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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.

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.

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

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 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, 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.

Table S1 Patients, donors, HLA-mismatches and conditioning; Table S2 Cell doses in stem cell transplant, engraftment and chimerism; Table S3 ADLI dose and timing and allostimulator source; Table S4 Patient outcomes; Figure S1 Schema for clinical study; Figure S2 Alloanergization efficiency of DLI by centre and by dose level; Figure S3 Residual alloreactivity in aDLI and occurrence of acute GvHD after T-cell depleted haploidentical HSCT and aDLI; Figure S4 Phenotype of CD4+ regulatory T-cell (Treg) in patient peripheral blood after T-cell depleted haploidentical HSCT and aDLI

Supplementary Data from DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks

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.

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.

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.

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

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/mm3. 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

Simple Summary Cytokine release syndrome is a potentially life-threatening complication of therapy with T-cell engaging bispecific antibodies. Here we evaluated the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome who received weekly intravenous infusions of the CD3xCD123 bispecific antibody APVO436. Cytokine release syndrome was encountered in 10 of 46 patients (21.7%) treated with APVO436 with a cumulative Grade 3/4 cytokine release syndrome incidence of 8.7%. Cytokine profiling in patients who developed cytokine release syndrome after APVO436 infusion indicated that the predominant cytokine in this inflammatory cytokine response was IL-6. The findings from this research provide new insights regarding the biology and effective management of cytokine release syndrome in leukemia patients treated with T-cell redirecting bispecific antibodies. Abstract 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.

This Viewpoint examines pathways that advocates, policy makers, states, and Medicaid agencies can take to identify opportunities for state Medicaid agencies to protect and promote perinatal health.

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

Simple Summary AML is a common form of blood cancer in adults. This study was undertaken to evaluate if AML patients who have failed the available standard treatment options could tolerate and potentially benefit from a new form of therapy. This new therapy activates patients’ own immune system against AML cells. The findings from this research may provide the foundation for a potentially more effective future form of standard therapy that is less likely to fail. Abstract 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.

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.

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.

Purpose To test the hypothesis that combination treatment with lenalidomide and prednisone will yield a higher erythroid response rate in patients with non-del(5q) lower-risk myelodysplastic syndromes compared to the historical clinical trial data with lenalidomide monotherapy, which reported a 26% transfusion independence rate. Patients and Methods The study enrolled 25 patients with lower-risk myelodysplastic syndromes by the International Prognostic Scoring System who were transfusion dependent or who had symptomatic anemia and prior erythroid stimulating agent failure or low chance of response. The planned dose of lenalidomide was 10 mg per day. Prednisone dose was 30 mg by mouth, daily cycle 1 tapered by 10 mg after each cycle to 5 mg by mouth every other day for those with response beyond cycle 6. The primary objective was best response (hematologic improvement–erythroid, HI-E) by International Working Group 2006 criteria within 24 weeks. Results The HI-E rate was 20% (5/25) and was 22% (5/23) for patients with evaluable data. All those with response became red blood cell–transfusion independent (5/23). The median time to response was 57 days. The median duration of response was 80 days (95% confidence interval, 69–91). Three of 5 of those with response did not have prior hypomethylating agent, while 14 of 20 those without response received a hypomethylating agent. Conclusion The combination was relatively well tolerated, with no additional observed toxicity to single-agent lenalidomide.

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.

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.

Mutations in the DNA methyltransferase 3A (DNMT3A) gene are recurrent in de novo acute myeloid leukemia (AML) and are associated with resistance to standard chemotherapy, disease relapse, and poor prognosis, especially in advanced-age patients. Previous gene expression studies in cells with DNMT3A mutations identified deregulation of cell cycle-related signatures implicated in DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here we tested whether pharmacologically-induced replication fork stalling creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations. We observed increased sensitivity to nucleoside analogs such as cytarabine in multiple cellular systems expressing mutant DNMT3A, ectopically or endogenously, in vitro and in vivo. Analysis of DNA damage signaling in response to cytarabine revealed persistent intra-S phase checkpoint activation, accompanied by accumulation of DNA damage in the DNMT3A(R882) overexpressing cells, which was only partially resolved after drug removal and carried through mitosis, resulting in micronucleation. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine wash-out demonstrated that cells with DNMT3A(mut) were able to restart replication but showed a higher rate of fork collapse. Gene expression profiling by RNA-seq identified deregulation of pathways associated with cell cycle progression and p53 activation, as well as metabolism and chromatin. Together, our studies show that cells with DNMT3A mutations have a defect in recovery from replication fork arrest and 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 DNA replication.

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.

HOTTIP lncRNA is highly expressed in acute myeloid leukemia patients carrying MLL rearrangement or NPM1 mutation to facilitate the formation of HOXA topologically associated domains (TADs) and drive aberrant transcription. However, the mechanism through which HOTTIP accesses CTCF chromatin boundaries and regulates CTCF-mediated leukemic genome topology remains unknown. Here, we show that HOTTIP directly interacts and regulates a fraction of CTCF-binding sites (CBSs) including key canonical beta-catenin target loci in the AML genome by forming R-loops that reinforce the CTCF boundary and facilitate formation of TADs to drives gene transcription. Either deleting CBSs or targeting RNaseH to eliminate R-loop in CBSs of beta-catenin TAD resulted in impaired CTCF boundary activity, inhibited promoter/enhancer interactomes, reduced beta-catenin target expression, and mitigated leukemogenesis in PDX mouse models with aberrant HOTTIP expression. Thus, HOTTIP-mediated R-loop formation directly reinforces CTCF chromatin boundary activity and TAD integrity to drive oncogene transcription and pathogenesis of leukemia.

The aim of this study was to establish the therapeutic relevance of the CD33D2 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 CD33FL or CD33D2 isoforms, unmodified acute myeloid leukemia (AML) cell lines and primary AML specimens representing different genotypes for the CD33 splicing single nucleotide polymorphism. CD33D2 was recognized on cells overexpressing CD33D2 and unmodified AML cell lines; however, minimal/no cell surface detection of CD33D2 was observed in primary AML specimens. Both isoforms were detected intracellularly using novel antibodies. Minimal cell surface expression of CD33D2 on primary AML/progenitor cells warrants further studies on anti-CD33D2 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 &ldquo, deKO.&rdquo, Fifty of 94 gene-KOs (53%) had no drug in development and comprised a drug discovery list termed &ldquo, disKO.&rdquo, 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.

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.

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

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.

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.

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.

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%.

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. Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

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 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, 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.

HOX gene dysregulation is a common feature of acute myeloid leukemia (AML). The molecular mechanisms underlying aberrant HOX gene expression and associated AML pathogenesis remain unclear. The nuclear protein CCCTC-binding factor (CTCF), when bound to insulator sequences, constrains temporal HOX gene-expression patterns within confined chromatin domains for normal development. Here, we used targeted pooled CRISPR-Cas9-knockout library screening to interrogate the function of CTCF boundaries in the HOX gene loci. We discovered that the CTCF binding site located between HOXA7 and HOXA9 genes (CBS7/9) is critical for establishing and maintaining aberrant HOXA9-HOXA13 gene expression in AML. Disruption of the CBS7/9 boundary resulted in spreading of repressive H3K27me3 into the posterior active HOXA chromatin domain that subsequently impaired enhancer/promoter chromatin accessibility and disrupted ectopic long-range interactions among the posterior HOXA genes. Consistent with the role of the CBS7/9 boundary in HOXA locus chromatin organization, attenuation of the CBS7/9 boundary function reduced posterior HOXA gene expression and altered myeloid-specific transcriptome profiles important for pathogenesis of myeloid malignancies. Furthermore, heterozygous deletion of the CBS7/9 chromatin boundary in the HOXA locus reduced human leukemic blast burden and enhanced survival of transplanted AML cell xenograft and patient-derived xenograft mouse models. Thus, the CTCF boundary constrains the normal gene-expression program, as well as plays a role in maintaining the oncogenic transcription program for leukemic transformation. The CTCF boundaries may serve as novel therapeutic targets for the treatment of myeloid malignancies.

A precision medicine approach is appealing for use in AML due to ease of access to tumor samples and the significant variability in the patients' response to treatment. Attempts to establish a precision medicine platform for AML, however, have been unsuccessful, at least in part due to the use of small compound panels and having relatively slow turn over rates, which restricts the scope of treatment and delays its onset. For this pilot study, we evaluated a cohort of 12 patients with refractory AML using an ex vivo drug sensitivity testing (DST) platform. Purified AML blasts were screened with a panel of 215 FDA-approved compounds and treatment response was evaluated after 72h of exposure. Drug sensitivity scoring was reported to the treating physician, and patients were then treated with either DST- or non-DST guided therapy. We observed survival benefit of DST-guided therapy as compared to the survival of patients treated according to physician recommendation. Three out of four DST-treated patients displayed treatment response, while all of the non-DST-guided patients progressed during treatment. DST rapidly and effectively provides personalized treatment recommendations for patients with refractory AML.