Mutant PPM1D and TP53 populate the hematopoietic compartment after peptide receptor radionuclide therapy (PRRT) exposure.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10605-10605
Author(s):  
Abhay Singh ◽  
Nuria Mencia-Trinchant ◽  
Elizabeth A. Griffiths ◽  
Medhavi Gupta ◽  
Matthew Gravina ◽  
...  
Keyword(s):  
Risk Mitigation ◽  
Clonal Evolution ◽  
Genomic Analysis ◽  
Peptide Receptor Radionuclide Therapy ◽  
Mitigation Strategies ◽  
Molecular Profile ◽  
Temporal Association ◽  
Primary Malignancy ◽  
Blood Samples ◽  
Serial Sample

10605 Background: Mutations in TP53 and PPM1D are putative drivers associated with therapy related-myeloid neoplasm (T-MN) and have been identified in pre-treatment blood samples obtained at the time of primary malignancy, predating clinically evident T-MN. Genomic analysis of patients(pts) who undergo leukemogenic therapies will help understand T-MN biology and devise risk mitigation strategies. PRRT (Lu 177) for neuroendocrine tumors is associated with enhanced risk of T-MNs. The mechanism for T-MN induced by PRRT is largely elusive due to the novelty of this drug. Methods: We analyzed initial (n=13) and serial blood samples (n=4) prior to and following PRRT for clonal mutations in order to elucidate the role of PRRT in exerting selective pressures on HSCs. Genomic DNA was analyzed using a targeted myeloid 100-gene panel and a variant allele frequency (VAF) cutoff 1% was used to call clonal hematopoiesis (CH). Results: Fifty-four percent pts had CH, despite relatively young age of cohort (median age 58 years, range 41-75) and minimal chemo-radiotherapy exposure; baseline characteristics and molecular profile of cohort is published [Singh et al. Blood 2020; 136 (Supplement 1): 35–36]. Serial sample analysis in 4 pts (Table 1) demonstrates that PRRT exposure is associated with clonal evolution and accompanying cytopenias in 75% (3/4) pts. Pt-1 (age 67) with normal baseline hemogram developed persistent cytopenias after PRRT, accompanied by emergence and expansion of mutant- PPM1D (m PPM1D; VAF 20%). These data suggest that cytopenias result from repopulation of the HSC compartment by m PPM1D cells. In Pts 2 and 3 (age 74 and 75), we note expansion of m TP53 and m PPM1D clones respectively, also associated with the development of cytopenias. Pt-4 was younger (age 59) and developed no cytopenias. Exposure to PRRT was associated with loss of m TET2 and m DDX41, possibly due to lack of clonal fitness of m TET2/DDX41 clones and the relatively young HSC microenvironment. Conclusions: We conclude that mutations in PPM1D and TP53 are clinically relevant, contribute to clonal cytopenias and may increase risk of future T-MN. The temporal association of m TP53 and m PPM1D expansion with PRRT exposure in our analysis suggests selection of these clones in response to PRRT-induced stress, outcompeting wild type and less therapy-resistant HSCs. Our study along with others will inform future efforts to strategize methods of surveillance and early detection for clonality assessment and chemoprevention, to reduce adverse effects of leukemogenic therapies.[Table: see text]

Mutant PPM1D- and TP53-Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy

2022 ◽  
Author(s):  
Abhay Singh ◽  
Nuria Mencia-Trinchant ◽  
Elizabeth A. Griffiths ◽  
Alaa Altahan ◽  
Mahesh Swaminathan ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Neuroendocrine Tumors ◽  
Radionuclide Therapy ◽  
Risk Mitigation ◽  
Peptide Receptor Radionuclide Therapy ◽  
Variant Allele ◽  
Hematologic Toxicity ◽  
Variant Allele Frequency ◽  
Blood Samples ◽  
Peptide Receptor

PURPOSE Hematologic toxic effects of peptide receptor radionuclide therapy (PRRT) can be permanent. Patients with underlying clonal hematopoiesis (CH) may be more inclined to develop hematologic toxicity after PRRT. However, this association remains understudied. MATERIALS AND METHODS We evaluated pre- and post-PRRT blood samples of patients with neuroendocrine tumors. After initial screening, 13 cases of interest were selected. Serial blood samples were obtained on 4 of 13 patients. Genomic DNA was analyzed using a 100-gene panel. A variant allele frequency cutoff of 1% was used to call CH. RESULT Sixty-two percent of patients had CH at baseline. Persistent cytopenias were noted in 64% (7 of 11) of the patients. Serial sample analysis demonstrated that PRRT exposure resulted in clonal expansion of mutant DNA damage response genes ( TP53, CHEK2, and PPM1D) and accompanying cytopenias in 75% (3 of 4) of the patients. One patient who had a normal baseline hemogram and developed persistent cytopenias after PRRT exposure showed expansion of mutant PPM1D (variant allele frequency increased to 20% after exposure from < 1% at baseline). In the other two patients, expansion of mutant TP53, CHEK2, and PPM1D clones was also noted along with cytopenia development. CONCLUSION The shifts in hematopoietic clonal dynamics in our study were accompanied by emergence and persistence of cytopenias. These cytopenias likely represent premalignant state, as PPM1D-, CHEK2-, and TP53-mutant clones by themselves carry a high risk for transformation to therapy-related myeloid neoplasms. Future studies should consider CH screening and longitudinal monitoring as a key risk mitigation strategy for patients with neuroendocrine tumors receiving PRRT.

scholarly journals Clonal Hematopoiesis in Patients with Neuroendocrine Tumors Receiving Peptide Receptor Radionuclide Therapy (PRRT)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Abhay Singh ◽  
Matthew Gravina ◽  
Rutaba Tajammal ◽  
Annmarie Nowak ◽  
Renuka Iyer ◽  
...  
Keyword(s):  
Radionuclide Therapy ◽  
Clonal Evolution ◽  
Peptide Receptor Radionuclide Therapy ◽  
Cancer Center ◽  
Blood Samples ◽  
Peptide Receptor ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasms ◽  
Increased Risk ◽  
Serial Samples

Background. Clonal hematopoiesis (CH) prevalence increases with age. Elderly (&gt;70 years) healthy individuals have a 10% incidence of CH. Cancer cohorts are at increased risk of harboring CH mutations (~25%). Specific tumor types such as thyroid, ovarian, and bladder, have previously been shown to be at the highest risk of CH due to increased exposure to radionuclide and chemo-radiotherapies. Radionuclide therapies in particular are associated with a high incidence of subsequent myeloid disorders. Exposure to peptide receptor radionuclide therapy (PRRT, Lu 177 dotatate) leads to an increased risk (~2-5%) of therapy related myeloid neoplasms (MNs). It is not known if baseline CH architecture of neuroendocrine tumors (NETs) contributes to the increased risk or the protracted course of NETs or exposure to leukemogenic therapies. With a broader view to understand emergence of therapy induced myeloid neoplasms in various malignancies, we aimed to characterize baseline rates of CH in patients (pts) with NETs and assess clonal evolution in serial blood samples procured prior to and after exposure to PRRT. Methods. The NET Biobank housed at Roswell Park Comprehensive Cancer Center contains banked serial samples for pts receiving PRRT since its FDA approval in 2018. In this retrospective analysis, we identified pre-PRRT blood samples from 13 pts with NET treated at our institute from 2018-19. Serial samples (post PRRT exposure) were available for 6 of 13 pts. Genomic DNA collected from pts before and after PRRT treatment initiation was analyzed for CH mutations using a custom panel targeting 93 genes. A VAF cut off of 1% was used to define putative CH mutations. Relationships among clinical, laboratory and mutational variables were examined using chi-square test, at a significance level of 0.05. Results. Pt characteristics (n=13) are shown in Table 1. Median age was 58 years. 70% were men. Only 1/13 pt had prior chemotherapy exposure, and 3/13 had prior RT exposure. The primary location of NETs was small bowel (46%) followed by pancreas (23%) and others (cecal, rectal or unknown - 31%). All pts had stage IV disease. Over half (54%) harbored CH mutations, despite their relatively young age. This prevalence is much higher than previously reported CH prevalence of 25.1% in pts with other solid tumors.1TET2 (25%) was the most commonly mutated gene, followed by ASXL1 (12.5%), CHEK (12.5%), PPM1D (12.5%) and TP53 (12.5%) which together accounted for 50% of all mutations. Other mutations (DNMT3A, JAK2, DDX41, SRCAP) were less common (Figure 1). DNMT3A mutations (usually most prevalent mutation in cancer cohorts) were uncommon in this cohort and did not occur in the R882 AML/MDS hotspot, previously described in CH. Frameshift mutations and truncations comprised 53.3% of all mutations, and these mutations had higher mean VAFs (6.14%) than single nucleotide variants (1.93%; p = 0.001). This may suggest that frameshift mutations and truncations provide survival advantage to the affected clone. Mutations were more common in smokers than in non-smokers (100% vs 40%, p = 0.067). As expected, mutations were more common in individuals age 61 and above (75% harbored 1 or more mutation) vs only 20% mutation occurrence was noted in age 60 or below (p=0.05). Conclusion. CH with a distinct mutation profile occurs in NET patients, and in higher prevalence (54%) than observed in other solid tumors (25%). High baseline prevalence of putative CH mutations in NET patients may be an important contributor to heightened risk of MN development after PRRT exposure. Ongoing serial sample evaluation will provide further insights into clonal evolution of the above detected CH mutations after exposure to PRRT. The results regarding clonal evolution may have implications in predicting risk of MN associated with PRRT therapy and influence treatment selection in pts planned for PRRT. References Coombs CC, Zehir A, Devlin SM, et al. Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell. 2017;21(3):374-382.e374. Acknowledgement: Data and samples for this study were provided by the Data Bank and BioRepository (DBBR), which is funded by the National Cancer Institute (P30 CA016056) and is a Roswell Park Cancer Institute Cancer Center Support Grant shared resource. Disclosures Iyer: Advanced Accelerator Applications: Consultancy. Guzman:SeqRx: Honoraria; Cellectis: Research Funding. Wang:Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Astellas: Consultancy; Macrogenics: Consultancy; Pfizer: Speakers Bureau; Bristol Meyers Squibb (Celgene): Consultancy.

Proactive Actions Based on a Resilient Approach to Urban Seismic Risk Mitigation

2020 ◽  
Vol 14 (1) ◽  
pp. 321-335
Author(s):  
Marco Vona
Keyword(s):  
Urban Planning ◽  
Emergency Management ◽  
Seismic Risk ◽  
Risk Mitigation ◽  
Housing Stock ◽  
Mitigation Strategies ◽  
Housing System ◽  
Management Tools ◽  
Natural Risk ◽  
Seismic Risk Mitigation

Background: Seismic risk mitigation is an important issue in earthquake-prone countries, and needs to be solved in those complex communities governed by complex processes, where urban planning, socioeconomic dynamics, and, often, the need to preserve cultural assets are present simultaneously. In recent years, due to limited financial resources, mitigation activities have often been limited to post-earthquake events, and only a few in periods of inactivity, particularly in urban planning. At this point, a significant change in point of view is necessary. Methods: The seismic risk mitigation (and more generally, natural risk mitigation) must be considered as the main topic in urban planning and in the governance of communities. In fact, in several recent earthquakes, significant socioeconomic losses have been caused by the low or lack of resilience of the communities. This is mainly due to the high vulnerability of private buildings, in particular, housing units. Results: Therefore, in recent years, several studies have been conducted on the seismic resilience of communities. However, significant improvements are still needed for the resilience assessment of the housing stock, both qualitatively and quantitatively. In this study, which is applied to the housing system, a proposal regarding a change in urban planning and emergency management tools based on the concept of resilience is reported. As a first application, a case study in Italy is considered. Conclusion: The proposal is focused on defining and quantifying the improvement of the resilience of the communities and this must be obtained by modifying the current Civil Protection plan. New tools are based on a new resilience community plan by encompassing urban planning tools, resilient mitigation strategies, and consequently, emergency management planning.

scholarly journals 307 A systems approach to understanding biosecurity decision-making

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 43-43
Author(s):  
Scott C Merrill ◽  
Christopher Koliba ◽  
Gabriela Bucini ◽  
Eric Clark ◽  
Luke Trinity ◽  
...  
Keyword(s):  
Decision Making ◽  
Negative Impact ◽  
Risk Mitigation ◽  
African Swine Fever Virus ◽  
The United States ◽  
Mitigation Strategies ◽  
Communication Strategy ◽  
Livestock Industry ◽  
Diarrhea Virus ◽  
Operational Level

Abstract Disease and its consequences result in social and economic impacts to the US animal livestock industry, ranging from losses in human capital to economic costs in excess of a billion dollars annually. Impacts would dramatically escalate if a devastating disease like Foot and Mouth Disease or African Swine Fever virus were to emerge in the United States. Investing in preventative biosecurity can reduce the likelihood of disease incursions and their negative impact on our livestock industry, yet uncertainty persists with regards to developing an effective biosecurity structure and culture. Here we show the implications of human behavior and decision making for biosecurity effectiveness, from the operational level to the owner/managerial level and finally to the systems level. For example, adjustments to risk messaging strategies could double worker compliance with biosecurity practices at the operational level. The improvement of our risk communication strategy may increase willingness to invest in biosecurity. Furthermore, the adaptation of policies could nudge behavior so that we observe a short disease outbreak followed by a quick eradication instead of a pandemic. Our research shows how the emergence of now-endemic diseases, such as Porcine Epidemic Diarrhea virus, cannot be adequately modeled without the use of a human behavioral component. Focusing solely on any one sector or level of the livestock system is not sufficient to predict emergent disease patterns and their social and economic impact on livestock industries. These results provide insight toward developing more effective risk mitigation strategies and ways to nudge behavior toward more disease resilient systems.

scholarly journals Use of failure modes and effects analysis to mitigate potential risks prior to implementation of an intravenous compounding technology

2021 ◽  
Author(s):  
Agnes Ann Feemster ◽  
Melissa Augustino ◽  
Rosemary Duncan ◽  
Anand Khandoobhai ◽  
Meghan Rowcliffe
Keyword(s):  
Medication Safety ◽  
Failure Modes ◽  
Risk Mitigation ◽  
New Technology ◽  
Hazard Index ◽  
Mitigation Strategies ◽  
Investigational Drug ◽  
Workflow Optimization ◽  
Proactive Approach ◽  
Risk Mitigation Strategies

Abstract Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose The purpose of this study was to identify potential failure points in a new chemotherapy preparation technology and to implement changes that prevent or minimize the consequences of those failures before they occur using the failure modes and effects analysis (FMEA) approach. Methods An FMEA was conducted by a team of medication safety pharmacists, oncology pharmacists and technicians, leadership from informatics, investigational drug, and medication safety services, and representatives from the technology vendor. Failure modes were scored using both Risk Priority Number (RPN) and Risk Hazard Index (RHI) scores. Results The chemotherapy preparation workflow was defined in a 41-step process with 16 failure modes. The RPN and RHI scores were identical for each failure mode because all failure modes were considered detectable. Five failure modes, all attributable to user error, were deemed to pose the highest risk. Mitigation strategies and system changes were identified for 2 failure modes, with subsequent system modifications resulting in reduced risk. Conclusion The FMEA was a useful tool for risk mitigation and workflow optimization prior to implementation of an intravenous compounding technology. The process of conducting this study served as a collaborative and proactive approach to reducing the potential for medication errors upon adoption of new technology into the chemotherapy preparation process.

Avoiding Compressor Surge During Emergency Shutdown Hybrid Turbine Systems

2013 ◽  
Vol 135 (10) ◽  
Author(s):  
Paolo Pezzini ◽  
David Tucker ◽  
Alberto Traverso
Keyword(s):  
Fuel Cell ◽  
System Analysis ◽  
Risk Mitigation ◽  
Dynamic Effect ◽  
Transient Behavior ◽  
Open Loop ◽  
Department Of Energy ◽  
Mitigation Strategies ◽  
Emergency Shutdown ◽  
Compressor Surge

A new emergency shutdown procedure for a direct-fired fuel cell turbine hybrid power system was evaluated using a hardware-based simulation of an integrated gasifier/fuel cell/turbine hybrid cycle (IGFC), implemented through the Hybrid Performance (Hyper) project at the National Energy Technology Laboratory, U.S. Department of Energy (NETL). The Hyper facility is designed to explore dynamic operation of hybrid systems and quantitatively characterize such transient behavior. It is possible to model, test, and evaluate the effects of different parameters on the design and operation of a gasifier/fuel cell/gas turbine hybrid system and provide a means of quantifying risk mitigation strategies. An open-loop system analysis regarding the dynamic effect of bleed air, cold air bypass, and load bank is presented in order to evaluate the combination of these three main actuators during emergency shutdown. In the previous Hybrid control system architecture, catastrophic compressor failures were observed when the fuel and load bank were cut off during emergency shutdown strategy. Improvements were achieved using a nonlinear fuel valve ramp down when the load bank was not operating. Experiments in load bank operation show compressor surge and stall after emergency shutdown activation. The difficulties in finding an optimal compressor and cathode mass flow for mitigation of surge and stall using these actuators are illustrated.

A Low-Fidelity Stochastic Model of Viral Spread in Aircraft to Assess Risk Mitigation Strategies

2021 ◽  
Author(s):  
Leigh McCue
Keyword(s):  
Large Scale ◽  
Risk Mitigation ◽  
Mitigation Strategies ◽  
Traffic Network ◽  
Computationally Efficient ◽  
Passenger Compartment ◽  
Stochastic Effects ◽  
Viral Spread ◽  
Risk Mitigation Strategies ◽  
Baseline Health

Abstract The purpose of this work is to develop a computationally efficient model of viral spread that can be utilized to better understand influences of stochastic factors on a large-scale system - such as the air traffic network. A particle-based model of passengers and seats aboard a single-cabin 737-800 is developed for use as a demonstration of concept on tracking the propagation of a virus through the aircraft's passenger compartment over multiple flights. The model is sufficiently computationally efficient so as to be viable for Monte Carlo simulation to capture various stochastic effects, such as number of passengers, number of initially sick passengers, seating locations of passengers, and baseline health of each passenger. The computational tool is then exercised in demonstration for assessing risk mitigation of intervention strategies, such as passenger-driven cleaning of seating environments and elimination of middle seating.

Administrative risks challenging the adoption of smart contracts in construction projects

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Asli Pelin Gurgun ◽  
Kerim Koc
Keyword(s):  
Construction Projects ◽  
Risk Mitigation ◽  
Research Question ◽  
Group Discussion ◽  
Mitigation Strategies ◽  
Risk Category ◽  
Smart Contracts ◽  
Content Type ◽  
Smart Contract ◽  
Criteria Weights

PurposeAs a remedy to usually voluminous, complicated and not easily readable construction contracts, smart contracts can be considered as an effective and alternative solution. However, the construction industry is merely known as a frontrunner for fast adoption of recent technological advancements. Numerous administrative risks challenge construction companies to implement smart contracts. To highlight this issue, this study aims to assess the administrative risks of smart contract adoption in construction projects.Design/methodology/approachA literature survey is conducted to specify administrative risks of smart contracts followed by a pilot study to ensure that the framework is suitable to the research question. The criteria weights are calculated through the fuzzy analytical hierarchy process method, followed by a sensitivity analysis based on degree of fuzziness, which supports the robustness of the developed hierarchy and stability of the results. Then, a focus group discussion (FGD) is performed to discuss the mitigation strategies for the top-level risks in each risk category.FindingsThe final framework consists of 27 sub-criteria, which are categorized under five main criteria, namely, contractual, cultural, managerial, planning and relational. The findings show that (1) regulation change, (2) lack of a driving force, (3) works not accounted in planning, (4) shortcomings of current legal arrangements and (5) lack of dispute resolution mechanism are the top five risks challenging the adoption of smart contracts in construction projects. Risk mitigation strategies based on FGD show that improvements for the semi-automated smart contract drafting are considered more practicable compared to full automation.Originality/valueThe literature is limited in terms of the adoption of smart contracts, while the topic is receiving more attention recently. To support easy prevalence of smart contracts, this study attempts the most challenging aspects of smart contract adoption.

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