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Context: Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy.Objective: To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina.Design, Setting, and Patients: A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011.Intervention: Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group).Main Outcome Measures: Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory.Results: Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement.Conclusion: Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT.Trial Registration: clinicaltrials.gov Identifier: NCT00824005. [ABSTRACT FROM AUTHOR]

Background/Objectives : Tobacco use remains a significant public health issue, particularly among individuals with low incomes, including Medicaid recipients who often face multiple barriers to quitting. This study aimed to identify barriers, from the perspective of Medicaid managed care organizations (MCOs), influencing Medicaid recipient participation in tobacco cessation programs. Methods : Focus group interviews were conducted with Florida Medicaid MCOs to elicit processes for case identification, outreach, referral, program participation, and incentives. Answers were synthesized into themes. Results : Medicaid recipients were primarily identified through nicotine dependency claim codes or Health Risk Assessments (HRAs). Individuals were referred to state and local community tobacco cessation programs through text messaging and outreach by MCO case managers. The MCOs identified the following as barriers: primary care physicians (PCPs) with limited knowledge about cessation programs and pharmacologic treatments for nicotine dependence, low availability of health coaches, long wait times for entry into cessation programs, weak coordination between MCOs and cessation programs, and insufficient incentives for individuals for program participation. Suggested strategies to overcome barriers were continuing medical education (CME) for PCPs about tobacco cessation programs and prescription therapies, increasing the training of health coaches, more investment in quitlines, increasing data sharing between MCOs and cessation programs, and increasing incentives for individuals. Conclusions : These findings highlight the importance of engaging MCOs in discussions about policy and program improvements, as their insights can drive meaningful changes in how tobacco cessation and other preventive health programs are structured and implemented. Targeted interventions are needed to enhance tobacco cessation program participation among Medicaid recipients.

Millions of US children and adolescents live in homes with loaded firearms, with only half of these homes securing their guns. Firearm-related deaths among youth have doubled over the past decade, making firearms the leading cause of death for children and adolescents in the United States. The recent advisory by the US Surgeon General, identifying firearm violence as a public health crisis, underscores the urgent need for responsible firearm ownership, including safe firearm storage. However, the healthcare community currently lacks durable medical equipment (DME) codes for firearm storage devices, limiting the ability of healthcare providers to support responsible gun ownership. We propose the establishment of DME codes for firearm storage and safety devices, which would facilitate insurance coverage of these vital prevention measures. Durable medical equipment codes would empower physicians and other healthcare providers to integrate anticipatory guidance and lethal means counseling of firearm safety into routine care and support hospital- and community-based efforts to prevent firearm-related injuries and deaths among children and adolescents., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Introduction: Secondhand smoke (SHS) poses a significant health risk. However, individuals who do not smoke may be unaware of their exposure, thereby failing to take protective actions promptly., Aims and Methods: We assessed the prevalence of underreported nicotine exposure in a nationally representative sample of US nonsmoking adults using data from the US National Health and Examination Survey. Individuals with underreported nicotine exposure were defined as those who reported no exposure to all tobacco products (traditional tobacco, nicotine replacements, and e-cigarettes) or SHS, yet had detectable levels of serum cotinine (>0.015 ng/mL). We fitted logistic regression models to determine sociodemographic and chronic condition factors associated with underreported nicotine exposure., Results: Our analysis included 13 503 adults aged 18 years and older. Between 2013 and 2020, the prevalence of self-reported SHS exposure, serum cotinine-assessed nicotine exposure, and underreported nicotine exposure among US nonsmokers were 22.0%, 51.2%, and 34.6%, respectively. Remarkably, 67.6% with detectable serum cotinine reported no SHS exposure. Males, non-Hispanic blacks, individuals of other races (including Asian Americans, Native Americans, and Pacific Islanders), and those without cardiovascular diseases were more likely to underreport nicotine exposure than their counterparts. The median serum cotinine value was higher in respondents who reported SHS exposure (0.107 ng/mL) than in those who reported no exposure (0.035 ng/mL). We estimate that approximately 56 million US residents had underreported nicotine exposure., Conclusions: Over a third of US nonsmokers underreport their nicotine exposure, underlining the urgent need for comprehensive public awareness campaigns and interventions. Further research into sociodemographic determinants influencing this underreporting is needed., Implications: Understanding the extent of underreported nicotine exposure is crucial for developing effective public health strategies and interventions. It is imperative to bolster public consciousness about the risks associated with SHS. Additionally, surveillance tools should also incorporate measures of exposure to outdoor SHS and e-cigarette vapor to enhance the quality of data monitoring. Findings from this study can guide tobacco control initiatives and inform smoke-free air legislation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate access to prenatal care for pregnant patients receiving medication for opioid use disorder (MOUD) under Medicaid coverage in Florida., Methods: A cross-sectional, secret shopper study was conducted in which calls were made to randomly selected obstetric clinicians' offices in Florida. Callers posed as a 14-week-pregnant patient with Medicaid insurance who was receiving MOUD from another physician and requested to schedule a first-time prenatal care appointment. Descriptive statistics were used to report our primary outcome, the callers' success in obtaining appointments from Medicaid-enrolled physicians' offices. Wait time for appointments and reasons the physician offices refused appointments to callers were collected., Results: Overall, 2,816 obstetric clinicians are enrolled in Florida Medicaid. Callers made 1,747 attempts to contact 1,023 randomly selected physicians' offices from June to September 2021. Only 48.9% of medical offices (n=500) were successfully reached by phone, of which 39.4% (n=197) offered a prenatal care appointment to the caller. The median wait time until the first appointment was 15 days (quartile 1: 7; quartile 3: 26), with a range of 0-55 days. However, despite offering an appointment, 8.6% of the medical offices stated that they do not accept Medicaid insurance payment or would accept only self-pay. Among the 60.6% of callers unable to secure an appointment, the most common reasons were that the clinician was not accepting patients taking methadone (34.7%) or was not accepting any new patients with Medicaid insurance (23.8%) and that the pregnancy would be too advanced by the time of the first available appointment (7.3%)., Conclusion: This secret shopper study found that the majority of obstetric clinicians' offices enrolled in Florida Medicaid do not accept pregnant patients with Medicaid insurance who are taking MOUD. Policy changes are needed to ensure access to adequate prenatal care for patients with opioid use disorder., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population., Methods: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m 2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy., Results: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts., Conclusions: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need., (© 2023 American Cancer Society.)

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral. We assessed patterns of consideration for and completion of HCT in patients with HR-MDS and AML enrolled between December 12, 2013, and March 6, 2020, in the Connect Myeloid Disease Registry at 164 CO/GOV and AC sites. Registry sites recorded whether patients were considered for transplantation at baseline and at each follow-up visit. The following answers were possible: "considered potentially eligible," "not considered potentially eligible," or "not assessed." Sites also recorded whether patients subsequently underwent HCT at each follow-up visit. Rates of consideration for HCT between CO/GOV and AC sites were compared using multivariable logistic regression analysis with covariates for age and comorbidity. Among the 778 patients with HR-MDS or AML enrolled in the Connect Myeloid Disease Registry, patients at CO/GOV sites were less likely to be considered potentially eligible for HCT than patients at AC sites (27.9% versus 43.9%; P < .0001). Multivariable logistic regression analysis with factors for age (<65 versus ≥65 years) and ACE-27 comorbidity grade (<2 versus ≥2) showed that patients at CO/GOV sites were significantly less likely than those at AC sites to be considered potentially eligible for HCT (odds ratio, 1.6, 95% confidence interval, 1.1 to 2.4; P = .0155). Among patients considered eligible for HCT, 45.1% (65 of 144) of those at CO/GOV sites and 35.7% (41 of 115) of those at AC sites underwent transplantation (P = .12). Approximately one-half of all patients at CO/GOV (50.1%) and AC (45.4%) sites were not considered potentially eligible for HCT; the most common reasons were age at CO/GOV sites (71.5%) and comorbidities at AC sites (52.1%). Across all sites, 17.4% of patients were reported as not assessed (and thus not considered) for HCT by their treating physician (20.7% at CO/GOV sites and 10.7% at AC sites; P = .0005). These findings suggest that many patients with HR-MDS and AML who may be candidates for HCT are not receiving assessment or consideration for transplantation in clinical practice. In addition, treatment at CO/GOV sites and age remain significant barriers to ensuring that all potentially eligible patients are assessed for HCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Etoposide is used to treat a wide range of malignant cancers, including acute myeloid leukemia (AML) in children. Despite the use of intensive chemotherapeutic regimens containing etoposide, a significant proportion of pediatric patients with AML become resistant to treatment and relapse, leading to poor survival. This poses a pressing clinical challenge to identify mechanisms underlying drug resistance to enable effective pharmacologic targeting. We performed a genome-wide CRISPR/Cas9 synthetic-lethal screening to identify functional modulators of etoposide response in leukemic cell line and integrated results from CRISPR-screen with gene expression and clinical outcomes in pediatric patients with AML treated with etoposide-containing regimen. Our results confirmed the involvement of well-characterized genes, including TOP2A and ABCC1, as well as identified novel genes such as RAD54L2, PRKDC, and ZNF451 that have potential to be novel drug targets. This study demonstrates the ability for leveraging CRISPR/Cas9 screening in conjunction with clinically relevant endpoints to make meaningful discoveries for the identification of prognostic biomarkers and novel therapeutic targets to overcome treatment resistance., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Neovascularization is a key therapeutic target for cancer treatment. However, anti-angiogenic therapies have shown modest success, as tumors develop rapid resistance to treatment owing to activation of redundant pathways that aid vascularization. We hypothesized that simultaneously targeting different pathways of neovascularization will circumvent the current issue of drug resistance and offer enhanced therapeutic benefits. To test this hypothesis, we made use of two distinct models of tumor-neovascularization, which exhibit equally dense microvasculature but show disparate sensitivity to anti-SDF-1 treatment. Lewis lung carcinoma (LLC) is primarily a vasculogenic-tumor that is associated with HSC functioning as a hemangioblast to generate circulating Endothelial Progenitor Cells contributing to formation of new blood vessels, and responds to anti-SDF-1 treatment. B16F0 melanoma is an angiogenic-tumor that derives new blood vessels from existing vasculature and is resistant to anti-SDF-1 therapy. In this study, we observed increased expression of the angiogenic-factor, Robo1 predominantly expressed on the blood vessels of B16F0 tumor. Blockade of Robo1 by the decoy receptor, RoboN, resulted in reduced microvascular-density and tumor-growth. However, this was associated with mobilization of BM-cells into the B16F0 tumor, thus switching the mode of neovascularization from angiogenic to vasculogenic. The use of a combinatorial treatment of RoboN and the monoclonal anti-SDF-1 antibody effectively attenuated tumor-growth and inhibited both angiogenic and BM-derived microvessels., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

While ≧10,000 Americans turn 65 years old every day, only 10% of American homes are "aging ready." Unsafe homes can exacerbate disability, lead to falls, and increase the likelihood of hospitalization. With increased investments in home and community-based services, public health stakeholders are considering home modifications to promote successful aging. While several home modification models exist, there is significant heterogeneity between models and no consensus on critical features. PubMed, EMBASE, and Web of Science were reviewed and twelve randomized controlled trials of home modifications for older adults were identified and evaluated for model structure, reported outcomes, and risk of bias. Overall, occupational therapist-driven home modifications supplemented with clinical, physical activity, and/or behavioral components saw the greatest success. This systematic review discusses the components of these models, highlights particularly effective and frequently used features, and the practice and research needed to create effective next-generation home modification models which promote healthy longevity.

Introduction: Tobacco smoking is the leading cause of preventable disease, disability, and premature death in the United States. Recent advances have led to two efficacious mobile health (mHealth) treatments for smoking cessation: iCanQuit, an Acceptance and Commitment Therapy-based behavioral treatment promoting cessation through accepting triggers and committing to values; and Motiv8, a contingency management intervention promoting smoking cessation with financial incentives via biochemically verified abstinence. This study will evaluate the comparative effectiveness of the Florida Quitline, iCanQuit alone, and iCanQuit+Motiv8 in a pragmatic trial among patients who smoke in underserved primary care settings., Methods: The study will be an individually-randomized controlled trial with three arms (Florida Quitline, iCanQuit alone, iCanQuit+Motiv8 combined) conducted in multiple primary care practices affiliated with the OneFlorida+ Clinical Research Consortium. Adult patients who smoke will be randomized to one of the 3 study arms (n = 444/arm), stratified by healthcare setting (academic vs. community). The primary outcome will be 7-day point prevalence smoking abstinence at 6 months post-randomization. Secondary outcomes will be 12-month smoking abstinence, patient satisfaction with the interventions, and changes in patient quality of life and self-efficacy. The study will also assess how and for whom the interventions help sub-group patients in achieving smoking abstinence by measuring theory-derived factors that mediate smoking outcome-specific baseline moderators., Conclusions: Results from this study will provide evidence for the comparative effectiveness of mHealth smoking cessation interventions in healthcare settings. Use of mHealth interventions can make smoking cessation resources more equitably accessible and have far-reaching impact on community and population health., Trial Registration: ClinicalTrials.gov, NCT05415761, Registered 13 June 2022., Competing Interests: Declaration of Competing Interest All authors declared no competing financial or non-financial interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML., Competing Interests: Declaration of interests C.E.T. receives research support from Notable Labs and serves as a scientific liaison for AstraZeneca. J.E.M. receives research funding from Gilead Pharmaceutical and serves on a scientific advisory board for Ionis Pharmaceuticals. M.W.D. serves on the advisory boards and/or as a consultant for Novartis, Incyte, and BMS and receives research funding from BMS and Gilead. C.S.H. receives research funding from Sellas. T.L.L. consults for Jazz Pharmaceuticals and receives research funding from Tolero, Gilead, Prescient, Ono, Bio-Path, Mateon, Genentech/Roche, Trovagene, AbbVie, Pfizer, Celgene, Imago, Astellas, Karyopharm, Seattle Genetics, and Incyte. D.A.P. receives research funding from Pfizer and Agios and served on advisory boards for Pfizer, Celyad, Agios, Celgene, AbbVie, Argenx, Takeda, and Servier. B.J.D. serves on the advisory boards for Aileron Therapeutics, Aptose, Blueprint Medicines, Cepheid, EnLiven Therapeutics, Gilead, GRAIL, Iterion Therapeutics, Nemucore Medical Innovations, the Novartis CML Molecular Monitoring Steering Committee, Recludix Pharma, the RUNX1 Research Program, ALLCRON Pharma, VB Therapeutics, Vincerx Pharma, and the Board of Directors for Amgen, and receives research funding from EnLiven and Recludix. B.J.D. is principal investigator or co-investigator on Novartis, BMS, and Pfizer clinical trials. His institution, OHSU, has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead, but he does not derive salary, nor does his laboratory receive funds, from these contracts. J.W.T. has received research support from Acerta, Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda, and Tolero and serves on the advisory board for Recludix Pharma. The authors certify that all compounds tested in this study were chosen without input from any of our industry partners. A subset of findings from this manuscript have been included in a pending patent application., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: In acute myeloid leukemia (AML), recurrent DNA methyltransferase 3A (DNMT3A) mutations are associated with chemoresistance and poor prognosis, especially in advanced-age patients. Gene-expression studies in DNMT3A-mutated cells identified signatures implicated in deregulated DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here, we tested whether pharmacologically induced replication fork stalling, such as with cytarabine, creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations., Experimental Design: Leukemia cell lines, genetic mouse models, and isogenic cells with and without DNMT3A(mut) were used to evaluate sensitivity to nucleoside analogues such as cytarabine in vitro and in vivo, followed by analysis of DNA damage and signaling, replication restart, and cell-cycle progression on treatment and after drug removal. Transcriptome profiling identified pathways deregulated by DNMT3A(mut) expression., Results: We found increased sensitivity to pharmacologically induced replication stress in cells expressing DNMT3A(R882)-mutant, with persistent intra-S-phase checkpoint activation, impaired PARP1 recruitment, and elevated DNA damage, which was incompletely resolved after drug removal and carried through mitosis. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine washout demonstrated a higher rate of fork collapse in DNMT3A(mut)-expressing cells. RNA-seq studies supported deregulated cell-cycle progression and p53 activation, along with splicing, ribosome biogenesis, and metabolism., Conclusions: Together, our studies show that DNMT3A mutations underlie a defect in recovery from replication fork arrest with subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during replication stress. See related commentary by Viny, p. 573., (©2021 The Authors; Published by the American Association for Cancer Research.)

During the first year of the coronavirus disease 2019 (COVID-19) pandemic, prevention measures included quarantining and facility closures. Because cancer screening is dependent on interventions in facilities, the extent of the COVID-19 impact on screening was questioned. A claims registry from a large health system was queried for colorectal and prostate cancer screening. A screening gap and screening loss ratio were calculated by comparing 2020 screening to historical reference years. All cancer screenings decreased in the first four months of the pandemic. Colorectal cancer screening returned to baseline in the latter six months of 2020. Prostate cancer screening exceeded baseline in the latter six months, but with a lesser gain than previous years. Populations disproportionately affected by decreased cancer screening included men and black people. To catch-up after the initial deficit in screening, it is estimated that the rate of colorectal cancer screening needs to increase by 50%.

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients' T-cells as evidenced by reduced numbers of circulating CD123 + CD34 + and CD33 + CD34 + peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential., Competing Interests: Author FU is employed by Ares Pharmaceuticals, he served as a consultant for Aptevo Therapeutics and he serves as a consultant to Reven Pharmaceuticals. Author CL is employed by Oncotelic Therapeutics, she served as a consultant to Aptevo Therapeutics and she serves as a consultant to Reven Pharmaceuticals. Author AS also served as a consultant to Aptevo. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Watts, Lin, Mims, Patel, Lee, Shahidzadeh, Shami, Cull, Cogle, Wang and Uckun.)

Resolvins and maresins, members of the specialized proresolving mediator (SPM) family, are omega-3 fatty acid-derived lipid mediators that attenuate inflammation. We hypothesized that they play a role in the pathophysiology of coronary microvascular dysfunction (CMD) in women with ischemia and no obstructive coronary disease. In a pilot study, we measured the D-series resolvins (D1, D2, D3, and D5), resolvin E1, maresin 1, docosahexaenoic acid, eicosapentaenoic acid (precursor of resolvin E1), and 18-hydroxyeicosapentaenoic acid by mass spectrometry in the peripheral blood of 31 women enrolled in the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial who had confirmed CMD assessed by coronary flow reserve. We compared SPM levels with 12 gender and age-matched reference subjects. Compared with the reference subject group, those with CMD had significantly lower plasma concentrations of resolvin D1 and maresin 1 and significantly higher levels of docosahexaenoic acid and 18-hydroxyeicosapentaenoic acid. In conclusion, insufficient or ineffective SPM production may play a role in the pathophysiology of CMD. If our results are validated in a larger cohort, omega-3 fatty acid supplementation could be tested as a novel treatment for these patients., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant ( p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions.

APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1-8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.

Introduction: The presence of ring sideroblasts (RS) and mutation of the SF3B1 gene are diagnostic of lower-risk (LR) myelodysplastic syndromes (MDS) and are correlated with favorable outcomes. However, information on testing and reporting in community-based clinical settings is scarce. This study from the Connect ® MDS/AML Disease Registry aimed to compare the frequency of RS and SF3B1 reporting for patients with LR-MDS, before and after publication of the 2016 World Health Organization (WHO) MDS classification criteria., Methods: Ring sideroblasts assessment and molecular testing data were collected from patients with LR-MDS at enrollment in the Registry. Patients enrolled between December 2013 and the data cutoff of March 2020 were included in this analysis., Results: Among 489 patients with LR-MDS, 434 (88.8%) underwent RS assessment; 190 were assessed prior to the 2016 WHO guidelines (Cohort A), and 244 after (Cohort B). In Cohort A, 87 (45.8%) patients had RS identified; 29 (33.3%) patients had RS < 15%, none of whom underwent molecular testing for SF3B1. In Cohort B, 96 (39.3%) patients had RS identified; 31 (32.3%) patients had < 15% RS, with 13 undergoing molecular testing of which 10 were assessed for SF3B1., Conclusions: In the Connect ® MDS/AML Registry, only 32% of patients with <15% RS underwent SF3B1 testing after the publication of the WHO 2016 classification criteria. There was no change in RS assessment frequency before and after publication, despite the potential impact on diagnostic subtyping and therapy selection, suggesting an unmet need for education to increase testing rates for SF3B1 mutations., (© 2020 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

(1) Background: Vaccine hesitancy and rejection are major threats to controlling coronavirus disease 2019 (COVID-19). There is a paucity of information about the attitudes of cancer patients towards vaccinations and the role of clinical oncologists in influencing vaccination acceptance. (2) Methods: Cancer patients and caregivers were invited to participate in a webinar and two surveys (pre- and post-webinar) assessing intention and thought processes associated with receiving COVID-19 vaccines. (3) Results: Two hundred and sixty-four participants participated in the webinar and registered to take at least one survey. Participants reported receiving most of their COVID-19 vaccine information from their doctor, clinic, or hospital. Before the webinar, 71% of participants reported the intention to receive a COVID-19 vaccine, 24% were unsure, and 5% had no intention of receiving a vaccine. The strongest predictors of vaccine enthusiasm were (a) planning to encourage the vaccination of family, friends, co-workers, and community, and (b) physician recommendation. The chief reason for vaccine hesitancy was a fear of side effects. After the webinar, 82.5% reported the intention to receive a vaccine, 15.4% were still unsure, and 2% stated that they had no intention of receiving a vaccine. The webinar shifted the attitude towards vaccine enthusiasm, despite an already vaccine-enthusiastic population. Communicating about vaccines using positive framing is associated with greater vaccine enthusiasm. (4) Conclusions: Patient education programs co-hosted by multiple stakeholders and delivered by oncologists can increase cancer patient enthusiasm for COVID-19 vaccination.

State cancer plans facilitate prioritization and stakeholder engagement in preventing and controlling cancer. Implementation plans further help stakeholders prioritize efforts, reduce redundancy, and find opportunities for work synergies. A review of cancer plan implementations plans was performed in the development of an implementation plan for the Florida Cancer Plan. This review sought to identify, characterize, and summarize the use of implementation plans that support comprehensive cancer control activities. Although 100% of states and territories published a cancer plan and 78% of states provided funding for implementing their state cancer plans, only 32% published an implementation plan. Commonalities and unique features of state cancer plan implementations are presented and discussed. An example implementation plan is provided for states without a plan to model.

Cancer data from population-based cancer registries under-report cancer cases, especially for cancers primarily diagnosed and treated in outpatient clinical settings, away from hospital-based cancer registrars. Previously, we developed alternative methods of cancer case capture including a claims-based method, which identified a large proportion of cancer cases missed by traditional population-based cancer registries. In this study, we adapted a claims-based method for statewide implementation of cancer surveillance in Florida. Between 2010 and 2017 the claims-based method identified 143,083 cancer abstracts, of which 42% were new and 58% were previously registered. The claims-based method led to the creation of 53,419 new cancer cases in the state cancer registry, which made up 9.3% of all cancer cases registered between 2010 and 2017. The types of cancers identified by the claims-based method were typical of the kinds primarily diagnosed and treated in outpatient oncology clinic settings, such as hematological malignancies, prostate cancer, melanoma, breast cancer, and bladder cancer. These cases were added to the Florida cancer registry and may produce an artefactual increase in cancer incidence, which is believed to be closer to the actual burden of cancer in the state.

Background: Participants in two recent National Academy of Medicine workshops identified a need for more multi-disciplinary professionals on teams to assist oncology clinicians in precision oncology., Methods: We developed a graduate school course to prepare biomedical students and pharmacy students to work within a multidisciplinary team of oncology clinicians, pathologists, radiologists, clinical pharmacists, and genetic counselors. Students learned precision oncology skills via case-based learning, hands-on data analyses, and presentations to peers. After the course, a focus group session was conducted to gain an in-depth student perspective on their interprofessional training experience, achievement of the course learning outcomes, ways to improve the course design in future offerings, and how the course could improve future career outcomes. A convenience sampling strategy was used for recruitment into the focus group session. A thematic content analysis was then conducted using the constant comparative method., Results: Major themes arising from student feedback were (1) appreciation of a customized patient case-based teaching approach, (2) more emphasis on using data analysis tools, (3) valuing interdisciplinary inclusion, and (4) request for more student discussion with advanced preparation materials., Conclusions: Feedback was generally positive and supports the continuation and expansion of the precision oncology course to include more hands-on instruction on the use of clinical bioinformatic tools.

The aim of this study was to establish the therapeutic relevance of the CD33 D2 isoform by developing novel antibodies targeting the IgC domain of CD33. Two novel IgC-targeting antibodies, HL2541 and 5C11-2, were developed, and CD33 isoforms were assessed using multiple assays in cells overexpressing either CD33 FL or CD33 D2 isoforms, unmodified acute myeloid leukemia (AML) cell lines and primary AML specimens representing different genotypes for the CD33 splicing single nucleotide polymorphism. CD33 D2 was recognized on cells overexpressing CD33 D2 and unmodified AML cell lines; however, minimal/no cell surface detection of CD33 D2 was observed in primary AML specimens. Both isoforms were detected intracellularly using novel antibodies. Minimal cell surface expression of CD33 D2 on primary AML/progenitor cells warrants further studies on anti-CD33 D2 immunotherapeutics.

Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival outcomes have yet to be proven. To further expand the arsenal for treating AML, we searched for druggable gene targets in AML by analyzing screening data from a lentiviral-based genome-wide pooled CRISPR-Cas9 library and gene knockout (KO) dependency scores in 15 AML cell lines (HEL, MV411, OCIAML2, THP1, NOMO1, EOL1, KASUMI1, NB4, OCIAML3, MOLM13, TF1, U937, F36P, AML193, P31FUJ). Ninety-four gene KOs met the criteria of (A) specifically essential to AML cell survival, (B) non-essential in non-AML cells, and (C) druggable according to three-dimensional (3D) modeling or ligand-based druggability scoring. Forty-four of 94 gene-KOs (47%) had an already-approved drug match and comprised a drug development list termed "deKO." Fifty of 94 gene-KOs (53%) had no drug in development and comprised a drug discovery list termed "disKO." STRING analysis and gene ontology categorization of the disKO targets preferentially cluster in the metabolic processes of UMP biosynthesis, IMP biosynthesis, dihydrofolate metabolism, pyrimidine nucleobase biosynthesis, vitellogenesis, and regulation of T cell differentiation and hematopoiesis. Results from this study serve as a testable compendium of AML drug targets that, after validation, may be translated into new therapeutics.

Background: Little is known about the shared decision-making between patients with transfusion-dependent (TD) myelodysplastic syndromes (MDS) and their physicians about the benefits, risks, and alternatives to reduce the need for blood transfusions., Methods and Materials: We conducted interviews and two cross-sectional surveys of MDS patients and MDS physicians in the US about the use of blood transfusions and disease-modifying therapies (DMTs). Responses from 157 MDS patients and 109 MDS physicians were analyzed., Results: The TD-MDS patient cohort had a median age of 69 years and a greater proportion of lower IPSS risk. The MDS physicians primarily practiced in large centers, evenly distributed between academic and community hospitals. There was a high level of independence and generally positive quality of life among patients, who were mostly concerned about effectiveness of blood transfusions and iron overload. MDS patients with shorter duration of disease (less than 5 years) were primarily concerned with transfusion reaction, while MDS patients with longer duration of disease were primarily concerned with iron overload. Approximately half of TD-MDS patients stated they had not discussed alternatives to reduce the need for blood transfusions with their physician. Patients with longer duration of disease were more likely to have a discussion with their physician about alternatives to blood transfusions. Physicians stated that they administered blood transfusions as primary therapy for MDS when it was patient preference, advanced age of patient, frailty, lower risk MDS, significant comorbidities, or failed prior treatments., Conclusions: While quality of life seemed generally positive in TD-MDS patients, there were differing perceptions about blood transfusions between patients and physicians. In the future, appraisal and optimization of the informed consent process between MDS patients and physicians are needed., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: There is an enormous and growing amount of data available from individual cancer cases, which makes the work of clinical oncologists more demanding. This data challenge has attracted engineers to create software that aims to improve cancer diagnosis or treatment. However, the move to use computers in the oncology clinic for diagnosis or treatment has led to instances of premature or inappropriate use of computational predictive systems., Objective: To evaluate best practices for developing and assessing the clinical utility of predictive computational methods in oncology., Evidence Review: The National Cancer Policy Forum and the Board on Mathematical Sciences and Analytics at the National Academies of Sciences, Engineering, and Medicine hosted a workshop to examine the use of multidimensional data derived from patients with cancer and the computational methods used to analyze these data. The workshop convened diverse stakeholders and experts, including computer scientists, oncology clinicians, statisticians, patient advocates, industry leaders, ethicists, leaders of health systems (academic and community based), private and public health insurance carriers, federal agencies, and regulatory authorities. Key characteristics for successful computational oncology were considered in 3 thematic areas: (1) data quality, completeness, sharing, and privacy; (2) computational methods for analysis, interpretation, and use of oncology data; and (3) clinical infrastructure and expertise for best use of computational precision oncology., Findings: Quality control was found to be essential across all stages, from data collection to data processing, management, and use. Collecting a standardized parsimonious data set at every cancer diagnosis and restaging could enhance reliability and completeness of clinical data for precision oncology. Data completeness refers to key data elements such as information about cancer diagnosis, treatment, and outcomes, while data quality depends on whether appropriate variables have been measured in valid and reliable ways. Collecting data from diverse populations can reduce the risk of creating invalid and biased algorithms. Computational systems that aid clinicians should be classified as software as a medical device and thus regulated according to the potential risk posed. To facilitate appropriate use of computational methods that interpret high-dimensional data in oncology, treating physicians need access to multidisciplinary teams with broad expertise and deep training among a subset of clinical oncology fellows in clinical informatics., Conclusions and Relevance: Workshop discussions suggested best practices in demonstrating the clinical utility of predictive computational methods for diagnosing or treating cancer.

Since the Coronavirus Disease 2019 (COVID-19) was identified as a global pandemic, health systems have been severely strained, particularly affecting vulnerable populations such as patients with cancer. In response to the COVID-19 pandemic, a variety of oncology specialty societies are making recommendations for standards of care. These diverse standards and gaps in standards can lead to inconsistent and heterogeneous care among governments, cancer centers, and even among oncologists within the same practice. These challenges highlight the need for a common nomenclature and crisis guidelines. For times of increased scarcity of resources, the National Academy of Medicine developed Crisis Standards of Care , defined as fairness, duty to care, duty to steward resources, transparency, consistency, proportionality, and accountability. However, we believe there is an urgent need to develop cancer-specific guidelines by convening a panel of experts from multiple specialties. These would be Crisis Oncology Standards of Care (COSCs) that are sensitive to both the individual cancer patient and to the broader health system in times of scarce resources, such as pandemic, natural disaster, or supply chain disruptions.

N 6 -methyladenosine (m 6 A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis. As an m 6 A demethylase, ALKBH5 has been shown to promote the development of breast cancer and brain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a tumor-suppressor role. Here, we show that ALKBH5 deletion is rare in human AML; instead, ALKBH5 is aberrantly overexpressed in AML. Moreover, its increased expression correlates with poor prognosis in AML patients. We demonstrate that ALKBH5 is required for the development and maintenance of AML and self-renewal of leukemia stem/initiating cells (LSCs/LICs) but not essential for normal hematopoiesis. Mechanistically, ALKBH5 exerts tumor-promoting effects in AML by post-transcriptional regulation of its critical targets such as TACC3, a prognosis-associated oncogene in various cancers. Collectively, our findings reveal crucial functions of ALKBH5 in leukemogenesis and LSC/LIC self-renewal/maintenance and highlight the therapeutic potential of targeting the ALKBH5/m 6 A axis., Competing Interests: Declaration of Interests C.H. is a scientific founder and a scientific advisor board member of Accent Therapeutics, and J.C. is a scientific founder and the President of Genovel Biotech Corp. Both hold equities with their corresponding company., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diagnostic and molecular genetic testing are key in advancing the treatment of acute myeloid leukemia (AML), yet little is known about testing patterns outside of clinical trials, especially in older patients. We analyzed diagnostic and molecular testing patterns over time in 565 patients aged ≥ 55 years with newly diagnosed AML enrolled in the Connect ® MDS/AML Disease Registry (NCT01688011) in the United States. Diagnostic data were recorded at enrolment and compared with published guidelines. The percentage of bone marrow blasts was reported for 82.1% of patients, and cellularity was the most commonly reported bone marrow morphological feature. Flow cytometry, karyotyping, molecular testing, and fluorescence in situ hybridization were performed in 98.8%, 95.4%, 75.9%, and 75.7% of patients, respectively. Molecular testing was done more frequently at academic than community/government sites (84.3% vs 70.2%; P  < .001). Enrolment to the Registry after 2016 was significantly associated with molecular testing at academic sites (odds ratio [OR] 2.59; P  = .023) and at community/government sites (OR 4.85; P  < .001) in logistic regression analyses. Better understanding of practice patterns may identify unmet needs and inform institutional protocols regarding the diagnosis of patients with AML., Competing Interests: DAP: AbbVie, Bristol‐Myers Squibb, Daiichi Sankyo – advisory board member and consultancy; Agios, Forty Seven, Pfizer – advisory board member; Takeda – consultancy; Glycomimetics – data safety and monitoring committee. TIG: Bristol‐Myers Squibb – consultancy; MA: Bristol‐Myers Squibb – advisory board, AbbVie, Bristol‐Myers Squibb, Gilead, Seattle Genetrix, Takeda – speaker panel; CRC, JPM, GGM: no conflicts to disclose; RB: AbbVie, Astex Daiichi Sankyo, Forty Seven, NeoGenomics – consultancy; Bristol‐Myers Squibb – consultancy, honoraria, research funding; Xian‐Janssen – honoraria; KF: Bristol‐Myers Squibb – advisory board member. DLG: AbbVie – consultancy; Alexion – speakers bureau; Astellas, Bristol‐Myers Squibb – advisory board member. RSK: Alexion, Jazz Pharmaceuticals, Novartis – speakers bureau; Agios, Bristol‐Myers Squibb, Daiichi Sankyo, Inc., Incyte, Janssen, Pfizer – consultancy. DAR: Allergan, Amgen, Bristol‐Myers Squibb, Takeda – research funding and consultancy. GJR: AbbVie, Actinum, Agios, Amphivena, Argenx, Astex, Astellas, Bayer, Bristol‐Myers Squibb, Celltrion, Daiichi Sankyo, Eisai, Janssen, Jazz Pharmaceuticals, Novartis, MEI Pharma, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda, Trovgene – consultancy, advisory board or data and safety monitoring committee; Cellectis – research funding. MRS: AbbVie – advisory board member, consulting; Boehringer Ingelheim – patents and royalties; Bristol‐Myers Squibb, Selvita – advisory board member; Incyte – advisory board member, research funding; Karyopharm – advisory board member, consultancy, equity ownership; Sunesis – research funding; Takeda, TG Therapeutics – advisory board member, research funding. BLS: Agios – speakers bureau; Alexion, Bristol‐Myers Squibb – advisory board member, consultancy, speakers bureau; Incyte – advisory board member, speakers bureau; Novartis – research funding. MAS: Bristol‐Myers Squibb, Pfizer, Takeda/Millenium – consulting. MAT: Adaptive, Bristol‐Myers Squibb, Doximity, GlaxoSmithKline, Strata Oncology, Syapse Precision Medicine Council, VIA Oncology, UpToDate – consultancy; Doximity – equity; AbbVie, Bristol Myers‐Squibb, CRAB CTC, Denovo, Hoosier Research Network, Lilly, LynxBio, Stata Oncology, Takeda, TG Therapeutics – institutional research funding; SEK: Agios and Bristol‐Myers Squibb – consultancy. CUL, MN, ASS, PK: Bristol‐Myers Squibb ‐ equity and employment. EDF: Bristol‐Myers Squibb – employment. DPS: Astex, Bristol‐Myers Squibb, Onconova, Pfizer, StemLine, Summer Road, Takeda – consultancy. HPE: Agios, Bristol‐Myers Squibb, Jazz Pharmaceuticals, Incyte, Novartis – speakers bureau; AbbVie, Agios, Amgen, Astellas, Bristol‐Myers Squibb, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz, MacroGenics, Novartis, Pfizer, Seattle Genetics – consultancy; AbbVie, Daiichi Sankyo, ImmunoGen, Macrogenics – research funding; Glycomimetics – data safety and monitoring committee; Covance – independent review committee., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Older adults have significantly worse morbidity and mortality after severe trauma than younger cohorts. The competency of the innate immune response decreases with advancing age, especially after an inflammatory insult. Subsequent poor outcomes after trauma are caused in part by dysfunctional leukocytes derived from the host's hematopoietic stem and progenitor cells (HSPCs). Our objective was to analyze the bone marrow (BM) HSPC transcriptomic [mRNA and microRNA (miR)] responses to trauma in older and younger adults. BM was collected intraoperatively <9 days after initial injury from trauma patients with non-mild injury [ISS ≥ 9] or with shock (lactate ≥ 2, base deficit ≥ 5, MAP ≤ 65) who underwent operative fixation of a pelvic or long bone fracture. Samples were also analyzed based on age (<55 years and ≥55 years), ISS score and transfusion in the first 24 h, and compared to age/sex-matched controls from non-cancer elective hip replacement or purchased healthy younger adult human BM aspirates. mRNA and miR expression patterns were calculated from lineage-negative enriched HSPCs. 924 genes were differentially expressed in older trauma subjects vs. age/sex-matched controls, while 654 genes were differentially expressed in younger subjects vs. age/sex-matched control. Only 68 transcriptomic changes were shared between the two groups. Subsequent analysis revealed upregulation of transcriptomic pathways related to quantity, function, differentiation, and proliferation of HSPCs in only the younger cohort. miR expression differences were also identified, many of which were associated with cell cycle regulation. In summary, differences in the BM HSPC mRNA and miR expression were identified between older and younger adult trauma subjects. These differences in gene and miR expression were related to pathways involved in HSPC production and differentiation. These differences could potentially explain why older adult patients have a suboptimal hematopoietic response to trauma. Although immunomodulation of HSPCs may be a necessary consideration to promote host protective immunity after host injury, the age related differences further highlight that patients may require an age-defined medical approach with interventions that are specific to their transcriptomic and biologic response. Also, targeting the older adult miRs may be possible for interventions in this patient population., (Copyright © 2020 Darden, Stortz, Hollen, Cox, Apple, Hawkins, Rincon, Lopez, Wang, Navarro, Hagen, Parvataneni, Brusko, Kladde, Bacher, Brumback, Brakenridge, Baker, Cogle, Mohr and Efron.)

Whereas lenalidomide is an effective therapy for del(5q) MDS patients, a minority of non-del(5q) MDS patients achieve hematologic improvement with lenalidomide. We used computational biology modeling and digital drug simulation to examine genomic data from 56 non-del(5q) MDS patients treated with lenalidomide, and then matched treatment response with molecular pathways. The computer inferred genomic abnormalities associating with lenalidomide treatment response in non-del(5q) MDS to include trisomy 8, del(20q), or RUNX1 loss of function mutations. Genomic abnormalities associating with lenalidomide resistance in non-del(5q) MDS patients included mutations in SF3B1 , TET2 , WNT3A amplification, MCL1 amplification, and/or PSEN2 amplification. These results may inform protocols for determining appropriateness of lenalidomide in non-del(5q) MDS.

Objective/background: Clinical predictors of delayed engraftment following autologous hematopoietic cell transplantation (AHCT) are poorly described in the literature. The purpose of this study was to identify pretransplant characteristics contributing to delayed engraftment (DE) following AHCT., Methods: A retrospective, single institution study of 1162 consecutive patients undergoing AHCT from January 1996 to August 2016 was studied for DE. DE was defined as platelet count ≤ 50,000/µl, hemoglobin ≤ 8 g/dL, or absolute neutrophil count ≤ 1000/mm 3 ., Results: Of the 1162 AHCT recipients, 263 (22.6%) were identified as having DE at 30-days post-AHCT with 80.0% being solely due to delayed platelet engraftment. Patients with Non-Hodgkin lymphoma (NHL) represented 18% of the original cohort, but accounted for 45% of those with DE, whereas multiple myeloma patients represented 59% of the initial cohort, but only 29% of those that had DE. At 3 months post-AHCT, transfusion dependence (p = .0083) prior to AHCT, low-infused CD34 + cell dose < 3 × 10 6 /kg (p = .0012), and low preAHCT platelet count < 150 × 10 3 /µL (p = .0027) were significantly associated with delayed engraftment., Conclusion: Transfusion dependence prior to AHCT, pre-AHCT platelet count, and CD34 + cell dose were the strongest predictors of delayed engraftment in patients undergoing AHCT., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Combretastatin A1 (OXi4503) is a dual-function drug with vascular disrupting and cytotoxic properties that has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML) and in a prior Phase 1A clinical study for relapsed/refractory (R/R) AML. The purpose of the present multicenter Phase 1B study was to define the maximum tolerated dose (MTD) and safety profile of OXi4503 and cytarabine (ARA-C) administered in combination (OXA). At four centers, 29 patients with R/R AML or myelodysplastic syndrome (MDS) were treated with OXA. The most common grade 3/4 treatment-emergent adverse events (AEs) were febrile neutropenia (28%), hypertension (17%), thrombocytopenia (17%), and anemia (14%). There were no treatment-emergent grade 5 AEs. Drug-related serious adverse events (SAEs) developed in 4/29 patients (14%) and included febrile neutropenia ( N = 2), pneumonia/acute respiratory failure ( N = 1), and hypotension ( N = 1). 9.76 mg/m 2 was defined as the MTD of OXi4503 when administered in combination with 1 g/m 2 ARA-C. In 26 evaluable AML patients, there were 2 complete remissions (CR), 2 complete remissions with incomplete count recovery (CRi) and one partial response (PR), for an overall response rate (ORR) of 19%. The median overall survival (OS) time for the four patients who achieved a CR/CRi was 528 days (95% CI: 434-NA), which was significantly longer than the median OS time of 113 days (95% CI: 77-172) for the remaining 22 patients who did not achieve a CR/CRi (Log Rank Chi Square = 11.8, p -value = 0.0006). The safety and early evidence of efficacy of the OXA regimen in R/R AML patients warrant further investigation in a Phase 2 clinical study.

One of the greatest challenges in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. Previously, we demonstrated a novel mechanism whereby AML-induced endothelial cell (EC) activation leads to subsequent leukemia cell adherence, quiescence and chemoresistance, identifying activated ECs as potential mediators of relapse. We now show mechanistically that EC activation induces the secretion of interleukin-8 (IL-8) leading to significant expansion of non-adherent AML cells and resistance to cytarabine (Ara-C). Through crystallography and computational modeling, we identified a pocket within IL-8 responsible for receptor binding, screened for small molecules that fit within this pocket, and blocked IL-8 induced proliferation and chemo-protection of AML cells with a hit compound. Results from this study show a new therapeutic strategy for targeting the sanctuary of an activated leukemia microenvironment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) are generally older and have more comorbidities. Therefore, identifying personalized treatment options for each patient early and accurately is essential. To address this, we developed a computational biology modeling (CBM) and digital drug simulation platform that relies on somatic gene mutations and gene CNVs found in malignant cells of individual patients. Drug treatment simulations based on unique patient-specific disease networks were used to generate treatment predictions. To evaluate the accuracy of the genomics-informed computational platform, we conducted a pilot prospective clinical study (NCT02435550) enrolling confirmed MDS and AML patients. Blinded to the empirically prescribed treatment regimen for each patient, genomic data from 50 evaluable patients were analyzed by CBM to predict patient-specific treatment responses. CBM accurately predicted treatment responses in 55 of 61 (90%) simulations, with 33 of 61 true positives, 22 of 61 true negatives, 3 of 61 false positives, and 3 of 61 false negatives, resulting in a sensitivity of 94%, a specificity of 88%, and an accuracy of 90%. Laboratory validation further confirmed the accuracy of CBM-predicted activated protein networks in 17 of 19 (89%) samples from 11 patients. Somatic mutations in the TET2 , IDH1/2 , ASXL1 , and EZH2 genes were discovered to be highly informative of MDS response to hypomethylating agents. In sum, analyses of patient cancer genomics using the CBM platform can be used to predict precision treatment responses in MDS and AML patients., (© 2019 by The American Society of Hematology.)

Background: Patients with relapsed and refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Genomically-defined personalized therapies are only applicable for a minority of patients. Therapies without identifiable targets can be effective but patient selection is challenging. The sequential combination of azacitidine with high-dose lenalidomide has shown activity; we aimed to determine the efficacy of this genomically-agnostic regimen in patients with R/R AML, with the intention of applying sophisticated methods to predict responders., Methods: Thirty-seven R/R AML/myelodysplastic syndrome patients were enrolled in a phase 2 study of azacitidine with lenalidomide. The primary endpoint was complete remission (CR) and CR with incomplete blood count recovery (CRi) rate. A computational biological modeling (CBM) approach was applied retrospectively to predict outcomes based on the understood mechanisms of azacitidine and lenalidomide in the setting of each patients' disease., Findings: Four of 37 patients (11%) had a CR/CRi; the study failed to meet the alternative hypothesis. Significant toxicity was observed in some cases, with three treatment-related deaths and a 30-day mortality rate of 14%. However, the CBM method predicted responses in 83% of evaluable patients, with a positive and negative predictive value of 80% and 89%, respectively., Interpretation: Sequential azacitidine and high-dose lenalidomide is effective in a minority of R/R AML patients; it may be possible to predict responders at the time of diagnosis using a CBM approach. More efforts to predict responses in non-targeted therapies should be made, to spare toxicity in patients unlikely to respond and maximize treatments for those with limited options., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background : The dichotomization or categorization of rural-urban codes, as nominal variables, is a prevailing paradigm in cancer disparity studies. The paradigm represents continuous rural-urban transition as discrete groups, which results in a loss of ordering information and landscape continuum, and thus may contribute to mixed findings in the literature. Few studies have examined the validity of using rural-urban codes as continuous variables in the same analysis. Methods : We geocoded cancer cases in north central Florida between 2005 and 2010 collected by Florida Cancer Data System. Using a linear hierarchical model, we regressed the occurrence of late stage cancer (including breast, colorectal, hematological, lung, and prostate cancer) on the rural-urban codes as continuous variables. To validate, the results were compared to those from using a truly continuous rurality data of the same study region. Results : In term of associations with late-stage cancer risk, the regression analysis showed that the use of rural-urban codes as continuous variables produces consistent outcomes with those from the truly continuous rurality for all types of cancer. Particularly, the rural-urban codes at the census tract level yield the closest estimation and are recommended to use when the continuous rurality data is not available. Conclusions : Methodologically, it is valid to treat rural-urban codes directly as continuous variables in cancer studies, in addition to converting them into categories. This proposed continuous-variable method offers researchers more flexibility in their choice of analytic methods and preserves the information in the ordering. It can better inform how cancer risk varies, degree by degree, over a finer spectrum of rural-urban landscape.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematological malignancy for which optimal therapeutic approaches are poorly characterized. Using computational biology modeling (CBM) in conjunction with genomic data from cell lines and individual patients, we generated disease-specific protein network maps that were used to identify unique characteristics associated with the mutational profiles of ETP-ALL compared to non-ETP-ALL (T-ALL) cases and simulated cellular responses to a digital library of FDA-approved and investigational agents. Genomics-based classification of ETP-ALL patients using CBM had a prediction sensitivity and specificity of 93% and 87%, respectively. This analysis identified key genomic and pathway characteristics that are distinct in ETP-ALL including deletion of nucleophosmin-1 (NPM1), mutations of which are used to direct therapeutic decisions in acute myeloid leukemia. Computational simulations based on mutational profiles of 62 ETP-ALL patient models identified 87 unique targeted combination therapies in 56 of the 62 patients despite actionable mutations being present in only 37% of ETP-ALL patients. Shortlisted two-drug combinations were predicted to be synergistic in 11 profiles and were validated by in vitro chemosensitivity assays. In conclusion, computational modeling was able to identify unique biomarkers and pathways for ETP-ALL, and identify new drug combinations for potential clinical testing., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite advances in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), overall survival rates remain low. The ability to predict treatment response based on individual cancer genomics using computational modeling will aid in the development of novel therapeutics and personalize care. Here, we used a combination of genomics, computational biology modeling (CBM), ex vivo chemosensitivity assay, and clinical data from 100 randomly selected patients in the Beat AML project to characterize AML sensitivity to a bromodomain (BRD) and extra-terminal (BET) inhibitor. Computational biology modeling was used to generate patient-specific protein network maps of activated and inactivated protein pathways translated from each genomic profile. Digital drug simulations of a BET inhibitor (JQ1) were conducted by quantitatively measuring drug effect using a composite AML disease inhibition score. 93% of predicted disease inhibition scores matched the associated ex vivo IC 50 value. Sensitivity and specificity of CBM predictions were 97.67%, and 64.29%, respectively. Genomic predictors of response were identified. Patient samples harbouring chromosomal aberrations del(7q) or -7, +8, or del(5q) and somatic mutations causing ERK pathway dysregulation, responded to JQ1 in both in silico and ex vivo assays. This study shows how a combination of genomics, computational modeling and chemosensitivity testing can identify network signatures associating with treatment response and can inform priority populations for future clinical trials of BET inhibitors., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown. Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution. Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (10 3 T cells/kg, n = 4), 2 (10 4 , n = 8), and 3 (10 5 , n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4 + T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells. Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098-109. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Thrombocytopenia is among the strongest predictors of decreased survival for patients with myelodysplastic syndromes (MDS) across all prognostic risk groups. The safety and efficacy of CC-486 (oral azacitidine) was investigated in early-phase studies; we assessed clinical outcomes among subgroups of MDS patients from these studies, defined by presence or lack of pretreatment thrombocytopenia (≤75 × 10 9 /L platelet count). Patients received CC-486 300 mg once-daily for 14 or 21 days of repeated 28-day cycles. Overall, 81 patients with MDS, median age 72 years, comprised the Low Platelets (n = 45) and High Platelets (n = 36) cohorts. Pretreatment median platelet counts were 34 × 10 9 /L and 198 × 10 9 /L, respectively. Grade 3-4 bleeding events occurred in 2 patients in the Low Platelets and 1 patient in the High Platelets groups; events resolved without sequelae. Treatment-related mortality was reported for 7 patients, 5 of whom had pretreatment platelet values <25 × 10 9 /L. Overall response rates were 38% and 46% in the Low Platelets and High Platelets groups, respectively. Five thrombocytopenic patients attained complete remission and 9 attained platelet hematologic improvement. In both cohorts, platelet counts dropped during the first CC-486 treatment cycle, then increased thereafter. Extended CC-486 dosing was generally well tolerated and induced hematologic responses in these patients regardless of pretreatment thrombocytopenia., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Multidrug resistance (MDR) is one major barrier in cancer management, which urges for new drugs to help treat MDR malignancies and elucidate MDR mechanisms. A series of chromene compounds (the CXL series) demonstrate increased antiproliferative activity toward MDR acute-myeloid-leukemia (AML) cells. The structure-activity relationship (SAR) of the antiproliferative potency has been partly characterized, whereas the structural determinants contributing to selectivity have not been investigated. In this study, three series of CXL compounds were synthesized and evaluated in HL60 and HL60/MX2 leukemia cells. The results not only confirmed previous SAR studies but also, for the first time, provided structural insights into the selectivity for MDR HL60/MX2 cells. Using the lead compounds as probes, we demonstrated that their modulation of intracellular-calcium homeostasis results in their antiproliferative potency and selectivity. Three candidates also demonstrate excellent in vitro safety profiles between cancer cells and normal cells, which will be evaluated in vivo in future studies.

Care coordination has been shown to have a positive effect on the management of chronic disease. Specific to the management of leukemia, coordination may occur between primary care physician, medical and radiation oncologists, surgeons, cardiologists, and genetics specialists. Experiencing gaps in communication and care coordination, many health consumers seek instrumental support in their social circles, including online forums and networks. The goal of this theory-guided study was to provide an in-depth assessment of how individuals use online forums to deliberate about their goals and plans for leukemia care coordination. Guided by the planning theory of communication, the data were collected from the American Cancer Society Cancer Survivors Network and included 125 original posts and 1,248 responses. Thematic analysis and axial coding were applied to analyze the data. Goal-related themes included overcoming the diffusion of care coordination and achieving health management cohesion. Planning themes included social health management, communication self-efficacy, and role deliberation. Online patient forums provide an interactive platform for patients and caregivers to engage in active conversations, which in turn can serve as identifiers of care coordination needs. Communication with those who share similar experiences allows cancer patients and survivors to accumulate functional health literacy, gain communication self-efficacy, and articulate a care coordination role acceptable to them.