tbuckley/cabot-search huggingface dataset:
THU0679 Can the use of new technologies improve the use of patient reported outcomes (PROS) and patient participation in a national registry?
Authors: L Cunha-Miranda, H Santos, F Barcelos, N Madeira, S Fernandes, J Borges, R Marques, C Silva, C Miguel, A Cardoso, R Trinca, A Faustino
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> PROs are especially useful in the management of rheumatic diseases in complement to physician evaluation. However they are time consuming and used in a limited manner in the daily clinical practice. Reuma.pt is the Portuguese national rheumatic diseases register and one of the few registries in Europe that allows the patient to do at home the PROs before the appointment. In our institute we have complemented that with the creation of a paper free day hospital with the use of touch screen computers that also allows the patient to do the PROs before the clinical evaluation by the rheumatologist. <h3>Objectives</h3> to compare the impact of the use off Reuma.pt at home PROs completion platform before and after the utilization of touch screen computers in the day hospital. <h3>Methods</h3> We determined the number of patients and appointments with the use at home of the PROs platform one year prior to the introduction of the touch screen computer at our day hospital (October 2014 –October 2015) and one year after the paper free day hospital was installed (November 2015-November 2016). To determine any change of pattern of the use at home of the platform and the relations between that and patients characteristics. <h3>Results</h3> When we analyse the available variables between the patients that performed the PROs at home we found for both periods considered that they were younger (45,2/49,8 vs 53,4/55,1 p&lt;0.001) they have more education (11.8/10.35 vs 8.2/ 7,9) no differences were found regarding gender. There is a tendency that with the continuous use of touchscreen computers at the day hospital less educated (T0 -11.8, T1–10.35 school years) and older patients (T0- 45,2/ T1 -49,8 years) are using more at home platform of Reuma.pt. <h3>Conclusions</h3> The use of technology could have a consider impact on the way we collected data from our patients. With the use of a touchscreen computer we have improved not only the overall completion of PROs but also increased the familiarity of patient to the online questionnaires. Number of appoitments with previous at home completion of the questionnaires more than double. This has a clear impact on patient participation, quality of data in the registry but even more impact on time and human resources at a day hospital. <h3>Disclosure of Interest</h3> None declared
AB0068 Hypoxia and rheumatoid phenotype decrease the capacity of synovial fibroblasts to suppress t helper cell proliferation through ido1-mediated tryptophan catabolism
Authors: L-O Tykocinski, N-C Kaul, I Adam, SR Mohapatra, S Krienke, CA Opitz, H-M Lorenz
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The pathogenesis of rheumatoid arthritis (RA) is linked to functional changes in synovial fibroblasts (SF) and local infiltration of T lymphocytes. Increased synovial inflammation is also associated with a hypoxic joint microenvironment. Oxygen levels in the joints of RA patients are significantly decreased compared to those of osteoarthritis (OA) patients with values of about 22.5mmHg corresponding to ambient oxygen tensions of 3.2%. So far, little is known about the effects of hypoxia on the interaction between fibroblasts and T lymphocytes and its implications on the pathophysiology of RA. <h3>Objectives</h3> The aim of this study was to compare the influence of SF from RA versus OA patients on T helper (Th) cell responses both under normoxic and hypoxic conditions. <h3>Methods</h3> SF were isolated from synovectomy tissues of OA or RA patients, Th cells were isolated from peripheral blood of RA patients or healthy donors. Cell cultures were performed under normoxic or hypoxic (3% O<sub>2</sub>) conditions. Th cell proliferation was determined by PKH26 labelling and flow cytometry. Cytokine secretion was quantified by ELISA. Indoleamine 2,3-dioxygenase 1 (IDO1) expression was analysed by Western Blot and expression of enzymes of the kynurenine pathway by real-time PCR. Tryptophan/ kynurenine levels in culture supernatants were quantified by HPLC. <h3>Results</h3> SF strongly inhibited the proliferation of co-cultured Th cells. Tryptophan was completely depleted within a few days in co-cultures of SF and Th cells, resulting in eukaryotic initiation factor (eIF)2α phosphorylation, TCRζ-chain down-regulation and proliferation arrest. Blocking of IDO1 completely restored Th cell proliferation, indicating that SF suppressed the proliferation of Th cells through IDO1-mediated tryptophan catabolism. Interestingly, RASF showed a significantly lower IDO1 expression, tryptophan metabolism and a weaker Th cell suppressive capacity compared to OASF. Under hypoxic conditions, the secretion of IFNg, the expression of IDO1, the tryptophan metabolism and the Th cell suppressive capacity of both OASF and RASF were significantly reduced. <h3>Conclusions</h3> SF suppressed Th cell growth through IDO1-mediated tryptophan catabolism. This mechanism may play an important role in preventing inappropriate Th cell responses under normal conditions. The reduced tryptophan metabolism under hypoxia together with the inferior efficiency of RASF to restrict T cell proliferation likely supports the development of synovitis in RA. <h3>Disclosure of Interest</h3> None declared
FRI0197 Adherence, satisfaction and fulfillment of expectations of patients with rheumatoid arthritis treated with subcutaneous biologicals. arco study
Authors: J Calvo-Alén, C Marras, I Monteagudo, G Salvador, T Vázquez-Rodríguez, J Tovar, P Vela, F Maceiras, M Bustabad, E Peirό, J Rosas, M Arteaga, S Fernández, L Cea-Calvo, Y Mestre, E Raya
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> In patients with rheumatoid arthritis (RA), we previously described that adherence to the subcutaneous (SC) biological treatment is better with monthly administration. <h3>Objectives</h3> We further assessed if there are differences in patients expectations and satisfaction with efficacy and tolerance that could contribute to explain such finding. <h3>Methods</h3> ARCO was a retrospective study on RA patients who had been prescribed a SC biological 11–18 months prior to the study. Adherence was calculated with the medication possession ratio (MPR). Satisfaction and expectations were assessed with the Spanish validated Carbonell questionnaire [1]. <h3>Results</h3> We included 364 patients (age 54.9 years [SD 12.5], 77.5% women, median duration of RA 7.8 years, period studied for the SC biological 14.8 months). Non-adherence (MPR ≤80%) was lower in patients with monthly (6.4%) than with weekly (17.4%, p=0.034) or every 2 weeks administration (14.4%, p=0.102). The % of satisfied patients (quite/very satisfied) was 86.2% for efficacy and 64.4% for side effects or tolerance. Non-adherence was similar in satisfied with efficacy and in neutral/unsatisfied patients (14.7% vs. 8.3%, p=0.399), or in patients satisfied/not satisfied with side effects (13.1% vs. 15.4%, p=0.504). The fulfillment of expectations is shown in the table. With regard to expectations on the effect, non-adherence was 15.5% (higher than expected), 12.6% (as expected) and 10.7% (lower than expected) (p=0.677), and with regard to discomfort/side effects, it was 15.6% (greater than expected), 18.5% (as expected) and 11.1% (lower than expected, or no side effect) (p=0.189). Fulfilment of expectation on efficacy was similar for the 3 dosing schemes, but the % reporting lower than expected discomfort or no discomfort was greater with fewer SC injections (table). In particular, the % reporting no discomfort/side effects with the administration were 17.8% (weekly), 29.3% (every 2 weeks), and 35.0% (monthly) (p=0.013). <h3>Conclusions</h3> RA patients on SC biological therapy show high satisfaction and fulfillment of expectations on efficacy, although both aspects lower for tolerance. Dosing regimen with lower number of SC injections seems to be associated with better fulfillment of expectations of tolerance. This finding, added to the lower number of injections itself, might explain the better adherence observed with monthly administration. <h3>References</h3> Carbonell J, Badia X; Grupo Expresar. Development and validation of a satisfaction questionnaire in patients with rheumatoid arthritis. Reumatol Clin 2006;2:137–45. <h3>Acknowledgements</h3> Funded by MSD, Spain. <h3>Disclosure of Interest</h3> None declared
FRI0418 Factors associated with steroid-free remission in patients with inflammatory myopathies. a retrospective analysis of a single-center cohort
Authors: Y Sato, K Kobayashi, K Minegishi, S Ohno, H Nakajima
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The inflammatory myopathies are a heterogeneous group of connective tissue diseases characterized by muscle weakness and inflammation. Corticosteroids are the standard main treatment for inflammatory myopathies. However, steroid therapy often causes a wide range of side effects. Although immunosuppressive drugs are used as steroid-sparing agents in an effort to prevent disease recurrence, the appropriate duration of steroid use remains unclear. <h3>Objectives</h3> We investigated whether steroid therapy can be safely withdrawn in patients with inflammatory myopathies followed in a single center. <h3>Methods</h3> We retrospectively reviewed clinical charts of 71 consecutive patients (age 51.9±15.7 y.o., female 69%) who met Bohan and Peter criteria for polymyositis (PM)/dermatomyositis (DM) and modified Sontheimer9s criteria for clinically amyopathic dermatomyositis (ADM), respectively. Steroid free remission was defined as a 3-month consecutive period of no disease activity without corticosteroid treatment. Factors associated with steroid free remission were examined. <h3>Results</h3> Of 71 identified patients, 29 patients (40%) were DM, 15 patients (21%) were PM, 9 patients (13%) were overlap myositis, and 18 patients (25%) were ADM. Thirty-seven patients (52%) had muscle weakness, 5 patients (7%) had malignancies and 43 patients (61%) had signs of interstitial lung disease. With a mean follow-up of 6.6±5.0 years, 9 patients (13%) died during follow-up period. The remaining 62 patients were treated with corticosteroids alone or in combination with immunosuppressants. Steroid-free remission was achieved in 21 of 62 patients (34%) patients with a mean time to steroid withdrawal of 5.5±4.0 years. Six of 21 patients (29%) relapsed 1.7±1.7 years after steroid withdrawal. There were no differences in onset of age, disease duration, positive ANA, positive Anti Jo-1 antibodies, serum creatine kinase levels, maximum dose of corticosteroids, skin, joint and lung involvement between steroid-free group and non-steroid-free group. Elevated inflammatiory markers were associated with long-term steroid use (p=0.038). Concominant immunosuppressants were more frequently used in non-steroid-free group than steroid-free group (p=0.002). <h3>Conclusions</h3> Steroid-free remission might be achieved in some patients with inflammatory myopathies. <h3>Disclosure of Interest</h3> None declared
Mechanical Ventilation–induced Diaphragm Atrophy Strongly Impacts Clinical Outcomes
Authors: Ewan C. Goligher, Martin Dres, Eddy Fan, Gordon D. Rubenfeld, Damon C. Scales, Margaret S. Herridge, Stefannie Vorona, Michael C. Sklar, Nuttapol Rittayamai, Ashley Lanys, Alistair Murray, Deborah Brace, Cristian Urrea, W. Darlene Reid, George Tomlinson, Arthur S. Slutsky, Brian P. Kavanagh, Laurent J. Brochard, Niall D. Ferguson
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Diaphragm dysfunction worsens outcomes in mechanically ventilated patients, but the clinical impact of potentially preventable changes in diaphragm structure and function caused by mechanical ventilation is unknown.To determine whether diaphragm atrophy developing during mechanical ventilation leads to prolonged ventilation.Diaphragm thickness was measured daily by ultrasound in adults requiring invasive mechanical ventilation; inspiratory effort was assessed by thickening fraction. The primary outcome was time to liberation from ventilation. Secondary outcomes included complications (reintubation, tracheostomy, prolonged ventilation, or death). Associations were adjusted for age, severity of illness, sepsis, sedation, neuromuscular blockade, and comorbidity.Of 211 patients enrolled, 191 had two or more diaphragm thickness measurements. Thickness decreased more than 10% in 78 patients (41%) by median Day 4 (interquartile range, 3-5). Development of decreased thickness was associated with a lower daily probability of liberation from ventilation (adjusted hazard ratio, 0.69; 95% confidence interval [CI], 0.54-0.87; per 10% decrease), prolonged ICU admission (adjusted duration ratio, 1.71; 95% CI, 1.29-2.27), and a higher risk of complications (adjusted odds ratio, 3.00; 95% CI, 1.34-6.72). Development of increased thickness (n = 47; 24%) also predicted prolonged ventilation (adjusted duration ratio, 1.38; 95% CI, 1.00-1.90). Decreasing thickness was related to abnormally low inspiratory effort; increasing thickness was related to excessive effort. Patients with thickening fraction between 15% and 30% (similar to breathing at rest) during the first 3 days had the shortest duration of ventilation.Diaphragm atrophy developing during mechanical ventilation strongly impacts clinical outcomes. Targeting an inspiratory effort level similar to that of healthy subjects at rest might accelerate liberation from ventilation.
SP0136 Multifactorial tissue growth factors
Authors: CP Denton
Journal: Annals of the Rheumatic Diseases (2017)

Connective tissue is a critical component of all organs and has special importance in the musculoskeletal system. In specialist tissues, such as bone, cartilage of muscle an in vascular structures and internal organs there is a mixture of less specialized connective tissue together with the specific tissue and organ specific cellular components. In addition to physiological function there are two other areas in which it plays a central role. Normal embryonic an postnatal growth and development, and tissue repair in response to injury. It has emerged that there are shared pathways, mediators and mechanisms in these different processes and that multifactorial tissue growth factors have an important role. In this way, these proteins can have a profound influence on multiple cell types and provide a mechanistic link in many complex chronic diseases. It is notable that pathways that are perturbed in one chronic disease, such as atherosclerosis or osteoarthritis may be similarly disrupted in different context in conditions such as lung fibrosis or scleroderma. Transforming growth factor beta family members are prototypic examples of this class of protein. This included TGFbeta isoforms but also the related bone morphogenetic (BMP) and activin family of proteins. They share chemical structure and an ability to regulate multiple cell types in a context specific way. In addition, there is remarkable complexity in their regulation with intrinsic inhibitory mechanisms to protect from inappropriate biological activity. Their role in repair means that activation of preformed protein may regulate biological effects. Proteins regulated by the TGFbeta family, such as the CCN family of matricellular proteins and some for the cardinal growth factors and cytokines share properties. There is functional and signaling redundancy and cross talk. Conceptually it is interesting to envisage dysfunctional networks of cytokines in disease that may be attenuated by extracellular blocking or antagonism. Insights for many areas of developmental biology and pathology have informed about this challenging area of molecular medicine. <h3>Disclosure of Interest</h3> C. Denton Grant/research support from: Inventiva, CSL Behring, GSK, Bayer, Consultant for: GSK, Actelion, Inventiva, Roche
Pembrolizumab for previously treated advanced cervical squamous cell cancer: Preliminary results from the phase 2 KEYNOTE-158 study.
Authors: Jan H.M. Schellens, Aurelien Marabelle, Susan Zeigenfuss, Jie Ding, Scott Knowles Pruitt, Hyun Cheol Chung
Journal: Journal of Clinical Oncology (2017)

5514 Background: In the phase 1b KEYNOTE-028 study, pembrolizumab showed promising activity as monotherapy in patients with advanced cervical cancers that expressed PD-L1. As part of the ongoing, multicohort, phase 2 KEYNOTE-158 study (NCT02628067), we assessed the antitumor activity of pembrolizumab in a larger cohort of patients with previously treated, advanced cervical squamous cell cancer who were enrolled without regard to tumor PD-L1 or other tumor biomarker expression. Methods: Key eligibility criteria for this cohort included age ≥18 years, histologically or cytologically confirmed advanced cervical squamous cell cancer, progression on or intolerance to ≥1 line of standard therapy, ECOG PS 0 or 1, and provision of a tumor sample for biomarker analysis. Patients received pembrolizumab 200 mg Q3W for 2 years or until progression, intolerable toxicity, or physician or patient decision. Clinically stable patients with progression could remain on treatment until progression was confirmed on subsequent assessment. Tumor imaging was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. PD-L1 positivity was evaluated retrospectively by IHC and was defined as a combined positive score ≥1%. Primary end point was ORR assessed per RECIST v1.1 by independent central radiologic review. Planned enrollment is ~100 patients. This efficacy analysis includes patients who had ≥18 weeks of follow-up as of Oct 19, 2016. Results: Among the first 47 patients with advanced cervical cancer who enrolled, ORR was 17% (95% CI, 8%-31%), with 3 confirmed and 5 unconfirmed responses. 41 (87%) patients had PD-L1–positive tumors, and ORR was independent of PD-L1 status. Among the 15 patients who had ≥27 weeks of follow-up, ORR was 27% (95% CI 8%-55%), with 3 confirmed responses and 1 unconfirmed response. Safety and updated efficacy data for 83 patients with ≥27 weeks of follow-up will be available for presentation. Conclusions: Preliminary data from KEYNOTE-158 suggest that pembrolizumab has promising antitumor activity in patients with previously treated advanced cervical squamous cell cancer. The observed ORR with pembrolizumab appears to increase with longer follow-up. Clinical trial information: NCT02628067.
SP0013 Widespread cutaneous thickening – could this be early diffuse cutaneous systemic sclerosis?
Authors: A Suarez
Journal: Annals of the Rheumatic Diseases (2017)

A case of diffuse sclerosing skin disease shall be presented. The features that initially led the treating team to consider a diagnosis of systemic sclerosis shall be discussed, alongside subsequent features that emerged that cast doubt over this diagnosis and led the team to undertake additional investigative studies. The presentation shall provide a chronological description of the clinical features, laboratory studies, microvascular imaging and histological studies that helped the team to reach a definitive diagnosis and plan management accordingly. <h3>Disclosure of Interest</h3> None declared
Effect of repetitive administration of doxorubicin encapsulated in sterically stabilized liposomes on plasma kinetics, tissue/brain tumor drug deposition, and tumor vascular permeability in rats
Authors: Robert D. Arnold, Jeanine E. Slack, Donald E. Mager, Robert M. Straubinger
Journal: Cancer Research (2004)

648   Incorporation of drugs such as doxorubicin (DXR) in long-circulating liposomes (SSL-DXR) can alter pharmacology compared to the free drug. Differences in drug biodistribution, bioavailability, and tissue-specific metabolism may underlie the overall changes in pharmacology. Repetitive administration of SSL-DXR recently has been shown to alter vascular dynamics and permeability in the 9L gliosarcoma rat brain tumor model. The effect of repetitive administration of SSL-DXR on plasma kinetics and tissue/brain tumor deposition was investigated. Intracranial tumors were established by stereotaxic injection of 4x10 4  9L-72 cells into the caudate/putamen region of the brain in Fisher 344 rats. Free DXR and SSL-DXR were administered as weekly i.v. injections of 5.67 mg/kg, beginning 7 days after implantation. Drug concentrations in the plasma, brain tumor, brain, and other tissues were measured by liquid chromatography - tandem mass spectroscopy (LC-MS/MS). A 35% decrease in the plasma elimination rate was observed for SSL-DXR upon repetitive administration. Concomitantly, SSL-DXR drug deposition increased 200-300% in brain tumors, but decreased in the liver (50%) and spleen (73%). No effect of repetitive administration was observed for SSL-DXR deposition in brain, heart and lung. Repetitive dosing of free DXR had no effect on the plasma kinetics or deposition in any of the tissues examined. Deposition of DXR in heart, an organ associated with dose-limiting toxicity, was approx. 3-fold greater with free DXR than with SSL-DXR, and repetitive dosing did not alter this relative difference. A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to determine whether increased DXR tumor deposition arises from simple accumulation of repetitive doses or from alterations in tumor vascular permeability. The model suggests that accumulation alone cannot explain enhanced tumor deposition upon repetitive dosing, and incorporation of a 5-6 fold increase in the rate of tumor deposition best fits the experimental data. The model also suggests an increase of at least 170% in tumor exposure to drug upon repeat dosing. Thus, repetitive administration of SSL-DXR decreased the elimination rate of DXR from the plasma, increased DXR deposition in brain tumor, and decreased deposition in liver and spleen. The PK/PD model supports the hypothesis that the observed increase in DXR deposition in brain tumors is mediated by increased tumor vascular permeability.
The Cohesin Subunit Rad21 Is a Negative Regulator of Hematopoietic Self-Renewal through Epigenetic Repression of HoxA7 and HoxA9
Authors: Joseph B. Fisher, Jonathan Peterson, Michael Reimer, Cary Stelloh, Kirthi Pulakanti, Zachary Gerbec, Alex M Abel, Jennifer Strouse, Christopher Strouse, Maureen McNulty, Subramaniam Malarkannan, John Crispino, Samuel Milanovich, Sridhar Rao
Journal: Blood (2016)