tbuckley/cabot-search huggingface dataset:
PS1567 UNCOUPLING INK PROTEINS FROM CDK4/CDK6 IN HSCS – UNCOUPLING PROLIFERATION FROM SENESCENCE
Authors: M. Prchal‐Murphy, F. Bellutti, V. Sexl, K. Kollmann
Journal: HemaSphere (2019)

Background: Cyclin‐dependent kinase (CDK) 4 and CDK6 are highly related cell‐cycle kinases that regulate progression from G1 to S‐phase. CDK4/6 are activated upon binding of D‐type cyclins and subsequently phosphorylate the retinoblastoma protein (Rb). CDK4/6 inhibitor proteins, the INK4 family (p16 INK4a , p15 INK4b , p18 INK4c , and p19 INK4d ) as major player, adds another layer of complexity. Hyperactivity of CDK4 or CDK6 is frequently observed in hematopoietic malignancies due to loss of p16INK4a. Besides, CDK6 has also been identified as transcriptional regulator driving complex transcriptional programs. CDK4/6 inhibitors are approved in breast cancer treatment and are currently tested in hematopoietic malignancies. Aims: We aimed to unravel the consequences of the loss of these inhibitory INK‐dependent mechanisms for hematopoiesis. Methods: We used knock‐in mice expressing a CDK6 (CDK6 R31C , Cdk6 R/R ) and/or a CDK4 (CDK4 R24C , Cdk4 R/R ) mutant insensitive to INK4‐mediated inhibition and analyzed stem cell populations. Further we tested the self‐renewal capacity of mutant hematopoietic progenitors under conditions of hematopoietic stress. Results: Despite comparable bone marrow cellularity, we found a significant reduction in LSK cells and HSC populations in mice harboring Cdk4 R/R or Cdk6 R/R mutation. The combination of Cdk4 R/R / Cdk6 R/R in double‐knock‐in mice rescued these defects in all progenitor stages. Serially transplanted Cdk4 R/R / Cdk6 R/R double‐knock‐in HSCs display enhanced stem cell proliferation. They maintain the ability to give rise to both myeloid and lymphoid lineages. In response to hematopoietic stress (5‐FU, serial and competitive total bone marrow transplantation), CDK4 R24C /CDK6 R31C prevents stem cell exhaustion and show robust recovery in stem cell numbers. Low‐input RNAseq of long‐term stress‐triggered HSCs will unravel mechanisms uncoupling proliferation from senescence. Summary/Conclusion: HSCs with disrupted CDK4/6 – INK4 binding show enhanced proliferation, reduced exhaustion and improved transplant ability. Analysis of the underlying molecular alterations may open novel therapeutic options for CDK4/6 hyperactive hematopoietic malignancies.
PF373 IMPACT OF ATM ALTERATIONS ON CHRONIC LYMPHOCYTIC LEUKEMIA IN GENERAL PRACTICE IN THE AREA OF NEXT GENERATION SEQUENCING
Authors: M. Ganard, R. Houot, C. Henry, M.‐L. Boulland, O. Luycx, J. Norwood, B. Bareau, I. Grulois, V. Launay, D. Jacomy, M. Roussel, M. De Tayrac, S. De Guibert, T. Fest, T. Lamy, C. Pastoret
Journal: HemaSphere (2019)

Background: Chronic Lymphocytic Leukemia (CLL) is characterized by a very heterogeneous clinical course. Del11q22–23 affecting ATM gene is the most common cytogenetic abnormality associated with poor prognosis. Clinical significance of ATM mutations, isolated or associated with del11q22–23, remains unclear specifically since the widespread use of new therapeutic agents. Aims: Evaluate frequency, associations and clinical significance of ATM alterations in a daily clinical practice cohort. Methods: We retrospectively analyzed a cohort of 268 CLL patients tested by NGS (Next Generation Sequencing) including ATM mutations in daily clinical practice. Results: We identified 50 different ATM mutations among 42 patients (15.7%) by NGS, including a majority of missense mutations and 35 del11q using FISH. Bi‐allelic ATM alterations ( ATM mutation and del11q) were found in only 13 patients (37.5% of the del11q patients and 31% of the ATM mutated patients). All but 11 patients with ATM alterations received anti‐CD20 combined chemotherapy directly after NGS realization. ATM alterations had no significant impact on overall survival (OS) but significantly affected time to first treatment (TTFT) in univariate analysis (median of 2.4 years versus 6.1 years (p = 0.004)) ( Figure 1A ) as well as in multivariate analysis (HR 1.6 IC 95% 1–2.6 ‐ p = 0.023). ATM alterations also affected significantly the time to next treatment (TTNT) with a median time of 2.0 years versus non‐reached in the absence of ATM alteration (p = 0.003) ( Figure 1B ).Outcome in the bi‐allelic ATM alterations subgroup was particularly pejorative with a median TTNT of 5.5 months (IC 95% 4.8–6.2 months). In multivariate analysis, only ATM mutation had a significant impact on TTNT (HR 3.98 IC 95% 1.45–10.9 ‐ p = 0.008) even when BCR‐inhibitors were used. Summary/Conclusion: ATM alterations are frequent in CLL either at diagnosis or at relapse. They confer worse disease evolutionary profile and earlier relapses, especially in case of bi‐allelic inactivation or multiple‐hit profile. These findings emphasize the importance of integrating ATM gene in a targeted NGS panel to better characterize CLL patients while waiting availability ofnew therapeutic agents targeting ATM deficiency. image
PS1503 ESTIMATING LIFE-YEAR LOSS OF LOWER-RISK MYELODYSPLASTIC SYNDROMES IN EUROPE
Authors: Z. Li, D. Tang, J. Tang, J. Morison, E.N. Oliva
Journal: HemaSphere (2019)

Background: Lower-risk (LR) myelodysplastic syndromes (MDS) are a group of hematologic disorders impacting patient survival and quality of life. Existing published survival data focus on describing duration of survival; however, it is difficult to interpret the seriousness of the disease objectively, since survival data have not been compared with data from the general population. Aims: To quantify the real-world life-year loss due to LR-MDS in comparison with the general population in Germany, France, Italy, Spain, and the United Kingdom (EU5). Methods: A simulation model was developed in Microsoft Excel using parameters sourced from a recently published report of the European LeukaemiaNet MDS (EUMDS) registry.1 The patient cohort comprised patients diagnosed with LR-MDS from December 2007 to December 2010, during which time recombinant human erythropoietin was available as treatment in most EU countries. Baseline demographics predictive of survival, including age, sex, and revised International Prognostic Scoring System (IPSS-R) risk score, were simulated using published patient characteristics.1 Survival (in years) of patients with LR-MDS was simulated using the exponential survival function. The exponential distribution parameter, modeled as a function of age, sex, and IPSS-R risk score, was estimated by Cox modeling using published survival curves and hazard ratios. Patient characteristics and survival statistics from the simulation sample were verified against those published by de Swart et al.1 Real-world life-year loss was defined as the difference between simulated survival time and the population-level life expectancy specific to patient age, sex, and country. Results: A total of 5,000 patients were included in the simulation; 1,000 patients from each country. The simulated sample generated similar patient characteristics, median survival, and hazard ratios as found by de Swart et al.1 As shown in Table 1, the mean life-year loss was estimated at 6.3 years (median 6.8 years; 5 and 95 percentile [−13.9, 23.4]), a 40% relative survival loss for patients with LR-MDS compared with the general population. Overall, 77% of patients were estimated to experience life-year loss. Patients experiencing more pronounced life-year losses than the general population were those <60 years (mean 13.4 years, 43% relative survival loss, 80% with life-year loss) and those with Intermediate IPSS-R risk score (mean 11.6 years, 76% relative survival loss, 96% with life-year loss). The results were consistent among the EU5 countries and when other similar European LR-MDS real-world studies were used as a data source.Summary/Conclusion: LR-MDS patients in 5 European countries experience significant real-world life-year loss when compared with the general population.
SAT0728-HPR REVISION OF THE DUTCH GUIDELINE FOR PHYSIOTHERAPY IN PATIENTS WITH HIP AND KNEE OSTEOARTHRITIS: RECOMMENDATIONS FOR DAILY PRACTICE
Authors: Wilfred F. Peter, Mitchell van Doormaal, Guus Meerhoff, Thea Vliet Vlieland
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Until 2018, the most recent update of the Dutch physiotherapy guideline for Hip and Knee Osteoarthritis (HKOA) was conducted in 2010. Since then, scientific developments changed the view on osteoarthritis and could have significant impact on daily practice. An update of the guideline was necessary with more applicable recommendations about the content of exercise therapy. <h3>Objectives</h3> To revise the Dutch guideline for physiotherapists in patients with HKOA <h3>Methods</h3> To develop more practical and widely supported guidelines, a guideline methodology was developed by the Royal Dutch Society for Physical Therapy (KNGF) in 2016. This methodology was based on GRADE, the most accepted approach in guideline development worldwide. According to the KNGF methodology, a guideline panel was formed out of 22 stakeholders, e.g. physiotherapists, general practitioners, orthopedic surgeons, patient representatives and healthcare insurers. Based on the scientific evidence and other considerations, the guideline panel formulated the recommendations in this guideline. <h3>Results</h3> Recommendations about diagnostics and therapeutic interventions formed the base of the new Dutch physiotherapy guideline for HKOA. Three indications were formulated, based on patient preferences, severity of the functional condition and existence of comorbidity. A fourth indication concerned pre- and postoperative physical therapy before or after a total joint replacement. It was recommended to restrict physical therapy in patients with minor functional limitations by informing and advising about osteoarthritis and how to deal with the disease. In contrast, extensive supervised exercise therapy was recommended in patients with severe functional restrictions and/or comorbidity. Besides informing and advising, supervised exercise therapy is stated as the intervention with the strongest recommendation. Frequency, Intensity, Type and Time (FITT factors) of exercise therapy are described extensively, based on evidence and strongly linked to (inter)national recommendation for physical activity. Besides informing and advising, other non-exercise therapeutic interventions were not recommended. <h3>Conclusion</h3> The new physiotherapy guideline for HKOA provides practical information and guidance to physiotherapists on diagnostics and therapeutic interventions. Extensive implementation is necessary to enhance conservative treatment of osteoarthritis and achieve uniform health care. <h3>Reference</h3> [1] Rausch, et al. EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. Ann Rheum Dis. 2018 Sep;77(9):1251-1260. <h3>Disclosure of Interests</h3> None declared
SP0045 CAN IMAGING PREDICT PROGRESSORS?
Authors: Jean-Pierre Raynauld
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Osteoarthritis (OA) is a highly heterogeneous disease with varying aetiologies, thus the manifestations of knee OA and response to treatment vary. This heterogeneity of clinical presentation and treatment response confounds interpretation of therapeutic clinical trials and complicates the care decisions for clinicians. Identifying factors to define patient profiles likely to progress more rapidly over time may help with subsequent therapeutic decision-making. Such characterisation could also help randomization strategies for clinical trials in attempting to balance comparator groups. Reasonable long-term goals among these rapid progressors would be to offer optimal quality of life and to postpone, if possible, the indication of joint replacement. Quantitative magnetic resonance imaging (qMRI) can precisely and accurately assess and quantify joint structural changes seen in OA. Such technology should logically help to identify patients with rapid OA progression and some of its predictors. This short presentation shall address whether MRI structural markers can be used to predict knee OA patient hard outcomes such as the total joint replacement. Data revealed that several articular tissue alterations have shown their potential for predicting patients with a rapid progression; global cartilage thickness/volume loss, presence and severity of meniscal damage, bone curvature, and presence of bone marrow lesions among others. However, clinical and demographics variables such as BMI, severe pain, and clinical knee synovitis and effusion are also strongly associated with articular tissue damage and should also be taken into careful consideration as they may independently also predict OA progression and potentially indication of joint replacement. Optimizing the selection of patients for whom an intervention with a DMOAD could prevent the development of the disease should lead to better response to treatment. Imaging may assist us at identifying the rapid progressors but should be used in a context of an overall patient assessment that also integrate the co-existing demographic and clinical variables. Such context may assist us in the emergence of personalized or precision medicine for patients suffering from this disease. <h3>Disclosure of Interests:</h3> Jean-Pierre Raynauld Consultant for: ArthroLab Inc.
Perioperative Management in Patients with Hemophilia Receiving Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia
Authors: Claude Negrier, Margaret V. Ragni, Pencho Georgiev, Toshko Jelev Lissitchkov, Huy Van Nguyen, Kate Madigan, K John Pasi
Journal: Blood (2017)
PF758 MULTI‐CENTER, PHASE II STUDY ON HAPLOIDENTICAL BONE MARROW TRANSPLANTATION USING A RIC REGIMEN AND POST‐TRANSPLANT CYCLOPHOSPHAMIDE IN PATIENTS WITH POOR PROGNOSIS LYMPHOMAS
Authors: L. Castagna, A. Dodero, F. Patriarca, F. Onida, A. Olivieri, D. Russo, I. Majolino, B. Sarina, J. Mariotti, S. Bramanti, C. De Philippis, E. Tagliaferri, C. Carlo‐Stella, R. Fanin, P. Corradini, A. Santoro
Journal: HemaSphere (2019)

Background: Allogeneic stem cell transplantation from haploidentical donor using unmanipulated bone marrow and post‐transplantation cyclophosphamide (PT CY) has been largely used to cure high‐risk lymphomas. Using nonmyeloablative conditioning regimen, the relapse incidence is considered a concerning issue. Aims: The aim of our study was to prospectively evaluate the efficacy and the feasibility of thiotepa‐based RIC regimen in high risk lymphoma patients. Methods: We enrolled 49 patients, and of these 47 were evaluable. The conditioning regimen consisted of thiotepa 10 mg/kg in 2 days, fludarabine 90 mg/m2 in 3 days, CY 60 mg/kg in 2 days, and TBI 2 Gy or TMI‐TLI 2 Gy. Unmanipulated bone marrow stem cells from a haploidentical family donor was infused at day 0. Graft versus host disease (GVHD) prophylaxis consisted of cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil and cyclosporine from day 5. The primary end point was the 1‐year progression free survival (PFS). Results: Patient characteristics are reported in the Table. Median age was 43 years (19–68). 49% of patients was affected by HL and 51% was in CR. The median time to absolute neutrophil count (ANC) and platelet recovery were 22 days (14–44) and 27 (17–151), respectively. The cumulative incidence (CI) of ANC engraftment at 30 days and platelet count at 60 days were 89% (75–95) and 84% (66–92). 2 patients (DSA negative) had a primary graft failure. The cumulative incidence at 6‐month of grade 2–4 acute GVHD and 2‐year moderate‐severe chronic GVHD was 26% (14–39) and 23% (13–37), respectively. After a median follow‐up of 35 months (12–64), the 1‐year and 3‐year PFS were 67% (51–79) and 67% (51–79), respectively. The 1‐year and 3‐year OS were 77% (62–86) and 67% (51–79), the 3‐year relapse incidence was 26% (14–39), and the 1‐year NRM was 15% (7–27). The 1‐year GRFS was 58% (43–71). The cause of death in 7 patients was: bilateral not documented pneumonia, acute GVHD, transplant‐associated microangiopathy, graft failure, CNS hemorrhage and other toxicities (2). Summary/Conclusion: In a prospective multicenter study in poor risk lymphoma patients, a thiotepa‐based RIC was well tolerated with an encouraging 1‐year PFS. Both relapse incidence and NRM were acceptable. A comparison with similar patients conditioned with a nonmyeloablative conditioning regimen has been planned. image
E-protein–regulated expression of CXCR4 adheres preselection thymocytes to the thymic cortex
Authors: Tejas Kadakia, Xuguang Tai, Michael Kruhlak, Jan Wisniewski, Il-Young Hwang, Sumedha Roy, Terry I. Guinter, Amala Alag, John H. Kehrl, Yuan Zhuang, Alfred Singer
Journal: The Journal of Experimental Medicine (2019)

Preselection thymocytes are normally retained in the thymic cortex, but the mechanisms responsible remain incompletely understood. We now report that deletion of genes encoding the E-protein transcription factors E2A and HEB disorders chemokine receptor expression on developing thymocytes to allow escape of preselection TCR−CD8+ thymocytes into the periphery. We document that CXCR4 expression normally anchors preselection thymocytes to the thymic cortex via interaction with its ligand CXCL12 on cortical thymic epithelial cells, and that disruption of CXCR4–CXCL12 engagements release preselection thymocytes from the thymic cortex. We further document that CXCR4 expression must be extinguished by TCR-mediated positive selection signals to allow migration of TCR-signaled thymocytes out of the thymic cortex into the medulla. Thus, E-protein transcription factors regulate the ordered expression pattern of chemokine receptors on developing thymocytes, and the interaction of the chemokine receptor CXCR4 with its ligand adheres TCR-unsignaled preselection thymocytes to the thymic cortex.
Development and validation of a methotrexate adherence assay
Authors: James Bluett, Isabel Riba-Garcia, Suzanne M M Verstappen, Thierry Wendling, Kayode Ogungbenro, Richard D Unwin, Anne Barton
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The first-line therapy for rheumatoid arthritis (RA) is weekly oral methotrexate (MTX) at low dosages (7.5–25 mg/week). However, ~40% of patients are non-adherent which may explain why some do not respond and need to start more expensive biological therapies. To monitor adherence more accurately and develop strategies to improve it, a validated objective MTX adherence test is required. <h3>Objective</h3> To develop and validate the diagnostic accuracy of a novel MTX adherence assay using high-performance liquid chromatography–selected reaction monitoring– mass spectrometry (HPLC-SRM-MS) based biochemical analysis of drug levels. <h3>Methods</h3> 20 patients with RA underwent MTX pharmacokinetic assessment using HPLC-SRM-MS MTX plasma concentration analysis over a 6-day period. Directly observed therapy was the reference standard. Pharmacokinetic model validation was performed using independent plasma samples from real-world patients (n=50) with self-reported times of drug administration. Following assay optimisation, the sensitivity of the assay to detect adherence was established using samples from an observational cohort study (n=138). <h3>Results</h3> A two-compartment pharmacokinetic model was developed and validated. Simulations described the sensitivity required for MTX detection over 7 days; subsequent assay optimisation and retesting of samples confirmed that all patients were correctly identified as MTX adherers. Using real-world samples, the assays sensitivity was 95%. <h3>Conclusion</h3> Non-adherence to MTX is common and can have a significant effect on disease activity. HPLC-SRM-MS plasma analysis accurately detects MTX adherence. The validated objective test could easily be used in clinic to identify patients requiring adherence support.
Use of Dupilumab in the Treatment of Papuloerythroderma of Ofuji
Authors: Yuichi Teraki, Ryokichi Taguchi, Saori Takamura, Tomoo Fukuda
Journal: JAMA Dermatology (2019)

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Compliance with needle-use declarations at two Olympic Winter Games: Sochi (2014) and PyeongChang (2018)
Authors: Wolfgang Schobersberger, Cornelia Blank, Richard Budgett, Andrew Pipe, Mark Campbell Stuart
Journal: British Journal of Sports Medicine (2019)

We describe compliance with the 'IOC Needle Policy' at two Winter Olympic Games (Sochi and PyeongChang) and compare these findings to those of the Summer Olympic Games of Rio de Janeiro.All needle-use declaration(s) (NUD) received during the course of the 2014 and 2018 Olympic Games were reviewed. We recorded socio-demographic data, the nature and purpose of needle use, product(s) injected, and route of administration. Data were analysed descriptively.In total, doctors from 22 National Olympic Committees (NOCs) submitted 122 NUD involving 82 athletes in Sochi; in PyeongChang, doctors from 19 NOCs submitted 82 NUD involving 61 athletes. This represented approximately 2% of all athletes at both Games, and 25% and 20% of all NOCs participating in Sochi and PyeongChang, respectively. No marked differences in the NUD distribution patterns were apparent when comparing the two Winter Olympic Games. The most commonly administered substances were as follows: local anaesthetics, non-steroidal anti-inflammatory drug and glucocorticoids. Physicians submitted multiple NUD for 24% of all athletes who required a NUD.A limited number of NOCs submitted NUD suggesting a low incidence of needle use or limited compliance (approximately 2%). A key challenge for the future is to increase the rate of compliance in submitting NUD. More effective education of NOCs, team physicians and athletes regarding the NUD policy, its purpose, and the necessity for NUD submissions, in association with the enforcement of the appropriate sanctions following non-compliance are needed.