Academic literature on the topic '551.82/099429 20'

Aim. The aim of this study was to determine the intra- and interobserver variability of two Scheimpflug based camera systems, Pentacam and Sirius. In addition, the comparability of the measurements was tested in healthy subjects, subjects with regular astigmatism, and keratoconus patients.Methods. Intra- and interobserver variability were assessed in 20 healthy corneas. Pachymetry values were also compared with ultrasound pachymetry as a reference measurement. To detect possible differences between the two devices, 82 eyes with clinically established keratoconus, 30 eyes with regular astigmatism (>1.5 D), and 60 eyes without corneal pathologies were included in this prospective study.Results. Pachymetry and keratometry showed good intra- and interobserver variability for both devices. Pachymetry values obtained with the Sirius system (579±58 μm) were significantly higher compared to the Pentacam system (551±40 μm,P<0.001) and to ultrasound pachymetry (550±43 μm,P<0.001). Significant interdevice differences were found regarding the majority of the detected keratometry parameters.Conclusions. Both devices show almost perfect reproducibility in healthy subjects. However, pachymetry and keratometry values of the two devices should not be used interchangeably.

Abstract With demand for grass-fed beef continuing to increase, there is an immediate need to determine animal performance and product quality from varying grass-fed systems. Therefore, using a whole systems approach, we investigated the performance and carcass quality of multiple grass-fed beef systems in California. The treatments included: 1) steers stocked on pasture, then feedyard finished for 140 days (CON); 2) steers grass-fed for 20 months (20GF); 3) steers grass-fed for 20 months with a 45-day grain finish (GR45); and 4) steers grass-fed for 25 months (25GF). The data were analyzed using a mixed model procedure in R. Final body weight (FBW) varied significantly between treatments (P &lt; 0.05) with the CON cattle finishing at 626 kg and GF20 finishing with the lowest FBW of 478 kg. There were no significant differences in FBW between GF45 and GF25 treatments (P &gt; 0.05), with FBW equaling 551 kg and 570 kg, respectively. Dressing percentage (DP) differed significantly between all treatments (P &lt; 0.05), with CON DP at 61.8%, followed by GR45 at 57.5%, GF25 at 53.4%, and GF20 at 50.3%. Marbling scores and quality grades were significantly higher for CON compared to all other treatments (P &lt; 0.05), with a marbling score of 421; 14% of CON animals graded select and 85% graded choice or upper choice. Cattle in the GR20 had the lowest marbling score of 285 (P &lt; 0.05); 59% of the GR20 cattle graded select and 41% graded standard. There was no difference in marbling when comparing the GF25 and GR45 (P &gt; 0.5). In addition, carcasses graded similarly between the two treatments with GF25 grading 13% standard 82% select, and 6% choice, GR45 graded 85% select and 15% choice. The findings from this study indicate that varying CA grass-fed beef production systems results in significant differences in both animal performance and meat quality.

Abstract In a large phase III trial (IRIS) comparing imatinib versus IFN/Ara-c, imatinib demonstrated significant higher rate of major (MCyR) and complete cytogenetic response (CCyR) and improved progression free survival (PFS). However a large number of pts (n= 354) assigned to the IFN/Ara-c arm crossed-over to imatinib therapy after a median of 9 months. Thus, we performed a retrospective analysis comparing outcome of pts assigned to imatinib in the IRIS trial (NEJM2003;348: 994) and pts assigned to IFN/Ara-c arm included in the French multicenter (CML 91) trial before imatinib became available (NEJM1997; 337: 223). Methods: Pts in the IRIS trial received imatinib 400 mg daily. Pts in the CML 91 trial received IFN alpha 2b 5 MIU/m2 daily plus monthly courses of Ara-c 20 mg/m2 for 10 days. Inclusion criteria of both studies were similar: pts with Ph+ CP CML diagnosed within 6 months before randomization; hydroxyurea or anagrelide were allowed if needed. We compared pts who actually received the assigned study treatment (n=551 for IRIS and n=325 for CML91). Results: We analyzed the results with a cut-off period of 42 months, median follow-up for alive pts being also 42 months in both groups. The imatinib treated population included more pts who were male, with high or unknown Sokal score and higher % of blasts, and with lower % of basophils at diagnosis than IFN plus Ara-c population. Evaluation included MCyR, CCyR, PFS (i.e. evolution to accelerated phase/blast crisis or death: to be consistent with the CML91 design), and overall survival. Results are summarized in the table below. Best response (CCyR) was observed in 81% (IRIS) and 32% (CML91) of pts. At the time of analysis 7% of all pts had never achieved confirmed MCyR but were still under study treatment in the IRIS; 8% were off treatment. These were 26% and 23% in the CML 91. Within all Sokal risk groups, imatinib was superior to IFN/Ara-c in terms of MCR, CCyR, PFS and overall survival. Using a landmark analysis, for pts who achieved MCyR at 1 year (n = 437 for IRIS and n = 125 for CML91), the survival at 36 months was similar in both groups: 95% for IRIS and 96% for CML 91. Conclusion: This historical comparison shows that for first line therapy for newly diagnosed CP CML, imatinib is superior to prolonged therapy with IFN/Ara-c for rate of MCyR, CCyR, PFS and overall survival. Pts who do not have access to imatinib may have long PFS and overall survival with IFN/Ara-c therapy. IRIS study CML 91 study logrank test** *95% CI ; ** by 42 months Estimated probability of MCR at 12 months 85 (82–88)* 39 (33–45) - Estimated probability of MCR at 36 months 93 (91–96) 61 (55–68) p&lt;0.0001 Estimated probability of CCyR at 12 months 70 (66–74) 14 (10–18) - Estimated probability of CCyR at 36 months 87 (83–90) 42 (35–48) p&lt;0.0001 Progression free survival at 12 months 98 (97–99) 96 (94–98) - Progression free survival at 36 months 90 (87–93) 82 (77–87) p = 0.004 Overall survival at 12 months 99 (98–100) 98 (96–100) - Overall survival at 36 months 92 (89–94) 84 (80–88) p&lt;0.0001

Abstract Background Allogeneic hematopoietic cell transplantation (HCT) likely prolongs survival in high and intermediate risk adults with acute myeloid leukemia (AML). Prior studies, however, suggest that only about 15-20% of AML patients especially older than 50 with abnormal cytogenetics receive HCT. In this report, we evaluated the impact of transplant and preparative regimen on high- or intermediate-risk AML patients treated in our center. Methods We retrospectively reviewed all patients who were diagnosed with AML (non promyelocytic) in our center between 2002 and 2012. Primary objective was to study the impact of HCT and preparative regimen in high and intermediate risk AML patients. Demographics and disease-related variables were collected. OS was defined as the time from diagnosis to the time of death or last follow up. Results Between 2002 and 2012, 123 patients with high or intermediate risk AML patients were treated at our center. Median age at diagnosis was 60 (range 19-89). 82 patients had high-risk features while 41 had intermediate risk features. Median OS for all patients was 368 days. Of these 124 patients, fifty-one patients (41%) received allogeneic HSCT at a median of 4.6 months from diagnosis. Median age of patients who received HCT was 53 while median age of patients who did not get HCT was 68. Of the 51 patients who received HCT, 13 patients with median age of 61 received a reduced toxicity/ Intensity conditioning regimen (RIC) while 37 patients with median age of 49 received a fully myelo-ablative regimen (MA). One got transplant elsewhere with unknown regimen. Median percentage of blasts in bone marrow at time of HCT was 3 and 3.5% for the RIC and MA regimens, respectively. Number of patients who had 10% or more blasts in the bone marrow at transplant was 9 of the 37 patients (24%) who received MA regimen and 3 of the 13 patients (23%) who received RIC regimen. Median OS for patients who received HCT was 551 days while it was 200 days for patients who did not receive HCT (p=0.0013) Fig1. The median OS for patients who got RIC was 1095 days but less at 434 days for MA patients but not statistically significant (p=0.64) Fig2. The cumulative incidence of relapse was not different between the two groups. Conclusion In this small cohort of consecutive patients from a single center, the results suggest that HCT can be performed in patients with high and Intermediate-risk AML patients including older patients using RIC. RIC in older patients and MA in younger patients did not differ in term of OS. However this is limited by the small number of patients and a larger prospective evaluation is needed taking into consideration better models encompassing performance status and co-morbidities. Disclosures: No relevant conflicts of interest to declare.

By decreasing the volume of the cryoprotective solution, we were able to dramatically increase the freezing speed and decrease the toxicity and osmotic side effects of the cryoprotectants (CP). Several carriers have been developed successfully (Vajta G et al. 1998 Mol. Reprod. Dev. 51, 53–58; Liebermann J et al. 2002 Reprod. Biomed. Online 4, 146–150; Park SP et al. 1999 Hum. Reprod. 15, 1787–1790; Chung HM et al. 2000 Fertil. Steril. 73, 545–551; Kuwayama M and Kato O 2000 Fertil. Steril. 74(Suppl. 3), S49 O-127; Matsumoto H et al. 2001 Cryobiology 42, 139–144; Lane M et al. 1999 Fertil. Steril. 72, 1073–1078; Dinnyés A et al. 2000 Biol. Reprod. 63, 513–518). The objective of our study was to vitrify Day 3 cleavage stage mouse embryos with the Vitroloop™ (Vitrolife, Kungsbacka, Sweden) cryopreservation technology. Vitrification was carried out in RapidVit™ Cleave (Vitrolife) solutions (holding, equilibration, and vitrification medium). Embryos were exposed to a 2-step loading of CP, ethylene glycol (EG), and propylene glycol (PG), before being placed in a small loop attached to the lid of a cryo-vial and rapidly submerged into liquid nitrogen (LN). First, the embryos were transferred from the G-MOPS holding medium to the equilibration medium containing 8% EG for 2 min. Then, embryos were transferred into a 20-μL drop of vitrification medium containing 16% EG, 16% PG, 10 mg mL–1 Ficoll 400, and 0.65 m sucrose for 30 s. After that, the embryos (maximum of 2 at a time) were transferred onto the loop, which was quickly sealed in a cryo-vial of LN and stored. After storage in LN, embryos were warmed by a 3-step dilution of the CP with sucrose (RapidWarmCleave™, Vitrolife) carried out at 37°C. First, the loop with the embryos was quickly immersed in 37°C warming medium 1 (0.65 m sucrose) for 20 s. Then, the embryos were transferred into warming medium 2 (0.25 m sucrose) for 1 min, then into warming medium 3 (0.125 m sucrose) for 2 min, and finally into warming medium 4 (G-MOPS medium) for 5 min. Following warming, embryos were cultured in G1 medium (Vitrolife) at 37°C with 6.5% CO2 and maximum humidity in air. Embryo viability was assessed by 48 h in vitro culture; the survival of embryos was based on morphological appearance in vitro after thawing and continued development to expanded blastocysts upon subsequent culture. The control embryos were treated likewise except that they were not vitrified. A total of 229 cleavage-stage embryos were vitrified and warmed; out of these, 11 were lost (11/229; 4.8%). Of the remaining 218 embryo, 202 survived vitrification (202/218; 92.7%) and 180 developed further to expanded blastocysts during in vitro culture (180/202; 82.6%). In the control group, 91.4% of the embryos developed to expanded blastocysts (75/82) indicating that the solutions used were not toxic. Our data show that a high percentage of cleavage-stage mouse embryos survived vitrification in the mixture of EG and PG combined with the use of cryoloop and developed normally in vitro after thawing. To our knowledge, this is the first report of the successful use of the Vitroloop™ vitrification procedure with cleavage-stage mouse embryos. The authors thank Vitrolife Ltd. (Kungsbacka, Sweden) and FertiCad Ltd. (Budapest, Hungary) for providing the solutions. The 3-month fellowship for Phillip Klambauer was provided by CEEPUS.

Abstract Background: AML and MDS disproportionately affect older-aged individuals. Hematopoietic cell transplantation (HCT) is the best established curative therapy but is generally not offered due to concerns about toxicity and poor outcome. Reduced-intensity conditioning (RIC) regimens have been developed to allow allografting in older patients; however, there is a paucity of data to support transplantation in patients over 65 years of age. Purpose: To better study age as a predictor of outcome, we retrospectively analyzed data reported to the CIBMTR from 1995–2005 among patients receiving RIC HCT for MDS (551 patients) and AML (565 patients) in first complete remission (CR). Patient and Methods: Outcomes analyzed for both disease groups included transplant-related mortality (TRM), engraftment, incidence of acute and chronic graft-versus-host disease (GVHD), leukemia-free (LFS) and overall survival (OS). Patients were stratified according to age cohorts for comparison: 40–54, 54–59, 60–64 and ≥65 years. Results: Clinical characteristics were well matched across age cohorts but notably, most AML patients presented with de novo disease (P=0.001) and received their allograft from a matched related donor (MRD) (P=0.001) with 51% of patients ≥65 years having a MRD. MDS patients more often had unrelated donors (URD), especially in the older cohorts (73% for ≥ 65 years); but donor type was not significantly different between groups. Most patients received peripheral blood (PB) allografts (76–97%), fludarabine-containing regimens for conditioning and cyclosporine-containing regimens for GVHD prophylaxis. Univariate analysis demonstrated no statistically significant differences in TRM across age cohorts and no overall difference in occurrence of acute (31–35% at 100 days) or chronic GVHD (36–53% at 2 years). Relapse rates were similar across all age groups (29–39% at 3 years) (Table). Multivariate analysis revealed no statistically significant impact of age on TRM, relapse, LFS, or OS (all p &gt; 0.4). Disease and status at transplant were significant risk factors for OS/LFS at 1 year while affecting TRM/relapse at 2 years. Performance status and HLA disparity were also significant at 2 years for nearly all outcomes. Conclusion: 1. The outcomes for older adults undergoing allogeneic HCT are not significantly different than for younger adults, even after adjusting for multiple risk factors; 2. Age by itself should not be the limiting factor for proceeding to allogeneic HCT in older patients with AML or MDS; 3. Continued participation in clinical trials should be encouraged to explore strategies that could improve treatment outcome. Univariate probabilities of patients age ≥40 years receiving allogeneic HCT for AML/MDS in first complete remission reported to the CIBMTR, 1995–2005. N 40–54 N 55–60 N 60–64 N &gt;65 AML TRM 220 150 132 63 100 days 11 (7–16)% 6 (3–10)% 13 (8–20)% 10 (4–18)% 1 year 20 (15–26)% 18 (12–24)% 24 (17–33)% 30 (19–42)% Relapse 1 year 27 (21–33)% 34 (26–42)% 31 (23–40)% 22 (12–33)% 3 years 32 (26–39)% 35 (27–43)% 39 (30–49)% 33 (21–46)% LFS 1 year 53 (46–60)% 49 (41–58)% 44 (35–53)% 48 (36–61)% 3 years 43 (36–51)% 41 (32–50)% 27 (19–37)% 34 (22–47)% OS 100 days 84 (78–88)% 92 (87–96)% 83 (76–89)% 89 (80–95)% 1 year 59 (52–65)% 60 (52–68)% 51 (42–60)% 51 (39–64)% 3 years 45 (40–54)% 47 (42–59)% 30 (25–43)% 36(24–49)% Follow-up (months) 37 (2–110) 25 (1–87) 36 (3–96) 29 (3–59) MDS TRM 219 150 127 55 100 days 17 (13–23)% 17 (11–23)% 14 (9–21)% 19 (9–30)% 1 year 31 (24–37)% 33 (25–41)% 32 (24–41)% 34 (22–47)% Relapse 1 year 26 (20–32)% 27 (20–35)% 26 (18–34)% 25 (14–37)% 3 years 29 (23–35)% 29 (22–37)% 31 (23–40)% higher 33 (20–47)% LFS 1 year 43 (36–50)% 40 (32–49)% 43 (34–51)% 42 (29–56)% 3 years 36 (29–43)% 27 (–2035)% 29 (21–39)% 23 (12–38)% OS 100 days 77 (71–82)% 77 (70–83)% 81 (74–87)% 76 (64–87)% 1 year 50 (43–56)% 46 (38–54)% 53 (44–62)% 48 (35–61)% 3 years 39 (32–46)% 29 (22–37)% 30 (21–40)% 29 (17–43)% Follow-up (months) 36 (2–86) 40 (3–86) 35 (3–68) 36 (3–85)

Abstract Introduction While novel agents have improved survival over the last decade, multiple myeloma (MM) remains incurable. Carfilzomib (CFZ), a second-generation proteasome inhibitor, was approved in July 2012 by the US Food and Drug Administration and had a label change in July 2015. During this study's data period, the label recommended Cycle 1 dose at 20 mg/m2/day and if tolerated increase Cycle 2 dose and subsequent cycles doses to 27 mg/m2/day. The purpose of this study is to assess baseline characteristics, CFZ dosing patterns and survival among MM patients in a US community oncology setting. Methods A retrospective study of MM patients from US Oncology Network practices that fully implemented McKesson Specialty Health's iKnowMed (iKM) oncology-specific electronic health records database was conducted on patients whose first treatment of CFZ (index) occurred between Jul-2012 and Nov-2014. Patients were eligible if they had a documented initial MM diagnosis date and had their first CFZ cycle documented in the database. Additionally, patients were required, before Dec-2014, to have either another visit to the practice post-index or a record of death and not have participated in interventional clinical trials during the previous 6 years. Data on eligible patients were collected up to March 2015. The death event was defined by the Social Security Death Index, supplemented by iKM; patients without the event were censored at the date of last observed visit. To adjust for clinical practice variations, a 10% variability was allowed for the recommended daily dose levels of 20 mg/m2 and 27 mg/m2. A subgroup was defined for patients with a 2nd cycle: "escalators" if they received 20 mg/m2/day doses throughout Cycle 1 and increased to 27 mg/m2/day on the first dose of Cycle 2; "non-escalators" if they received only 20 mg/m2 doses throughout Cycle 1 and did not increase to 27 mg/m2 on the first dose of Cycle 2; receiving any dose not equal to 20 or 27 mg/m2 were classified into "other". Survival after index was estimated using the Kaplan-Meier method with 95% confidence intervals (CI). A multivariable Cox proportional hazards (PH) model was conducted to evaluate the impact of escalation on survival accounting for selected baseline demographic and clinical characteristics. Results The cohort of 718 CFZ patients were identified with a median (interquartile range [IQR]) age of 68 (61-75) years at index, 57% (n=409) were male, and 12% (n=87) were Black and 77% (n=551) were Caucasian. At initial MM diagnosis, 19%, 27% and 42% were ISS Stage I, II, and III, respectively. Median (IQR) time from MM diagnosis to index was 3.6 (1.9-5.8) years. At index, 66% of patients had an ECOG performance status of 0-1, 21% of 2, and 2% of 3+; 54% (n=369) had moderate to severe renal impairment (eGFR<60 mL/min per 1.73 m2). Ninety percent (n=644) of patients started CFZ at 20 mg/m2, 4% (n=27) at 27 mg/m2 and 4% (n=25) at 15 mg/m2. Patients had a median (IQR) of 4 (2-7) cycles of CFZ and 45% (n=321) escalated to ≥27 mg/m2. Among these 321 patients, median (IQR) time to first escalation was 30 (28-56) days with 60% escalating in Cycle 2. The subgroup defined in "Methods" included 605 patients: 148 (24%) escalators, 342 (57%) non-escalators, and 115 (19%) other. Median (95% CI) duration from index to death was 21 (17.5-23.2) months. Unadjusted overall survival (OS) was significantly lower among non-escalators compared to escalators (log-rank p=0.024) [Figure 1]. Survival rates (95% CI) for non-escalators and escalators were 68% (62-74%) and 75% (66-82%) at year 1 and 42% (33-50%) and 61% (49-71%) at year 2, respectively. Within the multivariable Cox model, escalators showed a 33% significantly lower risk of death compared to non-escalators (HR=0.67, p=0.03) while also accounting for race, sex, age group, renal function per EGFR, and MM chain type. Other significant variables in this model were: EGFR < 15 and 15-29 vs 30-59 ml/min per 1.73m2 (HR=2.79, p<0.01; HR=1.64, p=0.04, respectively) and lambda vs kappa light chain (HR=1.55, p=0.03). Conclusions These results indicate escalation of CFZ at first dose of Cycle 2 is associated with better survival than dosing at 20 mg/m2 in Cycle 1 but not escalating at the start of Cycle 2. More research is needed to assess factors that impact physician decision-making on dose escalation to better inform physicians to improve the quality of multiple myeloma care. Disclosures Rifkin: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fonseca:McKesson Specialty Health, which received funding to conduct this research: Employment, Equity Ownership. Chen:Onyx Pharmaceuticals: Employment. Fox:McKesson Specialty Health, which received funding to conduct this research: Employment. Browning:Onyx Pharmaceuticals, An Amgen Subsidiary: Employment. Cong:Onyx Pharmaceuticals: Employment, Equity Ownership.

Abstract Introduction Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive malignancy commonly diagnosed in young adult females. In recent years, mutational and gene expression profiling has established genotypic and phenotypic similarity of PMBCL with both classical Hodgkin and diffuse large B-cell lymphoma (DLBCL). In-depth analyses of genomes and transcriptomes have highlighted several inactivating mutations (SOCS1, TP53), chromosomal amplifications (2p, 9p, Xp, Xq) and translocations (CIITA) thought to be integral in establishing and/or maintaining the PMBCL phenotype. Programmed death ligands (PDL) 1 (CD274) and 2 (PDCD1LG2), which are located on chromosome 9p24.1, are two emerging genes of interest that have been shown to be altered in PMBCL and can induce T-cell anergy by binding to the receptor, programmed death 1. Here, we describe the recurrence of chromosomal rearrangements of the PDL locus in various B-cell lymphomas and explore the association of these rearrangements with transcript levels. Methods To establish the frequency of CD274 and PDCD1LG2 aberration, we conducted fluorescence in situ hybridization (FISH) on 551 clinical samples and 20 established cell lines using in-house break-apart probes. Epstein-Barr virus encoded RNA in situ hybridization was also carried out on the clinical cohort. The clinical cases, sourced from the British Columbia Cancer Agency’s Centre for Lymphoid Cancer tissue repository, consisted of 125 PMBCLs, 216 DLBCLs, 130 primary DLBCL of the central nervous system (PCNSL), 12 nodular lymphocyte predominant Hodgkin lymphomas (NLPHL) and 68 follicular lymphomas (FL) with diagnoses based on the WHO classification. The DLBCL cohort could be further subdivided into 134 nodal DLBCLs and 82 testicular DLBCLs (T-DLBCL). Quantitative real-time PCR (qRT-PCR) was subsequently conducted on 17 cell lines and a clinical sub-cohort of 76 samples, for which fresh-frozen material was available, to determine the effect of mutations on transcript expression. We then characterized the PDL aberrations of two clinical PMBCL cases and three cell lines (DEV, L-428, L-1236), at base pair resolution, by applying the bioinformatic tools, nFuse, deFuse and destruct to both newly produced and previously published whole genome (WGS) and whole transcriptome (RNA-seq) libraries. Results FISH revealed a PDL locus (9p24.1) break-apart frequency of 20% (25/125) in PMBCL. There were no differences in any known clinical parameters or frequency of Epstein-Barr virus positivity between positive and negative PDL break-apart cases. Break-apart frequencies in other malignancies were calculated to be 3% in DLBCL, 7% in T-DLBCL and 1% in PCNSL; no positive cases were identified in either NLPHL or FL. The proportion of break-apart positive cases was significantly higher in PMBCL as compared to the other lymphomas surveyed (P < 0.05). Further, in agreement with the published literature, we observed an amplification frequency of the PDL locus in 36% (45/125) of PMBCLs. qRT-PCR established that PDCD1LG2 transcript levels were significantly higher in cases with 9p24.1 locus rearrangements compared to copy number neutral (P = 0.0003), gain (P = 0.001) and amplified cases (P = 0.005). Likewise, CD274 transcript levels were significantly higher in rearranged cases compared to copy number neutral cases (P = 0.03). Following the analysis of WGS and RNA-seq libraries, we were able to characterize four novel fusion transcripts involving the 9p24.1 locus: PDCD1LG2-NRG1 (PMBCL clinical case), PDCD1LG2-IGHV7-81 (L-1236), CIITA-PDCD1LG2 (DEV) and KIAA1432-CLDN14 (L-428). Aberrations involving both NRG1 and CIITA have previously been implicated in breast cancer and B-cell lymphomas, respectively. We also identified a translocation in another PMBCL clinical case with breakpoints in the intergenic spaces near LRMP and CD274, though this rearrangement did not produce a fusion transcript. Conclusion Taken together, our findings show that rearrangement of the PDL locus is recurrent in PMBCL, characteristic of PMBCL and leads to overexpression of PDL transcripts. Given the well-referenced function of PDLs in repressing the anti-tumor response, these data suggest that targeting the PDL axis in a subgroup of B-cell lymphomas holds clinical promise. Disclosures: No relevant conflicts of interest to declare.

Abstract Several direct oral anticoagulants (DOACs) have been developed that dose-dependently inhibit thrombin or activated factor X and offer potential advantages over vitamin K antagonists (VKAs), such as rapid onset and offset of action, absence of an effect of dietary vitamin K intake on their activity, and fewer drug interactions. DOACs have gained in popularity for the treatment and prevention of recurrence of venous thromboembolism (VTE), and the prevention of stroke/systemic embolism in patients with non-valvular atrial fibrillation (AF). However, the lack of routine monitoring means that their pharmacodynamic effect is rarely determined, leaving patients at potential risk of under- or over-anticoagulation. If adequately anticoagulated, the occurrence of thromboembolism (whether primary or recurrent) constitutes treatment failure; this has been reported in approximately 2% of patients in large DOAC clinical trials. The optimal management of such an event occurring with a DOAC remains unclear. In this study, we sought to characterise DOAC treatment failures in our institution, and to rationalise the subsequent anticoagulation strategies in this setting. All VTE patients starting a DOAC at our centre are followed in a consultant-led clinic. Cases of suspected treatment failure are also referred from other specialities and primary care. Between September 2014 and May 2018, we identified 59 consecutive patients (male/female: 34/25) in whom a DOAC treatment failure was diagnosed, including non-resolution of the presenting complaint, and recurrence of or a new thrombotic event. Patient mean age at DOAC initiation was 56 (23-89) years. The median time from DOAC initiation to failure detection was 42 (3-1055) days. 36/59 (61%) patients were receiving a DOAC for treatment of acute VTE, while 19/59 (32%) patients were treated for the prevention of recurrent VTE and 4/59 (7%) patients were on a DOAC for atrial fibrillation. 4 (7%) patients had a thrombophilia background while 5 patients (8%) had an active cancer diagnosis. On recognition of DOAC failure, 34 patients were on apixaban 5mg bd; 7 were on apixaban 2.5mg bd; 15 failed on rivaroxaban 20mg od; and 1 patient failed on each of rivaroxaban 10mg od, dabigatran 110 mg bd and edoxaban 30 mg od. All patients were compliant with their medication. For apixaban 5mg, the median time to failure was 29 (3-551) days; for apixaban 2.5mg it was 140 (26-441) days; for rivaroxaban it was 82 (20-1055) days. Two thirds of patients (39/59) were switched over to therapeutic low-molecular-weight heparin (LMWH), 6/59 patients (10%) were initiated to warfarin with appropriate LMWH bridging, and 11/59 patients (19%) were switched to an alternative DOAC. 3 patients (5%) continued their existing anticoagulant. Most patients (33/39, 85%) initially switched to LMWH following a median time on parenteral anticoagulation of 57 (14-472) days were subsequently switched to oral anticoagulants: 18% to warfarin, 82% to a DOAC. By the end of follow-up, 37/59 patients (63%) were taking a DOAC, including 8 patients who had been switched back to the anticoagulation regimen that failed at the outset, and a further 4 patients returned to the same drug at a higher dose. Of the remainder, 8 patients (14%) were taking a VKA, 8 patients (14%) remained on LMWH, 1 patient was on aspirin and 5 patients (8%) had stopped their anticoagulation treatment. A diagnosis of post-thrombotic leg was made in 15/36 (42%) patients with acute lower limb VTE who failed their DOAC. There is currently a lack of guidance on how to manage patients who fail initial treatment with a DOAC. To the best of our knowledge our study is the first to record the clinical experience in this challenging patient group. Based on our findings, a common strategy is to switch to therapeutic LMWH. After a successful period of parenteral therapy, most patients were switched back to oral treatment, typically another DOAC. Still this did not seem to prevent post-thrombotic syndrome in 42% of patients who were initially diagnosed with acute lower limb thrombosis. Treatment failure is a recognised risk of nearly all medical therapies including DOACs. It is therefore not surprising to encounter such patients in day-to-day practice. The growth in the number of anticoagulant choices has made it more difficult to know how to respond when one fails. As the use of DOACs continues to expand, this problem - and the need for an evidence-based solution - is likely to grow. Disclosures Smith: BMS: Honoraria, Speakers Bureau. Beale:Daiichi Sankyo: Speakers Bureau. Kartsios:Bayer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Boehringer Inglelheim: Consultancy, Honoraria, Speakers Bureau.

Abstract Background Polycythemia Vera (PV) constitutes one of the three BCR-ABL1-negative myeloproliferative neoplasms and is characterized by clonal erythrocytosis and the almost invariable presence of JAK2 mutation. An absolute monocyte count (AMC) of ≥1 x 10(9)/L defines chronic myelomonocytic leukemia (CMML) but can also be seen in other myeloid disorders including myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The presence or development of monocytosis has previously been shown to confer poor prognosis in both primary myelofibrosis (PMF), which is one of the three BCR-ABL1-negative MPN (Leukemia Research 2007;31:1503, Mod Pathol. 2013 Feb;26(2):204) and MDS (Haematologica. 1997;82:25). In the current study, we examined the clinical, prognostic and molecular correlates of monocytosis in PV. Methods Study patients were selected from our institutional database of MPN and fulfilled the 2008 World Health Organization (WHO) criteria for the diagnosis of PV (Blood. 2009;114:937). Cytogenetic and mutational analyses were performed according to conventional methods (Leukemia. 2014;28:2206) any assignment as unfavorable karyotype was per PMF criteria (Leukemia. 2011;25:82). Mutation screening included TET2, ASXL1 and SRSF2 because of their known association with CMML (Leukemia. 2014;28:2206) Statistical analyses considered clinical and laboratory parameters obtained at time of diagnosis. Results Patient characteristics: Analysis was conducted on 587 patients (median age 60 years; 48% males) who met WHO criteria for diagnosis of PV. Amongst them, accurate documentation of AMC was available in 237 patients, cytogenetic information in 239, and ASXL1, TET2 and SRSF2 mutational status in 133 patients. Median (range) values were for AMC 0.6 x 10(9)/L (0-4.7) and leukocytes 11.6 x 10(9)/L (3.8-171.6). 31% of 506 informative patients had palpable splenomegaly, 34% of 551 had microcirculatory symptoms, 30% of 566 had pruritus, 8% of 504 had erythromelalgia, 42% of 581 had hypertension, 9% of 584 had diabetes and 11% of 575 were active tobacco users. 25% of the patients presented with history of thrombosis and 22% developed thrombosis after diagnosis. Cytogenetic findings were abnormal in 19%, of whom 20% were unfavorable. TET2, ASXL1 and SRSF2 mutations were documented in 18%, 11% and 3%, respectively. During follow-up, 224 (38%) patients died and median follow-up for living patients was 109 months. Median survival was 16 years and leukemic or fibrotic transformations were documented in 4% and 14%, respectively. Comparison of patients with and without monocytosis: Among 237 informative patients, 32 (14%) displayed monocytosis (AMC ≥1 x 10(9)/L) at time of diagnosis. PV patients with monocytosis were older (p=0.006) and displayed higher leukocyte count (p<0.0001) and higher incidences of leukocytosis (p=0.024) and unfavorable cytogenetic abnormalities (p=0.02). There was no association between monocytosis and mutations for TET2 (p=0.1), ASXL1 (p=0.7) and SRSF2 (p=0.3) or thrombosis before (p=0.9) or after (p=0.5) diagnosis (p=0.5), palpable splenomegaly (p=0.6), pruritus (p=0.7) or microcirculatory symptoms (p=0.1). Among the 237 PV patients in whom information regarding AMC was available, 70 (30%) died during follow-up and 49 (21%), 23 (10%), 9 (4%) developed thrombosis, leukemic transformation or fibrotic progression, respectively. In univariate analysis, overall (p=0.009; HR 2.0, 95% CI 1.2-3.4) but not leukemia-free (p=0.79), myelofibrosis-free (p=0.13) or thrombosis-free (p=0.48) survivals were different between patients with or without monocytosis. Furthermore, the significant difference in survival was no longer apparent when analysis was adjusted for age (p=0.13), unfavorable karyotype (0.17) or leukocytosis (p=0.06). Conclusions Monocytosis (AMC ≥1 x 10(9)/L) is not infrequent in PV (14%). However, the presence of monocytosis does not appear to represent a significantly different phenotype in terms of molecular characteristics although it is associated with older age, leukocytosis and unfavorable karyotype. The latter associations account for the inferior survival seen in patients with monocytosis. Disclosures No relevant conflicts of interest to declare.