Honokiol, a well-tolerated natural product, can inhibit the proliferation of cancer cells. But its water insolubility hampers its systemic administration for therapy of cancer. As a drug delivery system, the pegylated liposome (PEGL) can increase the water solubility and targeting of the drug. Honokiol has been successfully encapsulated by PEGL in our laboratory. We wondered whether the combination treatment with pegylated liposomal honokiol (H-PEGL) and cisplatin (DDP) could improve the antitumor efficacy in ovarian carcinoma. H-PEGL could introduce apoptosis of SKOV3 cells in vitro, which was quantified by flow cytometric analysis, and the cellular morphologic changes were determined by propidium iodide staining. In a human ovarian carcinoma mouse model, combination treatment with H-PEGL (0.4 mg/day for 30 days; intraperitoneal) and DDP (5 mg/kg on days 7, 11, 15, 19; intraperitoneal) acted synergistically to inhibit tumor growth by 91.48% without notable toxicity, but H-PEGL and DDP alone only inhibit tumor growth by 66.83% and 52.5% as compared to the NaCl solution control, respectively. Assessment of microvessel density and apoptosis index by CD31 and terminal deoxynucleotidyl transferase-mediated nick end labeling immunohistochemistry respectively suggested that the antitumor activity of H-PEGL is mediated by angiogenesis inhibition and introduction of apoptosis. Our results showed us a splendid prospect of the clinical application of combination treatment on patients suffering from ovarian cancer with H-PEGL and DDP.

Background:Baricitinib (BARI) is an oral selective inhibitor of Janus kinase 1 (JAK1) and JAK2. In the EU and some other countries, baricitinib has been approved for the treatment of moderately to severely active rheumatoid arthritis (RA) in adult patients. This abstract reports efficacy and safety results from a phase 3, double-blinded, 52-week study (RA-BALANCE) that enrolled patients (pts) in China, Argentina and Brazil (NCT02265705).Objectives:To assess the efficacy and safety of BARI vs placebo (PBO) in the treatment of RA.Methods:Patients with moderately to severely active RA (tender joint counts ≥6 & swollen joint counts ≥6 & hsCRP≥6 mg/L) despite stable background methotrexate (MTX), were randomized 1:1 to PBO (n=145) or BARI 4-mg (n=145) once daily (QD), stratified by country and baseline joint erosion status. Background MTX was continued. Non-responders were rescued from Week 16. At Week 24, pts receiving PBO were switched to BARI 4-mg QD. ACR20 at Week 12 was the primary endpoint and there were multiple secondary endpoints e.g., assessing physical function, low disease activity and pain.Results:The primary ACR20 response was significantly greater for BARI than PBO (58.6% vs 28.3%, p≤0.001, Table). At Weeks 12 and 24, significant improvements were seen in pts receiving BARI vs PBO for ACR20/50/70, DAS28-hsCRP, CDAI low disease activity and SDAI low disease activity, many as early as by Week 1. At Week 16, significantly less radiographic progression was seen in pts receiving BARI vs PBO and numerical improvement was observed at Week 24. At Week 12, significant improvement in HAQ-DI minimum clinically important difference ≥0.3 (physical function), duration of morning joint stiffness, severity of morning joint stiffness numeric rating scale (NRS), worst tiredness NRS and reduced pain (0–100 mm VAS) were seen in pts receiving BARI vs PBO.During Weeks 0–24, treatment emergent adverse events and infections were reported in 74.5% and 42.1% of BARI pts and 62.1% and 28.3% of PBO pts, respectively. Serious adverse events were reported in 2.8% of pts in both groups. There was 1 nonserious esophageal candidiasis in the BARI group for Week 0–24. Four herpes zoster events (1 PBO, 3 BARI) were reported for Week 0–24. No major cardiovascular events, deaths, tuberculosis, venous thromboembolic events or malignancies were reported in the study through Week 24 for PBO and through Week 52 for BARI group. No unexpected safety signals were observed.Table 1Study RA-BALANCE efficacy measuresConclusions:Compared to PBO, BARI provided significant improvements in control of signs and symptoms, including pain and physical function with an acceptable safety profile.Disclosure of Interest:Z. Li Consultant for: Advisory board member of baricitinib, J. Hu: None declared, C. Bao Consultant for: Advisory board member of baricitinib, X. Li Consultant for: Advisory board member of baricitinib, X. Li Consultant for: Advisory board member of baricitinib, J. Xu: None declared, A. Spindler: None declared, X. Zhang Consultant for: Advisory boa...

Minimally-invasive surgery of hepatocellular carcinoma (HCC) can be limited by poor tumor visualization with white light. We demonstrate systemic administration of a Cy5.5-labeled peptide specific for epidermal growth factor receptor (EGFR) to target HCC in vivo in a mouse xenograft model. We attached a compact imaging module to the proximal end of a medical laparoscope to collect near-infrared fluorescence and reflectance images concurrently at 15 frames/sec. We measured a mean target-to-background ratio of 2.99 ± 0.22 from 13 surgically exposed subcutaneous human HCC tumors in vivo in 5 mice. This integrated imaging methodology is promising to guide laparoscopic resection of HCC.

Background:Iguratimod (IGU) has demonstrated efficacy and safety for active rheumatoid arthritis (RA) patients in double-blind clinical trials in China and Japan as a new disease-modifying anti-rheumatic drug (DMARD). There are no studies evaluating the radiographic progression of structural joint damage of IGU for the treatment of RA using the mTSS as the primary endpoint.Objectives:Our study was to evaluate the efficacy and safety of IGU monotherapy and IGU combined methotrexate (MTX) compared with MTX monotherapy, including the inhibitory effects of joint destruction.Methods:This randomized, double-blind, parallel-controlled, multicenter study in patients with active RA who have not previously used MTX and biological DMARDs (bDMARDs) (ClinicalTrials.gov Identifier NCT01548001) was carried out in China. Patients were randomized 1:1:1 to receive IGU 25 mg twice a day (bid), MTX 10mg once a week(qw) for the first 4 weeks and 15 mg once a week(qw) for week 5 to 52, or IGU combined MTX (IGU+MTX) for 52 weeks. The primary endpoints were to assess and compare American College of Rheumatology 20% (ACR20) response and the change of modified total Sharp scoring (mTSS) score over 52 weeks (Intention-to-treat, ITT analysis). The non-inferiority test was used to analyze the difference of ACR20 response at 52 weeks between the IGU monotherapy and the MTX monotherapy arms, and the non-inferiority limit value was 10%. The difference test was used for the comparison between the IGU+MTX and MTX monotherapy arms. Two-way ANOVA was used to analyze the difference of the changes of mTSS score of each arm compared with baseline value (0 week).Results:A total of 895 patients were randomized to IGU 25mg bid (n =297), MTX 10-15mg qw(n=293), and IGU+MTX (n=305). Baseline characteristics were comparable between the arms (Table 1).Table 1.Demographic and Other Baseline Characteristics (SAS)IGUMTXIGU+MTXNumber of Subjects297293305Age, mean (SD) years46.87(10.67)47.63(10.70)48.37(10.69)Female/male, %77.44/22.5679.18/20.8278.03/21.97Duration of RA, mean(SD) years11.67±7.1611.60±7.9811.67±7.27CRP, mean(SD) mg/L222.32±35.4720.67±26.6119.74±31.38Tender joint count, mean (SD)14.59±9.1614.83±9.3014.93±9.88Swollen joint count, mean (SD)9.81±6.639.73±7.209.51±6.22DAS28-CRP, mean (SD)5.084±0.9945.102±0.9795.103±0.956HAQ score, mean (SD)15.82±11.2515.24±10.9316.06±10.92SAS: Safety Analysis Set; CRP: C-reactive protein;DAS28: disease activity score; HAQ: Health Assessment QuestionnaireThe study met its primary endpoints. More concretely, IGU monotherapy and IGU+MTX were found to be superior to MTX at week 52 with a higher ACR20 response of 77.44%(230/297, P=0.0019) and 77.05%(235/305, P=0.0028) versus 65.87%(193/293) (fig 1). As shown in fig 1, the structural remission (ΔmTSS≤0.5) was statistically significant for IGU monotherapy (57.4%, P=0.0308) but not for IGU+MTX arm (55%) versus MTX monotherapy (47.8%).Overall incidence of the adverse events (AEs) leading to study discontinuation were reported in 13.8% (41/297) in IGU monotherapy arm, 11.26% (33/293) in MTX monotherapy arm and 11.51% (35/305) patients in IGU+MTX arm. The incidence of adverse drug reactions (ADR) leading to study discontinuation were 11.45% (34/297), 8.53% (25/293) and 9.21% (28/305), respectively. There was no one death and no significant difference in all the safety indicators among the three arms.Conclusion:Iguratimod alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX for patients with active RA who have not previously used MTX bDMARDs.Disclosure of Interests:None declared

BackgroundBiological disease modifying antirheumatic drugs (bDMARDs) are frequently used in combination with other drugs. Very limited data are available on concomitant therapy with bDMARDs in China.ObjectivesTo investigate the usage patterns and safety of concomitant drugs in Chinese RA patients receiving bDMARDs.MethodsPatients from 15 Chinese hospitals were recruited in this cross-sectional study. Consenting patients (aged ≥18 years) diagnosed with RA receiving bDMARDs were included.ResultsData collected from 802 patients with a mean (SD) age of 49.0 (13.9) years (81.3% women) were analyzed. Among these patients, 89.5%, 56.1%, 29.7%, and 19.1% were receiving concomitant conventional DMARDs (cDMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GC), and drugs for local application (LA drugs), respectively. In total, 718 patients were receiving concomitant cDMARDs. The proportion of patients using 1, 2, and 3 concomitant cDMARDs was 49.3%, 41.2%, and 9.5%, respectively. The most common cDMARDs were methotrexate, hydroxychloroquine, leflunomide, and sulfasalazine; used by 65.9%, 41.8%, 41.5%, and 6.3% patients at a mean (SD) daily dose (mg) of 1.4 (0.4), 340.3 (96.3), 15.4 (5.2), and 1753.3 (693.3), respectively. The respective mean (SD) duration of treatment (days) was 443.7 (845.8), 261.3 (409.4), 413.4 (578.5), and 429.1 (1039.9). Among the 238 patients on concomitant GC, 73.1% and 23.1% patients were receiving oral prednisone and methylprednisolone at a mean (SD) weekly dose (mg) of 57.8 (31.9) and 59.7 (151.6), respectively. In total, 17.6% patients reported at least one GC-associated adverse event (AE) at a mean (SD) duration of treatment (weeks) of 12 (28.3); the most common AEs were moon face (13.9%) and weight gain (4.2%). Among the 450 patients receiving concomitant NSAIDs, 43.1%, 20.2%, and 12.0% patients were receiving celecoxib, meloxicam, and loxoprofen sodium at a mean (SD) daily dose (mg) of 306.2 (100.1), 12.8 (3.5), and 143.9 (45.3), respectively. Most NSAID users were receiving NSAIDs at a dose lower than the daily maximum, except 2 patients using diclofenac acid at higher than daily maximum dose (150 mg). Only 3.6% NSAID users reported at least one AE; the most common AE was gastrointestinal discomfort (3.1%). A total of 153 patients were receiving concomitant LA drugs. The most common LA drugs were ketoprofen, diclofenac acid, and a Chinese herb medicine “Jia Wei Shuang Bai San”, used by 30.1%, 20.9%, and 10.5% patients, respectively. The corresponding mean (SD) treatment duration (weeks) was 2.0 (4.1), 7.8 (26.4), and 16.9 (28.0), respectively. The predominant reason (62.9% patients) for not using LA drugs was the lack of physician-directed prescription.ConclusionsThe usage patterns of concomitant cDMARDs and NSAIDs in Chinese RA patients receiving bDMARDs are similar to those in Western countries. The 17.6% concomitant GC users who reported at least one AE are receiving GC for longer time (12 weeks on average). LA drugs including traditional Chinese medicine offer a broad...

Background IgG4-related disease (IgG4RD) is a spectrum of systemic indications characterized by fibrosclerosis in various organs, tissue infiltrating IgG4+ plasma cells, and sometimes elevation of IgG4 in the serum. Mikulicz's disease (MD) is one of multiple IgG4RDs with single organ involvement including lachrymal, parotid, and submandibular glands. The pathogenesis of these diseases has been linked to infection and autoimmunity with a predominance of Th2- and Treg-cell cytokines driving increased levels of eosinophils, IgG4, and IgE, ultimately leading to cell infiltration and organ damage. To date, less is known about the molecular differences between IgG4RD and MD, as well as transcriptome-wide mediators of disease. Objectives We evaluated most altered molecular pathways in the blood of IgG4RD and MD patients. Methods Blood was procured from 13 MD (ages 32-65; 7 Male), 9 IgG4RD (ages 48-80; 9 Male), and 10 healthy control (ages 30-57; 7 Male) Chinese subjects and RNA was sequenced with Illumina HiSeq. Seven MD and 5 IgG4RD patients were treated with ≤20mg prednisone with one other glucocorticoid-sparing agent. In IgG4RD, 342 and 683 genes were over- and under-expressed, respectively and 35 and 33 genes were over- and under-expressed in MD (q<0.01; fold>2). Gene signatures were identified from ex vivo stimulation experiments with whole blood. All comparisons were relative to controls unless stated. Results IgG4 was the most over-expressed mRNA in both MD and IgG4RD (fold>32; qIgG4RD=0.001, qMD=0.002), with IgE mRNA among the top 10 most over-expressed (fold>8; qIgG4RD=0.0003, qMD=0.01) and both correlated with each other (r=0.85) and IL-5R mRNA (rIgG4=0.80; rIgE=0.64), which was suppressed in patients treated with prednisone compared to those not (pIgG4RD=0.008; pMD=0.0001). The same mRNA suppression of IgG4 and IgE was seen in MD patients on prednisone compared to those not (pIgG4=0.002 and pIgG4RD=0.004; pIgG4RD=0.03; pMD=0.03). Conclusions Our study shows the increase of IgG4 and IgE mRNAs, the activation of Th2, Treg, and other inflammatory cytokine pathways in both diseases compared to controls. A reduced B cell signature in the blood of IgG4RD and MD patients suggests infiltration to disease sites. Prednisone treatment suppresses IgG4 and IgE mRNAs in MD, IL-5R mRNA in both diseases, and activates IL-10 pathways in both diseases compared to treatment naïve patients. Further studies need to be conducted to confirm these observations and correlate them with clinical activity. Disclosure of Interest : B. Higgs Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Liu: None declared, J. Guo: None declared, C. Morehouse Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Sebastian Shareholder of: Astra Zeneca, Employee of: MedImmune, W. Zhu Shareholder of: Astra Zeneca, Employee of: MedImmune, L. Richman Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Yao Shareholder of: Astra Zeneca, Employee of: MedImmune, Z. Li: None declared DOI 10.1136/annrheumdis-2014-eular.2255

Background:In patients with rheumatoid arthritis (RA) and inadequate response (IR) to DMARDs, ph3 studies demonstrated efficacy of baricitinib (Bari) (2-mg and 4-mg).Objectives:To investigate the effects of Bari dose step-down in patients who achieved sustained disease control with Bari 4-mg.Methods:Patients with RA participating in the Bari ph3 long-term extension study who received Bari 4-mg for ≥15 months and who achieved sustained low disease activity ([LDA] – CDAI score ≤10) or remission ([REM] – CDAI ≤2.8) ≥3 months apart were re-randomised in a blinded manner to continue Bari 4-mg or step down to 2-mg. Patients could rescue to Bari 4-mg. Efficacy and safety were assessed through 48 weeks (wks) following re-randomisation.Patients Originating from RA-BEAM, RA-BUILD, RA-BEACON Combined† Wk 12Wk 24Wk 48 ContinuedBari 4-mgN=374SteppedDown toBari 2-mgN=376ContinuedBari 4-mgN=374SteppedDown toBari 2-mgN=376ContinuedBari 4-mgN=374SteppedDown toBari 2-mgN=376Efficacy measureNRI after rescue or for missing dataCDAI LDA ≤10338/374(90.4)310/376(82.4)**327/374(87.4)280/376(74.5)***300/374(80.2)254/376(67.6)***CDAI REM ≤2.8149/374(39.8)134/376(35.6)161/374(43.0)130/376(34.6)*145/374(38.8)121/376(32.2)NRI only for missing data (observed data used after rescue)CDAI LDA ≤10 338/374(90.4) 310/376(82.4)**334/374(89.3)304/376(80.9)**321/374(85.8)295/376(78.5)**CDAI REM ≤2.8 149/374(39.8) 134/376(35.6)164/374(43.9)137/376(36.4)*149/374(39.8)134/376(35.6)Safety measureWks 0–48n [EAIR]Continued Bari 4-mgN=374Stepped down to Bari 2-mgN=376SDEAE235 [69.30]202 [63.46] Infection108 [31.85]78 [24.50]SAE27 [7.96]26 [8.17] Serious infection10 [2.95]4 [1.26]AE →discontinuation9 [2.64]12 [3.74]Efficacy and safety data are n/N (%), and n [EAIR], respectively. †RA-BEAM=MTX-IR patients; RA-BUILD=csDMARD-IR patients; RA-BEACON=bDMARD-IR patients; EAIR=exposure-adjusted incidence rate; NRI=nonresponder imputation; SDEAE=step-down emergent adverse event; * p≤0.05, ** p≤0.01, *** p≤0.001 vs. continued Bari 4-mgFigure 1Data represent patients who have completed 48 weeks in the step-down period, or would have completed 48 weeks if not discontinued prior to the data cut-off date (April 1, 2017). Relapse defined as loss of step-down eligibility criteria, CDAI >10 for patients originating from RA-BUILD, RA-BEAM, or RA-BEACON. The p-value was computed using the Wilcoxon test.Results:The majority of patients in both groups maintained the state of LDA or REM over the 48 wks. However, dose reduction to 2-mg resulted in significant increases in disease activity at 12, 24, and 48 wks (Table). Dose reduction also resulted in a shorter time to relapse (defined as loss of step-down eligibility criteria); significantly more patients relapsed over 48 wks compared to the 4-mg group (figure 1). Rescue rates were 8.3% for Bari 4-mg, 16.6% for Bari 2-mg. Most rescued patients could regain LDA or REM. Dose reduction was associated with a lower rate of infections; rates of SAEs and AEs leading to discontinuation were similar across groups.Conclusions:These data indic...

BackgroundThe monoclonal gammopathy (MG) constitutes a group of diseases characterised by the proliferation of a single clone of plasma cells or B-lymphocytes. The spectrum of conditions capable of producing MG mainly includes a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS) and a group of malignant hematologic disorders. In previous studies, significantly increased risk of MG was seen in patients with a history of various rheumatic diseases. We analysed 41 hospitalised patients with underlying rheumatic diseases who were diagnosed with MG at out institute from 2010 to 2017, in order to identify clinical clues for early diagnosis, as well as the risk factors for MG and malignant hematologic neoplasias in patients with rheumatic diseases.ObjectivesTo analyse the clinical spectrum, laboratory characteristics and outcomes of monoclonal gammopathy (MG) in patients with rheumatic diseases.MethodsScreening for the presence of MG was performed in 872 inpatients with rheumatic diseases from January 2010 to July 2017. A total of 41 patients were enrolled. Their clinical and biological features in addition to outcomes were described. For each patient with primary Sjögren syndrome (pSS), 2 age- and sex-matched pSS patients without MG were selected as controls. Risk factors for the presence of MG and malignant haematological neoplasias were assessed.ResultsMG was observed in patients with various rheumatic diseases, with SS the most frequent type. Serum M protein was detected in 37 patients. M components were observed in urine in the other 4 patients. High ESR, albumin/globulin inversion, rheumatoid factor positicity, hypergammaglobulinemia, hypocomplementemia were common features, presented in more than half of the 41 patients. Patients with pSS, when complicated with MG, showed a higher rate of abnormal urine NAG (71.4% vs 15.8%, p=0.025), higher levels of ESR [55.0 (53.5) mm/h vs 21.0 (31.8) mm/h, p=0.001], ESSDAI [26.0 (25.0) vs 12.0 (9.0), p=0.006] and ClinESSDAI scores [24.0 (25.0) vs 10.5 (10.0), p=0.011]. Multivariate analysis revealed that the disease activity, assessed by either ESSDAI [adjusted OR 1.127 (95%CI 1.015–1.251), p=0.025] or ClinESSDAI [adjusted OR 1.121 (95%CI 1.011–1.242), p=0.030], was the only independent risk factor for the presence of MG. During the follow-up, 2 patients had transient serum M protein, 2 had isotype switch, 1 progressed to multiple myeloma (MM) and another 2 experienced renal injuries attributed by monoclonal or polyclonal plasma cell interstitial infiltration. Seven (17.1%) of the 41 MG patients presented haematological neoplasias, 4 with MM, 2 with smouldering multiple myeloma and 1 with B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. The presence of light-chain MG was associated with the development of MM [OR 17.5 (95%CI 1.551–197.435), p=0.041], but not with an increased risk of lymphoma or SMM.ConclusionsMG was observed in patients with various rheumatic disorders, with SS being the most common type. The presence of MG mi...