Impact of diagnostic genetics on remission MRD and transplantation outcomes in older patients with AML.

Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

Activated natural killer cells predict poor clinical prognosis in high-risk B- and T-cell acute lymphoblastic leukemia.

B- and T-cell acute lymphoblastic leukemia (B/T-ALL) may be refractory or recur after therapy by suppressing host anticancer immune surveillance mediated specifically by natural killer (NK) cells. We delineated the phenotypic and functional defects in NK cells from high-risk patients with B/T-ALL using mass cytometry, flow cytometry, and in silico cytometry, with the goal of further elucidating the role of NK cells in sustaining acute lymphoblastic leukemia (ALL) regression. We found that, compared with their normal counterparts, NK cells from patients with B/T-ALL are less cytotoxic but exhibit an activated signature that is characterized by high CD56, high CD69, production of activated NK cell-origin cytokines, and calcium (Ca2+) signaling. We demonstrated that defective maturation of NK cells into cytotoxic effectors prevents NK cells from ALL from lysing NK cell-sensitive targets as efficiently as do normal NK cells. Additionally, we showed that NK cells in ALL are exhausted, which is likely caused by their chronic activation. We found that increased frequencies of activated cytokine-producing NK cells are associated with increased disease severity and independently predict poor clinical outcome in patients with ALL. Our studies highlight the benefits of developing NK cell profiling as a diagnostic tool to predict clinical outcome in patients with ALL and underscore the clinical potential of allogeneic NK cell infusions to prevent ALL recurrence.

FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia.

Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML.

A Systematic Review of The Impact of Commercial Aircraft Activity on Air Quality Near Airports.

Commercial airport activity can adversely impact air quality in the vicinity of airports, and millions of people live close to major airports in the United States. Because of these potential impacts, a systematic literature review was conducted to identify peer reviewed literature on air quality near commercial airports and assess the quality of the studies. The systematic review included reference database searches in PubMed, Web of Science, and Google Scholar, inclusive of years 2000 through 2020. We identified 3,301 articles, and based on the inclusion and exclusion criteria developed, seventy studies were identified for extraction and evaluation using a combination of supervised machine learning and manual screening techniques. These studies consistently showed that ultrafine particulate matter (UFP) is elevated in and around airports. Furthermore, many studies show elevated levels of particulate matter under 2.5 microns in diameter (PM2.5), black carbon, criteria pollutants, and polycyclic aromatic hydrocarbons as well. Finally, the systematic review, while not focused on health effects, identified a limited number of on-topic references reporting adverse health effects impacts, including increased rates of premature death, pre-term births, decreased lung function, oxidative DNA damage and childhood leukemia. More research is needed linking particle size distributions to specific airport activities, and proximity to airports, characterizing relationships between different pollutants, evaluating long-term impacts, and improving our understanding of health effects.

Interpretative differences of combined cytogenetic and molecular profiling highlights differences between MRC and ELN classifications of AML.

Acute myeloid leukemia (AML) is typically characterized clinically for prognostic purposes using both cytogenetic and molecular characteristics. However, both cytogenetic and molecular risk stratification schemas are varied and few reports have studied correlations between these schemas. We have performed a single institution retrospective review of cytogenetic and molecular classifications of AMLs seen at Penn Medicine between 2013 and 2018. One-hundred fourty-four cases were characterized according to European Leukemia Net (ELN) or Medical Research Council (MRC) criteria for cytogenetics and results compared to molecular profiling. When we analyzed the most common sequencing study results within the risk groupings, negative sequencing studies and FLT3 mutations were common in favorable AMLs, intermediate AMLs had mutations in FLT3, NPM1, DNMT3A and IDH2, while adverse AMLs had a high prevalence of TP53 mutations. We next grouped the genes on the panel by their proteins' functions and found mutations in signaling pathway genes to be common in favorable AMLs while tumor suppressors were commonly mutated in adverse AMLs. AMLs grouped by the type of chromosomal abnormality present showed that FLT3 mutations were common in AMLs with a trisomy while TP53 mutations were common in AMLs with a monosomy or a deletion. TP53 mutations are especially common in AMLs with a monosomal karyotype and often overlap with 17p loss. Interestingly, although all AMLs with TP53 mutations have a defect in the response to DNA damage, expression of P53 protein before and after irradiation is not consistently predicted by phenotype. Overall, these studies confirm the genetic complexity of AML which does not fall into simple patterns of cooperating mutations.

Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL.

Children and adults with Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like B-ALL) experience high relapse rates despite best-available conventional chemotherapy. Ph-like ALL is driven by genetic alterations that activate constitutive cytokine receptor and kinase signaling, and early-phase trials are investigating the potential of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy to improve clinical outcomes. However, preclinical studies have shown that JAK or PI3K pathway inhibition is insufficient to eradicate the most common cytokine receptor-like factor 2-rearranged (CRLF2-rearranged) Ph-like ALL subset. We thus sought to define additional essential signaling pathways required in Ph-like leukemogenesis for improved therapeutic targeting. Herein, we describe an adaptive signaling plasticity of CRLF2-rearranged Ph-like ALL following selective TKI pressure, which occurs in the absence of genetic mutations. Interestingly, we observed that Ph-like ALL cells have activated SRC, ERK, and PI3K signaling consistent with activated B cell receptor (BCR) signaling, although they do not express cell surface µ-heavy chain (µHC). Combinatorial targeting of JAK/STAT, PI3K, and "BCR-like" signaling with multiple TKIs and/or dexamethasone prevented this signaling plasticity and induced complete cell death, demonstrating a more optimal and clinically pragmatic therapeutic strategy for CRLF2-rearranged Ph-like ALL.

Geographic Information Systems for healthcare organizations: a primer for nursing professions.

The sharing of spatial information among members of the health sector can have vast strategic and operational benefits. Geographic Information Systems, or GIS, can be a key technology in optimally using this information. There are two types of applications under GIS: (1) studying health outcomes and epidemiology and (2) studying and informing healthcare delivery. With the advent of GIS that can be used over the Internet, a wider audience of decision makers and stakeholders now has the opportunity to use these technologies through something as simple as a Web browser. There is a small but growing number of published articles giving examples of using GIS for nursing practice and research. However, increased efforts are needed to make nurses, other health professionals, and health organizations aware of the possibilities of these information products for empowering their decision making. An incremental "capacity building" approach is proposed as the best way forward for sustainable and sustained nursing GIS development. The aims of this article are (1) to provide a brief nontechnical overview for readers not familiar with GIS, (2) to provide a framework for the adoption of GIS in health service organizations, and (3) to identify ways in which GIS can impact on the nursing management of patients.

The elderly demographic time bomb - sharing the load with the active ageing: can eHealth technologies help defuse it?

This paper examines strategic health management and practical health service delivery issues inherent in the potential doubling in the number of over 65s over the next two decades. It considers the use of scarce and overloaded resources in providing care and support to this age group across the spectrum of community environments, and advocates the use of shared information services coupled with the deployment of 'smart' technologies to supplement available yet scarce professional resources as well as enabling elderly people to maintain a safe, active and independent lifestyle. An innovative approach to provide support both to an active ageing population, as well as the more frail or vulnerable members of society, is outlined. Based on an ongoing research programme, this centres on the extension of the Smart Home concept to create an overarching smart environment. This combines advanced information, communications and textile technologies with physiological monitoring and location based processes and services, to protect and support users by maintaining the range of services they need. Discussion of the behavioural dynamics inherent in organizational change concludes the paper.

Classes of ITD Predict Outcomes in AML Patients Treated with FLT3 Inhibitors.

PURPOSE: Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3-ITD mutations might not guarantee effective clinical response. Motivated by the heterogeneity of FLT3-ITD mutations, we investigated the effects of FLT3-ITD structural features on the response of AML patients to treatment.Experimental Design: We developed the HeatITup (HEAT diffusion for Internal Tandem dUPlication) algorithm to identify and quantitate ITD structural features including nucleotide composition. Using HeatITup, we studied the impact of ITD structural features on the clinical response to FLT3i and induction chemotherapy in FLT3-ITD-positive AML patients. RESULTS: HeatITup accurately identifies and classifies ITDs into newly defined categories of "typical" or "atypical" based on their nucleotide composition. A typical ITD's insert sequence completely matches the wild-type FLT3, whereas an atypical ITD's insert contains nucleotides exogenous to the wild-type FLT3. Our analysis shows marked divergence between typical and atypical ITD mutation features. Furthermore, our data suggest that AML patients carrying typical FLT3-ITDs benefited significantly more from both FLT3i and induction chemotherapy treatments than patients with atypical FLT3-ITDs. CONCLUSIONS: These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing toward personalized treatment of AML patients, and enable researchers and clinicians to unravel ITD complexity using the provided software.See related commentary by Gallipoli and Huntly, p. 460.

The safe implementation of research into healthcare practice.

Miscommunication, misunderstanding and outright error have all played significance roles in triggering Adverse Events across the spectrum of health care delivery. As a means of countering these effects this paper outlines a twin track approach. This firstly focuses on developing a care pathway modelling approach both as the basis for better understanding of interdisciplinary process interaction, and also as a means of rapid access to relevant clinical knowledge. This is then set in the context of the human behavioural issues that can all too easily prejudice patient safety. It also explores the potential to apply the large body of knowledge and experience in risk management techniques applied to life critical decision taking under high stress conditions.

A notary archive model for secure preservation and distribution of electrically signed patient documents.

The healthcare industry is moving from paper-based documentation into the digital era. Electronic health records (EHR) are playing a major role in this development. Electronic health records will not only to be shared among a growing number of healthcare providers but they have also to be archived over long periods of time. The required life cycle depends of national regulations, but typically the preservation time of patient data varies between 20 and 100 years. Availability, integrity, confidentiality and non-repudiation of stored data over these lengthy preservation periods needs to be fully proven, both to preclude loss and also ensure the ability to read and understand content is maintained. This document describes a co-operative trusted notary archive (TNA) which receives granular health data from different EHR-systems, stores data together with associated meta-information for long periods and distributes granular EHR-data objects. TNA communicates with EHR-systems and external users via archive request and distribution messages. TNA can store objects in XML-format and prove the non-repudiation and integrity of stored data with the help of event records, Time-stamps and archive e-signatures.

Developing a strategic framework for healthcare standards.

This paper uses the example of information security to consider ways of ensuring that standards development matches evolving market needs within appropriate timeframes. It then considers the use of simple process maps as a way to identify interdependencies between emergent standards within specific domains, as well as generic characteristics that cross domain boundaries. It concludes by briefly examining issues that lie beyond the traditional technical orientation to consider its extension to information content and safety.

e-Care integration: To meet the demographic challenge.

Current multi-agency models of care will be wholly unsustainable when faced with the forecast doubling of over 65s in the developed and developing nations to around 40% of their populations of the next decades. The resulting imbalance between demand and skilled resources is beginning to force radical change towards a fully "joined up" cross-disciplinary, cross-agency service that spans the wide spectrum of medical and social care. This paper offers a basis for a radically revised model that combines end-to-end service processes optimization; the use of integrated assistive technology systems to help the elderly maintain an independent lifestyle; personal risk reduction through medical and status monitoring; extended care-watch and service co-ordination. It then develops an IPTV based approach to provide the necessary infrastructure to underpin provision of these facilities both at home and in the community. These substantial benefits are reviewed and weighed against the inherent loss of privacy that can result from the pervasive computing aspects of the care watch approach, together with the trust building and change management aspects that are inevitably involved in the rationalisation process.