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Background: Hyperglycemia and increased glycemic variability are associated with infection and increased mortality. We evaluated the relationship between glycemic control during ...AML induction and outcomes by age. Methods: We retrospectively evaluated outcomes in 262 consecutive patients (pts) with newly diagnosed AML hospitalized for intensive induction at Wake Forest Baptist Hospital (2002-2009). Data on mean blood glucose (BG) (mg/dL) during hospitalization and standard deviation (SD) of BG (measure of glycemic variability, GV), complete remission ± incomplete count recovery (CR+CRi), and overall survival (OS) were collected. Modified Charlson Comorbidity Index (CCI), diabetes, age, gender, race, cytogenetics, hemoglobin, WBC, LDH, body mass index, and insurance were used in uni- and multi-variate models. We used logistic regression to evaluate CR+CRi, and Cox proportional hazard models for OS, stratified by age ( < 60 vs ≥60 yrs). Results: 124 pts were < 60 (median age 47, median OS 23.1 months), 138 were ≥60 yrs (median age 70, median OS 7.9 months). Older pts had higher baseline comorbidity (CCI > 1 60.1% vs 25.8%) and a higher prevalence of diabetes (20.3% vs 7.3%). The mean ±SD number of BG values obtained per patient during hospitalization was 61±71. The mean ±SD of each individuals mean BG during hospitalization was 111.6±16.4 in younger versus 121.7±25.9 older pts. The mean SD of BG values GV was 26.8±18.6 in younger versus 33±22.8 in older pts. In multivariable analysis higher mean BG was associated with lower odds of CR+CRi in younger (odds ratio (OR) 0.67, 95% CI 0.48-0.93) and older pts (OR 0.78, 95% CI 0.65-0.93) per 10 mg/dL BG increase. Higher mean BG was associated with shorter OS in older adults (HR 1.12, 95% CI 1.04-1.21). Higher GV was associated with lower odds of CR+CRi in younger (OR 0.73, 95% CI 0.56-0.96) and older (OR 0.71, 95% CI 0.57-0.88), as well as shorter OS in older pts (HR 1.17, 95% CI 1.08-1.26) for each 10 mg/dL SD increase in GV. Conclusions: Hyperglycemia and GV during intensive induction are associated with lower CR+CRi rates (all ages) and shorter OS among older adults.Glycemic control during induction may be a modifiable factor to improve AML outcomes.
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Background: Cardiovascular health (CVH) is of increasing concern to cancer survivors and their healthcare providers, since survivors of many early-stage cancers are more likely to ...die of cardiovascular disease than cancer. Our team adapted an existing EHR-based CVH data visualization application designed for the primary care setting to be used in the community oncology setting. We evaluated the acceptability of the Automated Heart-Health Application (AH-HA) among oncology providers and cancer survivors. Methods: We queried oncologists, physician assistants, and nurse practitioners (n=20) who provide care to survivors regarding their perceived usability of AH-HA. Oncologists’ responses were assessed on a 7-point Likert scale from strongly disagree (1) to strongly agree (7); we categorized responses of 5-7 as “agreeing”. We additionally asked cancer survivors (N=48) for their opinions of AH-HA. Patients’ responses were assessed on a 5-point Likert scale from strongly disagree (1) to strongly agree (5); responses of 4 or 5 were categorized as “agreeing”. Results: The majority (60%) of oncology providers (60% female, 65% medical oncologists) had been practicing for more than 5 years. Breast cancer survivors comprised the majority of the survivor sample (98%). Usability data are presented below. 85% of providers reported they would use the tool most or all of the time when providing survivorship care. 94% of patients thought oncologists should discuss heart health during survivorship care; 69% would like to use AH-HA with their oncologist. Conclusions: These usability data demonstrate acceptability and feasibility of implementing the AH-HA application in oncology practices and suggest that oncology providers and survivors would value the integration of such applications in survivorship care. Table: see text
ALCAM/CD166 is expressed from the onset of hematopoiesis in the yolk sac and in a variety of hematopoietic tissues throughout ontogeny. Both hematopoietic and stromal cells in the AGM region, fetal ...liver, and fetal and adult marrow express this molecule. CD166 double knockout mice are viable and fertile, without any major blood defects, but their microenvironment and hematopoietic stem cells (HSC) exhibit deficiencies in their ability to support and engraft long-term, respectively. In order to further study the role of CD166 in hematopoiesis, we characterized, during ontogeny, the origin, function, and sub-populations of CD166+ cells in different hematopoietic organs. To this end, we used flow cytometry, confocal microscopy, and colony-forming assays to analyze human fetal liver (FL) at 18 and 20 gestational weeks (gw), bone marrow (BM) from 10 to 20gw, and adult BM. Flow cytometric analysis of FL at 18 and 20gw demonstrated that although 3±1% of liver cells at this age were CD166+, less than 1% were endothelial CD166+CD34+ cells, and no hematopoietic CD166+CD34+CD45+ cells were detected. In fetal BM, CD166+ cells emerged after 15gw, expressed Flk-1 and CD34, and their percentage increased progressively with gestational age. Flow cytometric analysis at 20gw showed that 1.5±1% of cells were CD166+CD34+, of which 93±0.5% were CD45+. Human adult BM contained 2±0.5% of CD166+CD34+ cells, of which only 66±0.6% were CD45+. In order to functionally characterize CD166+CD34+ cells from adult and fetal BM (20gw), we plated these cells in mesenchymal cell growth medium (MSCGM), endothelial growth medium (EGM-2), and complete methylcellulose (MC). MSCGM and EGM-2 did not support growth and expansion of fetal or adult CD166+CD34+ cells. Quantification of the hematopoietic colony-forming potential of these cells demonstrated that fetal CD166+CD34+ generated/1000 cells: 8±1 Blast; 27±2 CFU-Mix; 51±10 CFU-GM; and 0 BFU-E, while adult CD166+CD34+ gave rise to 7 Blast; 17 CFU-Mix; 36 CFU-GM; and 10 BFU, demonstrating differences in the hematopoietic potential of these cells. Furthermore, at day 12 of MC culture, adherent stromal cells were detected underneath MC, but only in cultures from fetal BM. Characterization of these cells by flow cytometry showed that more than 90±2% of these cells were CD166+CD9+, and 30±5% were CD146+. Furthermore, these stromal CD166+ cells did not express CD34, CD45, CD31, CD209, or CD6. Immunostaining demonstrated that the CD166+CD146+ cells expressed osteopontin and Stro-1. A CD41+CD68+ population of cells was also found.
In conclusion, we found that, during ontogeny, expression of CD166 in FL is not associated with hematopoietic cells. In the BM, expression of CD166 is associated with CD34 and Flk2, and its expression on HSC commences later in gestation, suggesting that these cells either arise in the BM, or that CD166 expression is triggered at a certain time point in gestation, probably associated with rapid proliferation of HSC during this time period. Furthermore, we demonstrated that CD34+CD166+ cells from 20gw fetal BM contain hematopoietic and stromal cell populations, while adult BM-derived CD34+ CD166+ cells are exclusively hematopoietic.
No relevant conflicts of interest to declare.
During ontogeny, definitive hematopoietic stem/progenitor cells (HSC) are thought to arise from vascular endothelial cells, through an endothelial-to-hematopoietic transition, a natural process that ...occurs in unique, specialized embryonic hemogenic endothelial cells. Developmental studies, and experiments using pluripotent stem cells in an effort to recapitulate this process and thereby gain a better understanding of the emergence of definitive hematopoiesis, have collectively led to the prevailing view that the hemogenic endothelium constitutes a transient population of cells within the embryo that rapidly disappears during development and is absent in the adult. Herein, we provide the first evidence that at early time points of gestation, prior to the establishment of hematopoiesis, a unique subpopulation of Stro-1+ cells present within the inner part of the developing human bone marrow co-expresses APLNR, a marker of angiogenic mesoderm. Moreover, these Stro-1+APLNR+ cells express multiple other markers described for hemogenic endothelium, and subsequently contribute to the vasculature, cartilage, and bone. Importantly, we also show that cells expressing these same markers of primitive mesoderm/hemogenic endothelium persist at low frequency within the adult marrow. These adult-derived cells can be extensively expanded in vitro without loss of potential, but lack hematopoietic colony-forming potential in vitro. However, upon transplantation into a fetal microenvironment, clonally-derived populations of these adult Stro1+ isolated stromal progenitors (SIPs) not only contribute to the vasculature and nascent BM niches, but also efficiently generate, at a clonal level, hematopoietic stem cells (HSC) that are capable of robust, multilineage hematopoietic reconstitution, with generation of both myeloid and lymphoid cells upon serial transplantation. In conclusion, our studies have thus uncovered the latent potential of a highly expandable population of seemingly vestigial adult human somatic cells, whose ontogenic history includes a phenotype identical to that described for hemogenic endothelium. We have also shown that, if provided with the appropriate/necessary inductive factors, these unique adult cells are capable of giving rise to hematopoietic cells that fulfill the gold standard criteria for bona fide HSC. Therefore, these cells could potentially be more amenable to reprogramming technologies, to produce HSC that could be used to treat/cure a broad variety of blood diseases.
No relevant conflicts of interest to declare.
This study sought to determine the prevalence of American Heart Association/American College of Cardiology Foundation (AHA/ACCF) heart failure (HF) stages after potentially cardiotoxic chemotherapy ...was initiated.
For individuals receiving potentially cardiotoxic chemotherapy, the frequency of transitioning from Stage A to more advanced HF stages is not well described.
In 143 Stage A HF patients with breast cancer, lymphoma and leukemia, renal cell carcinoma, or sarcoma prior to and then at 3, 6, and 12 to 24 months after potentially cardiotoxic chemotherapy was initiated, we obtained blinded cardiac magnetic resonance measurements of left ventricular ejection fraction (LVEF).
Three months after potentially cardiotoxic chemotherapy was initiated, 18.9% of patients transitioned from Stage A to Stage B HF. A total of 83% and 80% of patients with Stage A HF at 3 months, respectively, exhibited Stage A HF at 6 and 12 to 24 months; 68% and 56% of those with Stage B HF at 3 months, respectively, exhibited Stage B HF at 6 and 12 to 24 months (p < 0.0001 and p = 0.026, respectively).
Transitioning from Stage A to Stage B or remaining in Stage A HF 3 months after potentially cardiotoxic chemotherapy was initiated relates to longer-term (6 to 24 months post-treatment) assessments of HF stage.
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Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis ...fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p<0.0001). The most common treatment-emergent adverse events (TEAEs) of any cause or grade reported in patients randomized to moga were: infusion-related reaction (33.2%), drug eruption (ie, skin rash attributed to moga 23.9%), diarrhea (23.4%), and fatigue (23.4%). This report provides the final safety results of MAVORIC as of the data available on January 3, 2019.
Methods: Patients were randomized 1:1 to moga 1.0 mg/kg administered intravenously on Days 1, 8, 15, and 22 of the first cycle and on Days 1 and 15 of subsequent cycles or vori 400 mg administered orally once daily. Patients randomized to vori were allowed to cross over to moga upon progression or intolerable toxicity. Safety was assessed by reported adverse events (AEs), changes in physical examinations, vital sign measurements, electrocardiograms, and laboratory analyses.
Results: In total, 372 patients were randomized (moga, 186; vori, 186), of whom 370 received study drug and were included in the safety analysis (moga, 184; vori, 186). For the final safety analysis, median duration of follow-up was 34.5 months (range, 0.13-70.0) in the randomized part of the study. Median treatment exposure was 170 days (range, 1-1813) for moga and 84 days (4-1230) for vori, which represent the same median values but broader ranges compared to the primary analysis (primary analysis, 170 days 1-1379 for moga and 84 days 4-1058 for vori). The type and frequency of AEs in either the moga or vori treatment groups (Table) were consistent with those reported in the primary analysis. TEAEs, regardless of causality, that were reported at similar rates in the two treatment groups included constipation, peripheral edema, headache, and anemia. TEAEs (all causality) that occurred at higher frequency in the moga vs vori arm included infusion-related reaction (33.2% vs 0.5%) and drug eruption (25.0% vs 1.1%); the majority of these events were grade 1 or 2 (Table). The types and frequencies of AEs attributable to moga (per Investigator assessment) included infusion-related reaction (33.2% 61/184), drug eruption (23.9% 44/184), and fatigue (18.5% 34/184), and for vori, diarrhea (55.4% 103/186), nausea (38.2% 71/186), and fatigue (33.3% 62/186).
In patients who crossed over from the vori to moga arm and received study drug (n=135), the most frequently reported AEs attributable to moga were infusion-related reaction (37.8% 51/135), drug eruption (24.4% 33/135), fatigue (7.4% 10/135), increased alanine aminotransferase (7.4% 10/135), and increased aspartate aminotransferase (7.4% 10/135). Discontinuation rates due to AEs were similar between treatment arms and in crossover patients (moga, 21.7% 40/184; vori, 23.7% 44/186; crossover, 25.9% 35/135). The most common AEs leading to discontinuation were drug eruption in the moga arm (7.1% 13/184) and fatigue in the vori arm (4.3% 8/186). Overall, the rates of drug-related serious TEAEs were similar between treatment arms and in crossover patients (moga, 19.6% 36/184; vori, 16.7% 31/186; crossover, 11.9% 16/135). After the data cutoff for the primary analysis, 1 additional patient randomized to moga (decreased appetite, general physical health deterioration, hypoalbuminemia) and 1 crossover patient (cerebral hemorrhage) experienced TEAEs with an outcome of death, all considered unrelated to study treatment per Investigator.
Conclusions: This final safety analysis from the MAVORIC study in patients with previously treated MF and SS demonstrates that moga was generally well tolerated. Longer follow-up and treatment exposure did not identify any new safety signals. The type and incidence of treatment-related AEs among patients receiving moga after crossover were similar to those observed for patients initially randomized to moga.
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Kim:Merck: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Neumedicine: Research Funding; miRagen: Research Funding. Bagot:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Duvic:Seattle Genetics: Consultancy, Honoraria, Research Funding; Eisai: Research Funding; Shape: Research Funding; UT MD Anderson Cancer Center: Employment; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Spatz Foundation: Research Funding; Tetralogic: Research Funding; Millennium (formerly Takeda): Research Funding; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; PleXus Communications: Speakers Bureau; Guidepoint Global: Consultancy; Evidera, Inc.: Consultancy; Cell Medica Inc.: Consultancy; Allos: Research Funding; Rhizen Pharma: Research Funding; Oncoceuticals: Research Funding; Soligenetics: Research Funding; Cell Medica Ltd.: Honoraria; Therakos: Speakers Bureau; Jonathan Wood & Assoc.: Speakers Bureau; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau. Morris:Guys Hospital: Employment. Kim:Medimmune: Research Funding; Soligenix: Research Funding; Kyowa Kirin: Research Funding; Galderma: Consultancy, Research Funding; Actelion: Consultancy, Research Funding. Musiek:Menlo: Other: Investigator; Helsinn: Membership on an entity's Board of Directors or advisory committees; Soligenix: Other: Investigator; Pfizer: Other: Investigator; Elorac: Other: Investigator; Kyowa: Honoraria, Other: Above honoraria: for Ad Board; miRagen: Other: Investigator. Ortiz-Romero:Actelion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; PLCG1: Patents & Royalties; miRagen: Membership on an entity's Board of Directors or advisory committees; MEDA: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; 4SC: Membership on an entity's Board of Directors or advisory committees. Eradat:Kyowa: Research Funding; Kite: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Research Funding. Magnolo:University Hospital of Muenster, Center of Innovative Dermatology: Employment. Scarisbrick:Kyowa Kirin: Consultancy, Membership on an
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