Strong Predictors of Chromosomal Aberrations and Myeloid Neoplasia Following Immunosuppression Therapy for Severe Aplastic Anemia: A Retrospective Cohort Study

Introduction: Immune aplastic anemia (AA) is effectively treated with either immunosuppressive treatment (IST) or allogeneic hematopoietic stem cell transplant (HSCT). Clonal evolution remains the most feared long-term complication after IST. We investigated predictor factors, genetic characteristics, and long-term outcomes of patients who developed either secondary myeloid neoplasia or isolated chromosomal abnormalities without morphologic dysplasia after immunosuppression. Methods: All patients with severe AA treated at the NIH Clinical Center with IST from 1989-2020 who underwent clonal evolution were categorized as "high-risk" (overt myeloid neoplasia, or isolated chromosome 7 abnormality / complex cytogenetics) or "low-risk" (isolated chromosome abnormalities without overt myeloid neoplasia or dysplasia; isolated chromosome 7 abnormality or complex cytogenetics were characterized as high-risk). Univariable analysis was performed using the Fine-Gray competing risk regression model using death as a competing risk to determine predictors of clonal evolution. Classification and regression tree analysis of time to clonal evolution was performed on continuous baseline variables to partition the data based on the best categorical cutoff. Long term outcomes assessed included overall survival (OS) and HSCT. Error corrected next-generation sequencing (ECS) was used to assess for pathogenic somatic variants in known myeloid cancer genes in clonal evolvers both at time of evolution and in serial samples prior when available. Results: Of 659 patients with severe AA included in this study, 95 developed clonal evolution: 59 high-risk and 36 low-risk. Age >48 years at diagnosis and pre-treatment ANC >0.87x10 9/L were strong predictors of high-risk clonal evolution. High-risk clonal evolution was increased in patients aged >48 years, with cumulative incidence (CI) of 13.9% by 5 years compared to patients aged <48 years of 3.8% by 5 years (p<0.001). Baseline ANC >0.87 x10 9/L (independent of age) predicted an even higher risk of evolution; CI for high-risk evolution was 17% by 5 years (p<0.001). Combined high ANC and older age (>48 years) were prognostic of the greatest risk of high-risk evolution, with a hazard ratio (HR) of 5.51; conversely, ANC <0.87 x10 9/L and age <48 years was protective, with HR 0.32. High-risk clonal evolution was not significantly increased by use of eltrombopag with IST versus IST only (p=0.3), but there was an increase when all clonal evolution was considered (p=0.02). Overall survival in high-risk evolution was 35% at 5 years and in low-risk evolution was 84% (p<0.001). Patients with high-risk evolution who underwent HSCT (n=26) had better OS compared to those treated with chemotherapy or supportive care (p=0.005). RUNX1 (13 variants in 8 [35%] patients) and ASXL1 (13 variants in 10 [43%] patients) were the most frequent mutated genes at time of clonal evolution in high-risk patients, and BCOR/L1 (14 variants in 8 [32%] patients) was the most frequently mutated in the low-risk group. Longitudinal data were available in five high-risk and eight low-risk patients. Three of five high-risk patients had acquisition or expansion of RUNX1 clones at evolution. Small RUNX1 variants were present in two patients as early as three years prior to high-risk evolution. Splicing factor genes and RUNX1 somatic variants were detected exclusively in the high-risk group; DNMT3A, BCOR/L1 and ASXL1 gene mutations were present in both groups. Conclusion: Age and pre-treatment ANC strongly predict high-risk clonal evolution in AA patients after IST and may be used determine at-risk patients for long term follow-up. Outcomes in patients with low-risk evolution are favorable but poor in high-risk evolution without HSCT. The clonal landscape differs between high-risk and low-risk evolution; MDS-associated genetic mutations are enriched in high-risk evolution, in particular RUNX1. Further study of the role of RUNX1 in high-risk clonal evolvers may give insight into leukemogenesis in AA. Figure 1: Cumulative incidence (CI) of clonal evolution since immunosuppression with death treated as competing risk. (A) CI for development of all clonal evolution in patients >37 years (B) and high-risk clonal evolution in patients >48 years (C) CI for development of all clonal evolution when baseline ANC >0.87x10 9/L and (D) high-risk clonal evolution when baseline ANC >0.87x10 9/L. Figure 1 Figure 1. Disclosures Young: Novartis: Research Funding.

Risk Evolution of Ship Oil Spill in the Three Gorges Reservoir Area

Ship oil spill accident will lead to enormous hazards in the Three Gorges Reservoir area. The risk mitigation of the ship oil spill is significant to the stakeholder of the maritime safety administration. To study the risk evolution of the ship oil spill in the Three Gorges Reservoir area, the framework of ship oil spill risk evolution was proposed according to the general definition of the risk; then, risk evolutions were analyzed from the perspectives of expected probability, system constraints of accident developing, and possible harmful consequences based on accidents analyses, simulation experiments, and structural equation model analysis. The results indicate that the system constraints of accident developing, such as the quantity of oil spills, free evolution time, and wind and flow conditions, have significant impacts on risk evolution of the ship oil spill after the occurrence of an accident in the Three Gorges Reservoir area.

Asymmetry of Risk Evolution in Crude Oil Market: From the Perspective of Dual Attributes of Oil

Investor emotional heterogeneity and oil dual attributes are the key factors that cause the asymmetry of risks in the international crude oil market. This paper uses the monthly data from April 2003 to October 2020 to identify the dynamic characteristics of oil’s commodity attribute and financial attribute, and this paper also analyzes the asymmetric characteristics of risk evolution and risk degree in the international crude oil market under the condition of oil returns heterogeneity. The empirical results show that: first, there is heterogeneity in the influence of oil attributes on the risk evolution and risk degree of the international crude oil market; second, the alternation of oil dual attributes has a significant asymmetric impact on the risk evolution of international crude oil market; third, the sudden change of international crude oil market risk caused by oil attributes is asymmetric under different oil returns trends. Based on the empirical conclusion, this paper puts forward the corresponding policy recommendations.

MODELING AND SIMULATION FOR MILITARY SUPPLY CHAIN RISK EVOLUTION BASED ON INFORMATION ENTROPY

Military supply chain risk is an important index in measuring the reliability of military logistics equipment support. It has the characteristics of dynamic development, and how to conduct profound research on the development and evolution process has important practical significance. On the basis of defining system elements, this paper firstly constructed a system dynamics model of risk evolution by using risk evolution system flow diagram of military supply chain, then determined the relevant model parameters through the method of information entropy. Finally, by using the simulation method, this paper studied the impact of impulse mutation, risk tolerance and risk response ability on the risk evolution process. The results show that improving the ability of risk tolerance and risk response plays an important role in effectively controlling of military supply chain risk.

The Risk Monitoring of the Financial Ecological Environment in Chinese Outward Foreign Direct Investment Based on a Complex Network

Aiming at the risk problem of financial ecological environment in outward foreign direct investment (OFDI), this paper constructs a risk monitoring model of the financial ecological environment based on complex network theory, and analyzes the general laws of financial risk evolution in Chinese OFDI by using data from 2008 to 2017 in 20 countries. First, the key risk factors are found through centrality analysis, then the correlation between risk indicators is obtained by cohesive subgroup analysis. Finally, we calculate network density, clustering coefficient and global efficiency to explore the time-spatial laws of the financial risk evolution in OFDI are obtained. At the same time, Kruskal’s algorithm is used to generate the minimum spanning tree (MST), and the change trend of risk transmission path is obtained. The results show that the following four risk indicators: M2/GDP, foreign exchange reserve, stock exchange turnover rate, total government debt as a percentage of GDP play an important role in the whole risk network and are the key nodes of risk evolution. The internal financial risks in Pakistan, the United States, Israel and Poland are more complex and highly transmissible. The risk transmission path based on MST shows that Australia and Bulgaria play an important role in risk transmission, and the length of risk transmission path has an overall upward trend. The conclusions of this study have guiding significance for overseas investment companies to prevent investment risks and ensure their sustainable development overseas.

The Use of Risk Evolution Models in Evaluation of Risk Levels for Diseases Developing under the Influence of Factors of Occupational Environment and Work Process

Background: The analysis of temporal changes in the value of occupational risk for workers based on evolutionary models helps predict long-term effects of occupational factors and develop effective preventive measures. The objective of our study was to test application of evolutionary modeling to assessing the relationship between prevalence rates of occupational and occupation-related diseases in workers induced by various factors of occupational environment and work processes. Materials and methods: We made epidemiological assessment of the association between workers’ health and working conditions in compliance with the requirements of Guidelines R 2.2.1766–03. The parameters of paired mathematical models constructed for different exposure levels were used for risk evolution models accounting for accumulation of functional changes attributed to external causes. Results and discussion: The results of risk evolution modeling showed that 20 years of high occupational noise exposures exceeding the maximum permissible level posed a very high risk of developing sensorineural hearing loss by the age of 48, this risk being high and moderate in the age ranges of 36–47 and 24–35, respectively. According to the same model, 20-year-long high occupational vibration exposures exceeding the maximum permissible level posed a moderate risk of developing diseases of the musculoskeletal system and connective tissue in workers aged 46–65. The risk of developing diseases of the nervous system posed by xylene exposures below the maximum permissible level was assessed as negligible.