The most common drugs used for prophylaxis were colchicine (78%) and nonsteroidal antiinflammatory drugs (32%). Prophylaxis drug combination was used by 45 patients (10.2%). Patients in the “receiving prophylaxis” group were more likely to have a gout duration of ≤ 1 year (n = 68, p < 0.001), ≥ 1 flare in the year previous to enrollment (p < 0.001), ≥ 1 healthcare uses in the last year [Emergency Department (p = 0.029); outpatient visit to primary care, rheumatologist, or urgent care clinic (p < 0.001)], have tophi (p < 0.001), report pain > 3 (p = 0.001), and have disease activity > 10 (p < 0.001) compared with patients in the “not receiving prophylaxis” group.Conclusion.Forty-two percent of patients with gout in the CORRONA Gout Registry were receiving prophylaxis. Prophylaxis was significantly more common in patients with a higher disease burden and activity, which is in agreement with the ACR guidelines. Our study highlights disease characteristics influencing prophylaxis and furthers our knowledge on current use of flare prophylaxis.

ObjectiveTo compare the characteristics of patients with psoriatic arthritis among patient groups stratified by degree of skin and joint involvement, and to evaluate the relationship between skin severity and joint activity.MethodsBody surface area (BSA) and Clinical Disease Activity Index (CDAI) at enrolment were analysed. Patient characteristics were stratified by skin severity and joint activity. Baseline patient characteristics, clinical and disease characteristics and patient-reported outcomes were compared. The strength of the relationship of skin severity and joint activity was evaluated using methods for categorical variables (χ2 test, Cramer’s V) and continuous variables (linear regression).Results1542 adult patients in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry enrolled between 21 May 2013 and 20 September 2016 were analysed. Most patients in the BSA >3%/CDAI moderate/high subgroup had worse clinical and patient-reported outcomes. A significant (pConclusionSkin severity is modestly correlated with joint activity, and patients with higher skin severity are two times more likely to have increased joint involvement. Clinicians need to address both skin severity and joint activity in treatment decisions.

Background The MBDA score, based on 12 serum proteins, is a validated tool for assessing disease activity in RA patients. MBDA biomarkers may be influenced by age, sex and adiposity. Objectives To develop and validate an adjusted MBDA score that accounted for these three factors, using BMI or serum leptin as proxies for adiposity. Methods The MBDA score as a continuous variable was adjusted to account for age, sex and a proxy for adiposity (serum leptin) using data from 325,781 RA patients for whom MBDA tests had been ordered as part of routine care. Leptin values came from the MBDA test. As an alternative to using leptin to adjust for adiposity, a cohort of 1411 patients from 5 studies/registries (BRASS, Corrona-CERTAIN, InFoRM, OPERA, RACER) was used to adjust for BMI, which was not available in the larger cohort, adding this BMI adjustment to that for age/sex from the larger cohort. Both types of adjusted MBDA score use the low, moderate, and high disease activity cutpoints of the original MBDA score. The two adjusted MBDA scores and other variables were evaluated for the prediction of radiographic progression (RP) in the 2 cohorts with available data (OPERA, BRASS) using univariate and multivariate linear regression analyses. Rate of RP was assessed as the change in modified total Sharp score (ΔmTSS) per year after MBDA testing. Results The MBDA score increased with age, BMI and leptin concentration. In univariate analysis of the combined OPERA and BRASS cohorts (n=555), the significant variables predicting ΔmTSS were leptin-adjusted MBDA score, seropositivity for RF or anti-CCP, BMI-adjusted MBDA score, MBDA score, BMI, CRP, baseline mTSS, disease duration, DAS28-CRP, SDAI, CDAI and DAS28* (table 1). The leptin- and BMI-adjusted MBDA scores were the first and third most significant univariate predictors of ΔmTSS. To compare them directly, DAS28-CRP, MBDA score, BMI-adjusted MBDA score and leptin-adjusted MBDA score were combined in pairs in regression analyses of ΔmTSS; the BMI-adjusted (p=0.0027) and leptin-adjusted MBDA score were significant (p=0.00063) after adjusting for DAS28-CRP (p=0.87 and 0.74, respectively) and the leptin-adjusted MBDA score was significant (p=0.024 and 0.020, respectively) after adjusting for either the MBDA (p=0.32) or BMI-adjusted MBDA scores (p=0.094). Conclusions We developed two adjusted MBDA scores that combine molecular and biometric variables to account for age, sex, and adiposity. The leptin-adjusted MBDA score, significantly outperformed DAS28-CRP and the original MBDA score in predicting radiographic progression in RA patients. These results suggest that the leptin-adjusted MBDA score may offer improved clinical utility for the personalised management of patients with RA. Disclosure of Interest J. Curtis Grant/research support from: Crescendo Bioscience Inc., Consultant for: Crescendo Bioscience Inc., D. Flake II Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience Inc., UCB, and Genzyme, Consultant for: Amgen, Bristol-Myers Squibb, Crescendo Bioscience Inc., UCP, and Genzyme, N. Shadick Grant/research support from: Bristol-Myers Squibb, Consultant for: Mallinckrodt, Amgen, Bristol-Myers Squibb, UCB, DxTerity, Sanofi, Crescendo Bioscience Inc., Janssen, and Merck, M. Ostergaard Grant/research support from: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Novartis, Orion, Pfizer, Regeneron, Roche, Takeda, and UCB, Consultant for: AbbVie, BMS, Celgene, Crescendo Bioscience Inc., Janssen, and Merck, M. Hetland Consultant for: AbbVie, Biogen, BMS, CelltrionRoche, Crescendo Bioscience Inc., Eli Lilly, MSD, Pfizer, and UCB, Speakers bureau: Orion, C. Heegaard Brahe: None declared, Y. Hwang Consultant for: Pfizer Inc., D. Furst: None declared, V. Strand Grant/research support from: Abbvie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Celltrion, CORRONA, Crescendo Bioscience Inc., EMDSerono, Genentech/Roche, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Protagen, Regeneron, Samsung, Sandoz, Sanofi, and UCB, C. Etzel Shareholder of: CORRONA, LLC, Grant/research support from: Merck, Employee of: CORRONA, LLC, D. Pappas Shareholder of: CORRONA, LLC, Employee of: CORRONA, LLC, Paid instructor for: Novartis Pharmaceutical, X. Wang Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., C. Hwang Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., E. Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., A. Gutin Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., E. Hitraya Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., J. Lanchbury Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc.

Background Until recently, treatment for moderate to severe psoriatic arthritis (PsA) mainly focused on conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and tumour necrosis factor inhibitors (TNFis). However, the persistence of TNFis alone or in combination with csDMARDs is not well understood. Objectives To assess real-word treatment patterns among patients with PsA receiving TNFi monotherapy, csDMARD monotherapy, or TNFi and csDMARD combination therapy. Methods This retrospective study utilised data from patients with PsA aged ≥18 years, enrolled in the Corrona PsA registry between March 21, 2013, and July 31, 2017, treated with a TNFi and/or csDMARD (index therapy), and with ≥6 months of follow-up time. Patients were stratified by prevalent (initiation before enrollment) or incident (initiation after enrollment) therapy use; cohorts were based on index therapy: TNFi monotherapy, csDMARD monotherapy, or combination therapy. Outcomes of interest were the percentage of patients who were persistent on their index therapy or had a therapy change (discontinued, switched, or restarted) 12 months after the index visit. Results There were 1266 patients in this study: 1144 prevalent and 122 incident (table 1). Patient characteristics at the index date were similar among patients; however, csDMARD monotherapy patients had higher disease activity than either TNFi group. Among prevalent patients, TNFi monotherapy patients were likely to be female (59%) and younger (51.9 years), nearly all patients had psoriasis, and BSA was similar and ≤5. At month 12, among patients with a follow-up visit within the 9–15–month window, the vast majority of prevalent patients and half of incident patients were persistent on their index therapy, and one quarter to one third of incident patients discontinued or switched therapy (table 1). Conclusions Most patients who were prevalent on therapy at the time of enrollment in Corrona remained persistent on their therapy for 12 months in this study, while roughly half of patients initiating therapy after enrollment remained persistent over the same period. Young, female patients were more likely to receive TNFi monotherapy; the TNFi monotherapy cohort was associated with the least disease activity. The incident group was not different from the prevalent group. Although the prevalent group is more likely to have patients who responded to treatment, the data suggest that most therapy changes occur within the first year of PsA treatment. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, and UCB, Consultant for: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, and UCB, Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer, and UCB, N. Accortt Shareholder of: Amgen Inc., Employee of: Amgen Inc., S. Rebello Employee of: Corrona LLC, C. Etzel Consultant for: Merck, Employee of: Corrona LLC, R. Harrison Employee of: Corrona LLC, G. Aras Shareholder of: Amgen Inc., Employee of: Amgen Inc., M. Gharaibeh Shareholder of: Amgen Inc., Employee of: Amgen Inc., J. Greenberg Shareholder of: Corrona LLC, Consultant for: Genentech, Janssen, Novartis, Pfizer, and Eli Lilly, Employee of: Corrona LLC, D. Collier Shareholder of: Amgen Inc., Employee of: Amgen Inc.

Background Few real-world studies have evaluated the impact of comorbidity burden or obesity on the effectiveness of tocilizumab (TCZ) for the improvement of rheumatoid arthritis (RA) disease activity. Objectives To compare the effectiveness of TCZ in treating RA in patients with high vs low comorbidity burden and in obese vs nonobese patients in US clinical practice. Methods Patients in the Corrona RA registry who initiated TCZ and had follow-up visits at 6 and 12 months after initiation were included. To assess the impact of comorbidity burden on TCZ effectiveness, outcomes were stratified by patients with low Charlson Comorbidity Index (CCI=1) vs high (CCI ≥2). To assess the impact of obesity, outcomes were stratified by patients with BMI 0.1 were identified as covariates for inclusion in adjusted comparisons. Outcomes were compared between cohorts using two-sample t-tests or χ2 tests in unadjusted analyses and linear or logistic regression models to adjust for covariates. Results Of 770 patients who initiated TCZ and had CCI data available at baseline (93.8% treated with intravenous [IV] TCZ and 6.2% with subcutaneous [SC] TCZ), 575 (74.7%) had a low CCI and 195 (25.3%) a high CCI. Patients with a high CCI were older (mean [SD] age, 61.5 [12.3] vs 56.9 [13.1] years), were more likely to be obese (52.8% vs 41.7%), had a longer disease duration (mean [SD], 12.8 [9.9] vs 11.6 [8.9] years) and had higher mean (SD) baseline CDAI (25.7 [13.4] vs 23.9 [13.9]) and HAQ (0.71 [0.57] vs 0.57 [0.51]) scores than those with a low CCI. Of the 805 TCZ initiators with BMI data available at baseline (93.9% treated with IV TCZ and 6.1% with SC TCZ), 449 (55.8%) were not obese and 356 (44.2%) were obese. Obese patients were younger (56.7 [12.0] vs 59.0 [13.7] years), had shorter disease duration (11.4 [8.6] vs 12.6 [9.7] years) and had higher baseline CDAI (25.4 [14.3] vs 23.6 [13.4]) and HAQ (0.65 [0.53] vs 0.57 [0.53]) scores than nonobese patients. Patients in all cohorts had improvement from baseline in CDAI at 6 and 12 months, with no significant differences between those with a low vs high CCI or between obese vs nonobese patients (table 1). Secondary outcomes yielded similar results (table 1). Conclusions In this real-world analysis, the effectiveness of TCZ for the improvement of RA disease activity was comparable among patients regardless of comorbidity burden or obesity. Acknowledgements This study is sponsored by Corrona, LLC. Corrona has been supported through contracted subscriptions in the last 2 years by AbbVie, Amgen, Boehringer Ingelheim, BMS, Celgene, Crescendo, Eli Lilly, Genentech, Gilead, GSK, Horizon Pharma USA, Janssen, Merck, Momenta Pharmaceuticals, Novartis, Pfizer Inc., Roche, UCB and Valeant. Disclosure of Interest D. Pappas Grant/research support from: Abbvie, Consultant for: Abbvie, Employee of: Corrona, LLC, C. Etzel Shareholder of: Corrona, LLC, Consultant for: Merck, Employee of: Corrona, LLC, M. Crabtree Employee of: Corrona, LLC, J. Best Shareholder of: Genentech, Inc., Employee of: Genentech, Inc, S. Zlotnick Shareholder of: Genentech, Inc., Employee of: Genentech, Inc, J. Kremer Shareholder of: Corrona, LLC, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Genentech, GlaxoSmithKline, Pfizer, Regeneron, Sanofi

Background Musculoskeletal ultrasound (MSUS) imaging in patients with rheumatoid arthritis (RA) can detect synovial inflammation with higher sensitivity compared to physical examination alone. 1 Not all rheumatologists have adopted the use of MSUS in their daily practice. Objectives To compare clinical outcomes in patients whose physicians use MSUS to assess joint inflammation vs those who do not. Methods Data from patients≥18 years old with a confirmed diagnosis of RA who had an index visit in the Corrona RA Registry from 01/01/2012 to 12/31/2015 with ≥12 months of follow-up were stratified into 2 groups: patients whose physicians use MSUS frequently—ie, in >50% of their patient encounters—(MSUS group) and patients whose physicians do not use MSUS at all (No-MSUS group). Frequency of MSUS can be recorded and updated by the rheumatologist in the registry questionnaires at every Corrona visit. The index visit was the first visit in which the physician reported the frequency of MSUS use. Outcomes included mean Clinical Disease Activity Index (CDAI) and the proportion of patients in low disease activity (LDA)/remission (CDAI ≤10) at each time point and were evaluated at index and 1, 2, and 3 years post-index. Comparisons between groups were made using 2-sample t -tests for mean CDAI and Chi-square tests for achievement of LDA/remission. Results 21 physicians reported using MSUS frequently compared with 111 who did not use MSUS at all. 5446 of their patients met the criteria for analysis; 1018 (18.7%) were in the MSUS group and 4428 (81.3%) were in the No-MSUS group. At the index visit, the MSUS group was younger (mean age 57.7 years vs 59.8 years, p Conclusions A greater percentage of patients whose physicians use MSUS were in LDA/remission over time. Average disease activity of these patients was lower compared with patients whose physicians did not use MSUS. This pattern was observed at 4 different time points over a 3 year period. Reference [1] Freeston, et al. Ann Rheum Dis2010;69:417–9. Acknowledgements Corrona has been supported through contracted subscriptions in the last 2 years by AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Crescendo, Eli Lilly and Company, Genentech, Gilead, GSK, Horizon Pharma USA, Janssen, Merck, Momenta Pharmaceuticals, Novartis, Pfizer Inc, Roche, UCB and Valeant. The design, study conduct, and financial support for the study was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the abstract. Medical writing services provided by Joann Hettasch of Fishawack Communications and funded by AbbVie. Disclosure of Interest D. Pappas Shareholder of: Corrona, Employee of: Corrona, Paid instructor for: Novartis, K. Saunders Shareholder of: Corrona, Employee of: Corrona, C. Etzel Shareholder of: Corrona, Employee of: Corrona, D. Hua: None declared, K. Deering Employee of: EPI-Q, P. Zueger Shareholder of: AbbVie, Employee of: AbbVie, V. Garg Shareholder of: AbbVie, Employee of: AbbVie

Performance of the ers-ra cardiovascular risk prediction tool : external validation in a large swedish cohort with ra

Objective Cardiovascular disease (CVD) is the leading cause of mortality in rheumatoid arthritis (RA), but CV risk prediction scores derived from the general population do not accurately predict CV risk in RA patients. The goal of these analyses was to develop and internally validate an expanded CV risk prediction score for RA. Methods Study participants were patients with RA and no known CVD from the Consortium of Rheumatology Researchers of North America registry. Two-thirds of the cohort were used to derive the CV risk prediction score, and one-third for internal validation. Traditional CV risk factors were included in the base Cox regression model, and RA-related variables were assessed in an expanded model predicting confirmed CV events. Fit and utility of the expanded model were evaluated. Results The study cohort included 23,605 RA patients with 437 CV events over a median followup of 2.2 years. The RA variables found to be significant in the regression models and included in the expanded risk model were disease activity (Clinical Disease Activity Index >10 versus ≤10), disability (modified Health Assessment Questionnaire disability index >0.5 versus ≤0.5), daily prednisone use (any versus none), and disease duration (≥10 years versus

Objective.Rebound may occur in patients with psoriatic arthritis (PsA) who discontinue TNF inhibitor (TNFi) therapy in low disease activity (LDA).Methods.Using physician and patient reports, we quantified rebound following TNFi discontinuation [defined as Clinical Disease Activity Index (CDAI) score > 10 or TNFi restart] and time to rebound in adults with PsA in LDA (CDAI score ≤ 10) at TNFi discontinuation.Results.Rebound occurred in 73% (69/94) of patients soon after discontinuation (median time to rebound 8.0 mos, 95% CI 6.0–12.0).Conclusion.Rebound occurred frequently in patients with PsA after TNFi discontinuation. TNFi discontinuation after achieving LDA should be carefully considered.

Background The multi-biomarker disease activity (MBDA) score measures 12 serum biomarkers to assess disease activity in patients with rheumatoid arthritis (RA) on a scale of 1–100. The MBDA score was validated in several different cohorts but has not been evaluated in a cohort consisting only of patients initiating TNF inhibitor therapy in clinical practice. We utilized patients enrolled in the Corrona-CERTAIN study to evaluate MBDA scores for patients initiating adalimumab (ADA) in several clinical practices in the US. Objectives Evaluate the ability of the MBDA score to assess response to treatment with ADA. Methods We studied 106 biologic-naive RA patients who had been treated with ADA for at least 12 months, had initiated ADA in CERTAIN while in moderate or high disease activity by CDAI, and for whom sera were available at baseline (BL) and Months 3 and 6. Changes (Δ) in MBDA score and DAS28-CRP were evaluated from BL to Months 3 and 6 by the one-sample paired t-test. ΔMBDA scores were evaluated for patients grouped by EULAR response categories, using the Cochran-Armitage test for trend. Receiver Operating Characteristic (ROC) analysis with bootstrap sampling (20,000 iterations) was used to evaluate MBDA score ability to discriminate ΔDAS28-CRP improvement >1.2 units at Month 3, and to determine the optimal MBDA threshold by maximizing the sum of sensitivity and specificity (Youden9s index criterion). Results At BL, median values were age 54.5 years, disease duration 2 years, BMI 28.2, DAS28-CRP 4.7, CDAI 24, SDAI 25.4; 74.5%/65.4% were RF+/ACPA+. Median MBDA score was 49 with 17 (16%) patients in low ( 44) MBDA categories. The relative magnitude and the direction of median change from BL to Months 3 and 6 were similar for MBDA score (−8, −9) and DAS28-CRP (−1.4, −1.8), with statistically significant changes from BL for each (line graphs in Figure). Similar results were observed for SDAI and CDAI. Pearson9s correlations with ΔMBDA score at Months 3 and 6 were 0.58, 0.59, respectively, for ΔDAS28-CRP; 0.48, 0.47 for ΔSDAI; and 0.42, 0.42 for ΔCDAI (all p 1.2 units (n=67) vs. ≤1.2 units (n=39) at Month 3 (15 vs. 2) and Month 6 (13 vs. 1.5) (both p 1.2 units at Month 3 was 0.82 (95% CI, 0.74–0.90). The optimal threshold for this discrimination was a reduction in MBDA score >9 units, with sensitivity/specificity=0.63/0.82 and PPV/NPV =0.86/0.56. Conclusions This study expands the previous validation of the MBDA score by demonstrating its ability to assess response to treatment with adalimumab in a US clinical practice cohort. The AUROC value of 0.82 for discriminating improvements in DAS28-CRP >1.2 units indicates a significant association between change in MBDA score and clinical improvement. Disclosure of Interest D. Pappas Grant/research support from: AbbVie, Consultant for: AbbVie, Employee of: CORRONA, LLC, E. Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., R. Bolce Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., X. Liu Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., C. Etzel Consultant for: Merck, Employee of: CORRONA, LLC

Background Prior studies have shown inconsistent relationships between skin and joint symptoms in patients with comorbid psoriasis (PsO) and psoriatic arthritis (PsA) 1–3 . Objectives To characterize the relationship between skin severity and joint activity in patients with comorbid PsA and PsO at enrollment. Methods Data from the U.S. Corrona PsA/spondyloarthritis (PsA/SpA) registry were obtained from the period 3/21/2013– 9/30/2016. Inclusion criteria included a diagnosis of PsA, a history of PsO, and age greater than 18 years. PsA patients were evaluated for skin severity as defined by Body Surface Area (BSA) and joint activity as defined by the level of clinical disease activity index (CDAI). Patient characteristics, including current and prior PsA medication use, were obtained during the enrollment visit. We evaluated the relationship of skin severity (BSA) and joint activity (CDAI) with multi-variable linear regression. Results 1,542 patients met inclusion criteria: 52.9% were women with mean (SD) age 53.7 (13.2) years, with median 9.0 years PsA disease duration, and 71 (4.6%) with fibromyalgia. 266 (18%) patients were on no DMARD therapy, 430 (29%) were on csDMARDs only, 616 (42%) were on first line biologic/targeted synthetic (ts)DMARD therapy, and 172 (12%) were on second line biologic/tsDMARD therapy. The relationship between skin severity and joint activity was statistically significant (p Conclusions The relationship between skin severity and joint activity is statistically significant and varies by age, gender, MDA, HAQ, and patient reported pain and fatigue. This suggests degree of skin involvement is important to take into account when evaluating PsA patients. References Gottlieb AB, Mease PJ, Mark Jackson J, Eisen D, Amy Xia H, Asare C, Stevens SR: Clinical characteristics of psoriatic arthritis and psoriasis in dermatologists9 offices. J Dermatolog Treat 2006;17:279–287. Jones SM, Armas JB, Cohen MG, Lovell CR, Evison G, McHugh NJ: Psoriatic arthritis: outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33:834–839. Cohen MR, Reda DJ, Clegg DO: Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Department of Veterans Affairs Cooperative Study Group on Seronegative Spondyloarthropathies. J Rheumatol 1999;26:1752–1756. Acknowledgements Corrona, LLC has been supported through contracted subscriptions in the last two years by AbbVie, Amgen, AstraZeneca, BMS, Crescendo, Eli Lilly and Company, Genentech, GSK, Horizon Pharma USA, Janssen, Momenta Pharmaceuticals, Novartis, Pfizer, Roche and UCB. Disclosure of Interest P. Mease Grant/research support from: Celgene, Novartis, Abbvie, Amgen, BMS, Janssen, Lilly, Pfizer, Sun, UCB, Consultant for: AbbVie, Amgen, BMS, Crescendo, Celgene, Corrona, Demira, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, Sun, Zynerba, Speakers bureau: Abbvie, Amgen, BMS, Celgene, Crescendo, Genentech, Janssen, Novartis, Pfizer, UCB, C. Etzel Consultant for: Merk, Employee of: Corrona, LLC, J. Lisse Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, A. Armstrong Grant/research support from: AbbVie, Janssen, Lilly; speaker9s bureau: AbbVie, Lilly, Consultant for: AbbVie, Amgen, Janssen, Merck, Lilly, Celgene, Novartis, and Pfizer, W. Huster Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Rebello Employee of: Corrona, LLC, R. Dodge Employee of: Corrona, LLC, T. Muram Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Al Sawah-Folian Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Murage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, J. Greenberg Shareholder of: Corrona, LLC, Consultant for: Genentech, Janssen, Novartis and Pfizer, Eli Lilly, Employee of: Corrona, LLC, W. Malatestinic Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company

Background To characterize the differences between women and men with gout. Methods We analyzed a US national cohort of gout patients cared for by rheumatologists. Results Compared with the 1012 men with gout, women with gout (n = 262) were older (71 vs. 61 years, p

BackgroundThere is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit.MethodsWe assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan–Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit.ResultsWe identified 717 eligible patients with RA from 35 656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit.ConclusionsDiscontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit.

Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case-control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68-6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13-71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05-5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26-3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3.

Objective To determine the duration of clinical benefit among patients with psoriatic arthritis (PsA) discontinuing tumour necrosis factor inhibitor (TNFi) therapy while in low disease activity (LDA), and to identify patient characteristics associated with prolonged clinical benefit. Methods We performed an observational cohort study assessing patients with PsA from the Consortium of Rheumatology Researchers of North America (CORRONA) registry who had discontinued TNFi after achieving LDA, defined as clinical disease activity index (CDAI) score ≤10 and physician's global assessment (PGA) of skin psoriasis ≤20/100. Kaplan–Meier method was used to estimate the duration of clinical benefit. Results Of the 5945 patients with PsA in CORRONA, 302 patients had discontinued TNFi (n=325) while in LDA and had follow-up data available. At time of discontinuation, mean PsA duration was 9.8 years, mean CDAI was 3.9, and mean duration of TNFi use was 1.5 years; 52.6% of patients had discontinued their first TNFi. Median time to loss of benefit was 29.2 months. 179 (55.1%) patients had persistent benefit at their previous clinic visit. An increased risk of losing clinical benefit was seen among patients with higher disease activity at discontinuation (CDAI≥3.2 vs

Several guidelines for patients with multiple endocrine neoplasia 2A (MEN2A) take into account genotype and family history of medullary thyroid carcinoma (MTC) disease aggressiveness. We sought to determine if an association exists independent of genotype, which could provide important information for counseling MEN2A patients in management of their MTC. Pedigrees of patients with ≥5 family members with MEN2A were retrospectively reviewed. Analysis was performed among kindreds with the most frequently observed codon mutation (RET 634). Familial MTC disease aggressiveness was evaluated using: (1) mean age at diagnosis of MTC, (2) current mean age of carriers without MTC, (3) proportion of kindred with MTC with metastatic disease at diagnosis, (4) proportion of kindred with MTC with metastasis/death from MTC as worst outcome, and (5) proportion of kindred with disease progression. 170 affected patients from 12 different MEN2A kindreds met inclusion criteria. The number of affected family members available for study per kindred ranged from 8 to 43 individuals. A difference in mean age of MTC diagnosis was found in screened patients (p = 0.01); mean age of MTC-free patients did not differ (p = 0.93). No differences were noted among kindreds in disease stage at presentation, worst outcome, or progression; marked variation in these measures was noted within families. In conclusion, a difference in age of MTC diagnosis among different RET 634 kindreds was identified. In contrast, notable intra-familial variability in disease aggressiveness was observed. Based on these findings, we recommend counseling patients with codon 634 mutations that their MTC disease course cannot be predicted by that of their relatives.

Purpose: The development of second primary tumors (SPT) or recurrence alters prognosis for curatively treated head and neck squamous cell carcinoma (HNSCC) patients. The 13-cis-Retinoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated whether genetic variants in the PI3K/PTEN/AKT/mTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence, while also predicting response to 13-cRA chemoprevention. Experimental Design: A total of 137 pathway single-nucleotide polymorphisms were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data. Results: Twenty-two genetic loci were associated with increased SPT/recurrence risk, with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54 × 10−4) dose–response relationship for SPT/recurrence risk, with patients carrying four to five high-risk genotypes having a 3.76-fold [95% Confidence Interval (CI), 1.87–7.57] increase in risk in the placebo group (n = 215). Patients carrying four to five high-risk loci showed the most benefit from 13-cRA chemoprevention, with a 73% reduction in SPT/recurrence (95% CI, 0.13–0.58) compared with those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables. Conclusions: These results show that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step toward personalized chemoprevention for HNSCC patients. Clin Cancer Res; 18(13); 3705–13. ©2012 AACR.

Background: Breast cancer is associated with treatment-related infertility and has been demonstrated to be a major concern for premenopausal survivors. Detection of a BRCA deleterious mutation may also affect attitudes regarding future childbearing. Preimplantation genetic diagnosis (PGD) allows women to use in vitro fertilization (IVF) to implant only those embryos without a BRCA mutation. The ability to test the fetus for BRCA mutations is also available through amniocentesis and chorionic villus sampling (CVS). The objective of this study was to evaluate attitudes about childbearing and fertility in women being evaluated for a BRCA mutation. Methods: Women with childbearing potential who were referred to the Clinical Cancer Genetics Clinic to be evaluated for a BRCA mutation were invited to participate in this survey. The questionnaire was administered prior to genetic counseling. A follow-up was administered after the BRCA results were disclosed. The survey queried participants regarding their attitudes on fertility, pregnancy as it may relate to cancer and the potential of a BRCA mutation. Other questions detailed attitudes regarding IVF, PGD, and CVS in these instances. Descriptive statistics were used. Results: One hundred and twenty-eight women completed pre-questionnaires and to date 76 have completed post results disclosure questionnaires. The mean age was 33 (range 21–44) with 69.5% with a diagnosis of breast cancer, 39.8% received chemotherapy and 60.9% already had at least 1 biological child. A future child was desired by 45.3% although 53.1% worried that their children would have an increased risk of cancer. Regarding PGD, although only 30.9% (38/123) said that they would use PGD, 80.2% felt that the testing should be available to families with inherited cancers. Regarding fetal testing via amniocentesis or CVS, 29.7% would have the fetus tested and 7% would consider termination if a genetic mutation was identified. Additionally, 69.5% felt it was important to receive fertility counseling and treatment at the same place where they receive their cancer care. To date 8 women have been diagnosed with a BRCA1 mutation and 4 with a BRCA2 mutation. When asked similar questions after their genetic results were disclosed, 2 women who had previously stated they would not use PGD changed their mind. Conclusions: Future pregnancies are important to many breast cancer survivors. BRCA mutation carriers have the option to have children without passing on their genetic risk for cancer. Although few would use these interventions, a large majority felt it was important to have information about these choices and to have options for fertility preservation options addressed at the center where cancer care is delivered. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-13-05.

Hereditary breast and ovarian cancer syndrome (HBOC) related to the breast cancer (BRCA) genes initially was identified in families with the use of genetic linkage analysis.1–3 Since then, over 5000 different mutations in these genes have been identified that are inherited in an autosomal-dominant fashion and are responsible for approximately 5% to 10% of breast cancer diagnoses.4 Carriers of this mutation have an elevated risk of developing both breast and/or ovarian cancer, and a meta-analysis estimate of the lifetime risk of breast cancer was 47% to 66% in BRCA1 carriers and 40% to 57% in the BRCA2 carriers, and the risk of developing ovarian cancer was 35% to 46% and 13% to 23%, respectively, in the same analysis.5 One of the major risk factors for HBOC is the development of breast cancer at a very young age, Thus, the National Comprehensive Cancer Network (NCCN) guidelines panel has recommend initiating screening at ages 20 to 25 years, or 5 to 10 years earlier than the youngest age at diagnosis in the family.6 Implementing screening techniques is meant to identify cancers at the earliest time possible; therefore, estimating the onset of disease is vital in timing the initiation of screening and interventions. Anticipation has been described as a phenomenon observed in inherited diseases such as Fragile X syndrome and Huntington disease, in which the disease occurs at younger ages or with increased severity of disease in subsequent generations.7,8 The cause of this anticipation has been identified as DNA instability, such as nucleotide repeats that change in length in subsequent generations, altering the phenotype of the disease. However, changes in disease phenotype in subsequent generations also have been identified in other disorders, such as in colon cancer, Alzheimer disease, and diabetes.9,10 With the increase in BRCA1 and BRCA2 testing, there also has been an increase in families being evaluated and screened for HBOC. There have been several reports of anticipation in breast cancer. To date, these reports have been based on very small cohorts; those studies indicated an earlier age at diagnosis and examined the absolute differences between matched pairs. Dagan and Gershoni-Baruch reported a statistically significant difference of approximately 4 years in BRCA2 mutation carriers and a statistically nonsignificant numerical difference in BRCA1 carriers.11 In addition, Peixoto et al and Paltiel et al also observed similar patterns of earlier age of diagnosis for subsequent generations in breast cancer registries.12,13 When discussing appropriate screening interventions for women with a known deleterious BRCA1 or BRCA2 mutation, potential interventions include clinical breast examination, magnetic resonance imaging, and mammography.14 Evaluating for patterns of inheritance like anticipation in families with known deleterious BRCA mutations may help promote understanding of these genes and provide further insight into the timing of screening initiation and starting other interventions. The objective of the current analysis was to evaluate any trends in age at diagnoses in families with known deleterious BRCA mutations at a single institution to add to the growing evidence of genetic anticipation in patients with HBOC. We evaluated families who were referred to the Clinical Cancer Genetic Program at our institution and analyzed age at diagnosis across 2 generations.

Background Neurocognitive impairment occurs in 20%-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy.

Lung cancer risk prediction models hold the promise of improving patient care and streamlining research. The ultimate goal of these models is to inform clinicians as to which interventions their individual patients should receive to reduce lung cancer-associated morbidity and mortality. In this paper, we discuss the history and current state of lung cancer prediction models, focusing on three models: the Bach model, the Spitz model, and the Liverpool Lung Project (LLP) model. We also discuss the prospects for further development of improved prediction models for lung cancer risk. Although current models can identify those smokers at highest risk for lung cancer, these models are presently of limited use in the clinical setting. Nevertheless, lung cancer risk prediction models can be used during study enrollment to select more appropriate study subjects, and may eventually be useful in identifying patients for lung cancer screening or to receive chemoprevention.

BackgroundCardiovascular (CV) risk stratification for patients with rheumatoid arthritis (RA) should facilitate evidence-based management. Prior work has derived an internally validated a CV risk score, the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), using US data. The aim of this study was to perform an external validation among unselected patients with RA from Europe.MethodsThree large, partially overlapping, cohorts of patients with RA from the Swedish Rheumatology Quality register were identified for external validation, two with information on smoking and two with close to 10 years of median follow-up. The 10 -year rate of first CV events was assessed using the Kaplan-Meier method. The performance of ERS-RA was assessed using C-index and comparisons of observed versus predicted risks.ResultsThe C-index for ERS-RA varied across the three RA cohorts, from 0.75 to 0.78. Predicted risks corresponded well to observed risks among individuals with ≤10 % observed 10- year CV risk, but underestimated risk in individuals with a higher observed risk. In the absence of data on smoking, ERS-RA underestimated the CV risk by 3.3%, whereas in the cohorts including data on smoking, the calibration was within 1% (0.06% and 0.7%). In the clinically relevant risk intervals (ConclusionsIn an unselected Swedish population with RA, ERS-RA performed well, although the 10-year CV risk was underestimated in high-risk groups and in the absence of data on smoking. ERS-RA could be considered as a risk stratification tool for targeted preventive interventions in clinical rheumatology practice.

Cancer risk assessment is a multidisciplinary process that goes beyond the scope of classical epidemiology to include the biological evaluation of individual differences to carcinogenic exposures. The inclusion of genetic biomarkers such as mutagen sensitivity or cytokinesis-blocked micronucleus (CBMN) assay end points into risk assessment models allows for a more comprehensive determination of cancer risk that includes known demographic (age and gender), lifestyle exposures (smoking and alcohol) and occupational or environmental exposures. The CBMN assay generates multiple correlated end points that, after applying data reduction methods, could be combined into a summary measure that incorporates information from each individual variable into a single (or possible multiple, uncorrelated) measure of risk. In this article, we highlight the use of the CBMN assay in radiosensitivity assessment. In addition, we demonstrate the potential use of the combined summary measures in cancer risk assessment as a result of chronic exposure to tobacco carcinogens. The simplicity, rapidity and sensitivity of the CBMN assay not only make it a valuable tool for screening but also the multiple end points simultaneously generated lead to a better understanding of the underlying mechanisms involved in the carcinogenic process that could in turn substantially improve risk predictions.

In genome-wide association studies, inherited risk of glioma has been demonstrated for rare familial syndromes and with common variants from 3–5 chromosomal regions. To assess the degree of familial aggregation of glioma, the authors performed a pooled analysis of data from 2 large glioma case-control studies in the United States (MD Anderson Cancer Center, Houston, Texas (1994–2006) and University of California, San Francisco (1991–2004)) and from the Swedish Cancer Registry (1958–2006) to measure excess cases of cancer among first-degree relatives of glioma probands. This analysis included 20,377 probands with glioma and 52,714 first-degree relatives. No overall increase was found in the expected number of cancers among family members; however, there were 77% more gliomas than expected. There were also significantly more sarcoma and melanoma cases than expected, which is supported by evidence in the literature, whereas there were significantly fewer-than-expected cases of leukemia, non-Hodgkin lymphoma, and bladder, lung, pancreatic, prostate, and uterine cancers. This large pooled analysis provided sufficient numbers of related family members to examine the genetic mechanisms involved in the aggregation of glioma with other cancers in these families. However, misclassification due to unvalidated cancers among family members could account for the differences seen by study site.

BACKGROUND: Overall, Latinas are more likely to be diagnosed with a more advanced stage of breast cancer and are 20% more likely to die of breast cancer than non-Hispanic white women. It is estimated that from 2003 to 2006, $82.0 billion in direct medical care expenditures, in addition to 100,000 lives annually, could be saved by eliminating health disparities experienced by Latinos and increasing the use of up to 5 preventive services in the United States. An additional 3700 lives could be saved if 90% of women aged ≥40 years were recently screened for breast cancer. METHODS: The authors examined the risk for breast cancer in a case-control, population-based sample of Mexican-origin women in Harris County, Texas (n = 714), where the rates of breast cancer mortality for Latina women have doubled since 1990. RESULTS: Half of breast cancer cases (n = 119) were diagnosed in women aged

Background: DNA strand breaks pose the greatest threat to genomic stability. Genetically determined mutagen sensitivity predisposes individuals to a variety of cancers, including glioma. However, polymorphisms in DNA strand break repair genes that may determine mutagen sensitivity are not well studied in cancer risk, especially in gliomas. Methods: We correlated genotype data for tag single-nucleotide polymorphisms (tSNPs) of DNA strand break repair genes with a gamma-radiation-induced mutagen sensitivity phenotype [expressed as mean breaks per cell (B/C)] in samples from 426 glioma patients. We also conducted analysis to assess joint and haplotype effects of single-nucleotide polymorphisms (SNPs) on mutagen sensitivity. We further validate our results in an independent external control group totaling 662 subjects. Results: Of the 392 tSNPs examined, we found that mutagen sensitivity was modified by one tSNP in the EME2 gene and six tSNPs in the RAD51L1 gene (P < 0.01). Among the six RAD51L1 SNPs tested in the validation set, one (RAD51L1 rs2180611) was significantly associated with mutagen sensitivity (P = 0.025). Moreover, we found a significant dose–response relationship between the mutagen sensitivity and the number of adverse tSNP genotypes. Furthermore, haplotype analysis revealed that RAD51L1 haplotypes F-A (zero adverse allele) and F-E (six adverse alleles) exhibited the lowest (0.42) and highest (0.93) mean B/C values, respectively. A similar dose–response relationship also existed between the mutagen sensitivity and the number of adverse haplotypes. Conclusion: These results suggest that polymorphisms in and haplotypes of the RAD51L1 gene, which is involved in the double-strand break repair pathway, modulate gamma-radiation-induced mutagen sensitivity.

Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model.We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes.We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeatsor=19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeatsor=19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset.Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.

BACKGROUND. The p53 tumor suppressor protein homolog p73 can be inactivated by oncoprotein E6 of human papillomavirus (HPV). Variation in p73 may alter the interaction between the E6 protein and p73 and, thus, alter the risk for HPV-associated carcinogenesis. It is believed that the p73 G4C14-to-A4T14 polymorphism affects p73 function by altering gene expression; however, whether that polymorphism also alters the risk of HPV type 16 (HPV-16)-associated squamous cell carcinoma of the oropharynx (SCCOP) is unknown. METHODS. The current case-control study included a case group of 188 non-Hispanic white patients with newly diagnosed SCCOP and a control group of 349 healthy individuals. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cases and controls stratified by p73 genotype, age, sex, smoking status, alcohol use, and HPV-16 status. The effects of p73 genotypes on the risk of HPV-16-associated SCCOP were explored with further stratification by smoking and drinking status. RESULTS. HPV-16 seropositivity was associated with an increased risk of SCCOP (adjusted OR, 5.98; 95% CI, 3.89-9.20), especially among never smokers (adjusted OR, 13.8; 95% CI, 5.91-32.1), never drinkers (adjusted OR, 14.9; 95% CI, 5.24-42.4), and individuals with p73 variant genotypes (GC/AT and AT/AT; adjusted OR, 7.96; 95% CI, 3.83-16.5). Moreover, the risk of HPV-16-associated SCCOP for individuals who had p73 variant genotypes was particularly high in never smokers and never drinkers. CONCLUSIONS. The p73 G4C14-to-A4T14 polymorphism may modulate the risk of HPV-16-associated SCCOP, and the p73 variant genotypes may be markers of genetic susceptibility to HPV-16-associated SCCOP, particularly in never smokers and never drinkers. Cancer 2008. © 2008 American Cancer Society.

Because existing risk prediction models for lung cancer were developed in white populations, they may not be appropriate for predicting risk among African-Americans. Therefore, a need exists to construct and validate a risk prediction model for lung cancer that is specific to African-Americans. We analyzed data from 491 African-Americans with lung cancer and 497 matched African-American controls to identify specific risks and incorporate them into a multivariable risk model for lung cancer and estimate the 5-year absolute risk of lung cancer. We performed internal and external validations of the risk model using data on additional cases and controls from the same ongoing multiracial/ethnic lung cancer case-control study from which the model-building data were obtained as well as data from two different lung cancer studies in metropolitan Detroit, respectively. We also compared our African-American model with our previously developed risk prediction model for whites. The final risk model included smoking-related variables [smoking status, pack-years smoked, age at smoking cessation (former smokers), and number of years since smoking cessation (former smokers)], self-reported physician diagnoses of chronic obstructive pulmonary disease or hay fever, and exposures to asbestos or wood dusts. Our risk prediction model for African-Americans exhibited good discrimination [75% (95% confidence interval, 0.67–0.82)] for our internal data and moderate discrimination [63% (95% confidence interval, 0.57–0.69)] for the external data group, which is an improvement over the Spitz model for white subjects. Existing lung cancer prediction models may not be appropriate for predicting risk for African-Americans because (a) they were developed using white populations, (b) level of risk is different for risk factors that African-American share with whites, and (c) unique group-specific risk factors exist for African-Americans. This study developed and validated a risk prediction model for lung cancer that is specific to African-Americans and thus more precise in predicting their risks. These findings highlight the importance of conducting further ethnic-specific analyses of disease risk.

The multi-endpoint cytokinesis-blocked micronucleus assay is used for assessing chromosome aberrations. We have recently reported that this assay is extremely sensitive to genetic damage caused by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and that the binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds in lymphocytes (chromosome damage endpoints measured by the assay) are strong predictors of lung cancer risk. In the current study, we refined our analysis to include toxicity endpoints (micronuclei in mononucleated cells, apoptosis, necrosis, and nuclear division index) to investigate the benefit of including these variables on improving the predictive value of the assay. Baseline and NNK-induced micronuclei in mononucleated cells were significantly higher in patients (n = 139) than controls (n = 130; P < 0.001). Baseline apoptosis was higher among cases; however, the controls showed a significant higher fold increase in NNK-induced apoptosis compared with baseline (P < 0.001). Principal components analysis was used to derive a summary measure for all endpoints and calculate the positive predictive value (PPV) and negative predictive value (NPV) for disease status. First principal component for NNK-induced chromosome damage endpoints (binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds) had an area under the curve = 97.9 (95% confidence interval, 95.9-99.0), PPV = 94.8, and NPV = 92.6. The discriminatory power improved when micronuclei in mononucleated cells were included: area under the curve = 99.1 (95% confidence interval, 97.9-100.0), PPV = 98.7 and NPV = 95.6. The simplicity, rapidity, and sensitivity of the assay together with potential for automation make it a valuable tool for screening and prioritizing potential cases for intensive screening. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1111–9)

Magnesium (Mg) is required for maintenance of genomic stability; however, data on the relationship between dietary Mg intake and lung cancer are lacking. In an ongoing lung cancer case–control study, we identified 1139 cases and 1210 matched healthy controls with data on both diet and DNA repair capacity (DRC). Dietary intake was assessed using a modified Block-NCI food frequency questionnaire and DRC was measured using the host-cell reactivation assay to assess repair in lymphocyte cultures. After adjustment for potential confounding factors including DRC, the odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer with increasing quartiles of dietary Mg intake were 1.0, 0.83 (0.66–1.05), 0.64 (0.50–0.83) and 0.47 (0.36–0.61), respectively, for all subjects (P-trend < 0.0001). Similar results were observed by histology and clinical stage of lung cancer. Low dietary Mg intake was associated with poorer DRC and increased risk of lung cancer. In joint effects analyses, compared with those with high dietary Mg intake and proficient DRC, the OR (95% CI) for lung cancer in the presence of both low dietary Mg and suboptimal DRC was 2.36 (1.83–3.04). Similar results were observed for men and women. The effects were more pronounced among older subjects (>60 years), current or heavier smokers, drinkers, those with a family history of cancer in first-degree relatives, small cell lung cancer and late-stage disease. These intriguing results need to be confirmed in prospective studies.

Background : After a prolonged period of increasing rates of lung cancer incidence and mortality for both men and women, incidence and mortality rates are decreasing in men and stabilizing in women. The goal of this study was to assess changes over 20 years in the prevalence of known risk factors for lung cancer and to elucidate possible predictors associated with lung cancer survival. Methods : The study included a total of 908 patients with primary lung cancer referred to The University of Texas M.D. Anderson Cancer Center over three study periods 1985–1989 ( N =392), 1993–1997 ( N =216), and 2000–2004 ( N =300). Detailed questionnaires were used to collect information from the patients. Hazard ratios were estimated by fitting a Cox proportional hazards model. Using the Kaplan–Meier method, survival in months was calculated up to 2 years from the date of diagnosis to achieve comparability in the three groups. Results : We observed a decrease in the proportion of patients who are current cigarette smokers and an increase in the proportion of patients who present with adenocarcinoma of the lung, are obese and patients who present with localized disease. We also found an increase in the number of patients who report a family history of lung cancer. The overall median survival duration has increased over the years from 12.0 months in 1985–1989 to 17.5 months in 2000–2004. Also, the probability of survival of patients who were alive at 2 years after diagnosis has also increased (26.5% in 1985–1989 to 40.8% in 2000–2004). Overall, women had a better median survival than men. Conclusions : The results show that the demographic, histologic, clinical, and outcome variables of patients with lung cancer have changed over the past 20 years. Most important, the survival of patients with lung cancer has improved.

Background Reliable risk prediction tools for estimating individual probability of lung cancer have important public health implications. We constructed and validated a comprehensive clinical tool for lung cancer risk prediction by smoking status. Methods Epidemiologic data from 1851 lung cancer patients and 2001 matched control subjects were randomly divided into separate training (75% of the data) and validation (25% of the data) sets for never, former, and current smokers, and multivariable models were constructed from the training sets. The discriminatory ability of the models was assessed in the validation sets by examining the areas under the receiver operating characteristic curves and with concordance statistics. Absolute 1-year risks of lung cancer were computed using national incidence and mortality data. An ordinal risk index was constructed for each smoking status category by summing the odds ratios from the multivariable regression analyses for each risk factor. Results All variables that had a statistically significant association with lung cancer (environmental tobacco smoke, family history of cancer, dust exposure, prior respiratory disease, and smoking history variables) have strong biologically plausible etiologic roles in the disease. The concordance statistics in the validation sets for the never, former, and current smoker models were 0.57, 0.63, and 0.58, respectively. The computed 1-year absolute risk of lung cancer for a hypothetical male current smoker with an estimated relative risk close to 9 was 8.68%. The ordinal risk index performed well in that true-positive rates in the designated high-risk categories were 69% and 70% for current and former smokers, respectively. Conclusions If confirmed in other studies, this risk assessment procedure could use easily obtained clinical information to identify individuals who may benefit from increased screening surveillance for lung cancer. Although the concordance statistics were modest, they are consistent with those from other risk prediction models.