Статті в журналах з теми "330.322.54 (043)"

AbstractAimIt is unclear whether body mass index (BMI) is a useful measurement for examining prostate motion. Patient’s subcutaneous adipose tissue thickness (SAT) and weight has been shown to correlate with prostate shifts in the left/right direction. We sought to analyse the relationship between BMI and interfraction prostate movement in order to determine planning target volume (PTV) margins based on patient BMI.Materials and methodsIn all, 38 prostate cancer patients with three implanted gold fiducial markers in their prostate were recruited. Height, mass and SAT were measured, and the extent of interfraction prostate movement in the left/right, superior/inferior and anterior/posterior directions was recorded during each daily fiducial marker-based image-guided radiotherapy treatment. Mean corrective shift in each direction for each patient, along with BMI values, were calculated.ResultsThe median BMI value was 28·4 kg/m2 (range 21·4–44·7). Pearson’s product-moment correlation analysis showed no significant relationship between BMI, mass or SAT and the extent of prostate movement in any direction. Linear regression analysis also showed no relationship between any of the patient variables and the extent of prostate movement in any direction (BMI: R2=0·006 (ρ=0·65), 0·002 (ρ=0·80) and 0·001 (ρ=0·86); mass: R2=0·001 (ρ=0·87), 0·010 (ρ=0·54) and 0·000 (ρ=0·99); SAT: R2=0·012 (ρ=0·51), 0·013 (ρ=0·50) and 0·047 (ρ=0·19) for shifts in the X, Y and Z axis, respectively). Patients were grouped according to BMI, as BMI<30 (n=25, 65·8%) and BMI≥30 (n=13, 34·2%). A two-tailed t-test showed no significant difference between the mean prostate shifts for the two groups in any direction (ρ=0·320, 0·839 and 0·325 for shifts in the X, Y and Z axis, respectively).FindingsBMI is not a useful parameter for determining individualised PTV margins. Gold fiducial marker insertion should be used as standard to improve treatment accuracy.

Background:Bimekizumab (BKZ), a monoclonal antibody that selectively neutralises interleukin (IL)-17A and IL-17F, is a potential therapeutic option in ankylosing spondylitis (AS).Objectives:To report 48-week (wk) patient-reported outcomes (PROs) in patients (pts) with AS treated with BKZ in a phase 2b dose-ranging study (BE-AGILE;NCT02963506).Methods:Pts with active AS (Bath AS Disease Activity Index [BASDAI] ≥4; spinal pain ≥4 [0–10]), fulfilling modified New York criteria (central reading), and inadequate response/intolerance to NSAIDs were randomised according to the study design (Figure 1). PROs included spinal pain, fatigue (BASDAI Q1), morning stiffness (mean of BASDAI Q5 + 6), Bath AS Functional Index (BASFI), Medical Outcomes Study (MOS) Sleep Problems Index II and AS Quality of Life questionnaire (ASQoL). Efficacy is reported for pts initially randomised to placebo (PBO) or BKZ 160/320 mg every 4 weeks (Q4W); treatment-emergent adverse events (TEAEs) are reported for pts who received ≥1 dose of study drug (Safety Set).Results:Of 303 pts, 181 were randomised to PBO or BKZ 160/320 Q4W mg at Wk 0; 179/181 completed Wk 12 and 161/181 completed Wk 48. At Wk 12, improvements in pain, fatigue, morning stiffness, BASFI, sleep and ASQoL were greater in BKZ pts vs PBO pts. Responses were further improved or maintained to Wk 48, with no meaningful differences between BKZ 160 mg and 320 mg (Table 1). Serious TEAEs occurred in 13/303 (4.3%) pts (Table 2), which included 2 major adverse cardiac events considered not related to study drug. Oral candidiasis occurred in 16 (5.3%) pts.Table 1.PRO efficacy endpoints to Week 48 (multiple imputation)Mean (SD)WkPBO – BKZ 160 mg(n=24)PBO – BKZ 320 mg(n=36)BKZ 160 mg(n=58)BKZ 320 mg(n=61)Spinal pain06.9 (1.4)7.0 (1.9)6.6 (2.0)7.3 (1.5)CfB12-1.5 (1.6)-0.7 (1.7)-2.6 (2.2)-3.6 (2.4)48-3.7 (2.0)-3.7 (2.6)-3.8 (2.4)-4.7 (2.1)Fatigue06.4 (1.7)6.8 (1.6)6.4 (1.7)6.4 (1.9)CfB12-0.7 (2.5)-1.0 (1.7)-2.1 (2.2)-2.1 (2.5)48-2.7 (2.2)-2.8 (2.4)-3.1 (2.1)-3.3 (2.4)Morning stiffness06.9 (1.7)6.7 (2.0)6.5 (1.8)6.6 (2.1)CfB12-1.5 (1.7)-1.1 (1.5)-2.8 (2.0)-3.4 (2.7)48-3.9 (2.2)-3.6 (2.4)-3.9 (2.2)-4.4 (2.4)BASFI05.8 (1.8)5.5 (2.2)5.5 (2.2)5.9 (2.0)CfB12-1.0 (2.1)-0.3 (1.7)-1.7 (1.8)-2.2 (2.0)48-2.9 (2.2)-2.4 (2.2)-2.5 (2.0)-2.9 (2.2)MOS Sleep Problems Index II045.5 (8.1)45.3 (7.9)46.9 (7.5)47.2 (9.4)CfB122.1 (8.3)1.8 (6.8)5.6 (6.7)6.8 (7.5)487.6 (8.7)8.0 (9.1)6.5 (6.1)8.0 (7.9)ASQoL08.4 (4.7)9.2 (4.7)8.4 (4.3)8.7 (4.3)CfB12-1.3 (5.5)-1.3 (3.7)-3.5 (4.3)-4.6 (4.8)48-4.2 (5.6)-5.3 (5.6)-4.9 (4.1)-5.4 (4.8)CfB: change from baselineTable 2.Overview of TEAEs to Week 48 (Safety Set; N=303)n (%)BKZ 160 mg(n=149)BKZ 320 mg(n=150)All BKZ [a](N=303)Any TEAE103 (69.1)122 (81.3)235 (77.6)Drug-related TEAEs48 (32.2)54 (36.0)110 (36.3)Serious TEAEs5 (3.4)6 (4.0)13 (4.3)Discontinuations due to TEAEs7 (4.7)10 (6.7)20 (6.6)[a] Includes TEAEs for 16 and 64 mg BKZConclusion:Pts with active AS demonstrated rapid and sustained improvements in PROs, sleep and quality of life over 48 wks of BKZ treatment. BKZ was generally well tolerated with no unexpected safety findings versus previous studies.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Lianne S. Gensler Grant/research support from: Pfizer, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, GSK, Novartis, UCB, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Mary Katherine Farmer Employee of: UCB Pharma, Dominique Baeten Employee of: UCB Pharma, Nadine Goldammer Employee of: UCB Pharma, Jason Coarse Employee of: UCB Pharma, Marga Oortgiesen Employee of: UCB Pharma, Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma

Abstract Background: Intracranial hemorrhage (ICH) is a serious complication of warfarin therapy. Plasma infusion is the current standard of care in the US, even though most guidelines recommend prothrombin complex concentrate (PCC) as the preferred therapy; PCC has several advantages over plasma including no ABO blood type requirement, no lengthy thawing and infusion process, and a very small volume of virally inactivated pure vitamin K-dependent factors (VKDF) content that causes neither volume overload nor TRALI. Ideal PCC should contain adequate amounts of all VKDF (4-factor). As our group reported at the 2006 ASH meeting, PCC currently available in the USA have a very low FVII content (hence called a 3-factor PCC), often resulting in an incomplete correction of supratherapeutic INR. PCC is, therefore, often supplemented with 1–2 units of plasma to provide FVII; however, many elderly patients on warfarin do not tolerate an additional fluid volume and there is an urgency to correct coagulopathy in ICH. Recombinant FVIIa (rFVIIa) has been used to reverse warfarin effect with variable success. An experimental model has shown that rFVIIa corrects PT/INR in vitro but fails to correct bleeding because it does not address FII and X deficiencies critical for thrombin generation in vivo when compared with PCC. Therefore, we developed a trauma coumadin protocol (TCP) for urgent warfarin reversal for ICH, which includes both PCC and a low dose rFVIIa. Methods: TCP was approved by the Blood Utilization Review Committee of the Parkland Memorial Hospital and consists of administration of 4000 IU PCC (Profilnine, Grifols) and 1.2 mg rFVIIa; 5 mg intravenous Vit K1 is also administered daily for 3 days. PCC contains FII no more than 150 units, FX no more than100 units, and FVII no more than 35 units for each 100 units of FIX. Pre- and post-TCP VKDF were measured when possible (Table 2). We compared 19 patients treated with TCP with a 12 patient-non-TCP control group (warfarin-ICH) treated either with plasma alone (n=3) or plasma plus PCC (n=9). We will also compare (software delay) the 2 groups for extension of hematoma volume; the radiologist will be blinded to the therapy. Results: The TCP group included 12 females and 7 males aged 46–87 years (median 64). The control group included 4 females and 8 males aged 53–89 years (median 73). TCP patients had significantly faster as well as complete correction of PT/INR as compared to the controls. (Table-1). Post-TCP CT scans showed stable hematomas. 1/19 TCP patients with pituitary adenoma had pre-TCP INR of 7.2 and post-TCP INR of 0.9. He developed thrombotic stroke and acute myocardial infarction 2 days later; he was discharged home. The patient received 2.4 mg of rFVIIa because initially the dose of rVIIa was stratified based on INR (1.2 mg for INR 5.0 or less and 2.4 mg for INR greater than 5.0). . Examination of post-treatment FVII levels (Table-2) led us to modify TCP rFVIIa dose to a 1.2 mg, irrespective of INR. Conclusion: TCP rapidly and effectively corrects warfarin-associated coagulopathy in patients with ICH. Because thrombotic complications remain a concern, 4-factor PCC should further be evaluated. Table 1. Test results Time relative to TCP treatment TCP group n=19 Control group n=12 p value INR Mean ± SD (range) Pre 3.1±2.0 (1.4–5.1) 3.2 ±1.6 (1.4–7.2) 0.991 Post 1.1±0.3 (0.9–2.0) 1.4 ±0.3 (0.9–2.0) 0.003 PT Mean ± SD (range) Pre 28.1±17.3 (13.5–65.1) 28.9±14.0 (13.7–62.6) 0.887 Post 10.7±2.2 (9.3–18.1) 13.8±2.8 (9.3–18.3) 0.002 PTT Mean ± SD (range) Pre 36.0±10.3 (21.8–59.8) 38.2 ±11.5 (25.4–60.6) 0.591 Post 24.7±4.2 (19.5–32.2) 27.8±4.5 (22.8–30.9) 0.058 Time from TCP to INR correction (min) Mean ± SD (range) 145.4±107 (22–329) 267±76 (83–697) 0.023 Median 111 240 Table 2. Test results INR PT PTT FII FVII FIX FX Pretreatment Mean ± SD (range) 3.3±2.0 (1.5–7.4) 29.6±17.3 (14.4.–65.1) 35.7±9.9 (30.1–54.7) 54±41 (6–117) 23 ±12 (6–37) 57 ±28 (17–96) 44 ±30 (5–74) Posttreatment Mean ± SD (range) 1.1±0.4 (0.9–2.0) 11.0±3.0 (9.4–18.1) 25.9±4.1 (19.5–32.2) 148±84 (27–323) 394±141 (114–600) 97±22 (58–130) 144±54 (89–268)

323 Background: In 2012 the ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit of mCRPC patients treated with Ra-223 over placebo. To date clinical outcomes of Ra-223 treatment in a non-study population have not been prospectively evaluated. Methods: The ROTOR registry aimed to include 300 patients in 20 Dutch hospitals prior to Ra-223 treatment at the physician’s discretion. Clinical parameters collected included: positioning of Ra-223, Adverse Events (AE’s; CTCAE v4.03), Skeletal Related Events (SRE) and survival data. SRE was defined as radiotherapy to a bone metastasis, a new pathological fracture, spinal cord compression and/or bone surgery. Progression-Free Survival (PFS) was defined as survival until radiological or clinical progression, subsequent treatment or death. Results: Between April 2014 and September 2017, 305 patients were included of whom 300 were evaluable. The mean age of patients was 72.6 (range 46.3-91.5) years, 255 (85%) had ≥ 6 bone metastases and 197 (65.5%) were pretreated with taxanes and/or abiraterone or enzalutamide (214 (71.3%)). Two-hundred and ninety (96.7%) patients were treated with Ra-223. Twenty-nine (9.7%), 104 (34.7%), 96 (32%) and 66 (22%) patients received Ra-223 as a first, second, third, ≥ fourth mCRPC treatment line, respectively. Patients received an average of 4.6 (SD 1.8) cycles of Ra-223, while 140 (46.7%) completed all six cycles. After a median follow-up of 13.2 months, PFS was 5.1 (CI 4.5-5.8) months and OS 15.2 (CI 12.8-17.6) months. Eighty-two (27.3%) patients were hospitalized during Ra-223 treatment (Serious AE). Grade ≥ 3 anemia, neutropenia and thrombocytopenia was found in 54 (18.0%), 8 (2.7%) and 11 (3.7%) patients, respectively. Other frequent AE’s (all grades) were nausea (90 (30%)), diarrhea (83 (27.7%)) and fatigue (178 (59.3%)). SREs were observed in 46 (15.3%) patients; 22 (7.3%) received radiotherapy, 6 (2%) developed pathologic fractures, 17 (5.6%) spinal cord compression and 1 (0.3%) received bone surgery during Ra-223 therapy. Conclusions: The non-study ROTOR population had characteristics, all grade AEs and OS comparable with the treatment arm of ALSYMPCA. Clinical trial information: NCT03223597.

We tested the validity and reliability of the BioSpace InBody 320, Omron and Bod-eComm body composition devices in men and women (n 254; 21–80 years) and boys and girls (n 117; 10–17 years). We analysed percentage body fat (%BF) and compared the results with dual-energy X-ray absorptiometry (DEXA) in adults and compared the results of the InBody with underwater weighing (UW) in children. All body composition devices were correlated (r 0·54–0·97; P ≤ 0·010) to DEXA except the Bod-eComm in women aged 71–80 years (r 0·54; P = 0·106). In girls, the InBody %BF was correlated with UW (r 0·79; P ≤ 0·010); however, a more moderate correlation (r 0·69; P ≤ 0·010) existed in boys. Bland–Altman plots indicated that all body composition devices underestimated %BF in adults (1·0–4·8 %) and overestimated %BF in children (0·3–2·3 %). Lastly, independent t tests revealed that the mean %BF assessed by the Bod-eComm in women (aged 51–60 and 71–80 years) and in the Omron (age 18–35 years) were significantly different compared with DEXA (P ≤ 0·010). In men, the Omron (aged 18–35 years), and the InBody (aged 36–50 years) were significantly different compared with DEXA (P = 0·025; P = 0·040 respectively). In addition, independent t tests indicated that the InBody mean %BF in girls aged 10–17 years was significantly different from UW (P = 0·001). Pearson's correlation analyses demonstrated that the Bod-eComm (men and women) and Omron (women) had significant mean differences compared with the reference criterion; therefore, the %BF output from these two devices should be interpreted with caution. The repeatability of each body composition device was supported by small CV ( < 3·0 %).

Background:Bimekizumab (BKZ), a monoclonal antibody that selectively inhibits interleukin (IL)-17A and IL-17F, has demonstrated clinical efficacy and safety in patients with ankylosing spondylitis (AS) treated over a period up to 96 weeks.1,2Objectives:To report 3-year interim safety and efficacy of BKZ in patients with active AS from a phase 2b dose-ranging study (BE AGILE; NCT02963506) and its ongoing open-label extension (OLE; NCT03355573).Methods:BE AGILE study design has been described previously.1 Patients treated with BKZ 160 mg or 320 mg every 4 weeks (Q4W) at Week 48 in BE AGILE were eligible for OLE entry. All OLE patients received BKZ 160 mg Q4W. Treatment-emergent adverse events (TEAEs) are reported for the BE AGILE safety set (patients who received ≥1 dose of BKZ on study entry) for total exposure to BKZ across BE AGILE and the OLE. Efficacy outcomes are reported for the OLE full analysis set (patients who entered the OLE and had ≥1 dose of BKZ and ≥1 valid efficacy variable measurement in the OLE), and include: ASAS40, ASAS20, ASAS PR, ASDAS, ASDAS-CII, ASDAS-MI, ASDAS-ID (<1.3) and ASDAS <2.1. Data are reported as imputed (multiple imputation [MI] based on the missing at random assumption, or non-responder imputation [NRI]) and as observed case (OC).Results:262/303 (86%) patients randomised at BE AGILE study baseline completed Week 48 on BKZ 160 mg or 320 mg. At Week 48, 255/262 (97%) patients entered the OLE (full analysis set: 254); 219 patients had an efficacy assessment at Week 156. Over the 156 weeks, the exposure-adjusted incidence rate (EAIR) per 100 patient-years (PY) of TEAEs was 143.5, with an EAIR of 5.8 for serious TEAEs, 1.3 for serious infections, and 3.8 for Candida infections (Table 1). All Candida infections were mild or moderate; none were systemic or led to study discontinuation. Over 156 weeks, the EAIR of inflammatory bowel disease (1.2), anterior uveitis (0.8), and injection site reactions (0.5) remained low. Efficacy demonstrated at Week 48 in BE AGILE was maintained or improved up to Week 156 (Figure 1). Mean ASDAS improved from 3.9 at BE AGILE baseline to 2.0 and 1.8 at Weeks 48 and 156 respectively (by MI). At Week 156 in the NRI analyses, ASAS40 and ASAS PR were achieved by 62.6% (OC: 72.6%) and 32.7% (OC: 37.9%) patients respectively. ASDAS-ID and ASDAS <2.1 responder rates (NRI) were maintained or continued to increase from Week 48, and by Week 156, responses were achieved by 28.0% (OC: 33.0%) and 57.1% (OC: 67.4%) patients respectively. ASDAS-MI responder rates (NRI) continued to increase from 44.9% at Week 48 to 46.5% at Week 156 (OC: 52.9%).Table 1.Safety for total exposure to BKZ across BE AGILE and the OLEBE AGILEWeeks 0–48BE AGILE + OLEWeeks 0–156n (%) [EAIR/100 PY]BKZ 160 mg(n=149;114.2 PY)BKZ 320 mg(n=150;119.6 PY)All BKZ(N=303;261.3 PY)All BKZ(N=303;781.0 PY)Any TEAE103 (69.1) [168.7]122 (81.3) [221.1]235 (77.6) [186.2]280 (92.4) [143.5]Serious TEAEs5 (3.4) [4.4]6 (4.0) [5.1]13 (4.3) [5.1]43 (14.2) [5.8]Key TEAEs of special monitoringSerious infections3 (2.0) [2.7]1 (0.7) [0.8]4 (1.3) [1.5]10 (3.3) [1.3]Candida infections10 (6.7) [9.1]9 (6.0) [7.9]19 (6.3) [7.5]28 (9.2) [3.8]Inflammatory bowel disease1 (0.7) [0.9]2 (1.3) [1.7]4 (1.3) [1.5]9 (3.0) [1.2]Anterior uveitis1 (0.7) [0.9]1 (0.7) [0.8]2 (0.7) [0.8]6 (2.0) [0.8]Study discontinuations due to TEAEs7 (4.7)10 (6.7)20 (6.6)38 (12.5)Drug-related TEAEs48 (32.2)54 (36.0)110 (36.3)149 (49.2)Deaths1 (0.7)01 (0.3)2 (0.7)TEAEs are reported for the BE AGILE safety set for total exposure to BKZ across BE AGILE and the OLE. There was one death in BE AGILE (cardiac arrest) and one in the OLE (road traffic accident); neither was considered treatment-related.Conclusion:The safety profile of BKZ in patients with AS was in line with previous observations.1.2 Patients treated with BKZ demonstrated sustained and consistent efficacy over 156 weeks.References:[1]van der Heijde D. Ann Rheum Dis 2020;79:595–604; 2. Baraliakos X. Arthritis Rheumatol 2020;72 (suppl 10).Acknowledgements:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma, Employee of: Director of Imaging Rheumatology, Atul Deodhar Speakers bureau: Janssen, Novartis, Pfizer, Consultant of: AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB Pharma, Lianne S. Gensler Consultant of: AbbVie, Eli Lilly, Gilead, GSK, Novartis, Pfizer, UCB Pharma, Grant/research support from: Pfizer, Denis Poddubnyy Speakers bureau: AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, Biocad, Eli Lilly, Gilead, GSK, MSD, Novartis, Pfizer, Samsung Bioepis, UCB Pharma, Grant/research support from: AbbVie, MSD, Novartis, Pfizer, Alan Kivitz Shareholder of: Pfizer, Novartis, Speakers bureau: Amgen, Eli Lilly, Pfizer, Novartis, Consultant of: Novartis, UCB Pharma, Maxime Dougados Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, Novartis, Pfizer, UCB Pharma, Natasha de Peyrecave Employee of: UCB Pharma, Marga Oortgiesen Employee of: UCB Pharma, Thomas Vaux Employee of: UCB Pharma, Carmen Fleurinck Employee of: UCB Pharma, Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, UCB Pharma, Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, UCB Pharma

ObjectiveTo elucidate current epidemiological, clinical profiles, and treatment of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome.MethodsWe conducted a nationwide survey in 2015 using an established epidemiologic method. Data processing sheets were sent to all neurology and hematology specialist departments throughout Japan to identify patients with POEMS who were seen between April 2012 and March 2015.ResultsThe estimated number of patients with POEMS was 392 (95% confidence interval [CI] 320–464), and the prevalence was 0.3 per 100,000. Detailed clinical profiles were available for 167 patients. Median age at onset was 54 years (range, 21–84 years), and the ratio of male to female was 1.5. All patients showed polyneuropathy; 89% had monoclonal plasma cell proliferation; and 84% had elevated vascular endothelial growth factor level in whom pretreatment serum or plasma was available (n = 87). Other common features were skin changes (84%), edema/effusion (81%), and organomegaly (76%). A total of 160 patients were treated with any of the following: radiation, corticosteroids, melphalan, thalidomide, lenalidomide, bortezomib, or autologous stem cell transplantation. Primary therapeutic options were thalidomide (n = 86) and autologous stem cell transplantation (n = 71). Thirty-nine patients (24%) were initially treated with corticosteroid alone. The 10-year overall survival was 93% (95% CI 86%–96%).DiscussionThis study showed current epidemiologic and clinical status of POEMS syndrome in Japan. A quarter of patients were still inadequately treated with corticosteroid alone, whereas either autologous stem cell transplantation or immunomodulatory drugs improved the prognosis.

Abstract Background: Congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) causes cortisol insufficiency and androgen excess. A phase 2 trial of crinecerfont, a CRF1 receptor antagonist, in 18 adults with 21OHD showed prominent decreases in ACTH, 17-hydroxyprogesterone, and androstenedione (A4), and in women, testosterone (T), after 14 days of treatment. In men with 21OHD, T derives from both adrenals and testes; in poor disease control, A4/T ratio is elevated due to disproportionately increased adrenal A4 production and decreased testicular T production. We sought to determine the impact of crinecerfont on both adrenal and gonadal androgen production in men with 21OHD in this phase 2 trial. Methods: A4 and T data were analyzed for 7 men who completed 1 or more of 4 oral dosing regimens: Cohort 1, 50 mg QHS, n=4; Cohort 2, 100 mg QHS, n=2; Cohort 3, 100 mg QPM, n=5; and Cohort 4, 100 mg BID, n=3 (14 total treatment periods). Mean 0600-1000 4-hour morning window (M4hMW) and mean 24-hour (M24h) A4, T, and A4/T ratios were analyzed from serial serum samples at baseline and on day 15. Results: Dose-dependent reductions in M4hMW A4 were observed [median (range)] in men, consistent with previously presented data in all subjects:Cohort 1: -21% (-84 to -12%);Cohort 2: -37% (-51% to -23%);Cohort 3: -43% (-85% to +140%);Cohort 4: -62% (-90% to -33%). In contrast, M4hMW T showed inconsistent changes [median (range)]: Cohort 1: +18% (-40% to +82%);Cohort 2: -4% (-4.3% to -3.8%);Cohort 3: +9% (-11 to +24%);Cohort 4: +9% (-3% to +27%). Thus, M4hMW A4/T ratios decreased with dose. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 0.9 (0.3–2.6), 0.6 (0.1–2.1), -26% (-91% to +23%);Cohort 2: 5.0 (4.8–5.2), 3.3 (2.5–4.2), -35% (-49% to -20%);Cohort 3: 0.6 (0.1–6.9), 0.3 (0.1–2.7), -54% (-85% to +178%);Cohort 4: 3.9 (0.6–5.9), 0.4 (0.3–2.1), -65% (-92% to -31%). M24h A4/T ratios similarly declined in all cohorts. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 1.0 (0.3–2.3), 0.4 (0.1–1.9), -33% (-92% to +2%);Cohort 2: 4.3 (3.8–4.9), 2.7 (2.4–3.0), -36% (-51% to -22%);Cohort 3: 0.5 (0.1–4.7), 0.4 (0.1–2.4), -59% (-78% to +310%);Cohort 4: 3.2 (0.4–4.1), 0.4 (0.3–1.7), -58% (-89% to -31%). Conclusions: Following crinecerfont therapy, A4 and A4/T decreased in a dose-dependent manner in men with 21OHD. In contrast to reductions in T observed in women with 21OHD, T did not change consistently and rose in some men. Preserved T values despite marked A4 reductions suggests testicular T production increased during crinecerfont therapy, perhaps due to release of gonadotropin suppression from adrenal-derived androgens. Long term studies are needed to determine if crinecerfont treatment improves additional measures of testicular function in men with 21OHD. Reference: RJ Auchus, et al. J Endocr Soc 2020;4(Suppl 1):OR25-03.

116 Background: Multiple barriers exist in providing quality palliative care to low-income patients with cancer. Such disparities may negatively influence effective management of symptoms including pain. Our objective was to compare referral patterns and characteristics (level of symptom distress) of uninsured vs insured patients. Methods: We reviewed randomly selected charts of 100 Indigent (IND) and 100 Medicaid (MC) patients and compared them with a random sample of 300 patients with insurance (INS) referred during the same time period (1/2010 to 12/2014) to our SCC. Data was collected for date of registration at the cancer center, diagnosis of Advanced Cancer (ACD), first visit to the SCC (PC1), symptom assessment (Edmonton Symptom Assessment Scale-ESAS) at PC1. We excluded self-pay patients. Results: Results for IND, MC and INS (n = 481) respectively are as follows: Mean (SD) Age in yrs. was 50 (12), 48 (11) and 63 (13); p < 0.001. Percentage of non-white was 44%, 51% and 19.5%; p < 0.001. Percentage of unmarried patients was 64%, 68% and 33%; p < 0.001. Mean (SD) ESAS score at PC1 for pain was 5.6 (3.2), 6.7 (2.5), 4.9 (3.2); p < 0.001. Percentage of patients on opioids upon referral was 86%, 62%, and 54%; p < 0.001. Mean (SD) for referral time in months from ACD to PC1 was 8.7 (SD 10.4), 12.3 (SD 18.1) and 12 (SD 19.9) p = 0.31; for no. of encounters with SC per month were 0.46 (0.45), 0.41 (0.46) and 0.3 (0.55); p = 0.01; for survival in months (PC1 to last contact) was 6.4 (5.8), 5.6 (6.4) & 6 (7.22) p = 0.77. Conclusions: Uninsured patients had significantly higher levels of pain, were more frequently on opioids, younger, non-white and not married. They also required a larger number of SCC encounters. Insurance status did not impact timing of SCC referral or SCC follow ups at our cancer center.

Background: Deep inferior epigastric perforator and muscle sparing transverse rectus abdominis muscle flaps are commonly used flaps for autologous breast reconstruction. CT-angiography allows to analyse the perforator course preoperatively. Our aim was to compare the different aspects of perforator anatomy in the most detailed study. Methods: CT-angiographies of 300 female patients with autologous breast reconstruction of 10 years were analysed regarding the anatomy of the deep inferior epigastric artery and every perforator. Results: Overall, 2260 perforators were included. We identified correlations regarding the DIEA branching point and number of perforators and their intramuscular course. The largest perforator emerged more often from the medial branch of the DIEA than the smaller perforators (70% (416/595) vs. 54% (878/1634), p < 0.001) and more often had a direct connection to the SIEV (large 67% (401/595) vs. small 39% (634/1634), p < 0.01). Medial row perforators were larger than the laterals (lateral 1.44 mm ± 0.43 (n = 941) vs. medial 1.58 mm ± 0.52 (n = 1304) (p < 0.001)). The larger and more medial the perforator, the more likely it was connected to the SIEV: perforators with direct connection to the SIEV had a diameter of 1.65 mm ± 0.53 (n = 1050), perforators with indirect connection had a diameter of 1.43 ± 0.43 (n = 1028), perforators without connection had a diameter of 1.31 mm ± 0.37 (n = 169) (p < 0.001). Medial perforators were more often directly connected to the SIEV than lateral perforators (medial 56% (723/1302) vs. lateral 35% (327/941), p < 0.001). A lateral perforator more often had a short intramuscular course than medial perforators (69% (554/800) vs. 45% (474/1055), p < 0.001), which was also more often observed in the case of a small perforator and a caudal exit of the rectus sheath. Conclusion: The largest perforator emerges more often from the medial branch of the DIEA and frequently has a direct connection to the SIEV, making medial row perforators ideal for DIEP flap transplantation.

The article provides a brief economic and biological characteristics of a new variety of field peas Vyatich, transferred to the State variety testing in 2020. The variety was created by individual selection from the hybrid population of Kazanets x K-3283. According to morphological characteristics, Vyatich belongs to the varieties of the mustachioed morphotype. The stem is simple, medium length (45-120 cm), purple flowers, inflorescence-2-3 axillary brush flowers. Seeds are greenish-brown with a purple speck, medium-small with a fused peduncle (weight of 1000 seeds 140-170 g). The variety is medium-ripened, Matures 2 days later than the standard. According to the competitive variety testing for 2016-2019, the average yield of Vyatich grain was 3.65 t / ha, green mass-32.2 t / ha, dry mass-5.67 t / ha, exceeding the ryabchik standard by 58.7%, 33.0% and 43.9%, respectively. According to the results of structural analysis, the Vyatich variety has an advantage in the number of beans and grains per plant (0.9 and 4.1 PCs higher than the standard). accordingly), the number of beans on the fruit node (more than 0.3 PCs.), the weight of seeds from the plant (more than 0.4 g). The average height of the new plant variety is 79 cm, and it is very resistant to lodging. The protein content in the grain averaged 20.6%, in the dry vegetative mass-14.2%. The gross yield of crude protein was 743 kg / ha for grain and 783 kg / ha for green mass, which is 60% and 54% higher than the standard, respectively. The Vyatich variety is recommended to be cultivated in single-species crops and used for forage purposes.

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 &gt;3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 &gt;200 nM; n=21) achieved a response. Among 70 patients with &gt;1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 &gt;3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 &gt;3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 &gt;3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD &gt;3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had &gt;1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 &gt;3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

Resistance training and maintenance of a higher protein diet have been recommended to help older individuals maintain muscle mass. This study examined whether adherence to a higher protein diet while participating in a resistance-based exercise program promoted more favorable changes in body composition, markers of health, and/or functional capacity in older females in comparison to following a traditional higher carbohydrate diet or exercise training alone with no diet intervention. In total, 54 overweight and obese females (65.9 ± 4.7 years; 78.7 ± 11 kg, 30.5 ± 4.1 kg/m2, 43.5 ± 3.6% fat) were randomly assigned to an exercise-only group (E), an exercise plus hypo-energetic higher carbohydrate (HC) diet, or a higher protein diet (HP) diet. Participants followed their respective diet plans and performed a supervised 30-min circuit-style resistance exercise program 3 d/wk. Participants were tested at 0, 10, and 14 weeks. Data were analyzed using univariate, multivariate, and repeated measures general linear model (GLM) statistics as well as one-way analysis of variance (ANOVA) of changes from baseline with [95% confidence intervals]. Results revealed that after 14 weeks, participants in the HP group experienced significantly greater reductions in weight (E −1.3 ± 2.3, [−2.4, −0.2]; HC −3.0 ± 3.1 [−4.5, −1.5]; HP −4.8 ± 3.2, [−6.4, −3.1]%, p = 0.003), fat mass (E −2.7 ± 3.8, [−4.6, −0.9]; HC −5.9 ± 4.2 [−8.0, −3.9]; HP −10.2 ± 5.8 [−13.2, –7.2%], p < 0.001), and body fat percentage (E −2.0 ± 3.5 [−3.7, −0.3]; HC −4.3 ± 3.2 [−5.9, −2.8]; HP −6.3 ± 3.5 [−8.1, −4.5] %, p = 0.002) with no significant reductions in fat-free mass or resting energy expenditure over time or among groups. Significant differences were observed in leptin (E −1.8 ± 34 [−18, 14]; HC 43.8 ± 55 [CI 16, 71]; HP −26.5 ± 70 [−63, −9.6] ng/mL, p = 0.001) and adiponectin (E 43.1 ± 76.2 [6.3, 79.8]; HC −27.9 ± 33.4 [−44.5, −11.3]; HP 52.3 ± 79 [11.9, 92.8] µg/mL, p = 0.001). All groups experienced significant improvements in muscular strength, muscular endurance, aerobic capacity, markers of balance and functional capacity, and several markers of health. These findings indicate that a higher protein diet while participating in a resistance-based exercise program promoted more favorable changes in body composition compared to a higher carbohydrate diet in older females.

PurposeTo analyze the outcome of allogeneic transplantation for mycosis fungoides and Sézary syndrome (MF/SS) in terms of nonrelapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) and to identify factors associated with the outcome.Patient and MethodsSixty patients with MF (n = 36) and SS (n = 24) who received a first allogeneic hematopoietic cell transplantation (HCT) from a matched related (mRD; n = 45) or unrelated donor (mUD; n = 15) between 1997 and 2007 and who were registered in the European Group for Blood and Marrow Transplantation database were analyzed: 37 men and 23 women, median age 46.5 years (range, 22 to 66 years). Forty-four patients had TNM stage IV, and 40 patients were at advanced phase at transplantation. Forty-four patients received reduced-intensity conditioning (RIC) regimens, and 25 underwent T-cell depletion (TCD).ResultsAllogeneic transplantation in MF/SS offers an estimated OS of 66% at 1 year and 54% at 3 years, primarily driven by donor type, disease phase, and type of conditioning. RIC decreased NRM (relative risk [RR] = 4.7; P = .008) without increasing REL, leading to a higher OS (RR = 2.8; P = .03). Advanced-phase disease increases REL (RR = 3.0; P = .03) and reduces PFS (RR = 4.4; P = .002) and OS (RR = 3.5; P = .023). Recipients of mRD allogeneic HCT had better PFS (RR = 2.7; P = .006) and OS (RR = 4.0; P = .001) than their mUD counterparts. The risk of REL increases with TCD (RR = 3.2; P = .005). Some patients who experience relapse can successfully undergo rescue treatment with donor lymphocyte infusions.ConclusionAllogeneic transplantation is a valid therapeutic alternative for high-risk patients with advanced-stage MF/SS. Our data also suggest the existence of a clinically relevant graft-versus-lymphoma effect in MF/SS.

Background: The benefits of platelet-rich plasma (PRP) for the treatment of rotator cuff tears remain inconclusive, as it is administered either as an adjuvant to surgical repair or as a primary infiltration without targeting the index lesion, which could dilute its effect. Purpose: To determine whether PRP infiltrations are superior to saline solution infiltrations (placebo) at improving healing, pain, and function when injected under ultrasound guidance within isolated interstitial supraspinatus tears. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: In this single-center, double-blinded, randomized controlled trial, 80 adults with symptomatic isolated interstitial tears of the supraspinatus, confirmed by magnetic resonance arthrography, were randomized to PRP or saline injections. Each patient received 2 injections with a 1-month interval. The primary outcome was the change in lesion volume, calculated on magnetic resonance arthrography, at 7 months. The secondary outcomes were improvements in shoulder pain and the Single Assessment Numerical Evaluation (SANE) score at >12 months. Results: Preoperative patient characteristics did not differ between the 2 groups. At 7 months, there were no significant differences between the PRP and control groups in terms of a decrease in lesion size (–0.3 ± 23.6 mm3 vs –8.1 ± 84.7 mm3, respectively; P = .175); reduction of pain on a visual analog scale (VAS) (–2.3 ± 3.0 vs –2.0 ± 3.0, respectively; P = .586); and improvement in SANE (16.7 ± 20.0 vs 14.9 ± 29.0, respectively; P = .650), Constant (8.6 ± 13.0 vs 10.7 ± 19.0, respectively; P = .596), and American Shoulder and Elbow Surgeons (19.5 ± 20.0 vs 21.9 ± 28.0, respectively; P = .665) scores. At >12 months, there were no significant differences between the PRP and control groups in terms of a reduction of pain on a VAS (–3.3 ± 2.6 vs –2.3 ± 3.2, respectively; P = .087) or improvement in the SANE score (24.4 ± 27.5 vs 23.4 ± 24.9, respectively; P = .846). At 19.5 ± 5.3 months, the incidence of adverse effects (pain >48 hours, frozen shoulder, extension of lesion) was significantly higher in the PRP group than the control group (54% vs 26%, respectively; P = .020). Conclusion: PRP injections within interstitial supraspinatus tears did not improve tendon healing or clinical scores compared with saline injections and were associated with more adverse events. Registration: NCT02672085 (ClinicalTrials.gov identifier).

Abstract Background: Many factors influence the choice of salvage therapy in relapsed/refractory multiple myeloma (RRMM), including various disease characteristics such as light chain and heavy chain subtypes. Patients with light chain only myeloma are a biologically and phenotypically distinct subset of patients from those with IgG, IgA, IgM, or IgD disease. Evidence exists that the presence of different paraprotein heavy and light chain subtypes may affect treatment outcomes. We investigated the effect of the presence of paraprotein heavy and light chain types on the efficacy and safety of pegylated liposomal doxorubicin (PLD) + bortezomib (B) versus B alone based on the phase III randomized trial of PLD+B vs. B alone in RRMM, which demonstrated improved time to progression (TTP) with PLD+B (Orlowski, JCO 2007). Methods: Eligible patients were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle (n=322) or to the same B regimen plus IV PLD 30 mg/m2 on day 4 (n=324) of each cycle. The subsets of patients with light chain and heavy chain multiple myeloma subtypes were analyzed retrospectively. Results: The presence of light chain myeloma was observed in 77 patients. Few patients had IgM/IgD subtype myeloma (4 and 6 patients, respectively), while the majority of patients had IgG (n=379) or IgA (n=265) subtypes. Time to disease progression (TTP) and complete response (CR) + partial response (PR) rates for PLD+B vs B alone in patients with light chain, IgG, and IgA myeloma subtypes are listed in the table. PLD+B B P valueb Hazard Ratioc a. Based on Kaplan-Meier product-limit estimates. b. Based on stratified Log-rank test. c. A hazard ratio &gt;1 indicates an advantage for PLD+B. d. Cochran-Mantel-Haenszel test controlling for Beta2 microglobulin and response to initial treatment. Light chain, N 40 37 TTP, Median days (95% CI)a 276 (171, n/a) 117 (85, 173) .003 3.09 (1.42, 6.73) Total CR+PR, n/evaluable (%) 22/39 (56) 10/33 (30) .030d IgG subtype, N 182 197 TTP 282 (221, 331) 199 (170, 222) .002 1.67 (1.20, 2.31) Total CR+PR 70/173 (41) 81/194 (42) .915d IgA subtype, N 88 77 TTP 250 (218, n/a) 205 (177, 236) .506 1.22 (0.68, 2.18) Total CR+PR 46/79 (58) 39/72 (54) .723d Results showed that the combination of PLD+B had significant benefit over B alone in TTP (PLD+B led to longer TTP than B alone) for IgG paraprotein and light chain subtypes. Safety profiles for the 2 regimens in these subsets of patients with heavy or light chain myeloma were consistent with the known toxicities of the 2 agents used. Conclusions: These data demonstrate that the combination of PLD+B is an important treatment option in patients with RRMM. Patients with light chain only disease had the largest incremental benefit from the addition of PLD with an absolute increase in TTP of 159 days as well as an increase in the overall response rate from 30% to 56%.

Abstract. Based upon 14 field surveys conducted between 2003 and 2008, we showed that the seasonal pattern of sea surface partial pressure of CO2 (pCO2) and sea–air CO2 fluxes differed among four different physical–biogeochemical domains in the South China Sea (SCS) proper. The four domains were located between 7 and 23° N and 110 and 121° E, covering a surface area of 1344 × 103 km2 and accounting for ~ 54% of the SCS proper. In the area off the Pearl River estuary, relatively low pCO2 values of 320 to 390 μatm were observed in all four seasons and both the biological productivity and CO2 uptake were enhanced in summer in the Pearl River plume waters. In the northern SCS slope/basin area, a typical seasonal cycle of relatively high pCO2 in the warm seasons and relatively low pCO2 in the cold seasons was revealed. In the central/southern SCS area, moderately high sea surface pCO2 values of 360 to 425 μatm were observed throughout the year. In the area west of the Luzon Strait, a major exchange pathway between the SCS and the Pacific Ocean, pCO2 was particularly dynamic in winter, when northeast monsoon induced upwelling events and strong outgassing of CO2. These episodic events might have dominated the annual sea–air CO2 flux in this particular area. The estimate of annual sea–air CO2 fluxes showed that most areas of the SCS proper served as weak to moderate sources of the atmospheric CO2, with sea–air CO2 flux values of 0.46 ± 0.43 mol m−2 yr−1 in the northern SCS slope/basin, 1.37 ± 0.55 mol m−2 yr−1 in the central/southern SCS, and 1.21 ± 1.48 mol m−2 yr−1 in the area west of the Luzon Strait. However, the annual sea–air CO2 exchange was nearly in equilibrium (−0.44 ± 0.65 mol m−2 yr−1) in the area off the Pearl River estuary. Overall the four domains contributed (18 ± 10) × 1012 g C yr−1 to the atmospheric CO2.

In vivo, the oocyte matures in a niche environment surrounded by somatic cells, and later in ovarian follicular development, by follicular fluid. Maternal diet influences the environment in which an oocyte matures but the mechanisms by which an altered metabolic profile, such as hyperinsulinemia, affects oocyte quality are not known. We investigated the use of a three dimensional follicle culture system allowing direct manipulation of the follicular environment thus circumventing systemic hormonal and metabolic effects. Secondary follicles (113.4 ± 1.02µm, n = 54) were isolated from mice at d12, encapsulated individually in 2µl of alginate matrix, and cultured in aMEM/5%FCS/10 mIU/mL LH/100 mIU FSH at 37°C/5%CO2, with media sampling and replacement every second day. Following 12 days of culture there was a significant 3-fold increase in follicle diameter (320 ± 10.1µm, n = 51). Histological analysis showed normal follicular morphology and antrum formation. Analysis of oestradiol (15.0ng/mL), androstenedione (7.8ng/mL) and progesterone (23.7ng/mL) in the media at d12 confirmed normal steroidogenesis and differentiation. Treatment of follicles with an ovulatory stimulus (1.5IU/mL hCG/5ng/mL Egf), resulted in cumulus expansion and hyaluronan localising to the cumulus oocyte complex (COC) and follicular basement membrane. These analyses were consistent with follicle growth and induction of ovulation in vivo. Further, COCs isolated from follicles and matured in vitro (IVM) in the presence of Egf and FSH, underwent cumulus expansion (CEI 2.8 ± 0.2) and were capable of fertilisation and blastocyst development. LH did not induce IVM COC expansion (CEI 1.36 ± 0.2), reflecting the normal in vivo differentiation process. However, culturing follicles in high insulin (5ug/mL) led to a significant increase in the degree of IVM cumulus expansion in response to LH (CEI 2.1 ± 0.3) indicating inappropriate cumulus cell differentiation, which may lead to poorer oocyte quality. These results demonstrate that this technique recapitulates normal in vivo folliculogenesis and is useful for manipulation of the follicular environment and assessment of oocyte outcomes.

Abstract Abstract 3081 Hematopoietic cell transplantation (HCT) is the only proven curative therapy for the hematological abnormalities in patients with Fanconi anemia (FA). In the mid-1990s, survival after alternative donor (AD)-HCT was reported to be 18% with excessive rates of regimen-related toxicity, graft failure, graft-versus-host-disease (GVHD) and opportunistic infections (OI). Between 1990 and 2010, 127 FA patients underwent AD-HCT at the University of Minnesota using one of 5 consecutive, prospective phase I-II total body irradiation (TBI) containing clinical trials, representing the largest single center experience. All patients received cyclophosphamide (CY, 40 mg/kg) and single fraction TBI. Sequential changes were made to prevent GVHD, graft failure and OI and ultimately enhance survival; in 1994, all patients received T cell depleted (TCD) bone marrow (BM) or umbilical cord blood (UCB) to reduce GVHD; in 1999, fludarabine (FLU) was added to enhance engraftment; in 2003, thymic shielding (TS) was added to reduce OI risk; and in 2006, TBI dose reduction was evaluated to reduce toxicity. Over this time period, HLA-matched unrelated donor BM was the donor of choice with partially HLA matched BM and UCB only used as alternatives. Neutrophil recovery was twice as likely after FLU-containing regimens than non-FLU containing regimens and was not deleteriously affected by TS or reducing TBI dose to 300cGy. Grade II-IV acute GVHD was significantly reduced by the use of TCD (18%) compared to T replete BM or UCB (50% and 38%, respectively: p<0.01). Similarly, chronic GVHD was significantly lower with TCD BM (9%) vs T replete BM or UCB (25% and 15%, respectively; p=0.04). For the entire cohort of 127 patients, the probability of survival was 61% at 1 year and 54% at 5 years with a median follow-up of 9 years. Mortality was higher in recipients who were older (>10 years) or CMV seropositive, received any transfusions before HCT, or developed OI before HCT (Table). Mortality was lowest using CY/FLU/ATG, TBI 300 cGy with TS (Trial 5, relative risk [RR] 0.1; p<0.01). For 10 patients on Trial 5 who had no prior history of transfusions or OI, incidences of neutrophil and platelet are 100% and 100%, acute and chronic GVHD 17% and 0%, and probability of survival is 92%. Table: Factors associated with 3 year mortality: Multivariate analysis Factors Relative Risk of Mortality (95% CI) P-value Trial* 2: CY/ATG/TBI 450-600, CSA/MP 1.0 3: CY/FLU/ATG/TBI 450, CSA/MP 0.3 (0.1–.7) <0.01 4: CY/FLU/ATG/TBI 450+TS, CSA/MP 0.2 (0.1–0.7) 0.01 5: CY/FLU/ATG/TBI 300+TS, CSA/MP or MMF 0.1 (0.04–0.3) <0.01 Donor Type Matched URD Marrow 1.0 Mismatched URD Marrow 0.3 (0.1–0.8) <0.01 Mismatched RD Marrow 0.3 (0.1–2.3) 0.22 Single or Double UCB 2.0 (0.9–4.6) 0.08 Age at Transplant <10 years 1.0 10–17 years 2.4 (1.2–5.0) 0.01 18+ years 3.1 (1.4–7.0) <0.01 Prior OI None 1.0 Yes 3.2 (1.5–6.9) <0.01 Prior Transfusions None Yes 2.4 (1.0–5.8) 0.05 CMV Serostatus Patient negative/donor negative 1.0 Patient negative/donor positive 1.5 (0.7–3.4) 0.34 Patient positive 2.2 (1.1–4.3) 0.03 * Trial 1 (CY/TBI 450, MTX/MP or CSA) was excluded as there were only 8 patients in this group and a number of demographic and disease factors were unknown. Substantial progress has been made in the successful application of AD-HCT for FA. These data support the urgency of transplant prior to the onset of severe pancytopenia when risk of OI and transfusions are more likely, particularly when a suitable BM donor is available. While other regimens are being explored, CY/FLU/ATG/TBI300 with TS should be considered a new standard of care for FA patients undergoing AD-HCT. Disclosures: No relevant conflicts of interest to declare.

Background:Imaging has been extensively used for the Calcium Pyrophosphate Deposition Disease (CPPD) diagnosis but the prevalence of joint calcifications at imaging in CPPD patients has not been thoroughly assessed.Objectives:This systematic literature review (SLR) is aimed to estimate the prevalence of calcium crystal deposition in peripheral joints by imaging in suspected or definite CPPD patients to establish relevant joints for CPPD monitoringMethods:After defining PICOs, Pubmed and Embase were searched from inception to October 2020 for identifying studies that evaluated the use of Conventional Radiography (CR), Ultrasound (US), Computed Tomography (CT) and Dual Energy Computed Tomography (DECT) in detecting calcifications at peripheral joints in patients with defined or probable CPPD. Search strategies based on MeSH terms and free text were applied. Six reviewers independently screened titles and abstracts, eligible article full texts were evaluated for inclusion and data extraction.Results:The SLR identified 1149 manuscripts. 524 papers entered in the full text evaluation and 181 articles were finally included. Considering excluded abstracts and full texts, 23 and 17 were excluded as duplicate, 156 and 9 for language, 171 and 48 for population, 171 and 20 for intervention, 57 and 117 for outcome, 47 and 70 for study type and 76 for full text unavailability. Among included, 41 papers considered patients with definite CPPD with a total population of 1239 patients, 908 cases and 331 controls and 140 papers referred to patients with suspected CPPD with a total population of 26785 patients, 2896 affected by CPPD and 23889 controls. The results about all joints are summarized in the Table 1. In patients with definite diagnosis, knee and wrist are the joints with the highest prevalence of calcifications at all imaging types, followed by hip and acromion-clavicular joint while in patients with suspected CPPD, the knee is the most prevalent followed by the wrist, hip and ankle (only sites with more than 50 patients assessed considered). The hand joints are characterized by CPPD lowest prevalence at imaging. Bilateral imaging findings varies depending on the technique used, the site and the patient’s type.Table 1.Definite CPPD DiagnosisKNEEWRISTHANDELBOWSHOULDERACHIPANKLEFOOTTMXRImaging positive cases/all cases330/584 57%214/409 52%43/158 27%54/212 25%65/249 26%37/84 44%140/293 48%30/255 12%15/59 25%0Cases positivebilaterally99/146 68%30/79 38%0/104/12 33%2/2 100%9/17 53%7/10 70%7/10 70%00USImaging positive cases/all cases155/252 62%86/118 75%4/42 9%2/2 100%0/304/30 13%47/80 59%30/255 12%15/59 25%0Cases positivebilaterally83/96 86%33/47 70%1/ 4 25%003/ 4 75%29/47 62%7/10 70%00CTImaging positive cases/all cases41/50 82%22/28 78%00000000Cases positivebilaterally27/30 90%000000000DECTImaging positive cases/all cases8/10 80%9/10 90%1/1 100%0000000Cases positivebilaterally001/1 100%0000000Suspected CPPD diagnosisKNEEWRISTHANDELBOWSHOULDERACHIPANKLEFOOTTMXRImaging positive cases/all cases1989/2442 81%549/1024 54%98/602 16%29/72 40%75/185 41%27/31 87%322/887 36%56/116 48%24/42 57%0Cases positive bilaterally611/1068 57%209/334 63%64/85 75%22/23 96%41/46 89%0/294/196 48%44/53 83%18/19 95%0USImaging positive cases/all cases241/261 93%125/185 68%2/39 5%1/1 100%4/12 33%02/2 100%27/78 35%8/37 22%0Cases positivebilaterally4/9 44%74/93 80%00000000CTImaging positive cases/all cases019/23 83%002/2 100%02/2 100%001/1 100%Cases positivebilaterally0000000001/1 100%DECTImaging positive cases/all cases1/1 100%2/2 100%00000000Cases positivebilaterally1/1 100%000000000Table 1 For each joint, are summarized the ratio between positive joints and overall evaluated joints and the ratio between the joints positive bilaterally and overall joints evaluated bilaterally.AC Acromion Clavicular, TM temporo mandibularConclusion:According to the results of this SLR, knees and wrists could be the sentinel joints for CPPD detection by imaging.Disclosure of Interests:None declared.

Background:As of the 25th of January 2021, more than 150 thousand deaths as consequence of COVID-19 have been reported in Mexico [1]. Advanced age, male gender and comorbidities have been described as risk factors for severe disease and mortality in general population [2]. COVID-19 mortality in Mexican patients with rheumatic and musculoskeletal diseases (RMDs) is unknown.Objectives:To describe characteristics of Mexican patients with RMDs and COVID-19, and to analyse factors associated with mortality.Methods:The Global Rheumatology Alliance COVID-19 (GRA) physician reported registry, is an international effort to collect information on COVID19 in adult patients with RMDs. GRA is an observational registry. The first patient from Mexico was registered on April 17, 2020. All Mexican patients registered in GRA until October 30, 2020 were included in this analysis. The association of mortality with demographic and clinical variables was estimated using logistic regression analysis.Results:A total of 323 patients were registered, with a median age of 52 (IQR 41-61) years old, 166 (51.4%) patients lived in Mexico City. The most frequent RMDs were rheumatoid arthritis, 149 (46.1%) and systemic lupus erythematosus, 24 (19.8%). Over a third of patients with RMDs and COVID-19 (119 (36.8%)) were hospitalized, and 43 (13.3%) died. Table 1 shows clinical and demographic characteristics. In the univariable analysis, the absence of comorbidities was a protective factor, OR 0.3 (95% CI 0.1-0.6). Factors associated with mortality at COVID-19 diagnosis were age over 65 years old, having type 2 diabetes, chronic renal insufficiency, treatment at COVID-19 diagnosis with corticosteroids or with CD20 inhibitors. In the multivariable adjusted analysis, these factors remained independently associated with mortality. No associations with other treatments or comorbidities at COVID-19 diagnosis were found.Conclusion:Mexican patients with RMDs and COVID-19 in the GRA physician reported registry had a mortality of 13.3%. Factors associated with mortality were those described in the general population, such as older age and being on corticosteroids and CD20 inhibitors treatment at COVID-19 diagnosis.References:[1]WHO. Coronavirus disease (COVID-19) pandemic. https://www.who.int/emergencies/diseases/novel-coronavirus-2019. (accessed 26 January, 2021).[2]Zhou F, et al. Lancet 2020;395(10229):1054-62.Table 1.Clinical and demographic characteristics of patients with rheumatic diseases and COVID-19 in Mexico and mortality.Characteristics at COVID-19 diagnosisTotalN=323Death43 (13.3)Survivors280 (86.7)UnivariableOR (95% CI)MultivariableOR (95% CI)Women, n(%)268 (82.9)33 (76.7)235 (83.9)0.6 (0.3-1.4)0.5 (0.2-1.3)Age >65 years old, n(%)62 (19.2)18 (41.9)44 (15.7)3.9 (1.9-7.7)3.9 (1.9-8.3)RMDs* n(%)-Rheumatoid arthritis149 (46.1)23 (53.5)126 (45.0)1.6 (0.7-3.7)-Systemic Lupus Erythemathosus64 (19.8)10 (23.3)54 (19.3)1.6 (0.6-4.3)-Spondyloarthritis (axial and others)33 (10.2)2 (4.7)31 (11.1)0.1 (0.1-2.8)-Others77 (23.8)8 (18.6)69 (24.6)1-Moderate/High disease activity1, n(%)57 (18.6)7 (17.9)50 (18.7)1.0 (0.4-2.5)-None comorbidities, n(%)136 (42.1)8 (18.6)128 (45.7)0.3 (0.1-0.6)-Hypertension*, n(%)88 (27.2)12 (27.9)76 (27.1)1.0 (0.5-2.1)-Type 2 Diabetes*, n(%)49 (15.2)13 (30.2)36 (12.9)2.9 (1.4-6.1)2.4 (1.1-5.4)Obesity*, n(%)21 (6.5)3 (6.9)18 (6.4)1.1 (0.3-3.9)-Chronic obstructive pulmonary disease*, n(%)15 (4.6)1 (2.3)14 (5.0)0.5 (0.1-3.5)-Chronic renal insufficiency*, n(%)17 (5.2)6 (13.9)11 (3.9)3.9 (1.4-11.4)3.4 (1.1-10.4)Cardiovascular diseases*, n(%)14 (4.3)2 (4.7)12 (4.3)1.1 (0.2-5.0)-Corticosteroids*, n(%)171 (52.9)30 (69.7)141 (50.3)2.3 (1.1-4.5)3.0 (1.4-6.5)CsDMARD*, n(%)247 (76.5)33 (16.3)214 (76.4)1.0 (0.5- 2.2)-CD20 inhibitor*, n(%)21 (6.5)7 (16.3)14 (5.0)3.7 (1.4-9.9)4.9 (1.7-14.5)*Overlapped, 1 307 patients.Disclosure of Interests:None declared

AbstractBackground and aimsPeripheral neuropathic pain (PNeP) is a chronic and disabling condition for which no predictors of response to treatment have yet been identified. Clinical studies show that while many patients with PNeP respond positively to treatment with the capsaicin 8% patch, others do not. This study used quantitative sensory testing (QST) to determine whether any patient characteristics can predict response to treatment with the capsaicin 8% patch.MethodsThis was a prospective, non-placebo-controlled, observational study. Patients used the Visual Analogue Scale (VAS) to assess their pain at baseline and then on Days 1, 7–10 (from here referred to as Day 7/10), 28 and 84 following treatment with the capsaicin 8% patch. QST was undertaken at the same timepoints on the painful area at the region of maximum PNeP and on a contralateral, control area. In addition, the size of the painful area was assessed at baseline and Days 7/10, 28 and 84.ResultsA total of 57 patients were treated. Among 54 evaluable patients, 19 (35.2%) achieved a ≥30% reduction in VAS pain score at Day 7/10 post-treatment compared with baseline — these were defined as ‘responders’. Analysis of the QST data showed that the PNeP area in responders, but not in non-responders, had a significantly lower pressure pain threshold compared with the control area at baseline (median 320 kPa vs. 480 kPa, respectively; p = .004). Furthermore, non-responders had approximately three times greater degree of allodynia at baseline compared with responders across tests using brush, cotton wool and Q-tip. These differences were significant for tests using brush and cotton wool (p = .024 and p = .046, respectively) and approached significance in the test using Q-tip (p = .066). Following treatment with the capsaicin 8% patch, responders showed a trend towards a reduction in warm perception and also appeared to show normalization of the pinprick hyperalgesia at some stimulus levels. Responders to therapy had significantly greater reductions than non-responders in the size of the painful area at Day 28 (p = .011) and Day 84 (p = .005) following treatment. However, both responders and non-responders had meaningful reductions in the size of the painful area compared with baseline values.ConclusionsThis study suggests that differences can be identified in the sensory profiles of patients with PNeP who respond to the capsaicin 8% patch and those who do not, specifically pressure pain threshold and degree of allodynia. Notably, both responders and non-responders experienced meaningful reductions in the size of the painful area following treatment.ImplicationsThe findings warrant further investigation in a larger number of patients and in prospective trials.

Abstract. During the Bonus-GoodHope (BGH) expedition (Jan–Mar 2008) we studied the water column distribution of total 234Th and biogenic particulate Ba (Baxs) in the Atlantic sector of the Southern Ocean. The objective was to assess the export flux of particulate organic carbon (POC) from the surface to the mesopelagic twilight zone along a section between the Cape Basin and Weddell Gyre. Export production of POC was estimated from steady state and non steady state export fluxes of 234Th which were converted into POC fluxes, using the POC/234Th ratio of large (>53 μm) suspended particles, collected via in-situ pumps. Deficits in 234Th activities were observed at all stations from the surface to the bottom of the mixed-layer. 234Th export fluxes from the upper 100 m ranged from 496 ± 57 dpm m−2 d−1 to 1195 ± 120 dpm m−2 d−1 for the steady state model and from 149 ± 18 dpm m−2 d−1 to 1217 ± 146 dpm m−2 d−1 for the non steady state model calculated for a time window of 15 to 22 days preceding the timing of the present cruise. The POC/234Thp ratio of large, potentially sinking particles (>53 μm), was observed to increase with latitude, from 1.9 ± 0.2 μmol dpm−1 and 1.7 ± 0.3 μmol dpm−1 in the Subtropical Zone (STZ) and Subantarctic Zone (SAZ), respectively, to 3.0 ± 0.2 μmol dpm−1 in the Polar Front Zone (PFZ), 4.8 ± 1.9 μmol dpm−1 at the Southern Antarctic Circumpolar Current Front (SACCF) to 4.1 ± 1.7 μmol dpm−1 in the northern Weddell Gyre, in line with an increasing contribution of larger cell diatoms. Steady state and non steady state POC export from the upper 100 m ranged from 0.9 ± 0.2 mmolC m−2 d−1 to 5.1 ± 2.1 mmolC m−2 d−1 and from 0.3 ± 0.0 mmolC m−2 d−1 to 4.9 ± 3.2 mmolC m−2 d−1, respectively. From the SAZ to the SACCF, non steady state POC export production represented only 15 to 54 % of the steady state POC flux, suggesting that the intensity of export had decreased over time partly due to the fact that regenerated-production based communities of small-sized phytoplankton became predominant. In contrast, for the HNLC area south of the SACCF, we found an excellent agreement between the two modeling approaches indicating that surface POC export remained rather constant there. Estimated POC export represented between 6 to 54 % of the potential export as represented by new production, indicating that export efficiency was particularly low throughout the studied area, except close to the SACCF. Below the export layer, in the mesopelagic zone, 234Th activities generally reached equilibrium with 238U, but sometimes were in large excess relative to 238U (234Th/238U ratio>1.1), reflecting intense remineralisation/disaggregation of 234Th-bearing particles. The accumulation of excess 234Th in the 100–600 m depth interval ranged from 458 ± 55 dpm m−2 d−1 to 3068 ± 368 dpm m−2 d−1. Using POC to 234Th ratio of sinking particles, we converted this 234Th flux into a POC remineralisation flux, which ranged between 0.9 to 9.2 mmolC m−2 d−1. Mesopelagic remineralisation was also evidenced by Baxs inventories which are related to bacterial degradation of sinking material and offer a means to quantify the flux of respired C. Highest biogenic particulate Ba (Baxs) contents were generally observed in the 200–400 m depth interval with values reaching up to >1000 pM in the northern PFZ. Depth weighted average mesopelagic Baxs (meso-Baxs) was high in the PFZ and low in the northernmost (STZ-SAZ) and the southernmost (SACCF-AZ-WG) parts of the BGH section; conversion into respired C flux yielded a range of –0.23 to 6.4 mmolC m−2 d−1. Excluding two outliers, we found a significant positive correlation for mesopelagic waters between POC remineralisation estimated from meso-Baxs and from 234Th excess (R2 = 0.73). Our results indicate that POC export production in this area of the Southern Ocean was strongly attenuated in the mesopelagic waters due to remineralisation, a process which thus appears to strongly impact on longer term bathypelagic zone sequestration of POC.

Abstract Abstract 2906 Background: Cardiac complications of transfusional iron overload are well documented in various inherited anemias. In regularly transfused MDS, the deleterious role of iron overload on cardiac disease is more disputed, due in particular to frequent concomitant causes of cardiac failure. Cardiac MRI T2* allows accurate and specific measurement of iron content. Methods: We prospectively evaluated in 4 centers of the GFM by standardized and transferable MRI methods both cardiac T2* according to Anderson (Eur Heart J. 2001Dec;22(23):2171-9) and liver iron content (LIC) according to Gandon (Lancet. 2004 Jan 31;363(9406):357-62), as well as cardiac function by routine echocardiography or MRI in regularly transfused MDS patients. Results: From Dec 2005 to March 2010, 73 patients (pts) were included (14 of them had more than one MRI evaluation over time): 38 M/35F, Median age 68 (24-86); WHO : RA=5, RARS=33, RMCD-RS=3, RMCD=1, RAEB1=9, RAEB2=5, RAEB-T/AML=1, 5q- syndrome=8 and unclassified=8; Karyotype: fav n=50, Int n=9, unfav n=4, failure n=10; IPSS: low n=29, Int-1 n=28, Int-2 n=5 and High n=1, unknown n=10. Median interval from MDS diagnosis and MRI T2* assessment was 49 months (range 0–324). Median serum ferritin at MRI assessment was 1750 ng/ml (range 282–7339) and 54/73 pts were on chelation therapy (CT) (median duration of CT prior to first MRI: 18 months, range 1–125). 37/73 pts had cardiac symptoms and 28 were on cardiac therapy. At first MRI T2* analysis, the median number of RBC units transfused was 68 (range 5–574). Median LIC was 330 micromoles/g/dw (range 40–908). Median Cardiac T2* was 27 ms (range 6–74). 14/73 pts had cardiac iron overload defined by MRI T2* ≤20 ms (19%) and among them 3/73 (4%) had severe cardiac iron overload (T2*≤ 10 ms). LVEF was below normal (55%) in 13/59 cases evaluated. A correlation was found between cardiac T2*and the number of RBC units transfused (Pearson correlation =-0.342, p=0.004) but not with LIC (p= 0.65) and serum ferritin (p=0.21). Cardiac overload was seen in 1/19 (5.5%) pts transfused <50 RBC units, 4/37(12.1%) pts transfused 50–150 units, 9/17 (52.9%) pts transfused >150 units (p= 0.0005). Those 3 pt subgroups also differed in median LIC (μmoles/g/dw) (<50 units= 250, 50–150 units=340, > 150 units=414) (p=0.044 Kruskall-Wallis' test), but not significantly in serum ferritin (p= 0.085). No significant correlation was found between decreased LVEF (< 55%) and cardiac T2* <20 ms (p=0.5), or T2*≤10 ms (p=0.23). In particular, 5/13 pts (38%) with LVEF <55% had T2*<20ms, vs versus 8/46 pts (17%) with LVEF >55% (p= 0.13). However, 1/14, 0/30 and 3/12 pts having received <50, 50–150 and > 150 RBC units had severe cardiac failure (ie LVEF≤35%)(p=0.012). 3/4 pts with severe cardiac failure had T2*< 20ms,compared to 8/54 pts without severe cardiac failure (p=0.023). 14 pts had another cardiac MRI 6 to 34 months (median 18) after the first. All were on CT and had received a median of 60 and 214 PRBC units at first and last MRI, resp. Median Cardiac T2* was 21.6 ms (range 8.5–35.3) and. 28 ms (range 6.4–41) at last and at first assessment, respectively (p=0.3) Conclusions: Moderate and severe post transfusional cardiac iron overload was seen in 19% and 4% of regularly transfused MDS, respectively. The level of cardiac iron overload was well correlated to the number of RBC transfused. The impact of cardiac overload on LVEF was unclear except in pts with severe cardiac impairment (LVEF <35%), possibly suggesting that iron overload is only one of the factors responsible for cardiac disease in many of those elderly patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: In 2010 an international expert working group (European LeukemiaNet, ELN) has published recommendations for the diagnosis and management of acute myeloid leukemia (AML) including a risk stratification by cyto- and molecular genetics, subdividing AML into four risk groups. Emerging data on molecular markers in AML has led to an update of stratification criteria by ELN in 2017 including the recommendation for screening of the high-risk (HR) molecular markers ASXL1, RUNX1, and TP53 that have been shown to confer poor prognosis. The identification of HR markers results in a shift of the prognostic stratification towards adverse risk. Aim: To investigate the mutational landscape and to assess the prevalence of HR markers in patients (pts) with newly diagnosed AML classified as intermediate-I or -II risk (inter-I/-II) based on the 2010 ELN criteria in a prospective real-world application. Methods: Using a next-generation targeted sequencing approach [HaloPlex HS (Agilent) on a Miseq (Illumina)], we performed a prospective analysis of all coding regions of 42 target genes including the HR marker ASXL1, RUNX1, and TP53 in 329 newly diagnosed intermediate risk AML pts all enrolled in the AMLSG Biology and Outcome (BiO)-Registry [NCT01252485] of the German-Austrian AML Study Group (AMLSG). Pt genetic features obtained at diagnosis were as follows: inter-I: normal karyotype, n=198 (60%); inter-II: trisomy 8, n=28 (9%), nullisomy Y, n=12 (4%), t(9;11)(p21.3;q23.3), n=7 (2%), others, n=83 (25%); FLT3-internal tandem duplication (FLT3-ITD+), n=75 (23%), mutations (mut) in tyrosine kinase domain of FLT3 (FLT3-TKDmut), n=12 (3.6%), NPM1mut, n=59 (18%); median age was 67 years (range: 21-89 yrs); 60% of pts were male. Results: Overall, 1253 mut in 315 pts (96%) were identified. Mut in at least one of the HR markers were identified in 50% (n=166) of the pts. Mut in ASXL1 occurred in 32% (105/329), followed by RUNX1 in 26% (87/329), and TP53 in 4% (13/329) of the pts, respectively. Pts with mut in one of the three HR markers showed lower WBC (median 7.63 vs 24.25 109/L, P=.003), lower hemoglobin value (median 8.8 vs 9.3 g/dl, P=.01), lower LDH serum level (median 330 vs 559 U/l, P<.0001) and were associated with older age at diagnosis (median 69.4 vs 66.8 yrs, P=.01). Furthermore, HR markers correlated with male gender (67% HR+ vs 51% HR-, P=.003). Mut in HR markers showed an inverse correlation with FLT3-ITD+ (6% vs 39%, P<.0001), NPM1mut (1% vs 34%, P<.0001), the genotype NPM1mut/FLT3-ITD+ (1% vs 37%, P<.0001), normal karyotype (54% vs 66%, P=.025) and KMT2A rearrangement (0% vs 5%, P=.0035). Further, pts with HR markers exhibited more mut per case (mean 4.6 vs 2.8, P=.0001) and more frequently had co-mut in splicing genes such as SRSF2 (37% vs 14%, P<0.0001) and SF3B1 (3% vs 0%, P=.029) and chromatin-cohesin genes such as EZH2 (9% vs 1%, P=.0009) and STAG2 (21% vs 4%, P<0.0001); here, co-mut with SRSF2 and SF3B1 were mutually exclusive. Pts with HR wildtype showed a significant association with NPM1 (34% vs 1%, P<.0001), DNMT3A (36% vs 20%, P=.0002), WT1 (8% vs 0.6 %, P=.0015) and GATA2 mut (7% vs 1.8%, P=.03) with significant co-mutational patterns such as WT1 with NPM1 (P=.03). Interestingly, we found BRAF mut in 3% (9/329) of the pt cohort with 5/9 pts harboring the p.V600E hotspot mut. Further analyses of survival data in these genotypes are currently ongoing. Conclusion: In this prospective study we could obtain real world mut data showing a high prevalence of HR marker mut in intermediate-I or -II risk AML pts as defined by 2010 ELN risk classification, thus revealing a significant proportion of pts (50%) harboring HR mut that confer an inferior survival. This high prevalence clearly demonstrates the clinical importance of HR marker screening as recommended by 2017 ELN criteria to identify pts, whose prognosis may be improved by more intensive therapy. Further, we could show that pts with HR marker mut differ significantly from HR wildtype pts with regard to clinical and molecular characteristics indicating a distinct biological subgroup which could potentially benefit from novel treatment approaches beyond conventional chemotherapy. Finally, novel genotypes such as NPM1mut/WT1mut will be further investigated with regard to their prognostic impact. Disclosures Bullinger: Bristol-Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer Oncology: Research Funding; Janssen: Speakers Bureau. Paschka:Sunesis: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel support; Jazz: Speakers Bureau; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Janssen: Other: Travel support; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Takeda: Other: Travel support. Lubbert:Celgene: Other: Travel Grant; Janssen: Honoraria, Research Funding; Teva: Other: Study drug. Salih:Several patent applications: Patents & Royalties: e.g. EP3064507A1. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Pfizer: Research Funding; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Abstract The recently discovered JAK 2 V617F activating tyrosine-kinase mutation has been found in 50–70% of Essential Thrombocythemia (ET) patients. Increased risk of thrombosis in patients with this mutation, especially homozygous for JAK2 V617F, has been reported. Other factors that increase the risk of thrombosis arising from ET itself include hereditary thrombophilic factors like antithrombin, protein C, and protein S deficiencies, the mutation of the prothrombin gene and the Leiden mutation of factor V, the MTHFR gene mutation, but also increase or decrease level of coagulation factors. In this study we explored if indeed JAK2 V617F mutation in ET patients correlates with the presence of risk factors that would contribute to thrombotic complication and a higher risk of thrombosis. We have examined 32 patients with ET (24 females and 8 males with a mean age 56.0±14.2, observed in our department since 1993). This group included: 10 untreated patients, 10 treated with anagrelide, 9 treated with hydroxyurea and 3 with the combination of both drugs. The control group consisted of 20 healthy volunteers: 6 males and 14 females (mean age 41.4±8.3). Mean platelet count was 785±320 G/l and 250±54 G/l for ET and the control group, respectively, p&lt;0.001. WBC count was higher in ET patients than in control group: 8.3±3.7 G/l and 5.4±1.4 G/l, p&lt;0.001. Concentration of uPA was statistically significantly higher in patient plasma as compared to the control group (0.635±0.232 ng/ml versus 0.447±0.115 ng/ml, p&lt;0.05). Mean uPA concentration measured in platelet lysates was similar in both groups (ET 0.317±0.135ng/109 platelets, control group 0.290±0.065ng/109 platelets). In 11 patients from ET group thrombotic complications occurred and in 7 ET patients clinically significant bleeding episodes were noticed. In two persons from control group minor thrombotic complications were observed. Patients with thrombotic complications as compared to those with bleeding episodes had higher fibrinogen and factor VIII level (420 mg/dl versus 302 mg/dl p&lt;0.05, and 115% versus 88% p&lt;0.05 respectively). In patients with thrombotic complications compare to patients without this complications a statistically significantly lower CD61/42b expression was detected (1.74% versus 10.00% p&lt;0.05) suggesting platelet activation. The JAK 2 V617F point mutation was detected in 18 (60%) of ET patients and none in control group. In all cases heterozygous genotypes were determined. In 10 (37%) of ET patients the MTHFR gene mutation was detected (in 6 patients simultaneously with JAK2 mutation). In 13 (65%) persons from control group the MTHFR gene mutation was also detected. In one person homozygous genotype was determined and this person had a thrombotic complication (DVT) after delivery. The other (12) subjects had heterozygous genotype and among them here was one had minor cerebrovascular event. In two ET patients and in two control subject heterozygous genotypes for Leiden mutation was detected. In two patients and in one of the control subject simultaneously heterozygous genotypes for Leiden and for MTHFR gene mutation were discovered. No prothrombin gene G20210A mutation was found in ET or in control group. In ET patients with JAK2 point mutation the higher level of red blood cells was found (4.38±0.57 T/l and 3.86±0.55 T/l, for patients with and without mutation, respectively, p&lt;0.05) confirming hypersensitivity of mutated hematopoietic progenitor cells to cytokines like EPO. The activity of factor XII in JAK2 positive patients was lower than in negative ones (83.2±25.5% and 109.0±20.4% respectively p&lt;0.05). In ET patients carrying MTHFR gene mutation the higher level of plasma urokinase was observed (0.747±0.3 ng/ml and 0.547±0.2 ng/ml, for patients with and without mutation, respectively, p&lt;0.05). This might indicate that fibrinolytic system is partly activated in ET patients, especially carrying MTHFR gene mutation, as a mechanism compensating hypercoagulable state present in these patients. In summary, in the group of patients with heterozygous JAK2 point mutation we have not observed increased frequency of thrombotic complication. To evaluate the risk of thrombosis it is necessary to assess not only JAK2 mutational status but also additional risk factors such as thrombosis and bleeding.

Abstract Activating mutations of the receptor tyrosine kinase FLT3 are seen at diagnosis in one-third of younger adults with acute myeloid leukemia (AML) and are associated with an increased risk of relapse. FLT3 remains the subject of intense clinical interest as a therapeutic target. To date FLT3-targeted monotherapy has produced only transient clinical responses with no prospective trial producing an overall survival benefit. Here we report the results of the first randomised trial of a FLT3 inhibitor (Lestaurtinib, CEP701) given sequentially to chemotherapy as first line treatment for newly-diagnosed AML. FLT3-mutated patients entering the UK MRC AML15 and UK NCRI AML17 trials between January 2007 and October 2012 were randomised to receive either oral Lestaurtinib 80mg bid, or placebo, for up to 28 days after each of 4 courses of chemotherapy. Based on early pharmacokinetic data provision was made for dose reduction to 40mg bid for patients on concomitant azole anti-fungal drugs. 500 patients were randomised (175 AML15, 325 AML17). Median age was 49yrs (5-68, only 5 were <16yrs.). 94% patients had de novo AML, 5% secondary AML and 1% high risk MDS. The majority of patients (89%) had cytogenetically intermediate risk disease with 6% favourable and 5% adverse risk. Median presenting WBC was 28.0x109/l (0.2-363); 381 patients (74%) had FLT3-ITD mutations, 127 (23%) FLT3-TKD point mutations and 12 (2%) both types; 207 patients (41%) had concomitant mutated NPM1. All characteristics were balanced between the arms. Results: No difference in remission rate was seen between the arms (CR/CRi: Lestaurtinib 92% vs Control 94%. OR 1.37 [0.68-2.78] p=0.4). The respective 5-year RFS was 40% vs 37%, HR 0.87 (0.68-1.12) p=0.3; cumulative incidence of relapse 52% vs 54%, HR 0.87 (0.67-1.13) p=0.3 and OS at 5 years 46% vs 43%, HR 0.89 (0.68-1.13) p=0.3 did not differ between arms. Figure 1 Figure 1. 43% of patients were transplanted in both Lestaurtinib and control arms (130/300 and 85/200 respectively); 133 transplants were in CR1, 63 in CR2; 188 were allografts. When the data were censored at SCT the lack of difference in clinical outcome persisted (HR 0.97 [0.71-1.33] p=0.8). Stratified analyses involving age, sex, diagnosis (de novo/secondary/MDS), cytogenetic group, performance status, ITD vs TKD, ITD allelic %, NPM1 status, Gemtuzumab ozogamicin (GO) or not in induction and concomitant use of azoles were undertaken to identify evidence of subgroup benefit with Lestaurtinib. No significant interactions were seen, with some evidence of survival benefit in patients receiving GO (p=0.09 for interaction). In patients receiving concomitant azole treatment there was a significant survival benefit with Lestaurtinib (HR 0.57 (0.36-0.92) p=0.02) although the test for interaction was not significant (p=0.2). Course 1 day 14 plasma trough Lestaurtinib levels were significantly higher in azole-treated patients than in those not receiving azoles (median 4517 vs 3085ng/ml, p=0.03). In AML17 patients treated with GO and azoles, survival with Lestaurtinib at 4 years was 61% compared to 28% in the control arm (p=0.02) Minimal difference in toxicity was seen between the 2 arms, with the exception of slight excess nausea/diarrhea with Lestaurtinib in course 2. Supportive care requirements were slightly increased with Lestaurtinib with a borderline-significant 1-day increase in median time to platelet recovery following course 2 (p=0.05). Conclusion: Lestaurtinib may be safely combined with intensive chemotherapy in younger patients with newly-diagnosed FLT3-mutated AML. No overall clinical improvement was seen with Lestaurtinib, although there was a suggestion of benefit in patients also receiving GO in induction: in Lestaurtinib-treated patients receiving both GO and azoles, survival was 61%. The potential clinical benefit of GO with adequate FLT3 inhibition requires prospective validation. (We are grateful to Cephalon for the provision of Lestaurtinib for this study) Disclosures Knapper: Cephalon: Consultancy, Research Funding. Off Label Use: Tyrosine kinase inhibitor Lestaurtinib (CEP701) used off-label in a randomised controlled trial in FLT3-mutated acute myeloid leukemia.

Abstract Background: APL is a highly curable malignancy with reported survival above 90% in many co-operative group studies. However these spectacular results are not evident in the general population. US SEER data and other population based studies from Swedish Cancer Registry and Brazil showed that early deaths (ED) can be as high as 30%, leading to a considerably lower survival compared to clinical trials where ED is around 5-10%. Decreasing ED remains a global challenge and the highest priority at all leukemia treatment centers and will result in population wide survival in this most curable leukemia. We report results of our prospective trial using a set of simplified treatment guidelines along with expert support designed to decrease ED. Methods: A network of leukemia treatment centers was established in Georgia, South Carolina and neighboring states. An aggressive outreach effort was made by visiting most of the leukemia treatment centers to publicize the concept and educate treating physicians in the community about ED in APL. The protocol provides a simplified two page treatment algorithm that emphasizes quick diagnosis, prompt initiation of therapy and proactive and aggressive management of the major causes of death during induction. Expert and treating physician communication was established very early when a diagnosis of APL was suspected and was maintained until the completion of induction. Study was approved by local IRBs (if applicable) and funded by the Lymphoma Leukemia Society (LLS). Informed consent was obtained upon confirmation of a diagnosis of APL and there were no exclusion criteria. Patient accrual was initiated in July 2013 and continued till May 2016 when the accrual goal of 120 was met on an intent to treat basis. Statistics are descriptive. Results: Between 7/2013 and 5/2016, 120 patients were enrolled at 5 large leukemia centers (n=54, 45%) and 24 community hospitals (n=66, 55%). Only 3 hospitals treated more than 3 APL patients/year. Median age was 54 years (range 21-84 years). 68 were male. 84% were low risk (WBC < 10,000/mm3) and median WBC count was 4.3 (range 0.3-170,000/mm3). ATRA was initiated at suspicion of APL diagnosis in 100% of patients and was the only treatment in 2(1.5%) patients. Arsenic was combined with ATRA in 93 (81.5%) patients while the other 17% received chemotherapy. 15(13%) had bleeding complications at presentation. Treatment course was complicated by infection and differentiation syndrome (DS) in 31(28%) and 40(34%) patients respectively. There were 12 early deaths, of which 1 was a Jehovah's Witness who declined transfusions and 1 who enrolled 12 days after diagnosis while in multi-organ failure. Incidence of ED was 10/118 (8.5%). The cause of death was disseminated intravascular coagulation (DIC) (n=4), DS (n=2), infection (n=1), anemia (n=1), multi-organ failure (n=4). With a median follow-up of 10.6 months, 2 low risk patients relapsed: I due to non-compliance 1 year after diagnosis and 1 with CNS relapse 3 months after completing consolidation. With a median follow up of 320 days (range 1-965) overall survival (Figure 1) was 87%. There were four late deaths; relapse (n=1), second cancer (n=1) and non-APL related comorbidities (n=2). Conclusions: Results of this prospective trial showed that a simplified treatment algorithm along with support from experts and co-management with treating physicians in the community decreased induction mortality (8.5%) and improved survival (87%) compared to SEER data (1 year relative survival of 71%). We believe our experience warrants large scale implementation and is presently approved as an ECOG/ACRIN trial (EA9131). This model can be applicable to other cancers and life-threatening diseases. Figure Overall Survival Figure. Overall Survival Disclosures Jillella: Leukemia Lymphoma Society: Research Funding. Heffner:AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Stuart:Astellas: Research Funding; Celator: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Bayer: Research Funding; Incyte: Research Funding. Gerber:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Grunwald:Medtronic: Equity Ownership; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

Introduction: The current coronavirus disease- 2019 (COVID-19) pandemic has caused a sudden increase in pneumonia cases, with a case-fatality rate of 10.9% in Mexico. Two inpatient groups have been defined, with different clinical evolution: cases of severe pneumonia and those with life-threatening disease (Acute respiratory distress syndrome [ARDS], invasive mechanical ventilation [IMV] requirement, and multiorgan involvement). Currently, there is no effective treatment. Convalescent plasma (CP) has been used to treat another viral infections and outbreaks since the last century. The rationale is that neutralizing antibodies contained in CP suppress viremia and produce immunoregulation. However, an established therapeutic dose during this pandemic is lacking. Aim: To evaluate in a phase I trial the minimum effective dose of CP in severe and life-threatening disease patients and then carry out a phase II study to establish the effectiveness (overall survival at 30 days) comparing it with a non-randomized control group. Methods and design. Our study is an open-label, multicenter, non-randomized and started in May, 2020 and was approved by the ethics committee at HGE & HCN Pemex; respectively. CP donor selection: pre-donors who were infected by SARS-CoV-2 were evaluated on +30 day by serum titration (≥1:320 IgG antibody); then connected to apheresis machine to obtain 600 ml of CP that were fractionated in 200 ml bags and stored. Patients: Two groups were formed: severe and life-threating disease. CP was offered to patients who were admitted on two hospitals. Patients should meet the following criteria: SARS-CoV-2 positive for qRT- PCR, respiratory rate&gt; 30 per minute or Kirby index &lt;300 or IMV requirement; be older than 18 years; and sign the informed consent. Statistics: For demographic variables, the differences were evaluated with parametric or non-parametric analysis. For survival, Kaplan Meier curves were assessed for each group. A p value &lt;0.05 was considered significant. Outcomes: A total of 110 CP bags have been transfused. The median serum IgG antibody titers were 1: 960. Dosing, phase 1. Severe group (n=14): 71% received two CP bags (400 ml) and 29% three CP bags (600 mL). Life-threatening disease group (n=10): 60% received 4 CP bags (800 ml) and 40% 3 CP bags (600 ml). Dose was established at 400 ml for the severe group and 800 ml for the life-threatening group. Security: CP infusions were well tolerated, with only 3 adverse events (2.72%) reported: one case of transfusion associated circulatory overload (TACO) that resolved with the use of loop diuretics as a serious adverse event; one fever episode (grade 1) and one case of rash (grade 1) after CP infusion. Phase II: The calculated n to be included in each arm (severe vs. life-threatening disease) is 68 and 52 patients, respectively. So far, we have included a total of 42 patients treated with CP. This entire cohort was compared with a historic group of COVID-19 patients who received other treatment strategies. Clinical characteristics on both plasma (PG) and control group (CG) are presented in table 1. We observed statistically significant differences on smoking habit, D-Dimer levels and ARDS severity between groups. The median overall follow- up was 24 days [PG 28 days vs. CG 21.5 days]. Overall Survival (OS) between PG and CG was 74% vs. 54% at 30-days respectively [HR=0.43 (C.I.95%=0.23 to 0.91, p=0.021); figure 1]. We analyzed OS by group stratification: COVID-19 severity (severe disease vs. life-threatening disease) and ARDS severity. We found no difference in OS between severe disease-PG and severe disease-CG; but we observed an OS difference between life-threatening-PG and life-threatening-CG [32% vs. 5.8% at 30-days; p=0.003]. ARDS-PG vs. ARDS-CG showed OS differences in moderate [59% vs. 25% at 30 days; p=0.01, respectively] and severe ARDS [63% vs. 0%; p=0.001, respectively]; however, there was not statistically significant difference between mild ARDS-PG and CG groups [89% vs. 86%; p=0.85, respectively]. Conclusion: This is the first phase I trial aiming to establish an effective CP dose for COVID-19 patients, at least in México. For severe and life-threatening disease, 2 and 4 CP bags were suggested. This treatment was secure, with &lt;3% of adverse events reported. OS could be modified using certain doses based on disease severity and pa02/Fi02 index. We will continue to include patients until the calculated n is reached. Disclosures Villela: Roche: Other: advisory board, Speakers Bureau; amgen: Speakers Bureau.

Abstract Mitochondria (mt) provide cells energy through oxidative phosphorylation (OXPHOS), regulate cell survival and death, and likely affect innate and adaptive immune system responses. Polymorphisms in mtDNA can be grouped into haplotypes (mthaps) that are associated with human global migration. Experiments using cybrids (identical cell clones that differ in mthaps) show differences in OXPHOS, reactive oxygen species generation and immune recognition. Numerous association studies have linked specific mthaps to disease occurrence, severity and/or therapy response. Since HCT is a period of high metabolic demand, we explored whether patient or donor mthaps are associated with HCT outcomes. Pre-transplant DNA was available from 437 adult and pediatric patients (6 months-69.6 years) who received an allogeneic transplant at the University of Minnesota for a hematological malignancy between 1995 and 2005, along with DNA from 327 donors. Of the HCTs, 213 were related donor (198 siblings, 15 other), 73 unrelated and 151 umbilical cord blood. Clinical and laboratory data were collected on all patients. Patient and donor DNA were genotyped for 11 common European mthaps (most to least common: H, J, U, T, Z, K, V, X, I, W, K2); 29 samples did not correspond with one of the 11 mtHaps and were labeled as ‘other’. Three separate analyses were performed: 1) sibling transplant outcomes (matched for mthap), 2) related and unrelated transplant outcomes based on patient mthap, and 3) related and unrelated transplant outcomes based on donor mthap. Multivariate models (adjusted for stem cell source, disease risk, conditioning regimen, patient CMV serostatus and patient sex as appropriate) were used to calculate relative risks (RR) and 95% confidence intervals (CI) comparing HCT outcomes to the most common haplotype (H). More than 80% of the 11 mthaps occurred in non-Hispanic whites, although 47% of Z (7/15 patients) were of other race/ethnicity. Among matched siblings, mthap did not differ with HLA mismatch (p=0.59). Compared to mthap H (43 events/83 patients, 52%), recipient siblings with I (5/6) and V (5/5) were significantly more likely to die within 5 years (RR=3.0, 95%CI 1.2-7.9, p=0.02; 4.6, 1.8-12.3, p<0.01, respectively). Patients with W (3/4) experienced significantly higher aGVHD II-IV events (RR=2.1; 1.1-2.4, p=0.03) than H (32/83, 39%), while K2 (0/4), K (1/8) and J (4/21) experienced no or fewer events. For aGVHD III-IV, patients with U (5/19) and V (2/5) experienced significantly higher events than H (9/83, 11%); there were no events for K and K2. Similar results were observed when considering outcomes for all recipients: compared to H (78/156, 57%), fewer aGVHD II-IV events were observed for J (17/59) and K (6/22) patients (0.5, 0.3-0.8, p<0.01; 0.4, 0.2-0.9, p=0.03, respectively). Lastly, when comparing donors relative to H (68/127, 54%), 6/7 recipients with I donors died within 5 years post HCT (2.7, 1.2-6.2, p=0.02), while only 1/7 and 1/4 patients receiving a transplant from a K2 or W donor, respectively, died. Further, compared to H donors (27/127, 23%), no patients who received a HCT from a K2 donor relapsed and only 4/34 patients from U donors relapsed. Ours is the first study to demonstrate that mthaps may be an important consideration in determining patient outcomes following HCT. Given interest in mthaps in disease susceptibility, we will conduct functional studies to better understand the role of patient and donor mthaps in OXPHOS and immune system responses in the presence of HCT. These preliminary results need confirmation in larger studies. If validated, it would be feasible to select donor mthaps associated with less GVHD and/or relapse (e.g., J, K2, U) or avoid use of donor mthaps associated with adverse outcomes (e.g., I,V). Disclosures No relevant conflicts of interest to declare.

Abstract Background: Therapy-related myeloid neoplasms develop after cytotoxic chemotherapy or radiation therapy. The available data on the outcome of pts with t-de novo AML without antecedent history of myelodysplastic syndrome (MDS) is limited. Methods: We reviewed the records of pts with newly diagnosed AML who presented to our tertiary care center from 1/2000 to 1/2014. t-de novo AML was defined as having at least 20% blasts in bone marrow with a history of any previous cytotoxic chemotherapy or radiation therapy, and without an antecedent history of MDS. Leukemia-free survival (LFS) was defined as time from achieving complete response (CR) to relapse or death. The overall survival (OS) and LFS in pts with t-de novo AML were compared to those of with de novo AML with normal karyotype (NK) and complex karyotype (CK). Results: Among 1677 pts with newly diagnosed AML, 383 had de novo NK-AML, 218 had de novo CK-AML, and 187 had t-de novo AML. The median follow-up was 9.3 months (range; 0.2-161.0). Pt characteristics and outcomes are described in Table 1. Among the 187 pts, 69 had a history of lymphoma; 63 pts breast cancer (Ca); 10 pts colon Ca; 10 pts sarcoma; 8 pts prostate; 7 pts bladder Ca; 6 pts uterine Ca; 5 pts lung Ca; 5 pts head and neck Ca; 30 pts other type of Ca. Among the pts with t-de novo AML, 15 pts (8%) had a favorable-risk karyotype by WHO, 53 pts (28%) intermediate-risk karyotype, and 119 pts (64%) poor-risk karyotype. The median LFS duration in t-de novo AML, NK-AML, and CK-AML were 7 months (95% confidence interval [CI]; 5.1-8.7), 19 months (95% CI; 13.0-25.2), and 6 months (95% CI; 9.0-13.5) (p<.001), respectively. The median OS duration in t-de novo AML, NK-AML, and CK-AML were 7 months (95% CI; 5.9-8.9), 21 months (95% CI; 16.2-25.5), and 12 months (95%CI; 10.6-13.5) (p<.001), respectively. The results of univariate (UVA) and multivariate analysis (MVA) associated with OS were summarize in Table 1. MVA identified age over 60, white blood cell count (WBC) over 10 x103/µL, thrombocytopenia below 30 x103/µL, non-favorable cytogenetic abnormalities, positive RAS mutation, and the absence of CR or CR with incomplete platelet recovery (CRp) as poor prognostic features related to OS. Conclusion: LFS and OS were shorter in patients with t-de novo AML than in those with NK-AML but did not differ significantly from patients with CK-AML. Abstract 2273. Table 1. Patient Characteristics and Outcomes t-de novo AML [n= 187] de novo AML with NK [n= 383] de novo AML with CK [n= 218] P Age at diagnosis, median (years) 64 (21-89] 63 (17-90) 67 (18-87) Prior radiation therapy, No. (%) 101 (54) 0 0 Prior chemotherapy, No. (%) 186 (99) 0 0 White blood cell count at diagnosis, median (x103/µL) 3.2 (0.2-191) 4.3 (0.2-390.0) 2.9 (0.5-278.2) Hemoglobin at diagnosis, median (g/dL) 9.1 (4.5-12.9) 9.1 (4-14.6) 9.0 (2.5-14.2) Platelet count at diagnosis, median (x103/µL) 34 (4-454) 51 (3-469) 42 (2-319) LDH at diagnosis, median (IU/L) 1359 (210-22090) 1189 (200-42000) 1274 (231-20572) Peripheral blood blast percent at diagnosis, median (%) 8 (0-98) 9.5 (0-98) 10 (0-98) Bone marrow blast percent at diagnosis, median (%) 41 (0-96) 44 (0-96) 33 (0-97) Molecular genetic abnormalities at diagnosis, No. (%) FLT3-ITD 17 (9) 96 (25) 5 (2) FLT3-D835 6 (3) 23 (6) 1 (1) NPM1 7 (4) 104 (27) 4 (2) JAK2 3 (2) 6 (2) 8 (4) RAS 17 (9) 50 (13) 8 (4) RUNX1-RUNX1T1 4 (2) 0 0 CBFb-MYH 6 (3) 0 0 Response, No. (%) <0.001 Complete response 89 (48) 237 (62) 76 (35) Complete response without platelet recovery 15 (8) 1 (0) 15 (7) 1-year LFS, (%) 33 60 27 <0.001 2-year LFS, (%) 33 52 20 <0.001 1-year OS, (%) 34 68 30 <0.001 2-year OS, (%) 24 46 13 <0.001 UVA and MVA of OS in t-de novo AML UVA MVA Hazard ratio 95% CI Age at diagnosis Age =< 60 years - Age >60 years < .001 .001 2.238 1.417-3.534 White blood cell count (WBC) (x103/µL) WBC =< 10.0 - WBC > 10.0 .002 .037 1.617 1.030-2.540 Hemoglobin (Hgb) (g/dL) Hgb >= 8 - Hgb < 8 .749 Platelet count (Plt) (x103/µL) Plt >= 30 - Plt < 30 .008 .004 1.852 1.224-2.803 LDH (IU/L) LDH =<1000 - LDH > 1000 .640 Peripheral blood blast percent (PB blast)(%) PB blast =< 10% - PB blast >10% .178 Bone marrow blast percent (BM blast) (%) BM blast =<40% - BM blast >40% .393 Cytogenetic abnormality Favorable - Non-Favorable .002 .019 5.836 1.342-25.370 FLT3-ITD Negative - Positive .768 RAS Negative - Positive .047 .003 2.576 1.367-4.856 Response CR or CRp - Non-CR or CRp <.001 .009 .331 0.145-0.757 CR - Non-CR <.001 0.903 .950 0.418-2.160 Figure 1. LFS and OS Figure 1. LFS and OS Disclosures Kantarjian: ARIAD, Pfizer, Amgen: Research Funding.

Abstract Introduction: Alpelisib (ALP), an inhibitor and degrader of phosphatidylinositol-3-kinase α (PI3Kα), + fulvestrant (FUL) demonstrated efficacy in PIK3CA-mutated, HR+, HER2- ABC in the phase 3 SOLAR-1 trial, which included only 20 patients (pts) with prior CDK4/6 inhibitor (CDKi) in the PIK3CA-mutated cohort. BYLieve (NCT03056755), a phase 2, open-label, 3-cohort noncomparative study, evaluates ALP + endocrine therapy (ET; FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC, progressing on/after prior therapies, including CDKi + ET. Cohorts A and B were restricted to pts receiving CDKi + (aromatase inhibitor [AI] or FUL), respectively, as immediate prior therapy, but Cohort C included pts whose cancer progressed on/after AI (in adjuvant or metastatic setting), and who received chemotherapy (CT; any line), or ET (FUL or LET monotherapy or with targeted therapy, including CDKi + FUL, but not CDKi + AI) as immediate prior treatment. Cohorts A and B demonstrated efficacy and safety of ALP + ET after prior CDKi. Here, we report primary results and biomarker analyses from Cohort C.. Methods: Pts in Cohort C received ALP 300 mg orally QD + FUL 500 mg intramuscular Q28D + C1D15. The primary endpoint was assessed in each cohort separately and is the proportion of pts with centrally confirmed PIK3CA mutation alive and without disease progression at 6 mo per local assessment; 95% CIs are calculated using Clopper and Pearson (1934) exact method. The 95% CI lower bound of the primary endpoint &gt;30% is clinically meaningful evidence of treatment effect. In an exploratory analysis of baseline biomarkers using ctDNA, progression-free survival (PFS) was estimated in pt subgroups per high (≥10%) or low (&lt;10%) ctDNA fraction and ESR1 mutational status via Kaplan-Meier estimation.. Results: 127 pts were enrolled in Cohort C (1 pt discontinued prior to treatment start) with ≥6 mo follow-up by the cutoff date (14 Jun 2021); 115 had a centrally confirmed PIK3CA mutation. Median follow-up was 11.4 mo (range, 0-23 mo); 79 (62.7%) pts had ≥2 prior lines of therapy in the metastatic setting, 58 (46.0%) pts had prior CT exposure in the metastatic setting, and 41 (32.5%) pts had prior FUL exposure in the metastatic setting. The primary endpoint was met, with 48.7% (95% CI, 39.3%-58.2%) of pts alive and without disease progression at 6 mo. Median PFS (mPFS) was 5.6 mo (95% CI, 5.4-8.1 mo). The most common all-grade adverse events (AEs) by preferred term were hyperglycemia (n=82, 65.1%), diarrhea (n=66, 52.4%), nausea (n=51, 40.5%), and rash (n=49, 38.9%). Grade ≥3 AEs (≥10%) included hyperglycemia (n=30, 23.8%) and rash (n=17, 13.5%). AEs leading to discontinuation occurred in 15.1% (n=19) of pts; most frequent AEs leading to discontinuation were rash (n=5, 4.0%) and hyperglycemia (n=4, 3.2%). Exploratory biomarker analyses in 74 pts who had available baseline biomarker samples at data cutoff showed that pts with a low ctDNA fraction (n=23) had longer mPFS than pts with high ctDNA fraction (n=51; 16.7 [95% CI, 10.4-19.5] vs 5.4 [95% CI, 2.9-7.2] mo; p&lt;0.001, HR=0.31 [95% CI, 0.2-0.6]). Efficacy was similar in pts with (n=20) and without (n=54) ESR1-mutated tumors (6.3 [95% CI, 2.8-8.3] vs 8.3 [95% CI, 5.5-16.7] mo; p=0.095, HR=0.59 [95% CI, 0.3-1.1]).. Conclusion: In Cohort A of BYLieve, efficacy of ALP + FUL suggests clinical benefit immediately after CDKi + AI; Cohort C confirms clinically relevant activity of ALP + FUL in a heterogeneous population, primarily treated in the third line or later, and potentially regardless of ESR1 status or ctDNA fraction, with no new safety signals detected. Together, these data confirm that ALP targets the effects of the PIK3CA-driver oncogene in HR+, HER2- ABC. Citation Format: Hope S Rugo, Patrick Neven, Isabel Saffie, Yeon Hee Park, Michelino De Laurentiis, Florence Lerebours, Eva Maria Ciruelos, Nicholas Turner, Dejan Juric, Ennan Gu, Christina H Arce, Mukta Joshi, Estelle Roux, Murat Akdere, Stephen Chia. Alpelisib + fulvestrant in patients with PIK3CA-mutated, HR+, HER2— advanced breast cancer (ABC) who received chemotherapy or endocrine therapy (ET) as immediate prior treatment: BYLieve Cohort C primary results and exploratory biomarker analyses [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-05.

Abstract Background: The need to repeat peripheral blood stem cell (PBSC) mobilization and collection arises infrequently in healthy donors, but may be required due to insufficient initial collection, graft failure, or relapse of the recipient’s disease. Currently no published data exists on the efficacy of remobilization of healthy PBSC donors. Studies of remobilization in patients undergoing autologous transplantation (ASCT) have largely focused on the use of alternative mobilization agents such as chemotherapy or plerixafor. Boeve et al (Bone Marrow Transplant, 2004) reported that remobilization with G-CSF in patients undergoing ASCT who failed initial mobilization with G-CSF, resulted in higher numbers of CD34+ cells collected than the initial collection, though this required a doubling of the dose of G-CSF. Patients/Methods: We performed retrospective chart review of 977 consecutive adult (>18 yrs) donors who underwent apheresis for PBSC donation at Washington University School of Medicine from 1995 through 2013. We identified 66 donors who had undergone more than one mobilization. Two cohorts of donors were identified for analysis: Group 1 included donors mobilized initially and again subsequently with G-CSF (10 ug/kg/day), or GM-CSF (5 ug/kg/day) + G-CSF (10 ug/kg/day). Group 2 consisted of donors mobilized with a CXCR4 antagonist, plerixafor (240-320 ug/kg) or POL6326 (1000-2500 ug/kg), and subsequently were remobilized with G-CSF (10 ug/kg/day). Statistical Analysis: Spearman correlations were performed to analyze the relationship between peak peripheral blood (PB) CD34+/uL level; the number of CD34+ cells collected per kg (recipient weight); and the number of CD34+ cells per L of apheresis collected during initial mobilization (MOB1) and remobilization (MOB2); and the interval (days) between MOB1 and MOB2. One-way ANOVA with repeated measures analyses were performed to determine the relationship of PB CD34+/uL, CD34+/kg and CD34+/L during MOB1 and MOB2. Results: Group 1 included 30 donors. The median age was 49 years (range 18-75) and 15 were male. The median number of days between MOB1 and MOB2 was 140 (range 26-2238). All 30 donors were remobilized due to graft failure or relapse of the recipient’s disease. PB CD34+/uL, CD34+/kg and CD34+/L all correlated between MOB1 and MOB2. The mean PB CD34/uL at MOB1 was 69 compared to 37 at MOB2 (p= 0.029); the mean CD34/kg collected at MOB1 was 5.6x106 compared to 3.3x106 at MOB2 (p= 0.002); and the mean CD34/L collected at MOB1 was 24.0x106 compared to 17.6x106at MOB2 (p= 0.023). The interval between MOB1 and MOB2 did not correlate with any of the MOB2 variables. Results from the analysis are summarized in Table 1. Group 2 included 32 donors. The median age was 51 years (range 21-67) and 18 were male. The median number of days between MOB1 and MOB2 was 20 (range 4-1123). 18 donors were remobilized due to mobilization failure, while 14 were remobilized due to graft failure or relapse of the recipient’s disease. The mean PB CD34/uL at MOB1 was 15 compared to 68 at MOB2 (p< 0.001); the mean CD34/kg collected at MOB1 was 2.5x106 compared to 7.1x106 at MOB2 (p< 0.001); and the mean CD34/L collected at MOB1 was 10.6x106 compared to 30.1x106at MOB2 (p< 0.001). The interval between MOB1 and MOB2 did not correlate with any of the MOB2 variables. Results from the analysis are summarized in Table 2. Conclusion: Remobilization with G-CSF or GM-CSF and G-CSF after initial successful mobilization with the same regimen results in poorer mobilization while remobilization with G-CSF after initial mobilization with a CXCR4 antagonist results in dramatically improved mobilization. The reason for this remains unclear, but in this study the interval between collections was not associated with successful remobilization. Abstract 850. Table 1 Group 1 MOB 1 MOB 2 One-way ANOVA Spearman Correlation PB CD34/ul 69 (13-417) 37 (1-115) F(1.0, 29.0) = 5.26, p= 0.029 r= 0.615, p< 0.001 CD34/kg (x106) 5.6 (0.8-13.8) 3.3 (0.3-10.6) F(1.0, 29.0) = 11.77, p= 0.002 r= 0.483, p= 0.007 CD34/L (x106) 24.0 (4.5-72.0) 17.6 (2.8-41.3) F(1.0, 29.0) = 5.74, p= 0.023 r= 0.566, p< 0.001 Abstract 850. Table 2 Group 2 MOB 1 MOB 2 One-way ANOVA Spearman Correlation PB CD34/ul 15 (2-54) 68 (14-358) F(1.0, 31.0) = 23.16, p< 0.001 r= 0.433, p= 0.013 CD34/kg (x106) 2.5 (0.2-19.7) 7.1 (1.7-42.4) F(1.0, 31.0) = 33.84, p< 0.001 r= 0.769, p< 0.001 CD34/L (x106) 10.6 (1.4-67.1) 30.1 (6.0-165.0) F(1.0, 31.0) = 34.70, p< 0.001 r= 0.774, p< 0.001 Disclosures No relevant conflicts of interest to declare.

Aims/Objectives/BackgroundGlobally, injuries cause more than 5 million deaths annually. Children and young people are a particularly vulnerable group and injuries are the leading cause of death in people aged 5–24 years globally and a leading cause of disability.In most low and middle-income countries where the majority of global child injury burden occurs, systems for routinely collecting injury data are limited. There is a continuing need for better data on childhood injuries and for injury surveillance.The aim of our study was to introduce a hospital-based injury surveillance tool – the first of its kind in Nepal and explore its feasibility. We undertook prospective collection of data on all injuries/trauma presenting to 2 hospital emergency departments to describe the epidemiology of paediatric hospital injury presentations and associated risk factors.Methods/DesignA new injury surveillance system for use in emergency departments in Nepal was designed and used to collect data on patients presenting with injuries. Data were collected prospectively in two hospitals 24 h a day over 12 months (April 2019 - March 2020) by trained data collectors using tablet computers.Abstract 432 Table 1Socio-demographic profile and characteristics of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020 (N=2696)CharacteristicsFrequencyGender Male 1778 Female 918 Age groups 0–4 years 653 5–9 years 866 10–14 years 680 15–17 years 497 Median year (IRQ) 8 (5 – 13) Ethnicity/caste Janajati 1384 Brahmin/Chhetri 892 Dalit 148 Madhesi 146 Muslim 74 Others 50 Unknown 2 Place where injury occurred Home/Compound 1576 Highway/road/street 636 School 233 Recreational area 138 Workplace 76 Other 37 Activities at the time injury occurred Leisure/Play 1889 Travelling (other than to/from school/work) 296 Work 202 Travelling (to/from school/work) 184 Education 42 Organised sports 11 Other 52 Unknown 20 Intent of injury Unintentional 2560 Intentional (self-harm) 61 Intentional (assault) 75 Unintentional (n=2560) Fall 912 Animal or insect related 728 Road traffic injury 356 Injured by a blunt force 201 Stabbed, cut or pierced 176 Fire, burn or scald 65 Poisoning 52 Suffocation/choking 36 Electrocution 12 Drowning and submersion 7 Other 13 Unknown 2 Self-harm (n=61) Poisoning 38 Hanging, strangulation, suffocation 12 Stabbed, cut or pierced 6 Injured by blunt object 4 Other 1 Assault (n=75) Bodily force (physical violence) 43 Injured by blunt object 18 Stabbed, cut or pierced 8 Pushing from a high place 2 Poisoning 2 Sexual assault 1 Other 1 Nature of injury (one most severe) Cuts, bites or open wound 1378 Bruise or superficial injury 383 Fracture 299 Sprain, strain or dislocation 243 Internal injury 124 Head Injury/Concussion 83 Burns 67 Other 115 Unknown 2 Not recorded 2 Severity of injury No apparent injury 125 Minor 1645 Moderate 813 Severe 111 Not recorded 2 Disposition Discharged 2317 Admitted to hospital 164 Transferred to another hospital 179 Died 21 Leave Against Medical Advice (LAMA) 11 Unknown 2 Not recorded 2 Note:Not recorded = missing cases95% CI calculated using one proportion test and normal approximation method in Minitab.Abstract 432 Table 2Distribution of injuries by age-group, sex and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups & Sex0 - 4 years5 - 9 years10–14 years15–17 yearsMaleFemaleTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 239 (26.2) 328 (36.0) 249 (27.3) 96 (10.5) 636 (69.7) 276 (30.3) 912 (100) Animal or insect related 175 (24.0) 260 (35.7) 190 (26.1) 103 (14.1) 470 (64.6) 258 (35.4) 728 (100) Road traffic injury 49 (13.8) 108 (30.3) 86 (24.2) 113 (31.7) 223 (62.6) 133 (37.4) 356 (100) Injured by a blunt force 54 (26.9) 74 (36.8) 49 (24.4) 24 (11.9) 150 (74.6) 51 (25.4) 201 (100) Stabbed, cut or pierced 20 (11.4) 56 (31.8) 49 (27.8) 51 (29.0) 127 (72.2) 49 (27.8) 176 (100) Fire, burn or scald 42 (64.6) 10 (15.4) 9 (13.8) 4 (6.2) 27 (41.5) 38 (58.5) 65 (100) Poisoning 33 (63.5) 6 (11.5) 5 (9.6) 8 (15.4) 26 (50.0) 26 (50.0) 52 (100) Suffocation/choking 24 (66.7) 5 (13.9) 2 (5.6) 5 (13.9) 20 (55.6) 16 (44.4) 36 (100) Electrocution 2 (15.7) 0 (0.0) 3 (25.0) 7 (58.3) 10 (83.3) 2 (16.7) 12 (100) Drowning and submersion 1 (14.3) 1 (14.3) 3 (42.9) 2 (28.6) 3 (42.9) 4 (57.1) 7 (100) Other 6 (46.2) 4 (30.8) 3 (23.1) 0 (0.0) 10 (76.9) 3 (23.1) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) 2 (100) Total 647 (25.3) 852 (33.3) 648 (25.3) 413 (16.1) 1702 (66.5) 858 (33.5) 2560 (100) Self-harm Poisoning 0 (0.0) 0 (0.0) 6 (15.8) 32 (84.2) 7 (18.4) 31 (81.6) 38 (100) Hanging 0 (0.0) 0 (0.0) 3 (25.0) 9 (75.0) 4 (33.3) 8 (66.7) 12 (100) Stabbed, cut or pierced 0 (0.0) 0 (0.0) 2 (33.3) 4 (66.7) 1 (16.7) 5 (83.3) 6 (100) Injured by blunt object 0 (0.0) 2 (50.0) 2 (50.0) 0 (0.0) 4 (100) 0 (0.0) 4 (100) Other 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) 0 (0.0) 1 (100) Total 0 (0.0) 2 (3.3) 13 (21.3) 46 (75.4) 17 (27.9) 44 (72.1) 61 (100) Assault Bodily force (physical violence) 3 (7.0) 1 (2.3) 11 (25.6) 28 (65.1) 37 (86.0) 6 (14.0) 43 (100) Injured by blunt object 2 (11.1) 8 (44.4) 4 (22.2) 4 (22.2) 13 (72.2) 5 (27.8) 18 (100) Stabbed, cut or pierced 1 (12.5) 0 (0.0) 2 (25.0) 5 (62.5) 7 (87.5) 1 (12.5) 8 (100) Pushing from a high place 0 (0.0) 1 (50.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 2 (100) Poisoning 0 (0.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 1 (50.0) 2 (100) Sexual assault 0 (0.0) 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Other 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Total 6 (8.0) 12 (16.0) 19 (25.3) 38 (50.7) 59 (78.7) 16 (21.3) 75 (100) Abstract 432 Table 3Association of injury location, nature and severity with age among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups0 – 4 years5 – 9 years10–14 years15–17 yearsTotalChi-SquareInjury characteristicsn (%)n (%)n (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 537 (34.1) 504 (32.0) 319 (20.2) 216 (13.7) 1576 (100) <0.001 Highway/road/street 85 (13.4) 196 (30.8) 190 (29.9) 165 (25.9) 636 (100) School 15 (6.4) 107 (45.9) 85 (36.5) 26 (11.2) 233 (100) Recreational area 9 (6.5) 44 (31.9) 55 (39.9) 30 (21.7) 138 (100) Workplace 1 (1.3) 4 (5.3) 19 (25.0) 52 (68.4) 76 (100) Other 6 (16.2) 11 (29.7) 12 (32.4) 8 (21.6) 37 (100) Total 653 (24.2) 866 (32.1) 680 (25.2) 497 (18.4) 2696 (100) Nature of injury Cuts, bites or open wound 328 (23.8) 506 (36.7) 314 (22.8) 230 (16.7) 1378 (100) <0.001 Bruise or superficial injury 81 (21.1) 99 (25.8) 118 (30.8) 85 (22.2) 383 (100) Fracture 48 (16.1) 101 (33.8) 112 (37.5) 38 (12.7) 299 (100) Sprain, strain or dislocation 48 (19.8) 78 (32.1) 72 (29.6) 45 (18.5) 243 (100) Internal injury 44 (35.5) 8 (6.5) 18 (14.5) 54 (43.5) 124 (100) Head Injury/Concussion 18 (21.7) 26 (31.3) 18 (21.7) 21 (25.3) 83 (100) Burns 42 (62.7) 9 (13.4) 10 (14.9) 6 (9.0) 67 (100) Other 41 (35.7) 38 (33.0) 18 (15.7) 18 (15.7) 115 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Severity of injury No apparent injury 39 (31.2) 45 (36.0) 26 (20.8) 15 (12.0) 125 (100) <0.001 Minor 419 (25.5) 535 (32.5) 406 (24.7) 285 (17.3) 1645 (100) Moderate 171 (21.0) 262 (32.2) 225 (27.7) 155 (19.1) 813 (100) Severe 23 (20.7) 23 (20.7) 23 (20.7) 42 (37.8) 111 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Abstract 432 Table 4Association of injury location, nature and severity with sex among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020SexMaleFemaleTotalChi-SquareInjury characteristicsn (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 979 (62.1) 597 (37.9) 1576 (100) <0.001 Highway/road/street 421 (66.2) 215 (33.8) 636 (100) School 176 (75.5) 57 (24.5) 233 (100) Recreational area 111 (80.4) 27 (19.6) 138 (100) Workplace 62 (81.6) 14 (18.4) 76 (100) Other 29 (78.4) 8 (21.6) 37 (100) Total 1778 (65.9) 918 (34.1) 2696 (100) Nature of injury Cuts, bites or open wound 959 (69.6) 419 (30.4) 1378 (100) <0.001 Bruise or superficial injury 246 (64.2) 137 (35.8) 383 (100) Fracture 200 (66.9) 99 (33.1) 299 (100) Sprain, strain or dislocation 154 (63.4) 89 (36.6) 243 (100) Internal injury 50 (40.3) 74 (59.7) 124 (100) Head Injury/Concussion 59 (71.1) 24 (28.9) 83 (100) Burns 27 (40.3) 40 (59.7) 67 (100) Other 79 (68.7) 36 (31.3) 115 (100) Unknown 2 (100) 0 (0.0) 2 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Severity of injury No apparent injury 81 (64.8) 44 (35.2) 125 (100) 0.048 Minor 1102 (67.0) 543 (33.0) 1645 (100) Moderate 533 (65.6) 280 (34.4) 813 (100) Severe 60 (54.1) 51 (45.9) 111 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Abstract 432 Table 5Distribution of injuries by outcome and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Outcome of injuryDischargedAdmittedTransferredDiedLAMAUnknownTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 787 (86.5) 65 (7.1) 53 (5.8) 0 (0.0) 4 (0.4) 1 (0.1) 910 (100) Animal/insect bite/sting 704 (96.7) 3 (0.4) 19 (2.6) 0 (0.0) 1 (0.1) 1 (0.1) 728 (100) Road traffic injury 260 (73.0) 47 (13.2) 44 (12.4) 5 (1.4) 0 (0.0) 0 (0.0) 356 (100) Injured by a blunt force 190 (94.5) 4 (2.0) 6 (3.0) 0 (0.0) 1 (0.5) 0 (0.0) 201 (100) Stabbed, cut or pierced 165 (93.8) 8 (4.5) 3 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 176 (100) Fire, burn or scald 52 (80.0) 12 (18.5) 1 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) 65 (100) Poisoning 30 (57.7) 4 (7.7) 16 (30.8) 1 (1.9) 1 (1.9) 0 (0.0) 52 (100) Suffocation/choking/asphyxia 24 (66.7) 4 (11.1) 6 (16.7) 1 (2.8) 1 (2.8) 0 (0.0) 36 (100) Electrocution 7 (58.3) 2 (16.7) 2 (16.7) 1 (8.3) 0 (0.0) 0 (0.0) 12 (100) Drowning and submersion 4 (57.1) 0 (0.0) 0 (0.0) 3 (42.9) 0 (0.0) 0 (0.0) 7 (100) Other 12 (92.3) 1 (7.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 2237 (87.5) 150 (5.9) 150 (5.9) 11 (0.4) 8 (0.3) 2 (0.1) 2558 (100) Self-harm Poisoning 5 (13.2) 8 (21.1) 23 (60.5) 0 (0.0) 2 (5.3) 0 (0.0) 38 (100) Hanging 1 (8.3) 0 (0.0) 1 (8.3) 10 (83.3) 0 (0.0) 0 (0.0) 12 (100) Stabbed, cut or pierced 6 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 6 (100) Injured by blunt object 4 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 17 (27.9) 8 (13.1) 24 (39.3) 10 (16.4) 2 (3.3) 0 (0.0) 61 (100) Assault Bodily force (physical violence) 34 (79.1) 5 (11.6) 3 (7.0) 0 (0.0) 1 (2.3) 0 (0.0) 43 (100) Injured by blunt object 18 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 18 (100) Stabbed, cut or pierced 6 (75.0) 1 (12.5) 1 (12.5) 0 (0.0) 0 (0.0) 0 (0.0) 8 (100) Pushing from a high place 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Poisoning 1 (50) 0 (0.0) 1 (50.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Sexual assault 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 63 (84.0) 6 (8.0) 5 (6.7) 0 (0.0) 1 (1.3) 0 (0.0) 75 (100) Abstract 432 Figure 1Seasonal variation of injuries identified by the injury surveillance system over a year among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Results/ConclusionsThe total number of ED patients with injury in the study was 10,154.2,696 were patients aged <18 years. Most injuries in children were unintentional and over half of children presenting with injuries were <10 years of age. Falls, animal bites/stings and road traffic injuries accounted for nearly 75% of all injuries with some (drowning, poisonings and burns) under-represented. Over half of injuries were cuts, bites and open wounds. The next most common injury types were superficial injuries (14.2%); fractures (11.1%); sprains/dislocations (9.0%). Child mortality was 1%.This is the biggest prospective injury surveillance study in a low or middle country in recent years and supports the use of injury surveillance in Nepal for reducing child morbidity and mortality through improved data.CHILD PAPER: RESULTS SECTIONTotal number of ED patients: 33046Total number of ED patient with injury: 10154 (adult=7458 & children=2696)8.2% (n=2696) patients with injury were children aged <18 yearsHetauda hospital: 2274 (84.3%)Chure hill hospital: 422 (15.7%)

Background: While most patients (pts) with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of pts will experience early progression, which is associated with inferior survival. Earlier identification of high-risk FL pts could allow for intervention with novel treatments to forestall early progression. Current prognostic tools are imperfect, particularly for pts receiving bendamustine-based regimens, and novel biomarkers are needed. In Hodgkin lymphoma, interim positron emission tomography (iPET) evaluated based on Deauville score (DS) is highly prognostic and is used to guide response-adapted therapy. The prognostic value of iPET using DS has not yet been assessed in a large population of FL pts receiving frontline CIT. We hypothesized that iPET would predict progression-free survival (PFS) in this population which could support PET-guided treatment approaches. Methods: We retrospectively identified pts with a diagnosis of FL (grade 1-3B) who initiated frontline CIT at Dana-Farber Cancer Institute from 1/2005-3/2019 and underwent an iPET after 2-4 cycles of CIT. Pts who received radiation (XRT) prior to CIT were included. Baseline, interim, and (when available) end-of-treatment (EOT) PET scans were reviewed by a nuclear medicine radiologist in a blinded fashion and assigned a DS of 1-5. Results: 118 pts were identified. The median age was 55 (range 26-82). 73 pts (62%) had grade 1-2 FL, 17 pts (14%) grade 3A, 15 pts (13%) grade 3B, 12 pts (10%) grade 3 NOS, and 1 pt (1%) grade not reported. FLIPI score was low for 32%, intermediate for 42% and high for 26%. In total, 5 pts (4%) received XRT before CIT. The most common CIT regimens were RCHOP (54%) and BR (42%) (Table 1). 107 pts (91%) received 6 cycles of CIT and 4 pts (3%) received 8 cycles, while 7 pts (6%) discontinued CIT after 4-5 cycles due to cytopenias (4), heart failure (1), infection (1), or pt decision (1). 88% of iPETs were performed after 3 cycles. iPET DS was 1 for 18%, 2 for 57%, 3 for 13%, 4 for 9%, and 5 for 3%. EOT PET was available for review for 112 pts (95%) and demonstrated DS of 1 for 32%, 2 for 56%, 3 for 3%, 4 for 4%, and 5 for 5%. After CIT, 29 pts (25%) received a median of 9 doses (range 1-13) of rituximab maintenance (RM) and 2 pts (2%) received consolidative XRT. With a median follow-up of 54 months (range 5-186), the 4-year (yr) PFS and overall survival (OS) for the entire cohort were 69% (95% CI 58-77%) and 94% (95% CI 87-98%), respectively. iPET was a significant predictor of PFS (p=0.0011 for 5 categories). Compared to pts with an iPET DS of 1-2, pts with a DS of 3 (HR 3.0, p=0.006) or a DS of 4-5 (HR 3.4, p=0.004) had inferior PFS (Figure 1) and were grouped together in a +iPET group (n=30) for all analyses. The 4-yr PFS for DS 1-2 and DS 3-5 pts were 77% and 46%, respectively (HR 3.2, p&lt;0.001). iPET had similar prognostic value among pts receiving BR (HR 3.3 p=0.033) or RCHOP (HR 3.6, p=0.005) and retained significance when pts with grade 3B FL were excluded (HR 2.6, p=0.007). iPET was not predictive of OS (HR 1.6, p=0.48). EOT PET was also a significant predictor of PFS (p&lt;0.0001 for 5 categories). 3 pts with a DS of 3 on EOT PET had favorable outcomes and were grouped with DS 1-2 pts. A positive EOT PET (defined as DS 4-5) was observed more frequently among pts with an iPET DS of 3-5 (9/29 pts; 31%) compared to an iPET DS of 1-2 (1/83 pts; 1%) (p&lt;0.001). To determine if iPET provides additional prognostic information beyond EOT PET, we sorted pts into 4 groups based on iPET/EOT PET status (i.e. -/-, +/-, -/+, and +/+). Compared to -/- pts, +/- pts (HR 2.4, p=0.039), -/+ pts (HR 3.6, p=0.045) and +/+ pts (HR 9.1, p=&lt;0.001) all had inferior PFS (Figure 2). A multivariable analysis confirmed that iPET (HR 2.9, p=0.017), EOT PET (HR 7.6, P&lt;0.001), high FLIPI (HR 2.5, p=0.011), and RM (HR 0.3, p=0.015) were significant predictors of PFS, while CIT regimen (p=0.94) and grade (p=0.21) were not. Conclusions: Our study suggests that iPET may be a useful prognostic marker in FL. Additionally, iPET interpretation may be different in FL compared to other lymphomas. In this cohort, pts with a DS of 3 on iPET had inferior PFS with outcomes similar to those of pts with a DS of 4-5. A DS of 3-5 on iPET appears to predict earlier progression independent of EOT PET while providing response-driven prognostic information earlier in a patient's treatment course. If validated, these results suggest that iPET could be investigated as a tool for response-adapted treatment strategies in FL. Disclosures Salles: BMS/Celgene: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Epizyme: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria; Takeda: Honoraria. Zelenetz:MEI Pharma: Research Funding; Celgene: Research Funding; Sandoz: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Celgene: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; MorphoSys: Research Funding; Gilead: Consultancy; Genentech/Roche: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Roche: Research Funding. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Crombie:AbbVie: Research Funding; Bayer: Research Funding. Davids:Ascentage Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Merck: Consultancy; Research to Practice: Honoraria; Syros Pharmaceuticals: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Jacobsen:Merck: Consultancy; Acerta: Consultancy; Astra-Zeneca: Consultancy; Pharmacyclics: Research Funding; F. Hoffmann-LaRoche: Research Funding; Novartis: Research Funding; Takeda: Honoraria. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; UptoDate: Patents & Royalties. Armand:Sigma Tau: Research Funding; Tensha: Research Funding; Pfizer: Consultancy; Affimed: Consultancy, Research Funding; IGM: Research Funding; Adaptive: Consultancy, Research Funding; Celgene: Consultancy; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Genentech: Research Funding.

Climate change induced sea-level rise (SLR) is on its increase globally. Regionally the lowlands of China, Vietnam, Bangladesh, and islands of the Malaysian, Indonesian and Philippine archipelagos are among the world’s most threatened regions. Sea-level rise has major impacts on the ecosystems and society. It threatens coastal populations, economic activities, and fragile ecosystems as mangroves, coastal salt-marches and wetlands. This paper provides a summary of the current state of knowledge of sea level-rise and its effects on both human and natural ecosystems. The focus is on coastal urban areas and low lying deltas in South-East Asia and Vietnam, as one of the most threatened areas in the world. About 3 mm per year reflects the growing consensus on the average SLR worldwide. The trend speeds up during recent decades. The figures are subject to local, temporal and methodological variation. In Vietnam the average values of 3.3 mm per year during the 1993-2014 period are above the worldwide average. Although a basic conceptual understanding exists that the increasing global frequency of the strongest tropical cyclones is related with the increasing temperature and SLR, this relationship is insufficiently understood. Moreover the precise, complex environmental, economic, social, and health impacts are currently unclear. SLR, storms and changing precipitation patterns increase flood risks, in particular in urban areas. Part of the current scientific debate is on how urban agglomeration can be made more resilient to flood risks. Where originally mainly technical interventions dominated this discussion, it becomes increasingly clear that proactive special planning, flood defense, flood risk mitigation, flood preparation, and flood recovery are important, but costly instruments. Next to the main focus on SLR and its effects on resilience, the paper reviews main SLR associated impacts: Floods and inundation, salinization, shoreline change, and effects on mangroves and wetlands. The hazards of SLR related floods increase fastest in urban areas. This is related with both the increasing surface major cities are expected to occupy during the decades to come and the increasing coastal population. In particular Asia and its megacities in the southern part of the continent are increasingly at risk. The discussion points to complexity, inter-disciplinarity, and the related uncertainty, as core characteristics. An integrated combination of mitigation, adaptation and resilience measures is currently considered as the most indicated way to resist SLR today and in the near future.References Aerts J.C.J.H., Hassan A., Savenije H.H.G., Khan M.F., 2000. Using GIS tools and rapid assessment techniques for determining salt intrusion: Stream a river basin management instrument. 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Abstract Background Mitral valve (MV) and tricuspid valve (TV) apparatus geometry are essential to define mechanisms and etiologies of regurgitation and to inform surgical or transcatheter interventions. Given the increasing use of cardiovascular magnetic resonance (CMR) for the evaluation of valvular heart disease, we aimed to establish CMR-derived age- and sex-specific reference values for mitral annular (MA) and tricuspid annular (TA) dimensions and tethering indices derived from truly healthy Caucasian adults. Methods 5065 consecutive UK Biobank participants underwent CMR using cine balanced steady-state free precession imaging at 1.5 T. Participants with non-Caucasian ethnicity, prevalent cardiovascular disease and other conditions known to affect cardiac chamber size and function were excluded. Absolute and indexed reference ranges for MA and TA diameters and tethering indices were stratified by gender and age (45–54, 55–64, 65–74 years). Results Overall, 721 (14.2%) truly healthy participants aged 45–74 years (54% women) formed the reference cohort. Absolute MA and TA diameters, MV tenting length and MV tenting area, were significantly larger in men. Mean ± standard deviation (SD) end-diastolic and end-systolic MA diameters in the 3-chamber view (anteroposterior diameter) were 2.9 ± 0.4 cm (1.5 ± 0.2 cm/m2) and 3.3 ± 0.4 cm (1.7 ± 0.2 cm/m2) in men, and 2.6 ± 0.4 cm (1.6 ± 0.2 cm/m2) and 3.0 ± 0.4 cm (1.8 ± 0.2 cm/m2) in women, respectively. Mean ± SD end-diastolic and end-systolic TA diameters in the 4-chamber view were 3.2 ± 0.5 cm (1.6 ± 0.3 cm/m2) and 3.2 ± 0.5 cm (1.7 ± 0.3 cm/m2) in men, and 2.9 ± 0.4 cm (1.7 ± 0.2 cm/m2) and 2.8 ± 0.4 cm (1.7 ± 0.3 cm/m2) in women, respectively. With advancing age, end-diastolic TA diameter became larger and posterior MV leaflet angle smaller in both sexes. Reproducibility of measurements was good to excellent with an inter-rater intraclass correlation coefficient (ICC) between 0.92 and 0.98 and an intra-rater ICC between 0.90 and 0.97. Conclusions We described age- and sex-specific reference ranges of MA and TA dimensions and tethering indices in the largest validated healthy Caucasian population. Reference ranges presented in this study may help to improve the distinction between normal and pathological states, prompting the identification of subjects that may benefit from advanced cardiac imaging for annular sizing and planning of valvular interventions.

IntroductionAssuming myokines underlie some of the health benefits of exercise, we hypothesised that ‘high responder trainer’ (HRT) rats would exhibit distinct myokine profiles to ‘low responder trainers’ (LRT), reflecting distinct health and adaptive traits.MethodsBlood was collected from LRT and HRT (N=8) rats at baseline (BL), immediately (0h), 1h, and 3h after running; repeated after 3-wks training. Myokines were analysed by ELISA (i.e. BDNF/Fractalkine/SPARC/Irisin/FGF21/Musclin/IL-6).ResultsAt baseline, Musclin (LRT: 84 ± 24 vs HRT: 26 ± 3 pg/ml, P=0.05) and FGF21 (LRT: 133 ± 34 vs HRT: 63.5 ± 13 pg/ml, P=0.08) were higher in LRT than HRT. Training increased Musclin in HRT (26 ± 3 to 54 ± 9 pg/ml, P&lt;0.05) and decreased FGF21 in LRT (133 ± 34 to 60 ± 28 pg/ml, P&lt;0.05). Training increased SPARC (LRT: 0.8 ± 0.1 to 2.1 ± 0.6 ng/ml, P&lt;0.05; HRT: 0.7 ± 0.06 to 1.8 ± 0.3 ng/ml, P=0.06) and Irisin (LRT 0.62 ± 0.1 to 2.6 ± 0.4 ng/ml, P&lt;0.01; HRT 0.53 ± 0.1 to 2.8 ± 0.7 ng/ml, P&lt;0.01) while decreasing BDNF (LRT: 2747 ± 293 to 1081 ± 330 pg/ml, P&lt;0.01; HRT: 1976 ± 328 to 797 ± 160 pg/ml, P&lt;0.05). Acute exercise response of Musclin (AUC) was higher in LRT vs HRT (306 ± 74 vs. 88 ± 12 pg/ml×3h-1, P&lt;0.01) and elevated in HRT after training (221 ± 31 pg/ml×3h-1, P&lt;0.01). Training elevated SPARC (LRT: 2.4 ± 0.1 to 7.7 ± 1.3 ng/ml×3h-1, P&lt;0.05; HRT: 2.5 ± 0.13 to 11.2 ± 2.2 ng/ml×3h-1, P&lt;0.001) and Irisin (LRT: 1.34 ± 0.3 to 9.6 ± 1.7 ng/ml×3h-1, P&lt;0.001; HRT: 1.5 ± 0.5 to 12.1 ± 1.9 ng/ml×3h-1, P&lt;0.0001).ConclusionExercise training alters how myokines are secreted in response to acute exercise. Myokine responses were not robustly linked to adaptive potential in aerobic capacity, making them an unlikely regulator of adaptive traits.

The Svalbard region faces drastic environmental changes, including sea-ice loss and “Atlantification” of Arctic waters, caused primarily by climate warming. These changes result in shifts in the sea-ice-associated (sympagic) community structure, with consequences for the sympagic food web and carbon cycling. To evaluate the role of sympagic biota as a source, sink, and transmitter of carbon, we sampled pack ice and under-ice water (0–2 m) north of Svalbard in spring 2015 by sea-ice coring and under-ice trawling. We estimated biomass and primary production of ice algae and under-ice phytoplankton as well as biomass, carbon demand, and secondary production of sea-ice meiofauna (&gt;10 µm) and under-ice fauna (&gt;300 µm). Sea-ice meiofauna biomass (0.1–2.8 mg C m–2) was dominated by harpacticoid copepods (92%), nauplii (4%), and Ciliophora (3%). Under-ice fauna biomass (3.2–62.7 mg C m–2) was dominated by Calanus copepods (54%). Appendicularia contributed 23% through their high abundance at one station. Herbivorous sympagic fauna dominated the carbon demand across the study area, estimated at 2 mg C m–2 day–1 for ice algae and 4 mg C m–2 day–1 for phytoplankton. This demand was covered by the mean primary production of ice algae (11 mg C m–2 day–1) and phytoplankton (30 mg C m–2 day–1). Hence, potentially 35 mg C m–2 day–1 of algal material could sink from the sympagic realm to deeper layers. The demand of carnivorous under-ice fauna (0.3 mg C m–2 day–1) was barely covered by sympagic secondary production (0.3 mg C m–2 day–1). Our study emphasizes the importance of under-ice fauna for the carbon flux from sea ice to pelagic and benthic habitats and provides a baseline for future comparisons in the context of climate change.

ABSTRACT: The purpose of this research was to study the histology and describe the microscopy findings of the epididymis epithelium of greater Rhea americana at three time periods: November 2005 (n=14), December 2006 (n= 20), and May 2007 (n= 20), to observe and compare the differences that occurred. We studied the epididymis from 54 rheas, bred in Santa Maria, Rio Grande do Sul, Brazil. The epididymis were collected during commercial slaughter and fixed in bouin. Optical microscopy was used to measure the cellular structure, types of cells, tubules, and stereological values like the epididymis epithelium diameters, lumen, thickness, and relative volume of the tissue structure. Additionally, electron microscopy was studied. In December 2006 and May 2007, the means of the epididymis tubular diameter were: 79.1 and 58.1 µm, epithelium thickness: 24.0 and 52.2 µm, and lumen diameter: 55.0 and 5.8 µm, respectively. Regarding the volumetric proportion, we reported the following values: epithelium volume 36.2 and 80.4%, lumen without spermatozoon 19.6 and 3.0%, lumen with spermatozoon 5.4 and 0.0%, interstitium 35.4 and 12.0%, blood vessels 3.5 and 4.6%, structures in cellular superficies 1.4 and 0%, lamina 1.4 and 3.2%, and artifacts 0.3 and 1.3%, respectively. The epididymis ducts had a circular form in transverse sections with spermatozoon only in November 2005 and December 2006. The Rhea’s epididymis morphology was found to be similar to ostriches, roosters, and Japanese quail. Here, we present data from stereological microscopy (tubular diameter, epithelium thickness, and lumen diameter), volumetric proportion (epithelium, lumen without spermatozoon, lumen with spermatozoon, interstitium, blood vessels, structures in cellular superficies; cilium, estereocilium, and lamina) in this species during the repose and sexual activity period (reproductive season).

Abstract Background Left ventricle (LV) dysfunction after chronic right ventricle (RV) pacing, also known as pacemaker induced cardiomyopathy (PICM) is a relatively common finding, ranging from 15–20% of patients. It has been associated to a high burden RV pacing, age, male gender and intrinsic and paced QRS duration. However, clinical relevance of LV dysfunction in this population has not been studied. Purpose The aim of the study was to identify predictors of heart failure (HF) hospitalization and cardiovascular (CV) mortality in patients with RV pacing. Methods Retrospective and unicentric study. We studied 2418 patients undergoing single or dual-chamber pacemaker implantation between 2012–2018. Patients were included if they had an echocardiogram prior to implantation and a repeated echocardiogram &gt;3 months after implantation. Baseline LV ejection fraction (LVEF) had to be &gt;50%. PICM was defined as ≥10% decrease in LVEF, resulting in LVEF &lt;50%. Alternative causes of LV dysfunction were excluded. Primary endpoint was heart failure hospitalization. Secondary endpoint was cardiovascular mortality. Competing-risk regression analysis was performed to identify predictors of HFH and CV mortality. Results Of 2418 patients, 495 meeting study criteria and 105 (21.2%) met PICM criteria. Follow-up period was 56.1±28.5months. There were no differences in basal LVEF (60.1±0.5% in non-PICM patients vs 59.5±0.5 in PICM patients, p=0.51). Mean LVEF at follow-up was 37.7±0.9 vs 56.7±0.3, p&lt;0.001. After logistic multivariable analysis, factors associated with PICM were alcohol consumption (OR 3.0, 95% CI 1.1–8.0,p=0.032), right bundle branch block (RBBB) (OR 1.9, 95% CI 1.06–3.51,p=0.031), higher RV pacing burden (OR 1.0, 95% CI 1.0–1.1,p=0.008) and higher basal LV end-diastolic diameter (OR 1.1, 95% CI 1.0–1.1,p=0.016). HFH occurred in 144 patients (29.1%). Factors associated with HFH after multivariable analysis were any decrease in LVEF (LVEF&gt;55% as reference: LVEF 46–55% (HR 2.1, 95% CI 1.3–3.3,p=0.002); LVEF 36–45% (HR=1.5, 95% CI 0.7–3.0; p=0.306), LVEF≤35% (HR 2.44, 95% CI 1.11–5.37,p=0.027), age (HR 1.0, 95% CI 1.0–1.1,p=0.037), alcohol consumption (HR 3.4, 95% CI 1.9–6.1,p&lt;0.001), presence of atrial fibrillation (HR 1.7, 95% CI 1.06–2.70,p=0.027) and paced QRS duration (HR 1.0, 95% CI 1.0–1.02,p=0.031). CV mortality occurred in 54 patients (10.9%). Factors associated with CV mortality after multivariable analysis were a decrease in LVEF (LVEF 46–55% (HR 1.6, 95% CI 0.8–3.2,p=0.217); LVEF 36–45% (HR=1.6, 95% CI 0.6–4.2,p=0.33); LVEF≤35% (HR 4.6, 95% CI 2.0–10.7,p&lt;0.001), RBBB (HR 2.1, 95% CI 1.1–3.9,p=0.026) and lower haemoglobin (HR 0.8, 95% CI 0.7–0.99,p=0.033). Conclusion In patients with RV pacing, factors associated with PICM were alcohol consumption, RBBB, RV pacing burden and basal LV end-diastolic diameter. HF hospitalization and CV mortality are common (29.1% and 10.9%). Any decrease in LVEF is associated with an increase in CV events. Funding Acknowledgement Type of funding sources: None.

Over 300 trunk, branch and stem samples with vascular discolouration, necrotic wood and shoot death were collected from olive (Olea europaea) orchards in Lecce, Brindisi, Bari and Foggia provinces (Apulia region, Italy) from October to May from 2013 to 2019. Small chips of symptomatic wood samples were surface sterilised (5% NaOCl, 3 min; 70% ethanol, 30 s), rinsed (sterile distilled water, ×3), and placed onto potato dextrose agar (PDA) plates amended with 500 ppm streptomycin sulphate. After 14 days at 25 °C in the dark, hyphal tips of growing fungi, including different taxa, for instance Phaeoacremonium and Botryosphaeriaceae spp., were transferred to new PDA plates and incubated until sporulation. Monoclonal colonies resembling Phaeoacremonium-like genus (Mostert et al. 2006) were selected for further study, and genomic DNA of 59 representative isolates was extracted (Carlucci et al. 2013). Partial actin and β-tubulin genes were amplified with primers ACT-513F/ACT-783R (Carbone & Kohn 1999), and T1(O’Donnell & Cigelnik 1997) and Bt2b (Glass & Donaldson 1995), respectively. The sequenced amplicons were compared by BLAST algorithms with reference strains of Phaeoacremonium spp. retrieved from GenBank. Forty-four isolates showed 99% to 100% similarity with reference strains P. italicum, P. minimum, P. parasiticum, P. scolyti and P. sicilianum (Carlucci et al. 2015), nine with P. oleae, and six with P. viticola. Actin and β-tubulin sequences of P. oleae (Pm14) and P. viticola (Pm34) were submitted to GenBank (MW714561, MW714563; MZ318697, MZ318696). Microscopy of P. oleae isolates showed: conidiophores branched and unbranched, (18.7–)21.9–57.1(–67.8) × (2.9–)3.3–4.7(–5.2) (mean, 38.9×4.1) μm (n=30); conidia oblong-ellipsoidal to obovoid or subcylindrical 3.4 to 5.5 μm long, and 1.5 to 2.4 (mean, 4.6 × 2.2) μm wide (n=30). Microscopy of P. viticola isolates showed: conidiophores subcylindrical, branched at base (6.7–)8.9–27.2(–29.3) × (2.0–)2.6–3.3(–3.7) (mean, 21.4 × 3.2) μm (n=30); conidia oblong-ellipsoidal to obovoid or subcylindrical 3.3 to 6.8 μm long, and 1.1 to 2.2 (mean, 4.2 × 1.6) μm wide (n=30). In spring 2020, artificial inoculations were carried out with P. oleae (Pm14, Pm46) and P. viticola (Pm34, Pm43) strains on 10 healthy, 2-year-old olive seedlings cultivar ‘Coratina’. Agar plugs (diameter, 0.3–0.5 cm) from 10-day-old cultures grown on water agar at 23 (±2) °C were inserted under the bark of small wounds in the stems (length, 0.4–1.0 cm) made with a sterile scalpel. After inoculation, the wounds were wrapped with wet sterile cotton wool and sealed with Parafilm. Ten control olive seedlings were inoculated with sterile agar plugs. The experiment was replicated three times. All inoculated young olive plants were grown in pots in a greenhouse without temperature control. After 120 days, inoculated plants showed decline symptoms, and when cut longitudinally, brown streaks were observed in the wood. For P. oleae these streaks measured 3.0-5.5 cm long (standard deviation [SD], 0.9 cm, and for P. viticola they were 1.8-3.5 cm (SD, 0.62). Both fungal species were re-isolated from the symptomatic wood from 85% and 80%, respectively, of these inoculated olive seedlings, fulfilling Koch’s postulates. No symptoms were observed from olive seedlings used as control. P. oleae was first described as a fungal pathogen of wild olive (Olea europaea subsp. cuspidate) in South Africa by Spies et al. (2018), and P. viticola as a fungal pathogen of grapevine in France by Dupont et al. (2000). To the best of our knowledge, this is the first report of P. oleae associated with olive trunk disease in Italy, and the first report of P. viticola associated with olive trunk disease worldwide. References: Carbone I. & Kohn L.M. 1999. Mycologia 91:553. Carlucci A. et al. 2015. Eur. J. Plant Pathol. 141:717. Carlucci A. et al. 2013. Phytopathol. Mediterr. 52:517. Dupont et al. 2000. Mycologia 92:499-504. Glass N. L. & Donaldson G. C. 1995. J. Cl. Microbiol. 41: 1332. Mostert L. et al. 2006. Stud. Mycol. 54:1. O’Donnell K. & Cigelnik E. 1997. Mol. Phylogenetics Evol 7:103. Spies et al. 2018. Persoonia 40:26.

<b><i>Introduction:</i></b> Accumulation of fat tissue around the kidneys is considered to be a risk factor for chronic kidney disease (CKD). The objective of the study was to investigate the association of pararenal fat tissue (PRFT) and renal dysfunction in patients without clinically significant cardiovascular diseases (CVDs). <b><i>Methods:</i></b> The study included 320 patients without CVDs (mean age 63.8 ± 13.9 years). All patients underwent anthropometric measurements, standard biochemical blood tests, including a lipid panel and uric acid concentration. Glomerular filtration rate (GFR) was calculated using the CKD-EPI formula. All patients underwent computed tomography of the abdomen with measurement of the PRFT thickness. The research results were processed using StatSoftStatistica 10.0 software. <b><i>Results:</i></b> The average PRFT thickness was 1.45 cm [0.9; 2.0]. It was significantly higher in obese individuals when compared with patients with normal body weight (1.9 cm [1.3; 2.6] vs. 1.0 cm [0.6; 1.7]) and overweight people (1.9 cm [1.3; 2.6] vs. 1.1 cm [0.8; 1.6]) (<i>p</i> &#x3c; 0.001). GFR was significantly higher in subjects with normal body weight when compared with obese patients (72 mL/min/1.73 m² [59; 83] vs. 61 mL/min/1.73 m² [51; 70]) and overweight patients (72 mL/min/1.73 m² [59; 83] vs. 61 mL/min/1.73 m² [54; 72]) (<i>p</i> &#x3c; 0.001). PRFT thickness was significantly higher in patients with stage 3 CKD when compared with those with stage 1 CKD (2.2 cm [1.6; 3.3] vs. 0.9 cm [0.9; 1.0]) and with stage 2 CKD (2.2 cm [1.6; 3.3] vs. 1.3 cm [0.9; 1.8]) (<i>p</i> &#x3c; 0.001). A significant correlation was found between PRFT thickness and body mass index (<i>r</i> = 0.49, <i>p</i> &#x3c; 0.05), waist circumference (<i>r</i> = 0.55, <i>p</i> &#x3c; 0.05), GFR (<i>r</i> = −0.47, <i>p</i> &#x3c; 0.05), and uric acid level (<i>r</i> = 0.46, <i>p</i> &#x3c; 0.05). Multiple linear regression analysis revealed a significant relationship between GFR and age (β ± SE −0.43 ± 0.15, <i>p</i> = 0.01), PRFT thickness (β ± SE −0.38 ± 0.14, <i>p</i> = 0.01) and with the level of low-density lipoprotein cholesterol (β ± SE −0.32 ± 0.12, <i>p</i> = 0.01). Logistic regression analysis showed that the risk of renal dysfunction development was associated with PRFT thickness (OR = 6.198; 95% CI: 1.958–19.617; <i>p</i> &#x3c; 0.05). ROC analysis determined the threshold values of PRFT thickness (&#x3e;1.68 cm, AUC = 0.875), above which the development of renal dysfunction can be predicted (sensitivity 63.2%, specificity 93.4%). <b><i>Conclusion:</i></b> The results of our study indicate the relationship between PRFT and visceral obesity and renal dysfunction in patients without clinically significant CVDs.

Естественные и искусственные алюмосиликаты являются актуальными объектами исследования благодаря широкому использованию в медицине, пищевой и химической промышленностях, в сельском хозяйстве. Целью работы является исследование возможных изменений под воздействием слабого импульсного электромагнитного поля атомного строения порошкообразных образцов трех минералов: клиноптилолита NaKNa2Ca2(SiSi29Al7)О72·24H2O монтмориллонита, монтмориллонита Ca0.2( AlMg)2Si4O10(OH))2·4H2O и палыгорскита AlSiMgAlSi4O10(OH)4·H2O относящихся к группе природных алюмосиликатов,, относящихся к группе природных алюмосиликатов, в которых кремний-кислородные и алюминий-кислородные тетраэдры связаны между собой общим атомом кислорода.Результаты исследований методами рентгеновской дифракции и ультрамягкой рентгеновской эмиссионной спектроскопии показали, что через 48 часов после воздействия слабого импульсного электромагнитного поля 71 мТл в течение 30 секунд атомная и электронная подсистемы образцов минералов все еще сохраняли изменения. Влияние слабого импульсного электромагнитного поля на атомную структуру минералов проявилось по-разному в трех образцах в виде одной-двух дополнительных слабых свехструктурных линий на дифрактограммах. Влияние слабого импульсного электромагнитного поля на локальное окружение кремния атомами кислорода в кремний-кислородных тетраэдрах проявилось в виде изменений тонкой структуры спектров ультрамягкой рентгеновской эмиссионной спектроскопии кремния SiLSiL2,3, указывающих на восстановление стехиометрии субоксидов кремния SiO1.8 в составе алюмосиликатов исходных порошков в стехиометрию, равную или близкую диоксиду кремния SiO2, во всех трех минералах. ЛИТЕРАТУРА Гак Е. Рик Т. О влиянии постоянного магнитного поля на кинетику движения ионов в водных растворах сильных электролитов. Доклады АН СССР. 1967;175(4): 856–858. Мартынова О. Гусев Б. Леонтьев Е. К вопросу о механизме влияния магнитного поля на водные растворы солей. Успехи физических наук. 1969;98: 25–31. Чеснокова Л. Вопросы теории и практики магнитной обработки воды и водных систем. М.:.: Цветметинформация с.; 1971. 75 с. Kronenberg K. Experimental evidence for the effects of magnetic fields on moving water. IEEE Transactions on Magnetics. 1985;21(5); 2059–2061. DOI: http://doi.org.10.1109/tmag.1985.10640195 Котова Д. Артамонова М. Крысанова Т. А., Василенко М. С., Новикова Л. А., Бельчинская Л. И., Петухова Г. А. Влияние воздействия импульсного магнитного поля на гидратационные свойства клиноптилолита и глауконита. Физикохимия поверхности и защита материалов. 2018; 54 (4): 327–331. DOI: http://doi.org./10.7868/s0044185618040010 Вернадский В. Курбатов С. Земные силикаты, алюмосиликаты и их аналоги. 4изд. М.: 1937.378с.– 1937. 378 с. CPD S - International Center for Diffraction Data. PDF Card 2012 00-039-1383 CPD S - International Center for Diffraction Data. PDF Card 2012 00-013-0135 CPD S - International Center for Diffraction Data. PDF Card 2012 00-029-0855 Зимкина Т. Фомичев В. Ультрамягкая рентгеновская спектроскопия. Ленинград: изд-во ЛГУ; 1971. 132 с. Шулаков А. Степанов А. Глубина генерации ультрамягкого рентгеновского излучения в SiO2. Поверхность. Физ. Хим. Мех. 1988.;10.: 150. Терехов В. Тростянский С. Селезнев А. Е., Домашевская Э. П. Изменение плотностилокализованных состояний в поверхностных слоях аморфного гидрогенезированного кремния при вакуумтермических отжигах. Поверхность Физ.. Хим. Мех. 1988;5: 74–80. Domashevskaya E. P., Peshkov Y. A , Terekhov V. A., Yurakov Y. A., Barkov K. A. Phase composition of the buried silicon interlayers in the amorphous multilayer nanostructures [(Co45Fe45Zr10)/a-Si:H]41 and [(Co45Fe45Zr10)35(Al2O3)65/a-Si:H]41. Surf. Interface Anal . 2018;50(12-13): 1265–1270. DOI: https://doi.org/10.1002/sia.6515 Мануковский Э. Ю. Электронная структура, состав и фотолюминесценция пористого кремния. Автореф. дис. … канд. физ. -мат. наук. Воронеж: ВГУ; 2000. 16 с. Домашевская Э. Терехов В. Турищев С. Ю ., Прижимов А. С., Харин А. Н., Паринова Е. В., Румянцева Н. А., Усольцева Д. С., Фоменко Ю . Л., Беленко С. В. Атомное и электронное строение аморфных и нанокристаллических слоев полуизолирующего кремния, полученных методом химического осаждения при низком давлении. Поверхность. Рентгеновские, синхротронные и нейтронные исследования. 2015;12 c 24-33