bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promoting Patient (pt) Adherence (PA) with Imatinib Treatment (IMRx) in Chronic Myeloid Leukemia (CML): Physicians (MD) Perceptions of Utility (Effectiveness [FX], Feasibility [FB], Cost [CO]) and Rankings of Clinical Applicability (CAPL) of 13 Adherence-Enhancing Strategies (AESs) - Results from the ADAGIO Study.
Authors: van Lierde Marie-Anne , Strobbe Eric , De Rop Larissa , Serra Filipo , MacDonald MacDonald , Vancayzeele Stefaan , De Geest Sabina , Letvak Laurie , Albrecht Tara , Abraham Ivo 
Published: October 2019

Abstract
BACKGROUND. Patterns, prevalence, and associated pt variables of CML pts’ nonadherence (PNA) with ImRx are being better understood. Reducing ImRx PNA may impact on treatment outcomes. Various AESs have been proposed but their perceived value and clinical applicability to treating MDs are unknown.
OBJECTIVES. 1. Describe the perceptions of ImRx prescribing MDs of the utility (in terms of FX, FB, CO) of 13 AESs. 2. Describe MD rankings of the applicability in daily practice of each AES.
DESIGN AND SUBJECTS. MD data subset from prospective, 90d observational, open-label, multicenter study [1]. 51 evaluable MDs: age 45.6±11.2 years (ys); ys of practice 17.7±8.1; 74% hematologists, 26% oncologists; 65.3% practicing in university(-affiliated) hospital, 34.7% in other hospitals.
MEASUREMENTS. Utility rated 0=none to 3=high. For applicability to daily practice, MDs were asked to give top 5 AESs (5=most applicable); nonranked AESs were given zero value.
RESULTS. See Table 1.
CONCLUSIONS. MDs tended to rate the utility and applicability of AESs higher if an AES involved active MD participation or decision-making. AESs requiring significant patient involvement, behaviorally or through assistive devices, were perceived as less helpful and applicable in clinical practice. Importantly, the critical role of patient education was recognized, thus challenging clinicians to accept greater responsibility for this AES. Nurses in particular may prove pivotal in patient education. These findings provide significant direction for interdisciplinary healthcare education, especially in terms of chronic illness management. Further research is needed to elucidate the physician-centric approach to adherence enhancement in CML pts on ImRx.
Table 1 - Physician Utility Ratings and Applicability Rankings of Adherence-Enhancing Strategies Utility (0–3) Applicability FX FB CO in Practice (0–5) M±SD M±SD M±SD M±SD Rx selection per pt characteristics 1.9±1.1 1.6±1.1 1.3±1.0 1.0±1.5 Pt education 2.6±0.6 2.1±0.8 1.4±0.8 3.1±1.9 Improved pt-MD communication 2.7±0.5 2.3±0.8 1.3±0.8 2.8±1.7 Simplifying Rx regimen 2.5±0.7 2.3±0.7 1.6±0.9 2.3±1.9 Pt self-monitoring 1.7±0.8 1.5±0.8 1.1±0.9 0.4±1.1 Pt health status diary 1.7±0.8 1.5±0.8 1.0±0.8 0.5±1.3 Memory aids 1.7±0.8 1.9±0.8 1.0±0.8 0.6±1.3 Spouse/family involved 2.2±0.9 2.0±0.9 0.6±0.8 1.3±1.4 Regular MD contact 2.4±0.5 2.2±0.7 1.7±0.8 2.2±1.8 MD monitoring of PA 2.2±0.7 1.8±0.9 1.4±0.8 0.7±1.1 Electronic reminders 1.5±0.9 1.2±0.8 2.3±0.9 0.3±1.1 Electronic Rx monitoring 1.6±0.9 1.3±0.7 2.3±0.9 0.3±1.1 Rewards for good PA 1.4±1.0 1.3±0.8 1.8±0.9 0.5±1.4
Identification and Characterization of a Series of Novel Jak2 Small Molecule Inhibitor Compounds.
Authors: Sayyah Jacqueline , Allen Robert W. , Braylan Raul C. , Keseru Gyorgy M. , Sayeski Peter P. 
Published: October 2019

Abstract
Recent work from our lab has been aimed at identifying novel Jak2 tyrosine kinase inhibitor molecules. Here, we refined our previous Jak2 molecular model using information obtained from the crystal structures of the Jak2 and Jak3 kinase domains. A total of 223,481 compounds within the NIH small molecule database were then screened in silico using FlexX 1.13.2 in order to identify compounds that specifically bind and inhibit Jak2. In what is now our third generation of Jak2 inhibitors, analysis of the highest scoring compounds identified a set of structurally diverse molecules that potently inhibited Jak2 autophosphorylation not only at Tyr 1007, but at all 49 tyrosine residues. These compounds significantly inhibited proliferation of the human erythroleukemia (HEL) cells, which express the Jak2-V617F mutation on both alleles (Fig. 1). One compound in particular, herein designated as G6, was further examined in greater detail. The mechanism by which G6 inhibits Jak2-V617F dependent cell growth is via a marked increase in cellular apoptosis (Fig. 2). We found that G6 does not inhibit c-Src and Tyk2 autophosphorylation at doses that completely inhibit Jak2, therefore suggesting a high degree of specificity. We found that both the G6 and the G13 compounds significantly reduced ex vivo megakaryocyte colony formation of cells taken from a patient diagnosed with essential thrombocythemia and harboring the Jak2-V617F mutation. Finally, we examined the ability of G6 to inhibit red blood cell formation in C57BL/6 mice following acute hemolytic anemia. We found that treatment of animals with G6 (10 mg/kg/day for five days, IP) resulted in a marked inability of these animals to increase their hematocrits following acute anemia when compared to vehicle control animals. Additionally, histological analysis of the bone marrow of G6 injected animals exhibited erythroid hypoplasia resulting in a skewed M:E ratio when compared to vehicle control animals. Collectively, our data demonstrate that these small molecule compounds inhibit Jak2 function in vitro, ex vivo, and in vivo. As such, they may have therapeutic value in treating diseases that are caused by aberrant Jak2 kinase function.
Figure 1 Figure 1. Figure 2 Figure 2.
A Novel Assay for Juvenile Myelomonocytic Leukemia Based on Aberrant Signaling Networks Measured Via Phospho-Specific Flow Cytometry Reduces Diagnosis Time from Weeks to Days.
Authors: Kotecha Nikesh , Flores Nikki J. , Irish Jonathan M. , Sakaguchi Debbie , Archambeault Sophie , Diaz-Flores Ernesto , Coram Marc , Shannon Kevin M. , Nolan Garry P. , Loh Mignon L. 
Published: October 2019

Abstract
Juvenile myelomonocytic leukemia (JMML) is an aggressive clonal malignancy characterized by over-production of myeloid lineage cells that infiltrate hematopoietic and non-hematopoietic tissues. The diagnosis and treatment of JMML can present great challenges for clinicians. Infants or young children are suspected of having this disease when presenting with hepatosplenomegaly and a peripheral blood monocytosis - criteria that are often present in more prevalent but potentially less lethal conditions such as viral infections. The diagnostic workup includes several clinical tests as well as the confirmation of abnormal numbers of granulocyte-macrophage colony forming units (CFU-GM) grown in low concentrations of granulocyte-macrophage colony stimulating factor (GM-CSF). The colony assays are laborious and can take up to 4–6 weeks for results. Using phospho-specific flow cytometry, a technique that allows simultaneous single cell measurements of cell type and signal, we have developed an assay that shows a specific cell signature in JMML patients that can reduce diagnosis time from weeks to days. The assay combines traditional surface marker phenotyping with signaling responses in low doses of GM-CSF to identify a population of CD38 intermediate cells that hyper-phosphorylate Stat 5 (pStat5). We applied this assay to primary cells obtained from 10 JMML patients and demonstrate that the cell signature is specific to JMML with respect to a wide panel of other diagnoses. For comparison purposes, we developed a statistical measure to summarize the signature and monitor its expression across varying doses of GM-CSF. The measure also ensures consistency by eliminating the need for additional manual data processing steps (e.g. gating) prior to comparison—an important step towards developing a diagnostic tool. In addition, this characteristic phospho-specific flow signature disappeared in patient samples in remission and reappeared at relapse—indicating that the signature may indeed be representative of the malignant population in JMML. Further characterization of these cells is ongoing. We conclude that phospho-specific flow cytometry is a robust methodology that can be used in primary human cells as a method to rapidly diagnosis JMML as well as to follow patients on therapy. Importantly, it is a powerful technical tool that will allow improved understanding of the complex signaling pathways that are perturbed in cancer cells.
Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia Vera.
Authors: Wernig Gerlinde , Kharas Michael G. , Okabe Rachel , Moore Sandra A. , Leeman Dena S. , Cullen Dana E. , Gozo Maricel , McDowell Elizabeth P. , Levine Ross L. , Doukas John , Mak Chi Ching , Noronha Glenn , Martin Michael , Ko Yon D. , Lee Benjamin H. , Soll Richard , Tefferi Ayalew , Hood John D. , Gilliland D. Gary 
Published: October 2019

Abstract
The JAK2V617F mutation is present in the majority of cases of myeloproliferative disease, including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), and is an attractive candidate for molecularly targeted therapy. However, the potential toxicities of JAK2 inhibition in vivo, and identification of appropriate surrogate endpoints for response, are challenges that may limit clinical usefulness in treatment of these relatively indolent diseases. We report efficacy and assessment of surrogate endpoints for response of a small molecule JAK2 inhibitor, TG101348 in a murine model of polycythemia vera. TG101348 is selective for JAK2 with an in vitro IC50 of ∼3 nM that is ∼334 fold more potent than for inhibition of JAK3. TG101348 showed therapeutic efficacy in the murine model of PV that included a statistically significant reduction in hematocrit, normalization of white blood cell count, a dose dependent reduction/elimination of extramedullary hematopoiesis in the spleen and liver, and marked attenuation of myelofibrosis. Consistent with its selective inhibition of JAK2 and not JAK3, there was no significant change in T-cell number in treated animals. These clinical responses correlated with surrogate endpoints for response, including reduction or elimination of JAK2V617F expressing clones based on quantitative genomic PCR, suppression of JAK2V617F positive endogenous erythroid colony growth of JAK2V617F MPD bone marrow, and inhibition of JAK-STAT signal transduction as assessed by phosphoflow cytometry for phosphorylated STAT5. Thus, TG101348 is efficacious in treatment of a murine model of PV, and surrogate endpoints have been identified that may be of value in clinical trials in humans.
Imatinib Mesylate Has a Stage-Specific Inhibitory Role in Generation of CD26highCD8+ Central Memory T Cells in Vitro and in Vivo.
Authors: Yokoyama Kazuaki , Nagamura-Inoue Tokiko , Nakayama Shin , Ishige Ikuo , Ogami Kazuo , Futami Munenori , Kobayashi Seiichirou , Tojo Arinobu 
Published: October 2019

Abstract
CD26 is a transmembrane glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) activity as well as costimulatory activity of mitotic signals triggered by the CD3/TCR complex. Based on the expression level of CD26, CD4+ and CD8+ T cells can be divided into 3 (high/intermediate/low or negative) subsets. The significance of CD26 has been studied mainly on CD4+ T cells, and CD26highCD4+ T cells are considered to represent effector memory T cells of a typical Th1 phenotype producing IL2 and IFNg. Furthermore, we reported a significant decrease of this subset in CML patients under imatinib therapy in comparison to those under IFNa therapy and normal volunteers. In contrast, the role of each subset of CD8+ T cells has not yet been clarified.
Multi-parameter flow cytometry analysis was performed to characterize CD8+ T cells differentially expressing CD26 in combination with intracellular detection of effector molecules such as perforin (P) and granzyme B (Gr). The capacity to secrete effector cytokines such as IFNg following short-term stimulation was also assessed. As a result, according to the expression level of CD26, we could clearly categorize CD8+ T cells as follows: CD26highCD8+ T cells are defined as central memory T cells which has a phenotype of CD45RO+CD28+CD27+ IFNg+Gr−P+/−, CD26intCD8+ T cells as naïve T cells of CD45ROCD28+ CD27+ IFNg−Gr−P−, and CD26lowCD8+ T cells as effector memory/effector T cells of CD45RO−/+ CD28−CD27−IFNg++Gr++P++, respectively. We next investigated the effects of imatinib on 3 distinct subsets during CD8+ T cell differentiation program. Peripheral blood mononuclear cells were primed with anti-CD3/CD28 MAb and subjected to the grading doses of imatinib for short term culture, followed by flow cytometory. CFSE labeling was used for monitoring cell proliferation. Intriguingly, we found that imatinib dose-dependently inhibits activation, cytokine production and proliferation of CD26highCD8+ central memory T cell subsets in a differentiation stage-specific manner. Finally, we compared the absolute number of peripheral blood CD26highCD8+ T cell subsets between 20 patients with CML in imatinib-induced CCR and 20 normal volunteers, clearly indicating a significant decrease of this subset in CML patients (22.30/ml vs 45.60/ml, p<0.01).
The present study offers another evidence for immunomodulatory effects of imatinib or the critical role of Abl (-related) kinase in T cell development, and draws special attention to susceptibility to viral infection of CML patients under long-term imatinib therapy.
Figure Figure
Leukemia Relapse after Allogeneic Transplants in AML: Predictive Role of WT1 Expression and Protective Effect of DLI.
Authors: Bacigalupo Andrea , Dominietto A. , Di Grazia C. , Pozzi S. , Bertolotti F. , Podesta’ M. , Lamparelli T. , Gualandi F. , Ibatici I. , Bregante S. , Pinto V. , Frassoni F. 
Published: October 2019

Abstract
Background: relapse remains a significant problem in patients with acute leukemia undergoing an allogeneic hemopoietic transplant (HSCT) and a predictive molecular marker of disease would be useful.
Aim of the study. Assess the role of WT1 expression in AML patients undergoing an allogeneic HSCT, to
predict relapse and drive immune intervention
Methods. We studied 81 patients with AML who received an allogeneic HSCT between 30/1/04 and 11/2/08 in our Unit: 52 patients were in first remission, and 29 patients had more advanced disease. Median age 45 (16–66), prepared with CY-TBI (n=52) or RIC regimen (n=29). WT1 mRNA levels of expression were normalized with respect to the number of ABL transcripts and expressed as WT1 copy numbers every 104 copies of ABL. Patients bone marrow cells were monitored for WT1 expression, and cytology, pretransplant, at day +30 and every month untill day +180, then at scheduled follow up. Patients were considered WT1 positive, when WT1 copy numbers were greater than 180. Escalating doses of donor lymphocyte infusions (DLI) were given, when possible, in WT1+ patients.
WT1 pre-transplant. WT1 pre-HSCT was available in 63 patients, 39 were WT1- and 24 WT1+: their relapse risk was 10% vs 62% (p=0.00002) and their crude survival 79% vs 29% (p=0.0001). When CR1 patients were selected, relapse was 10% vs 50% for WT1- vs WT1+ patients (p=0.02), and survival 81% vs 50% (p=0.9).
WT1 post-transplant. Fifty patients were always WT1- after HSCT, and 31 were found WT1+ at a median interval from HSCT of 80 days (range 24–696): relapse was 8% vs 68% for WT1- vs WT1+ patients (p=<0.0001), and survival 78% vs 26% (p=0.0001).
Cox analysis: in multivariate analysis on relapse WT1 pre-transplant (p<0.0001) and post-transplant (p<0.0001) were independent predictors, whereas disease phase (CR 1/>1) was not (p=0.39). Survival was predicted by all 3 variables, WT1+ pre (p=0.001), WT1+ post (p=0.03) and phase of disease (p=0.002).
Immune intervention. Of the 31 WT1+ patients, 13 had BM blasts on cytology (6– 80%) at the time of first WT1 positivity, and were treated with chemotherapy. 18 patients were WT1+ and had marrow in CR on cytology: 9 of these received DLI and 9 did not; hematologic relapses were seen in 2/9 and 7/9 respectively (p=0.02) and crude survival is 6/9 vs 2/9 (p=0.07). The median interval between WT1+ and relapse was 96 days (39– 246).
Conclusions. This study suggests that WT1 positivity before and after HSCT are independent predictors of relapse and survival in patients with AML. WT1 expression predicts relapse better than disease phase. The interval between WT1 positivity and relapse is approximately 3 months: the use of DLI in this time interval appears to protect against hematologic relapse.
Late Mortality and Relapse Following HLA-Identical Sibling Donor Marrow Transplantation for Chronic Myeloid Leukemia.
Authors: Copelan Edward , Crilley Pamela , Szer Jeffrey , Dodds Anthony J. , Stevenson Dustin E. , Phillips Gary , Elder Patrick , Nivison-Smith Ian , Avalos Belinda , Penza Sam , Topolsky David , Sobecks R. , Kalaycio Matt , Bolwell Brian J. 
Published: October 2019

Abstract
We studied the incidence and reasons for late failure following allogeneic transplantation for chronic myeloid leukemia (CML). Three-hundred thirty-five adult patients (median age 37, 229 chronic, 62 accelerated, 44 blastic phase) who underwent allogeneic marrow transplantation from HLA identical siblings at 7 institutions from 1984 – 1995 following preparation with busulfan and cyclophosphamide (BuCy2), the most commonly used regimen in this circumstance. Cyclosporine or tacrolimus-based regimens were used to prevent graft-versus-host-disease (GVHD). Median follow-up of surviving patients exceeded 14 years. Of 182 patients alive and free of leukemia at 3 years, 77.0% (95% CI: 65 to 83.6%) survive at 18 years and 61.9% (95% CI: 52.1 – 70.3%) survive without relapse. Twenty-seven (42.2%) of the 64 total relapses occurred beyond 3 years. Death occurred less frequently (P<.001) and the interval from relapse to death was longer (P=.01) in patients who relapsed late compared to those who relapsed early. The hazard rate for relapse fell rapidly from year 1 through 5, then remained low but constant through year 15. The cumulative incidence of late (beyond 3 years) relapse for patients alive and free of disease at 3 years was 22.8%.. The cumulative incidence of non-relapse mortality was 18.1% for those alive and leukemia-free at 3 years and in the 36 patients who died beyond 3 years, the primary cause of death was chronic GVHD in 11, relapse in 7, new malignancy in 6, organ failure in 6 (pulmonary in 4) and infection in 2. Multivariate analysis demonstrated that advanced disease stage (HR 2.75, P=.001) and older age (HR 1.39, P = .032) were associated with diminished LFS of patients alive and free of disease at 3 years. Overall survival was also adversely influenced by older age (HR 3.86, P < .001) and advanced stage (HR 1.54, P=.024). Advanced disease phase was associated with a higher incidence of late relapse (HR ≥ 2.50, P=.039) and late NRM (HR 3.18, P=.008). Acute GVHD and short interval from diagnosis to transplant influenced early, but not late failure. Chronic GVHD was associated with lower incidence of late relapse (HR=.30, P=.002) but did not significantly influence survival or LFS. Overall, nearly 2 of every 5 patients alive and free of leukemia at 3 years died or relapsed over the subsequent 15 years. No plateau in LFS was seen.
Figure Figure
Genetic Variations in CYP2B6 and Risk of Cyclophosphamide Toxicity in Patients Undergoing Myeloablative Stem Cell Transplantation.
Authors: Melanson Stacy E , Antin Joseph H. , Court Michael H. , Ho Vincent , Ritz Jerome , Kim Haesook T. , Kuo Frank C , Longtine Janina A , Jarolim Petr 
Published: October 2019

Abstract
In myeloablative stem cell transplantation (SCT), most patients receive cyclophosphamide (CPA) conditioning based on body weight or body surface area, under the assumption that each individual will metabolize the drug with the same efficiency. However, CPA requires biological activation, primarily by cytochrome P450 2B6 (CYP2B6), to exert its effects; therefore, patients with increased protein activity, as reported for *4 and *6 allelic variants, may have an increased risk for CPA-associated toxicity compared to patients with decreased protein activity, as reported for *5 and *7 allelic variants. In this study, we determine the relationship between allelic variants of CYP2B6 and toxicity outcomes and attempt to clarify the influence of CYP2B6 on the development of severe cardiac toxicity, veno-occlusive disease (VOD), and idiopathic pneumonia syndrome (IPS) early after SCT. A total of 259 DNA samples were obtained from patients who received 3.6 g/m2 or 120 mg/kg of CPA as part of a myeloablative allogeneic SCT between 2002 and 2006. Genotyping was performed using pyrosequencing to detect three SNPs, 516A>G, 785A>G and 1459C>T, associated with four allelic variants: *4 (785A>G), *5 (1459C>T), *6 (785A>G, 516G>T) and *7 (785A>G, 516G>T, 1459C>T). The patients’ clinical history was reviewed and any instance of hepatic VOD, severe cardiac toxicity (i.e. myopericarditis ≥ grade 3) or IPS from 0 to 100 days post-transplant was recorded. Overall, 60 (24%) patients experienced toxicity (cardiac = 20; VOD = 26; IPS = 14). The prevalence of the *4, *5, *6 and *7 alleles was 3%, 8%, 23% and 2%; respectively. Patients heterozygous for *4, *5, *6 and *7 allelic variants and homozygous for the *6 allelic variant had similar rates of toxicity to those patients without allelic variants of CYP2B6, even when comparing each toxicity separately (Table 1). However, patients with decreased protein activity, *1/*5 and *1/*7, had a lower rate of toxicity compared to those with wild-type or increased protein activity, *1/*1, *1/*4, *1/*6 and *6/*6 (14.6% (7/48) vs. 26.1% (53/203)). In conclusion, variant alleles of CYP2B6 may predict a decreased risk of VOD, IPS, or cardiac toxicity within the first 100 days of SCT, but do not appear to predict an increased risk of toxicity.
Table 1. Association of toxicities with genotypes
Genotype Patients All Toxicities Cardiac Grade ≥3 VOD IPS *One patient had both cardiac and VOD toxicity * 1/*1 97 27 (28%) 7 (7%) 12 (12%) 8 (8%) * 1/*4 8 3 (38%) 0 (0%) 2 (25%) 1 (13%) * 1/*5 38 5 (14%) 2 (6%) 1 (3%) 1 (3%) * 1/*6 80 18 (23%) 7 (9%) 8 (10%) 3 (4%) * 1/*7 10 2 (20%) 1 (10%) 1 (10%) 0 (0%) * 6/*6 18 5 (28%)* 3 (17%) 2 (11%) 1 (6%)