bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low Efficacy of Thalidomide in Improving Response after Induction in Myeloma Patients Candidate to High-Dose Therapy.
Authors: Corso Alessandro , Mangiacavalli Silvia , Barbarano Luciana , Zappasodi Patrizia , Banfi Luciano , Montalbetti Luigi , Mazzone Antonio , Fava Sergio , Frigerio Guido , Isa Luciano , Montanara Sergio , Perego Daniele , Savarè Maria , Uziel Lilj , Vismara Alessandro , Campiotti Leonardo , Fiumanò Mario , Lazzarino Mario , Morra Enrica 
Published: October 2019

Abstract
Background: In multiple myeloma (MM) patients (pts) undergone high dose therapy, the outcome of the transplant is better if a good response is achieved before the procedure. Therefore, different attempts have been made in intensifying pre-transplant chemotherapy to improve the response. Aim of the study was to evaluate the safety and efficacy of Thal-Dex in improving the response rate after initial VAD therapy.
Methods: 61 untreated MM pts aged ≤65 years were addressed to high dose program with a debulking therapy with 3 pulse-VAD cycles followed by Thal-Dex for 3 months at the following schedule: Thal 100 mg/d orally at bed time, continuously for 3 months, Dex 20 mg/d orally on days 1–4 and 14–17 every 28 days. Response at the end of each phase was defined as follows: complete remission (CR), disappearance of serum and urine monoclonal component (MC) by immunofixation and bone marrow plasmocytosis (BMPC) <5%; very good partial remission (VGPR)/partial remission (PR)/minimal response (MR)/stable disease (SD), reduction of at least 90%/50%/25%/<25% of serum and urine MC, and of BMPC; progression, increase of serum and urine MC or BMPC. Toxicity was registered according to WHO classification.
Results: Responses after VAD were evaluable in 60 pts: RC 7%, VGPR 38%, PR 27%, MR 10%, SD 10%, progression 8%. Four pts dropped out after pulse-VAD for progression and in 1 for toxicity. Responses after Thal-Dex in 52 evaluable pts were: RC 12%, VGPR 40%, PR 17%, MR 4%, SD 4%, Progression 23%. Three pts dropped-out during Thal-Dex, 1 for progression and 2 for toxicity. Of note, pts who obtained a scarce response to VAD, namely a MR or SD, showed a higher probability (85% of cases) to have a progression during or after the administration of Thal-Dex. Statistical analysis (Kendall Concordance Coefficient (p<0.0001); and non parametric Wilcoxon matched pairs test (p=0.12)) did not show any improvement of the response rate after Thal-Dex with respect to the evaluation after pulse-VAD cycles.The pulse-VAD related toxicity was as follows: 1 died for sepsis after the first pulse-VAD, 5 developed grade 2 WHO infections, 4 developed mild constipation. Side effects during Thal-Dex therapy were: grade 1–2 peripheral neuropathy in 7 pts, grade 1 constipation in 6 pts; 4 pts developed thrombotic events (TVP in 3, and a bowel infarction with subsequent colectomy in one).
Conclusions: The combination thalidomide-dexamethasone after pulse-VAD is not effective in improving response rate, and shows an additional toxicity. Thus it does not seem useful for the intensification before transplant.
Essential Thrombocythemia in Young Individuals: Frequency and Risk Factors for Vascular Events and Evolution to Myelofibrosis in 126 Patients.
Authors: Alvarez-Larran Alberto , Cervantes Francisco , Bellosillo Beatriz , Giralt Manuel , Julia Antoni , Hernandez-Boluda Juan Carlos , Hernandez-Nieto Luis , Clapes Victoria , Burgaleta Carmen , Bosch Alba , Salvador Carlos , Arellano-Rodrigo Eduardo , Colomer Dolors , Besses Carlos 
Published: October 2019

Abstract
Vascular events and evolution to either myelofibrosis (MF) and acute leukemia (AL) are the main causes of morbidity and mortality in individuals with essential thrombocythemia (ET). However, the frequency of these complications in young ET patients is not well known. The objective of the present study was to assess the frequency of vascular events and the incidence of MF and AL in young patients with ET and to identify the factors associated with the development of such complications. In 126 subjects diagnosed with ET at a median age of 31 years (range: 5–40), overall survival and probability of survival free of either thrombosis, bleeding, MF, AL, and polycythemia vera (PV) were analyzed by the Kaplan-Meier method, followed by the log-rank test. With a median follow-up of eleven years (range: 4–25) three patients have died, being the probability of survival 98% at ten years. A total of 31 thrombotic events were registered in 25 patients; thrombosis-free survival (TFS) was 84% at ten years. Tobacco use was the only factor associated with an increased thrombotic risk, since TFS at 10 years was 72% in smokers versus 90% in non-smokers (p=0.03). Severe hemorrhagic complications were observed in 11 patients, and the estimated probability of bleeding-free survival was 92% at ten years. Evolution to MF was seen in 6 patients, four of whom had never received treatment for ET. MF-free survival was 97% at 10 years, with the risk being higher in patients showing an increased reticulin network in the bone marrow biopsy performed at diagnosis of ET (p=0.005). Transformation to AL was registered in one patient. JAK2 was mutated in 33 out of the 87 assessable patients (38%) and the mutation was associated with higher Hb values at diagnosis (p = 0.001). ET evolved into PV in five patients, being the probability of evolution into PV of 15% in JAK2 V617F positive patients versus 0% in JAK2 V617F negative patients (p=0.01). In conclusion, severe vascular complications are not infrequent in young subjects with ET, whereas transformation to MF or AL is a rare event.
Risk Stratification for Survival and Leukemic Transformation in Essential Thrombocythemia: A Single Institutional Study of 605 Patients.
Authors: Gangat Naseema , Wolanskyj Alexandra , McClure Rebecca F. , Li Chin Y. , Schwager Susan M. , Wu Wenting , Tefferi Ayalew 
Published: October 2019

Abstract
Background
It is widely recognized that advanced age and prior thrombosis predict recurrent thrombosis in essential thrombocythemia (ET) and are used to risk-stratify patients. However, the paucity of large sample size and long-term follow-up has limited the development of similar prognostic models for survival and leukemic transformation (LT).
Methods
Data was abstracted from the medical records of a consecutive cohort of patients with WHO-defined ET seen at the Mayo Clinic. Cox proportional hazards was used to determine the impact of clinical and laboratory variables on survival and LT. Overall survival and leukemia-free survival was estimated by Kaplan-Meier plots.
Results
i. Patient characteristics and outcome
The study cohort included 605 patients of which 399 (66%) were females (median age, 57 years; range 5–91). Median follow-up was 84 months (range; 0–424). During this period, 155 patients (26%) have died and LT was documented in 20 patients (3.3%) occurring at a median of 138 months (range; 23–422) from ET diagnosis.
ii. Prognostic variables for overall survival
Univariate analysis of parameters at diagnosis identified age ≥ 60 years, hemoglobin less than normal (defined as < 12 g/dL in females and < 13.5 g/dL in males), leukocyte count ≥ 15 x 109/L, tobacco use, diabetes mellitus, thrombosis, male sex, and the absence of microvascular symptoms as independent predictors of inferior survival. All of the above except the last two (i.e. male sex and the absence of microvascular symptoms) sustained their prognostic significance on multivariate analysis. Based on the first three prognostic variables: age, hemoglobin level, and leukocyte count, we constructed a prognostic model for survival: low-risk (none of the risk factors), intermediate-risk (1of 3 risk factors), and high-risk (≥ 2 risk factors). The respective median survivals were 278, 200, and 111 months (p<0.0001; Figure 1)
iii. Prognostic variables for leukemic transformation
On univariate analysis of parameters at ET diagnosis, LT was significantly associated with platelet count ≥ 1000 x 109/L, hemoglobin less than normal, and exposure to P-32. However, on multivariate analysis, only hemoglobin less than normal and platelet count ≥ 1000 x 109/L maintained independent prognostic value. Accordingly, we utilized these two variables, to construct a prognostic model for LT: low-risk (none of the risk factors), intermediate-risk (1 risk factor), and high-risk (both risk factors). Only 1 of the 239 patients (0.4%) in the low-risk group vs. 14 of the 289 (4.8%) in the intermediate-risk and 5 of the 77 (6.5%) in the high-risk group underwent LT (p=0.0009; Figure 2).
Conclusion
The current study provides clinician-friendly prognostic models for both survival and LT in ET.
Figure 1 Figure 1. Figure 2 Figure 2.
Recruitment of RXRα by Homo-Oligomeric RARα Is a Key for RARα-Mediated Transformation.
Authors: Zeisig Bernd B. , Kwok Colin , Wilson Amanda J. , Zelent Arthur , Gronemeyer Hinrich , Dong Shuo , So Chi Wai Eric 
Published: October 2019

Abstract
Chimeric fusion proteins involving Retinoic Acid Receptor Alpha (RARα) invariantly associate with almost 100% of Acute Promyelocytic Leukemia (APL). While we and others have recently demonstrated an essential role of aberrant self-association in RARα fusions mediated transformation1,2, forced oligomerization of truncated transcription factors including MLL3 and AML14 has emerged as an important oncogenic property shared by these most common chimeric fusion proteins involved in AML. To further characterize the underlying mechanisms and its modes of action, the present study dissects the essential molecular properties and transformation mechanisms by oligomeric RARα-oncoproteins. Firstly, we define the oncogenic threshold of self-association by showing that homo-oligomerization rather than homo-dimerization is required for Stat5b-RARα mediated transformation of primary hematopoietic cells. Although constitutive transcriptional repression is believed to be the underlying mechanism for RARα-mediated transformation, oligomeric RARα fusion proteins can bind retinoic acid response elements (RAREs) either as homo-oligomers or higher order hetero-oligomers with RXRα. To gain further insights into the transcriptional control mediated by RARα fusions, we successfully constructed various Stat5b-RARα point mutants that maintained the homo-oligomerization properties but lost their abilities to bind DNA as homo-oligomers. These resulting mutants could still efficiently transform primary hematopoietic cells in spite of their lack of homo-oligomeric DNA binding ability. To investigate if this is unique to Stat5b-RARα or is a general phenomena that can also apply to other RARα fusions, we further demonstrated that the synthetic FKBP-RARα fusion, which closely mimick both biochemical and transformation properties of bona fide RARα fusion proteins, was incapable of binding DNA as homo-oligomers, suggesting that homo-oligomeric DNA-binding is dispensable for RARα-mediated transformation. Conversely we reveal that the higher-order RARα-fusion/RXRα hetero-oligomeric complex, which aberrantly recruits transcriptional co-repressor SMRT, represents the major functional DNA-binding module. Specific knockdown of RXRα expression using shRNA approach can suppress transformation mediated by both bona fide and synthetic RARα fusion proteins, thus indicating a critical functional role of RXRα in RARα-mediated transformation of primary hematopoietic cells. Finally to assess the possible therapeutic values of targeting RXRα-mediated pathways in RARα-mediated transformation, we also demonstrated specific inhibition of myeloid transformation mediated by various RARα oncoproteins using the panRXR-selective agonist, SR11237. Taken together, these results not only highlight the functional significance of higher-order RARα-fusion/RXRα hetero-oligomeric complex, but also attest RXRα as a potential therapeutic target for APL.
Identification and Characterization of a Novel Jak2 Tyrosine Kinase Inhibitor.
Authors: Sayyah Jacqueline , Ostrov David , Sayeski Peter 
Published: October 2019

Abstract
Jak2 is a cytoplasmic tyrosine kinase that has been linked to hematological malignancies. Recently, a somatic Jak2 mutation (Jak2-V617F) has been identified in several myeloproliferative disorders such as polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis. These myeloproliferative disorders are characterized by unregulated expansion of one or more cells in the blood. The presence of the Jak2-V617F mutation in cells results in uncontrolled cell division and resistance to the negative feedback mechanisms that govern normal cell growth. The availability of a Jak2 tyrosine kinase specific inhibitor would facilitate our understanding of these Jak2-related disorders and perhaps serve a clinical benefit for patients. However, the most widely used Jak2 inhibitor, AG490, suffers from a general lack of specificity. Here, we used a novel approach to identify Jak2-specific inhibitors. We used in silico homology modeling of the Jak2 kinase domain to identify solvent accessible exposed pockets on the surface of the Jak2 protein. We then used a high-throughput program called DOCK to predict the ability of 20,000 small molecules to interact with a structural pocket adjacent to the ATP binding site of murine Jak2. The predicted binding energies of interaction between each compound and the Jak2 kinase domain were calculated and the top six scoring compounds were tested for their ability to inhibit Jak2 tyrosine kinase function in vitro. One of these compounds, 2-methyl-1-phenyl-4-pyridin-2-yl-2-(2-pyridin-2-ylethyl)butan-1-one (Z3) effectively inhibited Jak2-V617F and Jak2-WT autophosphorylation. We were able to show that Z3 inhibits total Jak2 tyrosine phosphorylation as well as Jak2 phosphorylation at the critical tyrosine 1007 residue in both a dose-and time-dependent manner. Z3 is able to reduce growth hormone-dependent Jak2 activation and is a direct inhibitor of Jak2-WT and Jak2-V617F tyrosine kinase autophosphorylation as measured by an in vitro kinase assay. Moreover, we found that Z3 inhibits proliferation of human erythroleukemia (HEL) cells, which express the Jak2-V617F mutation. In summary, this work demonstrates proof-of-principle concept that in silico molecular modeling can be used as a means to identify specific tyrosine kinase inhibitors.
Z3 Inhibits Jak2 Tyrosine Autophosphorylation in a Dose-Dependent Manner Z3 Inhibits Jak2 Tyrosine Autophosphorylation in a Dose-Dependent Manner Z3 Inhibits Growth Hormone Mediated Jak2 Phosphorylation at Tyrosine 1007 Z3 Inhibits Growth Hormone Mediated Jak2 Phosphorylation at Tyrosine 1007
Impact of the JAK2 V617F Mutation on Survival in Patients with Catastrophic Intra-Abdominal Thromboses.
Authors: McMahon Christine , Abu-Elmagd Kareem , Bontempo Franklin A. , Kant Jeffrey A. , Swerdlow Steven H. 
Published: October 2019

Abstract
Catastrophic intra-abdominal thrombosis can result from a variety of hypercoaguable states, including the chronic myeloproliferative disorders (CMPD), even though the patient’s clinical and laboratory findings may not suggest such a diagnosis. Recently a somatic mutation in the tyrosine kinase, JAK2, has been reported in myeloid cells of 65–97% of patients with polycythemia vera and approximately 23–57% of patients with essential thrombocythemia or chronic idiopathic myelofibrosis, but not in normal individuals. To assess the prevalence and clinical implications of this mutation in the setting of intra-abdominal thrombosis, JAK2V617F genotyping was performed in 42 patients who had suffered catastrophic intra-abdominal thromboses that resulted in visceral transplants, as well as in 20 control subjects. The prevalence of V617F was compared to that of other hypercoaguable states for which molecular testing is routinely performed. The V617F mutation was detected in 7 patients (16.7%), who were not distinguishable from the 35 others on the basis of their peripheral blood counts. JAK2 V617F was not detected in any of the control subjects. Six patients were heterozygous (14.3%) for the factor V Leiden mutation and one patient was heterozygous for prothrombin 20210 G>A, all of whom had unmutated JAK2 genes. Evidence for a lupus anticoagulant was found in 7 patients, including one with the V617F mutation. Six of the 7 patients with the V617F mutation died within 36 months post-transplant from the following causes: an aggressive post-transplant lymphoproliferative disorder, sepsis secondary to bone marrow failure, allograft-liver failure, and three cases of sepsis preceded by mental status changes, possibly due to cerebral vascular disease. The median post-transplant survival of V617F-positive patients was 1.5 years compared to 9.8 years for the V617F-negative patients (ratio: 6.6; 95% CI 6.3–7.0). These results highlight the diagnostic utility of JAK2V617F testing in the setting of abdominal thrombosis and underscore the clinical significance of a positive result. The explanations for major thromboses in JAK2 V617F positive patients with clinically silent CMPD and the significantly shorter survival of the JAK2 V617 positive patients in the setting of visceral transplantion are uncertain. The optimal management of these patients also remains to be determined.
POST-TRANSPLANT SURVIVAL POST-TRANSPLANT SURVIVAL Median Peripheral Blood Counts at Presentation Platelets (109/L) Hemoglobin (g/dl) Hematocrit (%) Leukocytes (109/L) V617F 342 12.2 37.2 6.3 WT 239 11.4 33.3 7.2 p-value 0.22 0.59 0.46 0.89
Monocytosis Is an Independent Risk Factor for Survival in Agnogenic Myeloid Metaplasia.
Authors: Elliott Michelle A. , Dingli David , Schwager Susan M. , Li Chin Y. , Tefferi Ayalew 
Published: October 2019

Abstract
Background: Young (age < 60 years) patients with agnogenic myeloid metaplasia (AMM) are potential candidates for curative therapy with allogeneic stem cell transplantation. In such transplant-eligible patients, median overall survival (OS) is reported to be between 78 and 128 months. Because clinical course in an individual patients is markedly heterogeneous (survival ranges of months to decades), objective prognostic variables are essential for transplant decision making. Accordingly, we recently developed a modified Dupriez prognostic scoring system (PSS) that effectively discriminated between high (2 or more risk factors), intermediate (one risk factor) and low (no risk factor) risk patient groups based on the presence or absence of complete blood count (CBC)-derived adverse parameters; hemoglobin < 10 g/dl, leukocyte count < 4 or > 30 × 109/L, and platelet count < 100 × 109/L (Dingli et al. Cancer2006;106:623). In the current study, we identify absolute monocytosis of ≥ 1 × 109/L as an additional independent risk factor for survival in AMM.
Methods: A consecutive cohort of WHO-defined AMM patients diagnosed before the age of 60 years was identified. The impact of various clinical and laboratory parameters on overall survival was evaluated with univariate and multivariable analysis.
Results: The study included 129 patients (median age 52 years, range 18–60; 69 males) with AMM. An overall median survival of 75 months was univariately affected by platelet count < 100 × 109/L, hemoglobin level of < 10 g/dL, leukocyte count of either < 4 or > 30 × 109/L, monocytosis of ≥ 1 × 109/L, and, where cytogenetic studies were available (n=41), presence of unfavorable cytogenetic abnormalities (p < 0.01 in each instance). On multivariable analysis, all but leukocyte count maintained their significance. The independent prognostic value of monocyte count was also validated against the modified Dupriez score (see above) and thus allowed further refinement of the particular CBC-based PSS that included monocytosis of ≥ 1 × 109/L as a fourth risk factor; low-risk identified patients with none of the 4 risk factors, intermediate-risk with one risk factor, and high-risk with 2 or more risk factors (Figure 1). For comparison, Figure 2 illustrates survival curves according to the original Dupriez PSS.
Conclusion: Monocytosis of ≥ 1 × 109/L is an independent risk factor for inferior survival in AMM.
Figure 1. Mayo score Figure 1. Mayo score Figure 2. Dupriez score Figure 2. Dupriez score
Depletion of Regulatory T Cells Dramatically Improves DC-Based Immunization Against Acute Myeloid Leukemia.
Authors: Delluc Stephanie , Gaston Auguste , Marchiol-Fournigault Carmen , Fradelizi Didier , Regnault Armelle , Sang Kim Hanh Le Quan , Tourneur Lea , Chiocchia Gilles , Buzyn Agnes 
Published: October 2019

Abstract
Dendritic cell (DC)-based vaccination is a promising approach to enhance anti-tumor immunity that could be considered for patients with high risk acute myeloid leukemia (AML). We have already shown in human that DC pulsed with eluted peptides (EP) from autologous AML blasts (DC/EP) are able to induce CD4+ and CD8+ anti-leukemic immune response in vitro (Delluc S, Haematologica, 2005). In order to optimize this vaccination strategy for AML patients we developed a pre-clinical murine model. C57/Bl6 mice were vaccinated by DC pulsed or not with peptides eluted from the syngenic C1498 myelomonocytic leukemic cell line in a prophylactic setting. Injection of DC/EP induced an anti-leukemic response as shown by the cytotoxic activity of CD4 T cells, whereas the injection of unpulsed DC induced a NK cell-mediated cytotoxicity against C1498 cells. In vivo depletion of CD4 T cells or NK cells abrogated the protective effect induced by DC/EP (p=0.02) or DC (p=0.06) vaccination, respectively, confirming their critical role in preventing leukemic outgrowth. However, late C1498 re-challenge showed that the anti-leukemic immune response was insufficient to protect DC/EP vaccinated mice from death, suggesting an ineffective or absent long-lived memory response. Since several populations of T cells have regulatory properties potentially inhibiting anti-tumor responses, we hypothesized that CD25+ cell-depletion in vivo could enhance the protection induced by vaccination. Indeed, we observed a dramatic improvement of the survival of mice treated by an anti-CD25 antibody before vaccination compared to mice vaccinated by DC/EP alone (p<0.01). More interestingly, CD25 depletion allowed the generation of long-lived immune responses since mice were protected from a late re-challenge by C1498 cells. Our results strongly suggest that depletion of regulatory CD25 T cells before DC-based vaccination should be considered for immunotherapy of weakly immunogenic tumors such as AML.