Search

ObjectiveRecalled childhood adiposity is inversely associated with breast cancer observationally, including in Mendelian randomization (MR) studies, questioning its role. Breast cancer studies recruited in adulthood only include survivors of childhood adiposity and breast cancer. We assessed recalled childhood adiposity on participant reported sibling and maternal breast cancer to ensure ascertainment of non-survivors using MR.Study Design and SettingWe obtained independent strong genetic predictors of recalled childhood adiposity for women and their associations with participant reported own, sibling and maternal breast cancer from UK Biobank genome wide association studies (GWAS). We obtained MR inverse variance weighting estimates.ResultsChildhood adiposity in women was inversely associated with own breast cancer (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.52 to 0.84) but unrelated to participant reported sibling (OR 0.85, 95% CI 0.60 to 1.20) or maternal breast cancer (OR 0.84, 95% CI 0.67 to 1.05 respectively).ConclusionWeaker inverse associations of recalled childhood adiposity with breast cancer with more comprehensive ascertainment of cases before recruitment suggests the inverse association of recalled childhood adiposity with breast cancer is due to selection bias arising from preferential selection of survivors. Greater consideration of left truncation in public health relevant causal inferences is warranted.HighlightsRecalled childhood adiposity is inversely associated with breast cancer.Studies of childhood exposures recruited in adulthood are open to left truncation.Participant reports about family members include deaths before recruitment.We tested childhood adiposity on sibling breast cancer using Mendelian randomization.Childhood adiposity with sibling breast cancer was null, suggesting left truncation.

ObjectiveTo evaluate the long-term efficacy and safety of ustekinumab through 2 years in patients with active systemic lupus erythematosus (SLE).MethodsThis was a placebo-controlled (week 24), phase II study in 102 patients with seropositive active SLE. Patients were randomized to ustekinumab (approximately 6 mg/kg single intravenous infusion, then subcutaneous [SC] injections of 90 mg every 8 weeks) or placebo, added to background therapy. Placebo patients initiated ustekinumab (90 mg SC every 8 weeks) at week 24. Patients could enter an optional open-label study extension after week 40 (final ustekinumab administration at week 104). Efficacy assessments included Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), SLEDAI-2K Responder Index-4 (SRI-4), physician global assessment (PGA), and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Observed data are reported for the extension period. The final efficacy assessment was at week 112; safety was monitored through week 120.ResultsIn this subset of patients who entered the study extension, 24 in the ustekinumab group and 14 in the placebo crossover group completed study treatment. At week 112, 79% and 92%, respectively, had an SRI-4 response; 92% in both groups had ≥ 4-point improvement from baseline in SLEDAI-2K score; 79% and 93%, respectively, had ≥ 30% improvement from baseline in PGA; 86% and 91%, respectively, had ≥ 50% improvement in active joint (pain and inflammation) count; and 79% and 100%, respectively, had ≥ 50% improvement in CLASI Activity Score. No deaths, malignancies, opportunistic infections, or tuberculosis cases occurred. Safety events were consistent with the known ustekinumab safety profile.ConclusionOf the 46 patients who entered the voluntary extension of this phase II study, clinical benefit in global and organ-specific SLE activity measures was observed with ustekinumab through 2 years with no new or unexpected safety findings. [ClinicalTrials.gov: NCT02349061]

Landslides pose threats to the safety and property of people living in mountainous areas like Hong Kong. Dependence of landslide travel distance on initial conditions and travel routes has broad implications for assessing the landslide risks. In this study, the controlling topographic and geologic factors for travel distances of open hillslope landslides and channelized debris flows are examined based on the Enhanced Natural Terrain Landslide Inventory (ENTLI) in Hong Kong with 11,622 records during the period of 1984–2013. The mean values of the horizontal travel distances of open hillslope landslides and channelized debris flows are 24.1 and 86.3 m, respectively. Correlations combining horizontal travel distances, volumes and fall heights of open hillslope landslides have been derived. The horizontal travel distances (L) and fall heights (H) are closely related for both types of landslides. The use of the L/H ratio alone as a representation of natural terrain landslide mobility is not suggested. Because of the entrainment of loose materials, the travel distances of channelized debris flows are enlarged significantly on colluvium lands (with mean value of 142.6 m), compared with those on weathered mantles (with mean value of 74.2 m).

ObjectivesInterleukin-6 (IL-6) is implicated in rheumatoid arthritis (RA) pathophysiology. Unlike IL-6 receptor inhibitors, sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine. The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study (ClinicalTrials.gov identifierNCT01604343) evaluated the efficacy and safety of sirukumab in patients with active RA refractory to disease-modifying antirheumatic drugs.MethodsPatients were randomised 1:1:1 to treatment with sirukumab 100 mg every 2 weeks, 50 mg every 4 weeks or placebo every 2 weeks subcutaneously. Results through week 52 are reported.ResultsOf 1670 randomised patients, significantly more patients achieved American College of Rheumatology 20% (ACR20) response at week 16 (coprimary endpoint) with sirukumab 100 mg every 2 weeks (53.5%) or 50 mg every 4 weeks (54.8%) versus placebo (26.4%; both pConclusionsSirukumab 100 mg every 2 weeks and 50 mg every 4 weeks led to significant reductions in RA symptoms, inhibition of structural damage progression and physical function and quality of life improvements, with an expected safety profile.Trial registration numberNCT01604343; Results.

Objective To evaluate the efficacy and safety of ustekinumab through 1 year in a phase II trial in patients with systemic lupus erythematosus (SLE). Methods Eligible patients were diagnosed as having clinically active SLE (based on Systemic Lupus International Collaborating Clinics criteria), despite standard background therapy. Active disease was defined by an SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 as well as having ≥1 British Isles Lupus Assessment Group (BILAG) A organ domain score and/or ≥2 BILAG B organ domain scores present at screening. Patients (n = 102) were randomized (3:2) to receive either ustekinumab (~6 mg/kg of single intravenous infusion at week 0, then 90-mg subcutaneous injections every 8 weeks beginning at week 8) or a matching placebo added to standard therapy. At week 24, the placebo group crossed over to receive a subcutaneous 90-mg dose of ustekinumab every 8 weeks, and the original ustekinumab group continued to receive therapy through week 40. Maintenance of efficacy was assessed using the SLEDAI-2K, the SLE Responder Index 4 (SRI-4), physician global assessment, and mucocutaneous and joint disease measures in a modified intent-to-treat population. Results SRI-4 response rates were significantly greater in the ustekinumab group (62%) versus the placebo group (33%) in the week 24 primary end point analysis (P = 0.006) and were maintained at week 48 (63.3%) in the ustekinumab group. In the ustekinumab group, response rates across other disease measures were also maintained through week 48. Among patients in the placebo group who crossed over to ustekinumab treatment (n = 33), increased response rates across efficacy measures were noted. Among all ustekinumab-treated patients, 81.7% had ≥1 adverse event (AE), and 15.1% had ≥1 serious AE through week 56. No deaths, malignancies, opportunistic infections, or tuberculosis cases were observed. Conclusion Ustekinumab provided sustained clinical benefit in patients with SLE through 1 year, with a safety profile consistent with other indications.

Background Both IL-12 and IL-23 have been implicated in the pathogenesis of SLE. We have previously reported that treatment with an anti-IL-12/23 p40 monoclonal antibody ustekinumab (UST) resulted in greater improvement in several SLE disease measures through week 24 compared with placebo (PBO).1 Objectives Results of global and organ-specific disease measures and flares through 1 year are reported here. Methods We conducted a PBO-controlled phase 2 study in 102 patients with seropositive active SLE (defined by SLICC criteria, SLEDAI score ≥6, and ≥1 BILAG A and/or ≥2 BILAG B scores). Patients were randomized (3:2) to UST (6 mg/kg single IV infusion, then 90 mg SC q8w beginning at week 8, n=60) or PBO (n=42), both added to standard background therapy. Patients receiving PBO crossed over to UST (90 mg SC q8w) at week 24. The primary endpoint was the proportion of patients achieving SLE Responder Index (SRI)-4 response at week 24. Modified intention-to-treat (mITT) analyses across SLE disease measures were performed to evaluate maintenance of response with UST between week 24 and week 48 and severe BILAG flares (≥1 new BILAG A score). Safety was assessed through week 56. Results As previously reported, SRI-4 response rate at week 24 was significantly greater (p=0.0057) in patients receiving UST (62%) vs PBO (33%).1 In the UST group, SRI-4 (week 24: 62% vs week 48: 63%), SRI-5 (week 24: 43% vs week 48: 48%), and SRI-6 (week 24: 43% vs week 48: 47%) response rates were sustained at 1 year. Proportions of patients with ≥4-point improvement from baseline in SLEDAI-2K score (week 24: 65% vs week 48: 67%) and with ≥30% improvement from baseline in Physician’s Global Assessment score (week 24: 68% vs week 48: 75%) were also maintained in the UST group. UST response rates were also sustained through 1 year in organ-specific disease measures (≥50% improvement in active joint counts: week 24: 87% vs week 48: 87%; ≥50% improvement in CLASI activity score: week 24: 53% vs week 48: 69%). In PBO patients who crossed over to UST at week 24 (n=33), response rates across outcomes studied were 10-20% higher at week 48 vs week 24. Flare rates for patients with severe BILAG flares were 2.1/10,000 patient-days in week 0-24 and 1.1/10,000 patient-days in week 24-48 in the UST group. In the PBO group, severe BILAG flare rates were 8.4/10,000 patient-days in week 0-24 and, following UST crossover, were 4.6/10,000 patient-days in week 24-48. The occurrence of severe BILAG flares seemed to diminish after approximately 8 weeks (week 8 in UST arm, week 32 in PBO arm) of treatment with UST (Figure). No deaths, malignancies, opportunistic infections, tuberculosis cases, or unexpected serious AEs (SAEs) were observed. Incidences of ≥1 SAE were UST (week 0-24) 8.3%, PBO (week 0-24) 9.5%, UST (week 24-48) 8.9%, and PBO-UST (week 24-48) 12.1%. Safety events were consistent with the known UST safety profile. Conclusion UST provided sustained clinical benefit in global and organ-specific SLE-activity measures and reduced flares through 1 year, with a safety profile consistent with other indications. Thus, UST may have durable therapeutic benefit in SLE. Reference [1] van Vollenhoven RF, et al. Lancet2018;392:1330. Disclosure of Interests Ronald van Vollenhoven Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB, Consultant for: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex., Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex., George Tsokos Grant/research support from: Janssen Research & Development, LLC, Robert Gordon Employee of: Janssen Research & Development, LLC, Kim Hung Lo Employee of: Janssen Research & Development, LLC, Y Irene Gregan Employee of: Janssen Research & Development, LLC, Kaiyin Fei Employee of: Janssen Research & Development, LLC, Shawn Rose Employee of: Janssen Research & Development, LLC, Bevra H. Hahn Grant/research support from: Janssen Research & Development, LLC

Background While traditional Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI-2K) scoring assesses complete SLE response for individual disease manifestations, the SLEDAI-2K Responder Index-50 (S2K RI-50) evaluates responses using partial improvement (50%) in each of the 9 organ-systems of SLEDAI-2K and generates a total score. We aimed to evaluate the performance of S2K RI-50 at 24 weeks in a randomized, placebo (PBO) controlled trial of UST in patients with moderate-to-severe SLE disease activity to ascertain a minimal threshold of partial improvement. Methods The UST phase 2, PBO-controlled study enrolled adults with active disease (SLEDAI score 6 with 1 BILAG A and /or 2 BILAG B scores) despite standard-of-care therapy. Patients (n=102) were randomized (3:2) to receive UST IV~6 mg/kg or PBO at week (wk) 0, followed by SC injections of UST 90 mg q8w or PBO beginning at wk8, both added to standard of care. We calculated S2K RI-50 response in patients receiving UST (n=62) vs PBO (n=40) at wk24 using increasing S2K RI-50 reductions of 1, 2, 3, 4, 5, or 6 points from baseline to determine 50% improvement. In order to determine a minimal cut-off to discriminate a treatment effect reflecting partial improvement, nominal level was set at 0.05 for this post hoc analysis. Results The performance of S2K RI-50 in detecting the treatment difference between UST and PBO with various cut-offs is presented in table 1. A 2-point reduction in S2K RI-50 was the lowest threshold to demonstrate a p-value Conclusions S2K RI-50 captures partial improvement of 50% in SLE disease activity in the most common disease manifestations in SLE. S2K RI-50 could be used as an outcome in clinical trials as a clinically meaningful measure of partial improvement. Funding Source(s): Jannsen Research and Development, LLC, supported this study.

Background:In a Phase 2 study, Ustekinumab (UST) showed improvement at week (wk) 24 in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) response (≥4-point improvement from baseline [BL]) vs placebo (PBO).1Post hoc analysis revealed that more patients (pts) on UST vs PBO achieved ≥50% improvement in total CLASI activity score.Objectives:To examine the relationships of CLASI activity responses to SLEDAI-2K (S2K) mucocutaneous disease responses.Methods:Adults with SLE (S2K ≥6, ≥1 BILAG A and/or ≥2 BILAG B scores) despite standard of care (SOC) therapy were enrolled. Pts (n=102) were randomized (3:2) to UST ~6 mg/kg IV or PBO at wk 0, followed by UST 90 mg SC or PBO every 8 wks beginning at wk 8 + SOC. S2K index measures complete improvement from BL; S2K Responder Index-50 (S2K RI-50) evaluates partial improvement (≥50%) in S2K rash. CLASI rash: sum of erythema and scale/hypertrophy score. In post hoc analysis, improvement in CLASI activity score at wk 24 was calculated using increasing thresholds of BL disease activity and various cut points of improvement to define treatment response.Results:Complete improvement from BL in rash was concordant between CLASI and S2K (correlation coefficients [r] ≥0.997, Table 1). There was less agreement between CLASI and S2K RI-50 for assessing partial improvement in rash. Treatment difference (UST vs PBO) in % pts achieving partial improvement in rash was observed for CLASI (60% vs 38.5%), but not S2K RI-50 (51.1% vs 50%). Complete improvement from BL in mucosal ulceration was congruent between CLASI and S2K (r=1). Both instruments demonstrated greater proportions of responders to UST vs PBO. Treatment differences between UST and PBO in achieving ≥20%, ≥35%, and ≥50% improvement from BL in total CLASI activity score were noteworthy at various thresholds of disease activity (Table 2).Table 1.CLASI Activity Scores vs SLEDAI-2K Activity24-Week ImprovementTreatmentActivity Measure% (n/N*)r**CLASI RashSLEDAI-2K Rash100%PBO30.8 (8/26)30.8 (8/26)1.0000UST28.9 (13/45)31.1 (14/45)0.9997≥50%PBO38.5 (10/26)50.0 (13/26)0.9996UST60.0 (27/45)51.1 (23/45)0.8693CLASIMucosal UlcerSLEDAI-2KMucosal Ulcer100%PBO66.7 (8/12)69.2 (9/13)1.0000UST89.5 (17/19)89.5 (17/19)1.0000*N=Evaluated pts with BL SLEDAI rash present, total CLASI activity score >0, and CLASI rash or mucosal ulcer activity scores >0 in analyses of subcomponents; **Calculated using tetrachoric correlation.Table 2.Differences in Partial Improvement in Total CLASI Activity Score at Various BL Disease Activity ThresholdsCLASI Total Activity ScoreImprovementThreshold (%)PBO% (n/N*)UST% (n/N*)Difference % (UST vs PBO)BL >0≥2054.8 (17/31)74.5 (38/51)19.7≥3541.9 (13/31)60.8 (31/51)18.9≥5041.9 (13/31)54.9 (28/51)13.0BL ≥4≥2058.8 (10/17)71.9 (23/32)13.1≥3535.3 (6/17)62.5 (20/32)27.2≥5035.3 (6/17)53.1 (17/32)17.8BL ≥6≥2053.8 (7/13)72.0 (18/25)18.2≥3530.8 (4/13)60.0 (15/25)29.2≥5030.8 (4/13)52.0 (13/25)21.2BL ≥8≥2058.3 (7/12)70.6 (12/17)12.3≥3533.3 (4/12)58.8 (10/17)25.5≥5033.3 (4/12)47.1 (8/17)13.8*N=Evaluated pts with BL total CLASI activity score >0, ≥4, ≥6, ≥8 based on post hoc analysesConclusion:CLASI demonstrated partial improvement in active mucocutaneous disease that was not captured by S2K RI-50. Treatment effect favoring UST vs PBO was observed across range of thresholds of BL CLASI activity and cut points used to define improvement, which have previously been shown to be clinically meaningful.2Findings are based on a limited sample size and treatment duration; results will be confirmed in an ongoing Phase 3 UST trial (NCT03517722).References:[1]Van Vollenhoven R.Lancet. 2018;392:1330[2]Chakka S.JID.2019;139: S101 (#587)Disclosure of Interests:Victoria Werth Grant/research support from: Biogen, Celgene, Gilead, Janssen, Viela, Consultant of: Biogen, Gilead, Janssen, Abbvie, GSK, Resolve, AstraZeneca, Amgen, Eli Lilly, EMD Serono, BMS, Viela, Kyowa Kirin, Bevra H. Hahn Grant/research support from: Janssen Research & Development, LLC, George Tsokos Grant/research support from: Janssen Research & Development, LLC, Shawn Rose Employee of: Janssen Research & Development, LLC, Kaiyin Fei Employee of: Janssen Research & Development, LLC, Y Irene Gregan Employee of: Janssen Research & Development, LLC, Robert Gordon Employee of: Janssen Research & Development, LLC, Kim Hung Lo Employee of: Janssen Research & Development, LLC, Ronald van Vollenhoven Grant/research support from: AbbVie, Amgen, Arthrogen, Bristol-Myers Squibb, GlaxoSmithKline (GSK), Janssen Research & Development, LLC, Lilly, Pfizer, Roche, and UCB, Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo Bioscience, GSK, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, UCB and Vertex, Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo Bioscience, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Vertex

ObjectivesThe phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study evaluated long-term efficacy and safety of the interleukin (IL)-6 inhibitor, sirukumab, in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drugs (DMARDs).MethodsPatients were randomised 1:1:1 to sirukumab 100 mg every 2 weeks (q2w), 50 mg every 4 weeks or placebo q2w subcutaneously. Patients initially randomised to placebo were rerandomised at Weeks 18, 40 or 52 to one of the sirukumab groups until Week 104.ResultsOf 1670 randomised patients, 1402 were included in the full analysis set and 1269 in the radiographic analysis set at Week 104. American College of Rheumatology scores, Disease Activity Score based on C-reactive protein, Clinical Disease Activity Index and clinically meaningful improvements in patient-reported outcomes were sustained at Week 104 among patients initially randomised to sirukumab. Placebo patients subsequently rerandomised to sirukumab showed clinical improvements at Week 104 that were comparable to results among patients initially randomised to sirukumab. Radiographic progression from Week 52 to Week 104 was comparable between all groups whether initially randomised to sirukumab or subsequently rerandomised to sirukumab from placebo. No new safety signals were identified in the extended exposure period compared with the initial 52 weeks of treatment.ConclusionsSirukumab treatment resulted in sustained reductions in clinical signs and symptoms and minimal progression in radiographic damage over 2 years among patients with RA refractory to DMARDs. The safety profile of sirukumab was as expected for an anti-IL-6 agent, with no new signals reported.

Background Neutropenia has been reported with interleukin-6 (IL-6) pathway inhibitors and could potentially be associated with increased rates of infection. The reduced neutrophil counts seen with IL-6 inhibitors may be due to effects on margination of circulating neutrophils as opposed to a decrease in bone marrow production or reduced survival. Efficacy of sirukumab (SIR), a human anti-IL-6 cytokine monoclonal antibody, has recently been shown in several phase 3 trials. Objectives To assess incidence of neutropenia from completed and ongoing SIRROUND clinical studies. Methods Neutrophil counts were compared for SIR 50mg q4w and 100mg q2w doses vs placebo (pbo) in the pbo-controlled period (Wks 0–18) of 2 phase 3 trials and in long-term analysis for the 5-trial, phase 3 program. Results 2926 pts received SIR for up to 3.4y with a median duration of 1.46y. For the 18-wk pbo-controlled period, neutropenia was more frequent in both SIR groups compared with pbo. Across all groups, the majority of the decreases in neutrophil counts were National Cancer Institute Common Terminology Criteria for Adverse Events grade 0/1, within the normal range, and the incidence of grade 3/4 decreases was low across groups (Table). Neutropenia began at Wk 2 and persisted through the study period. In long-term analysis, the proportions of pts with grade 1, 2, or 3 neutropenia were slightly higher than in the 18-wk pbo-controlled period, suggesting the majority of events occurred early. No dose relationship was observed in the grade or frequency of neutropenia. Grade 3/4 neutropenia was mostly transient and resolved after interrupting the dose or resolved within the dosing interval such that no change in dose schedule was required. The majority of grade 4 decreases in neutrophils were not correlated with infections; 2 cases of serious infections occurred with grade 4 neutropenia. The distribution of neutropenia by grade was similar in pts who did or did not use disease-modifying antirheumatic drugs (DMARDs) at baseline. Conclusions Across phase 3 studies, there was no dose effect of SIR on neutropenia, and the use of DMARDs did not have an apparent effect on neutropenia. The majority of grade 4 neutropenia with SIR was not associated with infections. Disclosure of Interest T. Takeuchi Grant/research support from: Astellas Pharma, Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., and SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol-Myers K.K., and Nipponkayaku Co. Ltd., Speakers bureau: AbbVie GK., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Astellas Pharma, Daiichi Sankyo Co., Ltd., Celtrion, and Nipponkayaku Co. Ltd., Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, and Eisai, Speakers bureau: Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Teijin, Asahi-kasei, YL Biologics, Sanofi, Janssen, Eli Lilly, and GlaxoSmithKline, M. Schiff Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, UCB, Speakers bureau: AbbVie, M. Harigai Grant/research support from: AbbVie Japan, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Ono Pharmaceuticals, Santen Pharmaceutical, Takeda Pharmaceutical, UCB Japan, Teijin Pharma, Consultant for: AbbVie Japan, Janssen Pharma, Chugai Pharmaceutical, Teijin Pharma, Eli Lilly Japan, and Zenyaku Kogyo, K. Brown Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, R. Rao Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, S. Popik Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, K. Yoshizawa Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, Q. Wang Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Received 27 November 2012; revised 25 January 2013; accepted 28 January 2013 Background: To determine the prevalence and clinicopathological features of ROS1 fusions in Chinese patients with non-small-cell lung cancer (NSCLC). Methods: Formalin-fixed and paraffin-embedded (FFPE) tissue sections from 392 patients with NSCLC were screened for ROS1 fusions by multiplex RT–PCR and all ROS1 fusions were validated by direct sequencing. The relationship between ROS1 fusions and clinicopathological features and the prognostic effect of the ROS1 fusion status on survival were analyzed. Results: In this study, 8 of 392 (2.0%) evaluable samples were found to harbor ROS1 fusions. Of the ROS1-positive patients, seven presented with adenocarcinoma, and one with adenosquamous carcinoma. The ratio of female to male and never smoker to smokers in a ROS1 fusion-positive group was 5:3. There was no statistically significant difference in age, sex, smoking history, histological type and pathological stage between ROS1 fusion-positive and ROS1 fusionnegative patients. ROS1 fusion-negative patients had a significantly longer survival when compared with ROS1 fusionpositive patients (P= 0.041). Lower pathological stage, younger age and ROS1 fusion-negative status were significantly associated with better prognosis on multivariate analysis. Conclusions: ROS1 fusions occurred in ∼2.0% of Chinese patients with NSCLC and had no specific clinicopathological feature. ROS1 fusion-negative patients may have a better survival than ROS1 fusion-positive

Vibrating screen sifts materials via screen mesh, vibration displacement and velocity. In order to completing optimal design of vibrating screen’s vibration frequency. Firstly, Using the CAD function of the three dimensional software UG NX 6.0 to achieve vibrating screen modeling. Secondly, modal simulation analysis was carried out using the simulation soft NX NASTRAN. Numerical simulation experimental result indicates: this designed vibrating screen’s natural vibration frequency are 27.79Hz, 32.58 Hz, and 46.39Hz, consequently, designing this vibrating screen should avoid identical or approaching these natural vibration frequencies as far as possible, while choosing the vibration frequency.

Carbon dioxide bubble removal at the anode of a direct methanol fuel cell (DMFC) is an important technique especially for applications in the portable power sources. This paper presents numerical investigations of the two-phase flow, CO 2 bubbles in a liquid methanol solution, in the anode microchannels from the aspect of microfluidics using a thermal lattice Boltzmann model (TLBM). The main purpose is to derive an efficient and effective computational scheme to deal with this technical problem. It is then examined by a commercially available software using Navier–Stokes plus volume of fluid (VOF) method. The latter approach is normally employed by most researchers. A simplified microchannel simulation domain with the dimension of 1.5 μm in height (or width) and 16.0 μm in length has been setup for both cases to mimic the actual flow path of a CO 2 bubble inside an anodic diffusion layer in the DMFC. This paper compares both numerical schemes and results under the same operation conditions from the viewpoint of fuel cell engineering.

The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist.Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2-24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports.Telcagepant 300 mg was more effective (por= 0.001) than placebo on all primary endpoints and the key secondary endpoint, as was telcagepant 150 mg (por= 0.05). Telcagepant 300 mg showed a slight numeric advantage over telcagepant 150 mg on most measures. Telcagepant 50 mg values were numerically intermediate between placebo and telcagepant 150 mg and 300 mg. The percentages of patients with adverse experiences were 32.2% for telcagepant 50 mg, 32.0% for telcagepant 150 mg, 36.2% for telcagepant 300 mg, and 32.2% for placebo.This study confirmed previous findings that telcagepant 300 mg was effective at relieving pain and other migraine symptoms at 2 hours and providing sustained pain freedom up to 24 hours. In this study, telcagepant 150 mg was also effective. Telcagepant was generally well tolerated.

This paper describes a case history of a geogrid-reinforced and pile-supported (GRPS) highway embankment with a low area improvement ratio of 8.7%. Field monitored data from contact pressures acting on the pile and soil surfaces, pore-water pressures, settlements and lateral displacements are reported and discussed. The case history is backanalyzed by carrying out three-dimensional (3D) fully coupled finite-element analysis. The measured and computed results are compared and discussed. Based on the field observations of contact stresses and pore-water pressures and the numerical simulations of the embankment construction, it is clear that there was a significant load transfer from the soil to the piles due to soil arching. The measured contact pressure acting on the pile was about 14 times higher than that acting on the soil located between the piles. This transfer greatly reduced excess positive pore water pressures induced in the soft silty clay. The measured excess pore water pressure ratio B¯ max in t...

By means of microfluidic analysis with a thermal lattice-Boltzmann method, we investigated the hydrophilic, thermal and geometric effects on the dynamics of CO2 bubbles at anode microchannels (e.g., porous layers and flow channels) of a micro-direct methanol fuel cell. The simulation results show that a more hydrophilic wall provides an additional attractive force to the aqueous methanol in the flow direction and that moves the CO2 bubble more easily. The bubble propagates quicker in the microchannel with a positive temperature gradient imposed from the inlet to the exit, mainly due to the Marangoni effect. Regarding the geometric effect of the microchannel, the bubble moves more rapidly in a divergent microchannel than in a straight or convergent channel. On the basis of the quantitative evaluation of hydrophilic, thermal and geometric effects, we are able to design the bubble-removal technique in micro fuel cells.

This paper investigates the nano-fluidic contact angle measurement by performing molecular dynamics simulations. The contact angle between a nano-water droplet and a platinum surface is important for the design of the porous catalyst layer in low-temperature fuel cells. The measurement can generally be conducted by an atomic force microscope (AFM). However, the interaction force between the water droplet and the probe tip of the microscope may influence the measurement results. This paper employs the molecular dynamics technique to investigate the offset of the contact angle measurement. Calculations are in two sets, one simulated the water molecules clustering on the platinum surface, and the other involved the AFM measurement of the contact angle. The former case presents the original contact angle between the nano-scale water droplet and the platinum surface; the offset of the contact angle measurement due to intrusion of the AFM probe is predictable from the latter case. For engineering purposes, we present a correlation between the offset angle and the AFM measurement locations.

The removal of carbon dioxide (CO2) at the anode of a micro direct methanol fuel cell (μDMFC) is critical. The bubbles are generated at the anode and may block part of the catalyst/diffusion layer, causing the μDMFC to malfunction. This work discusses the CO2 bubble dynamics of microfluidics in a μDMFC from a microscopic perspective. A two-dimensional, nine-velocity lattice-Boltzmann model was adopted in this work to simulate the two- component (CO2 bubble plus methanol solution) two-phase (gaseous and liquid) micro flow in a microchannel. The liquid–gas surface tension, the buoyancy force and the fluid–solid wall interaction force play the major roles in the bubble dynamics. They are treated as source terms in the lattice momentum equation. Simulation results indicate that the methanol stream flow rate, the pore size and the channel incline angle significantly affect the removal of CO2 bubbles. The effect of the incline angle is substantial at low stream flow rates. The critical pore size in the microchannel for removing bubbles at all angles under various flow conditions has been predicted quantitatively.

Background Efficacy and safety of sirukumab, a selective, high-affinity human monoclonal antibody to IL-6, have recently been evaluated in a global Phase 3 study in patients (pts) with active rheumatoid arthritis (RA) refractory to conventional disease-modifying anti-rheumatic drugs (DMARDs). Objectives To compare efficacy and radiographic progression of sirukumab in subgroups of pts with active RA despite DMARD treatment who previously received biologic therapy (biologic-experienced) and who previously only received synthetic DMARDs (biologic-naive). Methods Pts were randomized (1:1:1) to sirukumab subcutaneous (SC) 50mg q4w, sirukumab SC 100mg q2w, or placebo SC q2w. Pts on placebo with insufficient ( Results Improvements were observed in all outcomes for sirukumab vs placebo, regardless of prior biologic use (all P P P =0.02). No differences between prior biologic-naive and -experienced pts were observed in either sirukumab dose group for the co-primary endpoints (both P ≥0.1) as well as for Wk 24 ACR50 response, DAS28 (CRP) remission, or Wk 52 mean DAS28 change from BL (all P ≥0.1). Conclusions Both sirukumab doses significantly reduced RA signs/symptoms and inhibited radiographic progression vs placebo within prior biologic use categories, with comparable efficacy observed between biologic-naive and -experienced pts for both sirukumab doses. Disclosure of Interest C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, G. Karpouzas Consultant for: Janssen, Speakers bureau: Janssen, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, S. Xu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Kurrasch Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Background Agents intercepting the IL-6 pathway have been associated with abnormalities in liver enzymes, neutrophils, and platelets. Objectives To evaluate laboratory results from 2 Phase 3 studies (1 global, 1 Japanese) of sirukumab, a selective human anti-IL6 monoclonal antibody, in patients with active rheumatoid arthritis (RA), and to compare patients using concomitant methotrexate (MTX) or not. Methods In the global study, patients with active RA and inadequate response to disease-modifying anti-rheumatic drugs were randomly assigned (1:1:1) to sirukumab SC 50mg q4w, sirukumab SC 100mg q2w, or placebo SC q2w. Approximately 86% were taking MTX at baseline in the global study. In the Japanese study, 122 patients with active RA refractory to MTX or sulfasalazine were assigned (1:1) to monotherapy with sirukumab SC 50mg q4w or sirukumab SC 100mg q2w. Descriptive hematology and chemistry results through Wk 24 were summarized for the 2 sirukumab dose groups, and results were stratified by MTX use. No inferential statistical testing was conducted. Results As has been observed with other IL-6 pathway inhibitors, sirukumab was associated with increases in alanine transaminase (ALT) and aspartate transaminase (AST) and decreases in neutrophil and platelets. The proportion of patients with maximum toxicity grade >1 at Wk 24 for lab results of interest were similar across the sirukumab dose groups (Table). The proportion with increased ALT and AST grade ≥2 (>3x Upper Limit of Normal) through Wk 24 was numerically greater for patients on concomitant MTX in the global study vs those not on MTX. Similarly, continued MTX exposure numerically amplified the effect of sirukumab treatment on liver test abnormalities in the 121 Japanese patients in the global study (on MTX), vs the Japanese monotherapy study. Neutrophil and platelet decreases were similar between groups with and without MTX. Conclusions Numeric differences in abnormally elevated liver enzyme tests for RA patients treated with sirukumab were observed between patients on MTX and not on MTX, including patients from the global and Japanese studies. In these 2 Phase 3 studies, there was no clear dose-dependent effect on ALT, AST, neutrophils, or platelets between the 2 sirukumab doses. Disclosure of Interest G. Karpouzas Consultant for: Janssen, Speakers bureau: Janssen, C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers, Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen, H. Yamanaka Grant/research support from: Teijin Pharma, Chugai, Astellas, Bristol-Meyers, AbbVie, Daiichi-Sankyo, Mitsubishi-Tanabe, Takeda, UCB, Consultant for: Teijin Pharma, Bristol-Meyers, AbbVie, M. Harigai Grant/research support from: Abbvie Japan Co., Ltd., Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Ono Pharmaceuticals, Pfizer Japan Inc., Sanofi-Aventis K.K., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and UCB Japan, T. Ota Employee of: Janssen Pharmaceutical K.K., S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, S. Xu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Kurrasch Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Background Sirukumab, a human monoclonal antibody that selectively binds to the IL-6 cytokine with high affinity, is under development for rheumatoid arthritis (RA) and other diseases. Objectives To evaluate efficacy and safety of sirukumab in patients (pts) with RA refractory to conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs). Methods In this Phase 3 global study, 1,670 pts with active RA and inadequate response to DMARDs were randomized (1:1:1) to sirukumab subcutaneous (SC) 50mg q4w, sirukumab SC 100mg q2w, or placebo SC q2w. Pts on placebo with insufficient improvement ( Results For both co-primary endpoints, sirukumab 50mg q4w and 100mg q2w showed significant improvement vs placebo (Table; all P Conclusions In DMARD-inadequate responders, sirukumab SC 50mg q4w and 100mg q2w reduced signs/symptoms of RA, inhibited radiographic progression, and improved health-related quality of life. The safety profile of sirukumab was consistent with the known safety profile of anti-IL-6 treatment. Disclosure of Interest T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, G. Karpouzas Consultant for: Janssen, Speakers bureau: Janssen, S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, R. Rao Shareholder of: GSK, Employee of: GSK, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Background Improvement in physical function and morning stiffness are important goals of rheumatoid arthritis (RA) treatment. Sirukumab, a selective human anti-IL6 monoclonal antibody, has recently been evaluated in a global, Phase 3 study for the treatment of RA in patients (pts) with active disease that did not respond adequately to conventional, synthetic disease-modifying antirheumatic drugs (DMARDs). Objectives To evaluate the effects of sirukumab treatment on physical function and morning stiffness in pts with active RA refractory to DMARDs. Methods In this study, eligible pts with active RA and inadequate response to DMARDs were randomized (1:1:1) to treatment with sirukumab SC 50mg q4w, sirukumab SC 100mg q2w, or placebo SC q2w. In the placebo group, pts with insufficient ( 1 and a normal HAQ-DI score was defined as ≤0.5. The average duration of daily morning stiffness during the previous week in minutes (0–1440 minutes) was evaluated at the same visits as the HAQ-DI. Results A significantly greater improvement from BL in the mean HAQ-DI score was observed for both doses of sirukumab compared with placebo at all time points from Wk 2 through to Wk 52 (all P ≤0.006; Table). Improvements from BL in the HAQ-DI score were clinically meaningful (change of −0.22) for a significantly greater proportion of pts with sirukumab (both dose regimens) compared with placebo from Wk 4 onwards (all P P P ≤0.022). Conclusions Sirukumab treatment in pts with active RA refractory to DMARDs was associated with early, sustained, and clinically meaningful improvement in both physical function and morning stiffness, which are key treatment goals for pts with RA. References Maska L, et al. Arthritis Care Res. 2011;63(S11):S4-S13. Disclosure of Interest C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, G. Karpouzas Consultant for: Janssen, Speakers bureau: Janssen, K. McQuarrie Employee of: Janssen Research & Development, LLC, S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, S. Peterson Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Ganguly Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, C. Han Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Background Treatment-related improvements in the ability to perform work and general health status are key outcomes from the perspective of a patient with rheumatoid arthritis (RA). Sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine with high affinity and is under development for RA and other diseases. Objectives To evaluate the effects of sirukumab on work productivity/interference and general health status in patients with active RA refractory to conventional, synthetic disease-modifying anti-rheumatic drugs (DMARDs). Methods In a randomized, double-blind, Phase 3 global study, patients with active RA and inadequate response to DMARDs were randomly assigned (1:1:1) to treatment with sirukumab SC 50 mg q4w, sirukumab SC 100 mg q2w, or placebo SC q2w. Patients on placebo with insufficient ( Results Mean WLQ production loss scores improved significantly from baseline for both sirukumab 50 mg q4w and 100 mg q2w compared with placebo at Weeks 24 and 52 (all P P P ≤0.002). Conclusions In patients with active RA refractory to DMARDs, sirukumab treatment was associated with significant improvements in work-related productivity and general health status, consistent with disease improvement demonstrated with sirukumab treatment. Disclosure of Interest T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, G. Karpouzas: None declared, C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, K. McQuarrie Employee of: Janssen Research & Development, LLC, S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, S. Peterson Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Ganguly Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, C. Han Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Background Rheumatoid arthritis (RA) may have a substantial negative impact on physical and emotional well-being and fatigue. Sirukumab, a selective, high-affinity human anti-IL6 monoclonal antibody, is being evaluated for RA treatment. Objectives To evaluate the effects of sirukumab on health-related physical and emotional well-being (based on Short Form-36 [SF-36] health survey) and fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scale) in patients (pts) with RA refractory to Disease-Modifying Anti-Rheumatic Drugs (DMARDs). Methods This Phase 3 study evaluated 2 sirukumab doses in pts with active RA and inadequate response to DMARDs. Pts were randomized (1:1:1) to double-blind treatment with sirukumab subcutaneous (SC) 50 mg q4w, sirukumab SC 100 mg q2w, or placebo SC q2w. In the placebo group, pts with Results Significantly greater mean increases (improvements) from BL in mean SF-36 PCS and MCS, all 8 SF-36 domain scores, and the FACIT-Fatigue score were observed for sirukumab 50mg q4w and 100mg q2w vs placebo at Wks 8, 16, 24, 36, and 52 (all P P Conclusions Sirukumab treatment yielded early, durable, statistically significant and clinically meaningful improvements in health-related physical and emotional well-being and fatigue in patients with DMARD-refractory RA compared to placebo throughout Wk 52. Disclosure of Interest G. Karpouzas Consultant for: Janssen, Speakers bureau: Janssen, C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, K. McQuarrie Employee of: Janssen Research & Development, LLC, S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, S. Peterson Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Ganguly Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, C. Han Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

On the basis of identification of two gravity-related esterases (grEST1 and grEST2) in carrot callus cells (Cai et al. 1998), we continued the study of the characteristics of these two esterases. They have the very special characteristic of SDS resistance. Their activities could be inhibited partially by deoxycholate. beta-Phenylpropionic acid, AgNO3 and CuSO4 had no inhibitory effect on their activities. The activities of grEST1 and grEST2 could be decreased by ascorbic acid and cysteine, and the influence by cysteine was particularly obvious. The molecular weights of grEST1 and grEST2 were shown to be near the ranges of 49-66 kD and 43-59 kD respectively by non-denaturing electrophoresis containing deoxycholate, Triton X-100 and SDS respectively, and the isoelectric points were approximately pH 5.4 and 4.9 respectively. Besides, grEST1 and grEST2 were found in the fraction precipitating at value between 30% and 40% saturation with (NH4)2SO4.

Objectives Assess safety and efficacy of GLM+MTX over 1yr in a multicenter, randomized, placebo (PBO)-controlled study of Chinese pts with active RA despite MTX therapy. Methods 264 pts were randomized (1:1) to subcutaneous PBO+MTX (Group1) or GLM 50mg+MTX (Group2) q4wks. All pts received stable doses of oral MTX (7.5-20mg/wk). Group1 pts with inadequate treatment response entered blinded early escape to GLM 50mg+MTX at wk16. All remaining Group1 pts switched to GLM 50mg+MTX at wk24. Blinding to randomization assignment was maintained through wk 56. The last GLM injection was at wk48; the last efficacy assessment was wk52. The primary endpoint was ACR20 at wk14. Efficacy assessments included DAS28-CRP, HAQ-DI, SF-36 PCS and MCS, and FACIT-Fatigue scores. Adverse events (AEs) were monitored through wk56. Results Baseline demographics and disease characteristics were generally similar between the groups; median age was 49 yrs and 81.1% of pts were female. 23 (8.7%) pts discontinued treatment through wk56. Efficacy results are shown in the table. At wk14, 15.9% of Group1 pts and 40.9% of Group2 pts had ACR20 response (p Conclusions Among Chinese pts with RA, GLM+MTX-treated pts had significantly greater improvements in RA signs/symptoms vs. PBO+MTX-treated pts through wk24, and responses were maintained through wk52. GLM+MTX was well tolerated and no unexpected safety events occurred through wk56. In Chinese pts, GLM+MTX demonstrated efficacy and acceptable safety similar to that in a global population in the GO-FORWARD trial. Disclosure of Interest : Z. Li Grant/research support from: Janssen R&D, LLC, F. Zhang Grant/research support from: Janssen R&D, LLC, J. Kay Grant/research support from: Janssen R&D, LLC, K. Fei Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, C. Han Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, Y. Zhuang Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, Z. Wu Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, E. Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC

Background A multicenter, randomized, placebo (PBO)-controlled study of golimumab (GLM) was performed in Chinese pts with ankylosing spondylitis (AS). Objectives To assess efficacy and safety of golimumab (GLM) through wk56 in Chinese pts with active AS. Methods Chinese pts aged≥18yrs with a diagnosis of active AS (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]≥4, and a visual analogue scale [VAS] for total back pain≥4, each on a scale of 0-10cm) for ≥3 months prior to screening were eligible. Pts with prior exposure to anti-TNF agents and those with complete ankylosis of the spine were excluded.213 pts were randomized to q4wk SC injections of PBO from wks 0 to 20, followed by GLM 50mg from wks 24 to 48 (Group1, n=105) or GLM 50mg from wks 0 to 48 (Group2, n=108). Group1 pts with Results Baseline demographics were comparable in the 2 groups; median age was 29yrs, median weight of 62.0kg, and 83.1% were males. ASAS20 at wk14 was achieved by 49.1% of pts in Group2 vs. 24.8% in Group1 (p . 0.113; p Conclusions GLM significantly reduced AS symptoms/signs and functional limitations and improved health-related quality of life in Chinese pts with active AS. Treatment with GLM was well tolerated and without unexpected safety concerns. Disclosure of Interest C. Bao Grant/research support from: Janssen R&D, LLC, F. Huang Grant/research support from: Janssen R&D, LLC, M. Khan Grant/research support from: Janssen R&D, LLC, K. Fei Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, Z. Wu Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, Y. Zhuang Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, T. Gathany Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, C. Han Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, E. Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC

Expression of HLA class I antigens is closely controlled in the placental trophoblast cells, which interface directly with maternal cells during pregnancy. In this study, the possibility that peptide transporter (TAP-1, TAP-2) or proteasome (LMP7) genes might be involved in regulating antigen expression in these or other cells that comprise placentas was investigated. Analysis by Northern blot hybridization showed that transcripts from all three genes were present in samples of first trimester and term placental RNA. TAP-1 and TAP-2 messages were consistently more abundant in early than in late gestation placentas, whereas the reverse was observed for LMP7 mRNA. Futher experiments were done on two trophoblast cell lines. One line, Jar, is negative for HLA class I, and the second, JEG-3, expresses HLA-G as well as other HLA class I genes. Both Jar and JEG-3 cells contained TAP-1, TAP-2 and LMP7 mRNA. With the exception of LMP7 in JEG-3 cells, message from all three genes was increased by treating the trophoblast cells with interferon-gamma. While no evidence was collected to support the postulate that the HLA class I negative status of some trophoblast cell subpopulations could be related to absent or dysfunctional TAP-1, TAP-2 or LMP7 mRNA, the data are consistent with the postulate that placental cell expression of HLA class I antigens could be influenced by the availability of peptide transporters and proteasome components.

6521 Background: We surveyed breast cancer patients in New York City to understand why women did not receive radiotherapy (RT) following lumpectomy, chemotherapy, or hormonal therapy for hormone receptor negative or positive tumors >1 cm, respectively. Methods: 258 New York City women recently surgically treated for a new primary stage I or II breast cancer were surveyed about their experience of care, knowledge and beliefs about breast cancer and its treatment. Adjuvant treatment data were obtained from in and out-patient chart abstraction. Principal components factor analysis was used to create scales of adjuvant treatment beliefs and knowledge, medical mistrust, physician communication about treatment and social support. Scales were scored to 100. Bivariate and multivariate analyses were conducted to determine differences between treated and untreated women; odds ratios were converted to adjusted relative risks. Results: Compared to treated women, untreated women were less likely to know adjuvant therapies increase survival (66 vs 75; p < 0.0001), had greater mistrust (64 vs 53; p = 0.001), and less self efficacy (92 vs 97; p < 0.05); there was no association between physician communication of treatment information and patient knowledge and beliefs about adjuvant treatment (r = 0.8; p = 0.21). Multivariate analysis found that compared to those who were treated, untreated women were more likely to be 70 years or older (OR = 4.46; 95%CI: 1.9–10.7), more likely to have a comorbidity (OR = 3.39;1.5–7.9), more likely to express mistrust in the medical delivery system (OR = 1.03;1.0–1.1), and less likely to believe adjuvant treatments beneficial (OR = 0.91; 0.87–0.96) (model c = 0.84; p =< 0.0001). Conclusions: Patient knowledge and beliefs about treatment and medical mistrust are mutable factors associated with underuse of adjuvant therapies. Despite physicians' discussion of treatment, patients do not have a clear understanding of treatments' benefits and risks. This disconnect between what is said and what is heard may be mediated and addressed by dealing with patients' trust in and concerns about the medical delivery system. No significant financial relationships to disclose.

The paper summarizes the utility of currently available analytical techniques for the detection of heroin and other opiates in nonbiological samples. It focuses on the following techniques: thin-layer chromatography/high-performance thin-layer chromatography, gas-liquid chromatography, high-performance liquid chromatography, gas chromatography/mass spectrometry. Recent innovations for the identification of compounds using high-performance liquid chromatographic techniques are also discussed. The applications of each methodology based on the experience of the authors are outlined.