tbuckley/cabot-search huggingface dataset:
FRI0553 CANAKINUMAB AS A FIRST-LINE AND SECOND-LINE BIOLOGIC FOR TREATMENT OF SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS IN CHILDREN UNDER 4 YEARS OF AGE
Authors: Ekaterina Alexeeva, Tatyana Dvoryakovskaya, Ksenia Isaeva, Rina Denisova, Margarita Soloshenko, Anna Fetisova, Anna Mamutova, Maria Rudnitskaya, Dariya Vankova, Ivan Kriulin, Kristina Chibisova, Alina Alshevskaya, Andrey Moskalev
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Development of biologics and their launching into clinical practice has yielded significant progress in pediatric rheumatology. Nevertheless, treatment of severe disorders, and systemic JIA in particular, still remains a challenge. JIA often has the early-onset form. If its course is aggressive and persistent, patients exhibit poor response to treatment with first-line biologics. Effectiveness of the second-line and subsequent biologics, as well as the optimal sequence of prescribing drugs belonging to different classes to children younger than 4 years, remains an open question <h3>Objectives</h3> To compare the efficacy of canakinumab (CAN) in children with sJIA younger than 4 years (in biologic-naïve patients and when prescribed as a second-line biologic). <h3>Methods</h3> The study was conducted as a subanalysis of the prospective cohort study to evaluate the efficacy of biologics in children with sJIA. Comparative analysis involved 17 patients who had initiated CAN treatment at the National Medical Research Center of Children's Health (Moscow, Russia) when aged &lt; 4 years (9 biologic-naïve patients (the naïve group) and 8 patients switched from tocilizumab therapy (the switched group)). Treatment efficacy was evaluated according to the dynamics of clinical and laboratory signs using the ACRPedi criteria. The Wallace criteria were used to evaluate whether or not remission had been achieved. Treatment safety was evaluated according to the data presented in the Adverse Event Reports <h3>Results</h3> At baseline, patients had comparable duration and severity of the disease. The biologic proved efficacious already after 4 weeks of treatment. Five (55.6%) patients in the naïve group and 4 (50%) patients in the switched group achieved ACR90 (p&gt;0.999) within one year of treatment. A state of inactive disease according to the Wallace criteria was achieved in one patient in each group, (12.5% and 11.1%, respectively (p&gt;0.999). JADAS-71 decreased significantly from 12.8 (IQR 10.4-16.2) to 4.4 (IQR 2-6.8) in the naïve group (p=0.012) and from 11.6 (IQR 8-13.88) to 2.35 (IQR 1-3.03) in the switched group (p=0.017). <h3>Conclusion</h3> CAN was found to be highly efficacious and have a good safety profile in children younger than 4 years regardless of prior biologic treatment. <h3>Disclosure of Interests</h3> None declared
FRI0338 ANTI-MDA5 IDIOPATHIC INFLAMMATORY MYOSITIS (IIM) CONFERS POOR PROGNOSIS BUT NEGATIVE MYOSITIS SPECIFIC ANTIBODY (MSA) IS NOT BENIGN EITHER
Authors: Sin Ngai Ng, Chun Man Ng, Chu Oi Ciang, Moon Ho Leung
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> MSA test is useful to diagnose IIM and subcategorize patients by disease phenotypes. <h3>Objectives</h3> The study aims to evaluate the survival of IIM patients of different MSA patterns. <h3>Methods</h3> An IIM registry had been set up in a tertiary referral centre since 2014 by recruiting prevalent and incident cases. Patients were followed-up prospectively. This study included patients fulfilling the 2017 EULAR/ACR classification criteria for IIM<sup>1</sup> and excluded those aged &lt; 18 at disease onset. Immunoblot EUROLINE autoimmune inflammatory myopathies 16 antigens strip (EUROIMMUNE AG, Lubeck, Germany) was used. Information including baseline demographic data, disease manifestations, MSA results, co-existing malignancy, duration of survival and causes of death were collected. IIM patients were divided into seven groups, which included 1) anti-aminoacyl tRNA synthetase (ARS) 2) anti-MDA5, 3) anti-TIF1γ/anti-NXP2, 4) double positive MSA, 5) other MSAs, 6) negative MSA/MAA (myositis associated antibodies) and 7) positive MAA only. Survival probabilities were compared among different MSA groups by using the Kaplan-Meier method and log-rank test. A two-tailed probability value (p) &lt; 0.05 was considered significant. The study was approved by Kowloon Central Cluster Ethic Committee (ref.: KC/KE-17-0177/ER-3) <h3>Results</h3> Among 112 IIM patients, 79 (70.5%) were female, and the median age of onset was 55 (18-90) years old; 63.4% were dermatomyositis (DM), 17.9% polymyositis (PM) and 18.8% clinically amyotrophic DM (CADM). Co-existing interstitial lung disease (ILD) was common and found in 65 (58%) patients; 16 (14.3%) had rapidly progressive interstitial lung disease (RPILD), and 16 (14.3%) died within the observed period. Overall, the commonest cause of death was RPILD, followed by infection and malignancy. While anti-MDA5 was strongly associated with RPILD (odds ratio = 33.0 [95% CI: 7.2-151.8], p&lt;0.001), anti-MDA5 group had the worst survival, with 1-year and 5-year survival both at 43%, compared to above 80% in all other groups (log-rank test p&lt;0.001) (Table 1). There were nine patients with double positive MSA and 28 had negative MSA/MAA. Analysis between MSA sub-groups found that the double positive MSA, MAA only and other MSAs group had no mortality during study period while the negative MSA/MAA group had the second highest mortality following the anti-MDA5 group (Figure 1). Infection and malignancy were the two major causes of death in the MSA/MAA negative group. <h3>Conclusion</h3> Anti-MDA5 associated RPILD was the leading cause of mortality in IIM. However, those tested negative for both MSA and MAA by current immunoblot technique also had guarded prognosis related to the risk of infection and malignancy. <h3>References</h3> [1] Lundberg IE, et al.. ARD2017;76(12):1955-1964. <h3>Disclosure of Interests</h3> None declared
PB1842 ROLE OF THROMBOELASTOGRAPHY IN THE MONITORING OF PROPHYLACTIC TREATMENT IN PATIENTS WITH SEVERE HAEMOPHILIA A
Authors: V. Krasivska, O. Stasyshyn, M. Semerak, O. Tushnytskyi
Journal: HemaSphere (2019)

Background: According to many experts, during prophylactic treatment, the activity of factor VIII (FVIII) is not a sufficient predictor of the effectiveness of prevention and does not reflect the level of risk of bleeding. During monitoring of the therapy with activated partial thromboplastin time (APTTT) and FVIII activity, the cause of the discrepancy may be unaccounted content of the tissue factor, the amount and the aggregative function of the thrombocytes, which are also involved in the coagulation process. Therefore, global laboratory methods, in particular thromboelastography (TEG), are used to control therapy Aims: To study the role of TEG in the monitoring the prophylactic treatment of clotting factors concentrates in patients with haemophilia Methods: The study was performed in 9 patients with severe haemophilia A, who received prophylactic treatment by prolonged recombinant FVIII concentrate at a dose of 45 ± 5 IU/ kg two times a week. According to international recommendations all the patients were tested for incremental recovery (IR) of the administered concentrate FVIII in a dose of 60 ± 5 IU/kg during their routine visits. Pre‐ and post‐infusion coagulation tests and TEG (TEG 5000® Haemoscope Corp., Niles IL) were performed Results: Pre‐infusion the indicators of coagulation tests that characterized coagulation hemostasis (APTT‐72,9 sec, FVIII‐1,1%) were prolonged. 30 minutes post‐infusion the abnormal value came to the norm. The prothrombin time (PT), the fibrinogen level and quantity of platelets in the IR test did not differ from the corresponding values of healthy individuals. In TEG, the prolonged reaction time to clot formation R (21,9 sec), the time of maximum amplitude TMA (46,5 sec), the time of initial fibrin formation SP (19,1 min), the reduced rate of initial clot strengthening α‐Angel (33,0°), negative value of coagulation index CI (‐3,0) indicate a violation of the enzymatic phase of blood clotting. Post‐infusion of the calculated dose of the medication, all of the abnormal parameters returned to normal. In IR test, TEG parameters that characterize strength, quality, hemostatic capabilities, lysis of the clot and depend on the level of fibrinogen and platelets do not differ from those of healthy individuals Summary/Conclusion: TEG can be a reliable method for monitoring prophylactic treatment and IR in patients with hemophilia A without inhibitors in combination with coagulation tests (APTT, FVIII activity). The following parameters should be analyzed: the reaction time to clot formation R, the time of maximum amplitude TMA, initial fibrin formation SP, the rate of initial clot strengthening α‐Angel, the total coagulation potential CI
PF653 TARGETED NEXT-GENERATION SEQUENCING IDENTIFIES NOVEL GENE VARIANTS IN JAK2V617F NEGATIVE PATIENTS WITH ERYTHROCYTOSIS AND JAK2 GGCC_46/1 HAPLOTYPE
Authors: L. Anelli, P. Orsini, A. Minervini, A. Zagaria, N. Coccaro, E. Parciante, C.F. Minervini, C. Cumbo, G. Tota, L. Impera, A. Ricco, I. Attolico, S. Mallano, M.R. Conserva, G. Specchia, F. Albano
Journal: HemaSphere (2019)
PS1221 LONG‐TERM EFFICACY AND SAFETY OF INOTERSEN FOR HEREDITARY TRANSTHYRETIN AMYLOIDOSIS: NEURO‐TTR OPEN‐LABEL EXTENSION 2‐YEAR UPDATE
Authors: T. Brannagan, M. Waddington Cruz, A.K. Wang, M.J. Polydefkis, P.J. Dyck, S. Khella, V. Plante‐Bordeneuve, J.L. Burk, F. Barroso, G. Merlini, I. Conceição, S.G. Hughes, J. Kwoh, S.W. Jung, S. Guthrie, M.P. Pollock, M.D. Benson, M. Gertz, T. Coelho
Journal: HemaSphere (2019)

Background: Hereditary transthyretin amyloidosis (hATTR) is a rare protein misfolding disorder that causes progressive and debilitating polyneuropathy. A randomized, controlled phase 3 trial (NEURO‐TTR; NCT01737398) demonstrated efficacy and safety of inotersen in patients with hATTR polyneuropathy (Benson 2018 NEJM ). Aims: To provide an update on the long‐term efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of transthyretin protein production, in patients with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy. Methods: Patients who completed NEURO‐TTR were eligible to enroll in an ongoing open‐label extension (OLE) study (NCT02175004). We report an update on the long‐term efficacy and safety of inotersen in patients with hATTR polyneuropathy after 24 months in the OLE. Assessments included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7), Norfolk Quality of Life–Diabetic Neuropathy questionnaire total score (Norfolk QoL‐DN), Short Form 36 Health Survey version 2 (SF‐36v2) physical component summary (PCS), and safety monitoring. Results: Of 139 patients who completed NEURO‐TTR, 135 (97.1%) enrolled in the OLE. As of 5/31/2018, some patients were ongoing but had not yet completed 24 months in the OLE, and longest inotersen exposure in both studies was 5.2 years. Patients who switched from placebo to inotersen in the OLE demonstrated slowing of neurologic disease progression by mNIS+7 and Norfolk QoL‐DN as early as 6 months after starting inotersen (mean change from OLE baseline to month 6/year 2: 6.22/5.08 for mNIS+7 and 0.54/2.26 for Norfolk QoL‐DN). Patients who received inotersen for 39 months (15 months NEURO‐TTR + 24 months OLE) continued to show benefit (mean change from OLE baseline to year 2: 11.18 for mNIS+7 and 5.22 for Norfolk QoL‐DN). Patients who continued inotersen also showed stabilization of health‐related quality of life measured by SF‐36v2 PCS. No evidence of increased risk for grade 4 thrombocytopenia or severe renal events has been observed with increased exposure duration; no new safety concerns have been identified. Summary/Conclusion: In the OLE, inotersen improved, halted, or slowed progression of hATTR polyneuropathy, with greater stabilization observed in patients who initiated inotersen earlier.
Neuropilin-1 largely concentrates at cell junctions on endothelial cells separately from VEGFR-2
Authors: Mathew von Wronski, Natarajan Raju, Helen Fan, Michael Tweedle, Adrian Nunn
Journal: Cancer Research (2008)

1087  Tuftsin is a short immunostimulatory peptide with the sequence TKPR whose receptor was reportedly restricted mainly to certain immune cells. We previously noted that tuftsin is very similar to the exon 8-encoded tail of VEGF and discovered that tuftsin and the tuftsin antagonist peptide TKPPR selectively bind to neuropilin-1 (NP-1), a dual receptor for VEGF and class 3 semaphorins on endothelial and receptor-positive tumor cells, competitively with VEGF. A radiolabeled tetrameric TKPPR molecule accumulated rapidly and substancially (5.2 % ID/g at 1 h) in a receptor-positive mouse xenograft model (PC-3 tumors) with low uptake in most other tissues excluding the kidneys. In contrast, a monomeric TKPPR probe produced only modest localization in PC-3 tumors, consistent with the much greater avidity of the tetramer for NP-1.  One of neuropilin-1’s important roles is to act as a coreceptor for VEGF with VEGFR-2 on endothelial cells, greatly increasing the angiogenic signaling produced by VEGF. It is not clear however, whether this is the sole or even the main function of NP-1 on these cells. In new in vitro studies, we compared the cell-surface localization of VEGFR-2-targeted quantum dots (Qdots) and NP-1-targeted (TKPPR-conjugated) quantum dots. By using Qdots with non-overlapping emission spectra for each targeting molecule, the locations of both VEGFR-2 and NP-1 were simultaneously imaged on the same cultured endothelial cells. The VEGFR-2-targeted Qdots bound diffusely and mostly evenly on the surface of the endothelial cells. The NP-1-targeted Qdots, on the other hand, produced both a diffuse even-binding component as well as a much more abundant concentrated binding component at cell-cell contact points or on lateral edges and filapodial projections where endothelial cells were not in contact. This result is consistent with several recent publications suggesting roles for NP-1 in cell adhesion and migration, some of which are proposed to be at least partly independent of VEGFR-2. In addition, this result highlights the value of TKPPR and similar peptides as biological probes in studies of NP-1 function separate from their ability to deliver imaging and therapeutic moieties to sites with increased NP-1 expression, such as in cancer, angiogenesis, and inflammation.
PF187 LEUKEMIA AND DEPLETED URANIUM IN KOSOVO
Authors: H. Latifi‐Pupovci, M. Selmonaj, B. Ahmetaj‐Shala, M. Dushi, V. Grajqevci
Journal: HemaSphere (2019)

Background: Prolonged exposure and overexposure to depleted uranium (DU) is leukemogenic and genotoxic due to its radiological (alpha particle) and chemical (metal) components. The use of DU in the 1999 Kosovo War raised concern about the increase of new cases of leukemia. Aims: The aim of this study was twofold: 1) to analyze the incidence rates of leukemia in Kosovo in the pre‐war (1995–1998) and two post‐ war periods (2000–2003 and 2012–2015); and 2) to examine if there is any association between the use of DU rounds and incidence rates of leukemia in different regions of Kosovo. Methods: Patients diagnosed with leukemia in the University Clinical Centre of Kosovo for the period 1995–2015 were subject of this study. Annual incidence crude rates per 100,000 persons/year were calculated for seven regions of Kosova in three periods (1995–1998, 2000–2003 and 2012–2015). The number of DU rounds by region was determined from accurate NATO records containing geographic coordinates. Regional distribution, difference in incidence between pre‐war period and first and last post‐war period were calculated. In addition, to examine possible links between the presence of DU ordnance and incidence rates of leukemia, we analyzed the correlation between rounds/km2 and average annual incidence rates in the 27 municipalities. Results: Difference of incidence rates between the pre‐war (1995–1998) and the first post‐war period (2000–2003) for the entire territory of Kosovo shows that leukemia increased by 12.63% whereas between pre‐war and last post war period by 68.95% (Table 1). Region of Gjakova and Peja, the first and third most exposed regions to DU ordnance (7.73 rounds/km 2 and 4.78 rounds/km 2 respectively) ranked first and second in difference in leukemia incidence whereas Prishtina, Gjilan and Ferizaj, regions with the least number of rounds/km2, were characterized by declining in incidence rates of leukemia. After 15 years, still the difference in leukemia between pre‐war period and the last post‐war period remains larger in Gjakova and Peja. In the first post‐war period (2000–2003), significant moderate Spearman correlation was found between the DU rounds/km2 and cases of leukemia (Figure 1). image Figure 1. Correlation between rounds/km 2 and annual average incidence rates by municipalities for leukemia in the period 2000–2003. Data was analysed using the Spearman correlation test and significance accepted when p &lt; 0.05. Summary/Conclusion: The rise in incidence of leukemia in Kosovo may be partially induced by the use of DU during the war, but further studies are needed to explore this. image
PB2144 PRESCRIPTION PATTERNS AND OUTCOMES OF FIRST‐LINE THERAPY FOR NON‐TRANSPLANT ELIGIBLE MULTIPLE MYELOMA REAL‐LIFE PATIENTS ACCORDING TO AGE: A RETROSPECTIVE ANALYSIS OF THE 2012‐2016 PERIOD
Authors: M. J. Cejalvo, A. Sureda, E. González, J. Vázquez‐Álvarez, R. García, Á. Ramírez, E. Pérez‐Persona, E. Abella, S. Garzón, A. García, I. Jarque, M. S. González, A. Sampol, C. Motlló, J. M. Martí, M. Alcalá, R. Duro, Y. González, J. L. Sastre, J. Sarrà, G. Lostaunau, R. López, J. de la Rubia
Journal: HemaSphere (2019)

Background: Multiple myeloma (MM) affects elderly individuals with two‐thirds of patients aged &gt;65 years at diagnosis, 35% ≥75 and 10% ≥80. In general, routine clinical practice is based on the results of large, multicenter, randomized clinical trials. However, despite efforts from cooperative groups, patients enrolled in trials are generally younger and presumably healthier than the typical older patient with MM Aims: To describe prescription patterns for first‐line treatment of non‐transplant eligible MM patients in the setting of real‐life practice and to analyze treatment outcome according to patients’ age Methods Retrospective analysis of newly diagnosed MM patients not eligible for transplantation, who started anti‐myeloma treatment between 2012‐2016 in 20 Spanish hospitals. Variables collected included patients’ characteristics at diagnosis (ECOG, laboratory parameters, ISS, and cytogenetics/fluorescent in situ hybridization), characteristics of first‐line treatment, overall survival (OS), progression‐free survival (PFS), and overall response rate (ORR), defined as partial response or better Results: The retrospective cohort included 421 patients with a median age of 76 years (41‐90); 203 (49%), 106 (26%), and 104 (25%) were ≤75, 76‐80, and &gt;80 years old, respectively; 28 (12%) had ECOG &gt;2. ISS staging was I, II, III in 57 (18%), 93 (30%), and 160 (52%) patients, respectively; 73 (25%) patients had high‐risk cytogenetics. The most frequently prescribed regimen was VMP (208 patients), followed by other bortezomib‐based regimens (130 patients) (Table 1). Overall, median treatment duration was 6 months (95%CI 5‐7) and the ORR was 74% (for patients ≤75, 75‐80, and &gt;80 years old: 76%, 80%, and 62%; P = 0.025). Overall, 188 (45%) patients required a dose adjustment and 225 (81%) started second‐line treatment. Median OS and PFS were 32 (95% CI 29‐37) and 15 months (95% CI 14‐17), respectively. OS and PFS of patients ≤75, 75‐80, and &gt;80 years old were 44 and 16 months, 28 and 17 months, and 23 and 12 months ( P &lt; 0.01 for age‐group differences in both OS and PFS). Summary/Conclusion: In real‐life practice, there is high variability in treatment regimens, being bortezomib‐based the most frequently prescribed regimens in the study period. Besides the clinical characteristics of MM patients, age influenced survival in our cohort of real‐life patients, suggesting that treatment choice for elderly patients should be based on a specific pre‐treatment assessment of risks and benefits. image
AB0677 TREATMENT OF IDIOPATHIC INFLAMMATORY MYOPATHIES – A SINGLE CENTRE EXPERIENCE
Authors: Jaka Ostrovrsnik, Ziga Rotar, Matija Tomsic, Alojzija Hocevar
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> There is no consensus or recommendations for the treatment of idiopathic inflammatory myopathies (IIM). <h3>Objectives</h3> We explored how we treated incipient IIM patients in our secondary/tertiary rheumatology centre. <h3>Methods</h3> We retrospectively included cases with IIM diagnosed between January 2010 and June 2018, who were followed at least 6 months. The remission inducing treatment and the treatment at the last follow-up were recorded. <h3>Results</h3> During the 102-month period we identified 102 IIM cases (71.6% female, median (IQR) age 62.7 (52.2–72.1) years): 27.5% dermatomyositis, 22.5% anti-synthetase syndrome, 14.7% myositis in an overlap syndrome, 13.7% immune mediated necrotizing myopathy, 11.5% polymyositis, 6.9% cancer associated myositis, 2.9% inclusion body myositis (IBM), 1% unspecified myositis. 94 (92.2%) patients received glucocorticoids (GC), 18/94 (17.6%) as monotherapy. The remaining 81 (79.4%) were treated with additional immunomodulatory agents (Table 1), most commonly methotrexate. In addition to therapy presented in Table 1, 13 (12.7%) also received human immunoglobulins (IVIG), one (1%) received plasma exchange therapy. Of the 8 (7.8%) cases who were not treated with GC 3 received methotrexate, 1 rituximab, and 4 no additional treatment (1 paraneoplastic polymyositis received chemotherapy, 2 IBM, 1 mild polymyositis in elderly, multimorbid patient). In the first 6 months following diagnosis, 11 patients died (3 due to infection, 2 as a consequence of IIM, 1 due to haemorrhagic shock, 5 of unknown causes), and 5 were lost to follow-up. The remaining 86 patients were followed for a median (IQR) 37.7 (20.2–62.6) months. At last follow-up 49 (57%) patients were still receiving GC, 8 (9.3%) in monotherapy. 9 (10.5%) cases were off GC and other maintenance treatment. Maintenance treatment at last follow-up is presented in Table 2. Treatment was changed in 13 (15.1%) patients (due to progression of pulmonary involvement in 3, active myositis in 4, pulmonary involvement progression and active myositis in 1 and due to intolerance to medication in 6 cases). In addition to therapy presented in Table 2, 2 (2.3%) patients received IVIG (1 concurrently with rituximab and mycophenolic acid due to recalcitrant anti-synthetase syndrome and 1 due to IBM complicated with dysphagia). <h3>Conclusion</h3> GC, methotrexate and cyclophosphamide (in case of pulmonary involvement) were the cornerstone treatment in our cohort. <h3>References</h3> <h3>Disclosure of interests</h3> None declared
A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease
Authors: Elliott Vichinsky, Carolyn C. Hoppe, Kenneth I. Ataga, Russell E. Ware, Videlis Nduba, Amal El-Beshlawy, Hoda Hassab, Maureen M. Achebe, Salam Alkindi, R. Clark Brown, David L. Diuguid, Paul Telfer, Dimitris A. Tsitsikas, Ashraf Elghandour, Victor R. Gordeuk, Julie Kanter, Miguel R. Abboud, Joshua Lehrer-Graiwer, Margaret Tonda, Allison Intondi, Barbara Tong, Jo Howard
Journal: New England Journal of Medicine (2019)

Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor.