tbuckley/cabot-search huggingface dataset:
OP0045 Synovial B Cell Status Determines Intensity of Rituximab Therapy Required in Rheumatoid Arthritis
Authors: E. M. Vital, Y. El-Sherbiny, J. Freeston, A. Brown, R. Reece, S. Dass, M. Buch, F. Ponchel, P. Emery
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Not all RA patients respond to a first cycle of rituximab. Previous synovial studies indicate that synovial B cells are depleted but higher pre- and post-treatment plasma cell numbers are associated with clinical non-response, as are higher numbers of plasmablasts in peripheral blood. <h3>Objectives</h3> To find synovial determinants of plasma cell persistence and clinical response to rituximab <h3>Methods</h3> 35 RF/CCP positive RA patients received licensed dose rituximab at baseline with a repeat cycle at 6 months in non-responders and at clinical relapse in responders. Peripheral blood B cell subsets were enumerated using flow cytometry. Knee synovitis was assessed using arthroscopic biopsy at baseline and 16 or 26 weeks and ultrasound power Doppler ultrasound (PDUS) at the same times. Synovial biopsies were analysed using immunohistochemistry for B cells (CD19) and plasma cells (CD138) with digital image analysis and real-time quantitative PCR (qPCR) using a 48 gene custom assay including genes for cell lineage markers, inflammatory cytokines, immunoglobulins, BAFF system molecules, chemokines and adhesion molecules. PDUS was scored semi-quantitatively 0-3 for 5 knee compartments and scores summated. qPCR data were analysed for relationships with IHC findings by Spearman’s correlation with Bonferroni-Holms correction for multiple comparisons, and using hierarchical clustering. <h3>Results</h3> IHC and qPCR both indicated a significant reduction in synovial B cells/CD19 mRNA but no significant overall change in plasma cells. CD138+ cell count after rituximab was associated with baseline CD138+ cell count and CXCL13 mRNA expression (R=0.738, p&lt;0.001). Hierarchical clustering demonstrated a “B cell signature” in a subset of patients defined by clustering of high expression for CD19, CD138, CXCL13, BAFF receptor and immunoglobulin genes together with TNFalpha and IL-1. These patients had worse disease activity and clinical response. This was also marked on PDUS, which was almost completely abolished in patients without B cell signature. However, after a second cycle of rituximab, responses in the B cell signature group improved achieving a similar change in DAS28 from baseline as non-B cell signature patients. B cell signature patients had greater plasmablast repopulation in peripheral blood at 6 months (p=0.041). <h3>Conclusions</h3> Outcome of rituximab treatment is worse in patients with high expression of synovial B cell markers and CXCL13, probably indicating aggregate or germinal centre synovial architecture. This appearance is associated with greater plasmablast repopulation in peripheral blood. “B cell signature” patients ultimately achieved the same response to rituximab as patients who do not have this synovial appearance, but needed more intensive therapy. <h3>Disclosure of Interest</h3> None Declared
Lamotrigine for epilepsy may not increase risk of birth defects, study shows
Authors: Jacqui Wise
Journal: BMJ (2016)

Babies born to pregnant women who are taking the epilepsy drug lamotrigine seem not to be at increased risk of birth defects such as cleft lip, cleft palate, or club foot, research published in Neurology has shown.1

Lamotrigine is a commonly used treatment for epilepsy and bipolar disorder. Maintaining epilepsy treatment during pregnancy is important because seizures may harm the fetus. The Medicines and Healthcare Products Regulatory Agency added a warning about the specific risk of …
P1-12-18: Change in HER2 Status in HER2 Positive Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without Anti-HER2 Therapy: Analysis of Two Consecutive Cohorts.
Authors: E Barbieri, F Piacentini, MV Dieci, G Ficarra, S Bettelli, P Conte, V Guarneri
Journal: Cancer Research (2011)

Abstract Introduction: emerging literature data have shown a change of HER2 expression from primary tumors to metastatic deposits. Tumor heterogeneity, genetic drift as well as selective pressure of adjuvant therapy have been suggested to explain this phenomenon. Aim of the present analysis is to evaluate the change in HER2 expression after neoadjuvant chemotherapy with or without anti-HER2 agents. Methods: two consecutive cohorts of HER2+ breast cancer patients treated with neoadjuvant therapy were identified from a prospectively maintained database including 310 patients. The first cohort (A) includes 38 patients enrolled before 2005, treated with chemotherapy alone. The second cohort (B) includes 48 patients treated with neoadjuvant chemotherapy in combination with antiHER2 agents (trastuzumab or lapatinib). HER2 expression was evaluated by IHC on pre-treatment core biopsy (tru-cut with 14 gauge needle) and on surgical specimen after neoadjuvant therapy. FISH analysis was performed on IHC 2+ samples. Results: The two cohorts were balanced in respect of tumor stage, patient age, and HR expression. In particular, a co-expression of HER2 and HR was observed in 60% of the patients in cohort A and in 70% of the patients in cohort B (p=0.2). Patients in cohort B have a significantly higher rate of pathologic complete response (pCR) in comparison to cohort A (45% vs 11%, p=0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 39% of the patients in cohort A vs 12% of the patients in cohort B (p=0.02). No patients with pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (50% vs 19%, p=0.018). Conclusion: contrary to our expectations, patients not receiving anti-HER2 therapy as part of neoadjuvant therapy were more likely to have a change in HER2 status vs patients receiving anti-HER2 neoadjuvant therapy. The change in HER2 status has a negative prognostic impact. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-18.
THU0334 Functional Restoration Programs for Chronic Low Back Pain Patients are not Just a Sports Facility! Change in Muscle (OR LEAN) Mass Assessed through DXA in 95 Patients, A Monocentric Study
Authors: C. Desthieux, S. Dadoun, V. Foltz, S. Rozenberg, F. Roure, B. Fautrel, L. Gossec
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Functional restoration programs (FRP) improve patients9 functional capacity and return to work in non specific low back pain (LBP). The mechanism underlying the improvement is debated: muscle mass increase, improvement in coping skills, and/or optimized physical behaviours. <h3>Objectives</h3> To assess the change in muscle and fat masses in chronic LBP patients undergoing FRP. <h3>Methods</h3> An observational prospective study was conducted in a single tertiary centre and included all patients with chronic LBP who took part in our centre9s FRP from January 2010 to March 2013 and underwent a dual X-ray absorptiometry (DXA) at baseline, 1 month and 6 months. FRP included 7-hours daily physical training, psychological support and therapeutic education, 5 days a week, over a period of 4 weeks. The endpoint was the absolute change in the lean (muscle) and fat masses, on DXA between the 3 timepoints as well as overall body weight. The statistical analysis relied on parametric paired tests (student9s t) on the total population. <h3>Results</h3> 95 patients were included, 40 men and 55 women: mean age was 41±8 years, mean body mass index 26.6 kg/m<sup>2</sup>, 38 patients (60%) where overweight or obese. Mean lumbar pain visual analogic scale (0-100 VAS) was 52 (±22). 76% patients were on sick leave with a mean duration of 9 months. At 6 months after FRP, functional scores were significantly improved after the FRP and 62% patients were back in the work force. At 1 month, there was an increase in lean mass (average 1.3 kg) and a decrease in fat mass (average 0.6 kg) (p&lt;0.001 both). At 6 months however, patients had experienced no significant weight loss (- 0.3 kg versus baseline, p=0.44) nor increase in lean mass (+ 0.3 kg versus baseline, p=0.08) or decrease in fat mass (- 0.5 kg versus baseline, p=0.10). <h3>Conclusions</h3> Although FRP had clinically relevant effects on functional and working capacity, body weight and fat and lean masses were not significantly modified at 6 months. This suggests that FRP is not only a “sports facility” and that the benefits of FRP can also be attributed to improvement in patient knowledge, as well as coping skills. <h3>References</h3> Poulain C et al. Long-term return to work after a functional restoration program for chronic low-back pain patients: a prospective study. Eur Spine J. 2010 Jul;19(7):1153-61. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1916
Evaluation of the Notification Procedure for Physician-Assisted Death in the Netherlands
Authors: Paul J. van der Maas, Gerrit van der Wal, Ilinka Haverkate, Carmen L.M. de Graaff, John G.C. Kester, Bregje D. Onwuteaka-Philipsen, Agnes van der Heide, Jacqueline M. Bosma, Dick L. Willems, Gerrit van der Wal, Paul J. van der Maas, Jacqueline M. Bosma, Bregje D. Onwuteaka-Philipsen, Dick L. Willems, Ilinka Haverkate, Piet J. Kostense
Journal: New England Journal of Medicine (1996)

In the Netherlands, a notification procedure for physician-assisted death has been in use since 1991. It requires doctors to report each case to the coroner, who in turn notifies the public prosecutor. Ultimately, the Assembly of Prosecutors General decides whether to prosecute. Although physician-assisted death remains technically illegal, doctors are extremely unlikely to be prosecuted if they comply with the requirements for accepted practice. In 1995, the ministers of health and justice commissioned an evaluation to determine the adequacy of the notification procedure.
297 THE POSTTRANSCRIPTIONAL DYSREGULATION OF METHIONINE ADENOSYL-TRANSFERASES IS CRUCIAL FOR THE PROGRESSION OF RAT AND HUMAN LIVER CANCER
Authors: F. Maddalena, M.I. Demartis, M.L. Tomasi, G. Latte, M.A. Seddaiu, M.M. Simile, F. Feo, R.M. Pascale
Journal: Journal of Hepatology (2012)
The Cardiovascular Response of Normal Humans to the Administration of Endotoxin
Authors: Anthony F. Suffredini, Robert E. Fromm, Margaret M. Parker, Matthew Brenner, Joseph A. Kovacs, Robert A. Wesley, Joseph E. Parrillo
Journal: New England Journal of Medicine (1989)

Marked abnormalities in cardiovascular function accompany septic shock, and bacterial endotoxin is believed to be one of the principal mediators of these abnormalities. To evaluate the cardiovascular effects of endotoxemia in humans, we measured hemodynamic variables in nine normal subjects given an intravenous bolus dose of endotoxin (Escherichia coli, 4 ng per kilogram of body weight) and in six normal subjects given a bolus dose of saline, before and three hours after administration. All the subjects then underwent volume loading with normal saline (mean, 2217 ml) during the fourth and fifth hours after administration of the bolus, and the measurements were repeated. Three hours after the administration of endotoxin and before volume loading, the cardiac index had increased by 53 percent and the heart rate by 36 percent (both changes were significant; P less than or equal to 0.008), and the systemic vascular-resistance index had decreased by 46 percent (P = 0.004). After volume loading (five hours after the administration of endotoxin), the left ventricular ejection fraction decreased by 1 percent of the base-line value in the subjects given endotoxin, but increased by 14 percent in the controls (P = 0.008). The left ventricular end-diastolic and end-systolic volume indexes increased by 18 percent (P = 0.07) and 24 percent (P = 0.042), respectively. Left ventricular performance, as measured by the ratio of the peak systolic pressure to the end-systolic volume index, was depressed (a decrease of 0.90 in the subjects given endotoxin vs. an increase of 0.76 in the controls; P = 0.024). We conclude that the administration of endotoxin to normal subjects causes a depression of left ventricular function that is independent of changes in left ventricular volume or vascular resistance. The changes in function are similar to those observed in septic shock and suggest that endotoxin is a major mediator of the cardiovascular dysfunction in this condition.
The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation
Authors: Carina Götestam Skorpen, Maria Hoeltzenbein, Angela Tincani, Rebecca Fischer-Betz, Elisabeth Elefant, Christina Chambers, Josè da Silva, Catherine Nelson-Piercy, Irene Cetin, Nathalie Costedoat-Chalumeau, Radboud Dolhain, Frauke Förger, Munther Khamashta, Guillermo Ruiz-Irastorza, Angela Zink, Jiri Vencovsky, Maurizio Cutolo, Nele Caeyers, Claudia Zumbühl, Monika Østensen
Journal: Annals of the Rheumatic Diseases (2016)

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.
THU0198 Patient Evaluations of Autoinjectors for Delivery of Subcutaneous Golimumab for Treatment of Rheumatoid Arthritis
Authors: H. Schulze-Koops, R. Giacomelli, W. Samborski, S. Rednic, M. Herold, R. Yao, M. Govoni, N. Vastesaeger, H. H. Weng
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Self-injection of subcutaneous (SC) golimumab (GLM) using an autoinjector device may be useful for patients with rheumatoid arthritis (RA), especially if they have functional impairment in the joints of the hand and fingers. An autoinjector designed to account for RA patient disability may improve patient satisfaction. <h3>Objectives</h3> To measure the acceptability, ease of use, and preferences for use of a SmartJect autoinjector for SC GLM administration; effects of patient age and functional impairment were evaluated. <h3>Methods</h3> GO-MORE was an open-label, multinational, prospective study in biologic-naïve patients with active RA (DAS28-ESR ≥3.2). Patients self-injected 50-mg SC GLM once monthly for 6 months. At months 4 and 6, patients reported their use preferences and opinions of the autoinjector device on a questionnaire. Responses were analyzed descriptively. Effects of patient age and functional impairment on responses were evaluated. <h3>Results</h3> Overall, the vast majority of patients found the autoinjector to be easy to use, to cause mild or no discomfort, and to cause mild or no pain (table). At month 6, most of the efficacy-evaluable patients reported they preferred to self-inject in the thigh (75.2%; 1563/2077), followed by the abdomen (17.5%; 363/2077) and the upper arm (7.3%; 151/2077). More than 85% of patients indicated that they used their right hand for self-injection. More than 95% of patients were sure or very sure that when they used the autoinjector, the treatment had been fully injected; and 92.1% were satisfied or very satisfied with the monthly autoinjection frequency. Responses did not differ by patient age group. Patients with minimal or no functional impairment (HAQ-DI ≤0.5) at baseline tended to have more favorable responses, including greater ease of injection and less pain with injection, than those with functional impairment. At month 6, the overall self-injection experience was considered extremely favorable by 53.7% and favorable by 39.5% of patients without impairment and extremely favorable by 42.5% and favorable by 49.1% of patients with impairment. <h3>Conclusions</h3> Most patients had very favorable evaluations of the SmartJect autoinjector device for GLM, reporting it to be easy to use, with minimal pain or discomfort upon injection and satisfactory administration frequency. <h3>Disclosure of Interest</h3> H. Schulze-Koops Consultant for: Abbott, Actelion, Biotest, BMS, Chugai, Essex, GSK, MSD, Medac, Merck, Mundai Pharma, Novartis, Nycomed, Pfizer, Roche, UCB., R. Giacomelli: None Declared, W. Samborski: None Declared, S. Rednic: None Declared, M. Herold: None Declared, R. Yao Employee of: Merck, M. Govoni Employee of: Merck, N. Vastesaeger Employee of: Merck, H. Weng Employee of: Merck
P355 GENE EXPRESSION ANALYSIS IDENTIFIES IMMUNE SIGNALING AND COMPLEMENT PATHWAYS IN IgG4-RELATED DISEASE
Authors: E.L. Culver, E. Marchi, C. Manganis, W. Smit, M. Makuch, N. Ramamurthy, T. Rispens, P. Klenerman, E. Barnes
Journal: Journal of Hepatology (2014)
1241 DECREASE IN EXPRESSION OF HEPATIC MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN INDUCED BY ENDOTOXIN RESULTS IN PATHOLOGICAL PROGRESSION IN A MURINE NAFLD MODEL
Authors: K. Imajo, M. Yoneda, K. Fujita, Y. Shinohara, S. Kato, H. Mawatari, Y. Nozaki, W. Shibata, H. Kirikoshi, K. Wada, S. Saito, A. Nakajima
Journal: Journal of Hepatology (2012)
Syphilitic Bone Destruction on FDG PET/CT
Authors: Xinlu Wang, Jilin Yin, Xiaodong Chen
Journal: Clinical Nuclear Medicine (2011)

A 35-year-old man underwent PET/CT scan to evaluate suspected osseous metastases from a presumed tumor of unknown origin. PET images demonstrated multiple foci of increased FDG uptake in all extremities, corresponding to the osseous destruction on the concurrent CT images. However, no primary tumor was identified. Instead, the bone lesions were subsequently proven due to syphilis infection.
Enhancement of Transgene Expression by Combining Glucocorticoids and Anti-mitotic Agents during Transient Transfection Using DNA-Cationic Liposomes
Authors: Rajesh R. Nair, John R. Rodgers, Lindsay A. Schwarz
Journal: Molecular Therapy (2002)

The anti-mitotic drugs colchicine and paclitaxel increase transfection efficiency of cationic liposomes. Using combined lipid-mediated transfection with anti-mitotic agents for gene therapy of cancer has been limited due to the likely development of multi-drug resistance (MDR). We treated human cancer cell lines and normal liver cells with glucocorticoids in combination with the antimitotics paclitaxel or colchicine before transient, cationic lipid-mediated transfection. Colchicine and paclitaxel each enhanced transgene expression in several cell lines. Moreover, glucocorticoid, combined with paclitaxel or colchicine, significantly increased reporter gene expression above that seen in cells treated with each drug alone. P-glycoprotein (PGP), a drug exporter encoded by <i>ABCB1</i>, exports both paclitaxel and colchicine. To determine the influence of PGP in colchicine- or paclitaxel-mediated enhancement of transgene expression, cells were treated with a histone deacetylase inhibitor, trichostatin A (TSA), known to induce <i>ABCB1</i> expression, before treatment with colchicine or paclitaxel. TSA significantly reduced colchicine-mediated increases in reporter gene expression. Addition of glucocorticoid to colchicine pretreatment significantly attenuated TSA-mediated inhibition of colchicine-induced increases in transgene expression. TSA accelerated and glucocorticoid blocked export of rhodamine 123, a molecule known to be exported by PGP. The glucocorticoid/paclitaxel combination also increased reporter gene expression in BE(2)C cells, which constitutively express high levels of PGP. Thus, the degree of enhancement of transgene expression mediated by these anti-mitotics seems to be dependent on PGP activity. Glucocorticoids augment colchicine- or paclitaxel-mediated enhancement of transgene expression most likely by reducing drug egress through PGP.
Managing Depression in Medical Outpatients
Authors: Mary A. Whooley, Gregory E. Simon
Journal: New England Journal of Medicine (2000)

Depression is second only to hypertension as the most common chronic condition encountered in general medical practice.1 At least 1 in 10 outpatients has major depression, but most cases are unrecognized or inappropriately treated,24 leading to loss of productivity, functional decline, and increased mortality.59 Appropriate therapy improves the daily functioning and overall health of patients with depression.10,11 DiagnosisMajor depression is defined by depressed mood or loss of interest in nearly all activities (or both) for at least two weeks, accompanied by a minimum of three or four of the following symptoms (for a total of at . . .