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3195 Genomic Analysis of Primary Plasma Cell Leukemia reveals Complex Cytogenetic Alterations and High Risk Mutational Patterns
- Carolina Schinke, Eileen Boyle, Cody Ashby, Yan Wang, Davies Christopher Wardell, Sharmilan Thanendrarajan, maurizio Zangari, Frits van Rhee, Gareth Morgan, Brian Walker
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, pp. 11-12
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OBJECTIVES/SPECIFIC AIMS: 1) Determine the mutational landscape, including translocation, mutations and mutational signatures as well as copy number variations of pPCL and identify significant differences to non pPCL MM. 2) Determine whether genetic changes pertinent to pPCL could be explored as therapeutic targets to improve the dismal prognosis of this patient population. METHODS/STUDY POPULATION: Samples from overall 19 pPCL patients that presented to the Myeloma Center, UAMS between 2000-2018 were used for this study. We performed gene expression profiling (GEP; Affymetrix U133 Plus 2.0) of matched circulating peripheral PCs and bone marrow (BM) PCs from 13 patients. Whole exome sequencing (WES) was performed on purified CD138+ PCs from BM aspirates from 19 pPCL patients with a median depth of 61x. CD34+ sorted cells, taken at the time of stem cell harvest from the same 19 patients, were used as controls. Translocations and mutations were called using Manta and Strelka and annotated as previously reported. Copy number was determined by Sequenza. RESULTS/ANTICIPATED RESULTS: 1) GEP from the BM and circulating peripheral PCs showed that the expression patterns of the two samples from each individual clustered together, indicating that circulating PCs and BM PCs in pPCL result from the same clone and are biologically clearly related. 2) The clinical characteristics from the patient cohort used for WES analysis were as follows: median age was 58 years (range 36–77), females accounted for 74% (14/19), an elevated creatinine level was found in 78% (14/18) and an elevated LDH level in 71% (10/14). All patients presented with an ISS stage of III. Median OS of the whole dataset was poor at 22 months, which is consistent with OS from previously reported pPCL cohorts. 3) Primary Immunoglobulin translocations were common and identified in 63% (12/19) of patients, including MAF translocations, which are known to carry high risk in 42% (8/19) of patients [t(14;16), 32% and t(14;20), 10%] followed by t(11;14) (16%) and t(4;14) (10%). Furthermore, 32% (6/19) of patients had at least one MYC translocation, which are known to play a crucial role in disease progression. 4) The mutational burden of pPCL consisted of a median of 98 non-silent mutations per sample, suggesting that the mutational landscape of pPCL is highly complex and harbors more coding mutations than non-pPCL MM. 5) Driver mutations, that previously have been described in non-pPCL MM showed a different prevalence and distribution in pPCL, including KRAS and TP53 with 47% (9/19) and 37% (7/19) affected patients respectively compared to 21% and 5% in non-PCL MM. PIK3CA (5%), PRDM1 (10%), EP300 (10%) and NF1 (10%) were also enriched in the pPCL group compared to previously reported cases in non-pPCL MM. 6) Biallelic inactivation of TP53 – a feature of Double Hit myeloma - was found in 6/19 (32%) samples, indicating a predominance of high risk genomic features compared to non-pPCL MM. Furthermore, analysis of mutational signatures in pPCL showed that aberrant APOBEC activity was highly prevalent only in patients with a MAF translocation, but not in other translocation groups. DISCUSSION/SIGNIFICANCE OF IMPACT: In conclusion we present one of the first WES datasets on pPCL with the largest patient cohort reported to date and show that pPCL is a highly complex disease. The aggressive disease behavior can, at least in part, be explained by a high prevalence of MAF and MYC translocations, TP53 and KRAS mutations as well as bi-allelic inactivation of TP53. It is of interest that only KRAS but not NRAS mutations are highly enriched in pPCL. From all highly prevalent genomic alterations in pPCL, only KRAS mutations offer a potential for already available therapeutically targeting with MEK inhibitors, which should be further explored.
Competency in Chaos: Lifesaving Performance of Care Providers Utilizing a Competency-Based, Multi-Actor Emergency Preparedness Training Curriculum
- Lancer A. Scott, Derrick A. Swartzentruber, Christopher Ashby Davis, P. Tim Maddux, Jennifer Schnellman, Amy E. Wahlquist
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- Journal:
- Prehospital and Disaster Medicine / Volume 28 / Issue 4 / August 2013
- Published online by Cambridge University Press:
- 26 April 2013, pp. 322-333
- Print publication:
- August 2013
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Objective
Providing comprehensive emergency preparedness training (EPT) to care providers is important to the future success of disaster operations in the US. Few EPT programs possess both competency-driven goals and metrics to measure performance during a multi-patient simulated disaster.
MethodsA 1-day (8-hour) EPT course for care providers was developed to enhance provider knowledge, skill, and comfort necessary to save lives during a simulated disaster. Nine learning objectives, 18 competencies, and 34 performance objectives were developed. During the 2-year demonstration of the curriculum, 24 fourth-year medical students and 17 Veterans Hospital Administration (VHA) providers were recruited and volunteered to take the course (two did not fully complete the research materials). An online pre-test, two post-tests, course assessment, didactic and small group content, and a 6-minute clinical casualty scenario were developed. During the scenario, trainees working in teams were confronted with three human simulators and 10 actor patients simultaneously. Unless appropriate performance objectives were met, the simulators “died” and the team was exposed to “anthrax.” After the scenario, team members participated in a facilitator-led debriefing using digital video and then repeated the scenario.
ResultsTrainees (N = 39) included 24 (62%) medical students; seven (18%) physicians; seven (18%) nurses; and one (3%) emergency manager. Forty-seven percent of the VHA providers reported greater than 16 annual hours of disaster training, while 15 (63%) of the medical students reported no annual disaster training. The mean (SD) score for the pre-test was 12.3 (3.8), or 51% correct, and after the training, the mean (SD) score was 18.5 (2.2), or 77% (P < .01). The overall rating for the course was 96 out of 100. Trainee self-assessment of “Overall Skill” increased from 63.3 out of 100 to 83.4 out of 100 and “Overall Knowledge” increased from 49.3 out of 100 to 78.7 out of 100 (P < .01). Of the 34 performance objectives during the disaster scenario, 23 were completed by at least half of the teams during their first attempt. All teams except one (8 of 9) could resuscitate two simulators and all teams (9 of 9) helped prevent anthrax exposure during their second scenario attempt.
ConclusionsThe 1-day EPT course for novice and experienced care providers recreated a multi-actor clinical disaster and enhanced provider knowledge, comfort level, and EPT skill. A larger-scale study, or multi-center trial, is needed to further study the impact of this curriculum and its potential to protect provider and patient lives.
. ,Scott LA ,Swartzentruber D ,Davis CA ,Maddux PT ,Schnellman J .Wahlquist AE Competency in Chaos: Lifesaving Performance of Care Providers Utilizing a Competency-Based, Multi-Actor Emergency Preparedness Training Curriculum . Prehosp Disaster Med.2013 ;28 (4 ):1 -12