bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transformation to Myelofibrosis and Blastic Transformation of PV Are Associated with Higher JAK2 Mutation Levels.
Authors: Koren-Michowitz Maya , Amariglio Ninette , Landman Joseph , Rechavi Gideon , Ribakovsky Elena , Cohen Yoram , Nagler Arnon 
Published: April 2020

Abstract
The JAK2 V617F mutation is found in 80–97% of polycythemia vera (PV) pts. The aim of the current study was to correlate the JAK2 mutation level with clinical symptoms and complications including vascular events and late hematological complications. Thirty-nine JAK2 V617F positive PV pts were included; M-19, F- 20; mean age at diagnosis was 55 (range 25–89) years. JAK2 mutation was analyzed in the PB using a quantitative MALDI-TOF based assay (Leuk Res 2007) after a mean of 130 (range 0–429) months from diagnosis. There was no correlation between the JAK2 mutation level and the time elapsed between the diagnosis and JAK2 mutation analysis. The mean JAK2 mutation level was 59% (range 2.5–95%). A negative correlation was found between the JAK2 mutation level and the pts age both at diagnosis (r=−0.3439, p=0.0321) as well as at the time of analysis (r=−0.3285, p=0.0412). JAK2 mutation levels were higher in pts with late hematological complications including transformation to myelofibrosis and blastic transformation compared to those without hematological complications (mean mutation level 77% vs. 51%, respectively p=0.0019). The best cut off value for the development of late hematological complications was above 50% (p=0.0336) which suggests the presence of homozygous JAK2 clones in pts that develop these complications. Similarly, there was a trend towards higher mean mutation levels in symptomatic pts (69% vs. 54%, p=0.096), pts with splenomegaly (62% vs. 47%, p=0.077) and pts that received cytoreductive therapy (63% vs. 47%, respectively p=0.077), while there was no difference between the levels of mutation in pts with thrombotic events compared to those without thrombotic complications. Our findings of:
association between the JAK2 mutation level and late hematological complications and no association between the JAK2 mutation level and thrombotic events concur with the results of Vannucchi et al (Blood 2007) that reported on a higher rate of transformation to myelofibrosis in PV patients with homozygous JAK2 status and no association between homozygosity for the JAK2 mutation in PV and thrombotic events.
In conclusion, we found that late hematological complications including transformation to myelofibrosis and blastic transformation in PV pts are associated with higher JAK2 mutation levels while thrombotic events are not associated with higher JAK2 levels. These results may be of clinical and therapeutic significance pending their further confirmation by a larger cohort of patients.
Both Discordant and Concordant Bone Marrow (BM) Involvement Predict for a Poorer Outcome Independent of the IPI in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP.
Authors: Sehn Laurie H. , Chhanabhai Mukesh , Singh Suman , Saville Wayne , Matso Dan , Spinelli John J. , Connors Joseph M. , Gascoyne Randy D. 
Published: April 2020

Abstract
Recently, it has been suggested that concordant but not discordant BM involvement is a negative predictor of outcome in DLBCL patients treated with CHOP (Chung et al, Blood 2007). The significance of BM involvement in pts treated in the current era of therapy including rituximab has not been fully examined. We evaluated the prognostic impact of BM involvement in DLBCL patients treated with the current standard of care, R-CHOP.
Patients: We identified 282 patients with biopsy proven de novo DLBCL treated in British Columbia (BC) with an R-CHOP regimen between 01/01/2001 and 01/01/2005 with complete clinical information and staging bone marrows available for review. Cases were identified using the Lymphoid Cancer Database of the BC Cancer Agency. Median follow-up is 44 mos (range 1–77).
Results: 234/282 (83%) had a negative staging BM, 27 pts (10%) had a positive BM with concordant histology (Con-BM) and 21 (7%) had a positive BM with discordant histology (Dis-BM) with predominantly small B-cells present. Clinical characteristics for the entire cohort were as follows: median age 64 y (range 18–88); 66% male; 65% stage III/IV; 39% PS&gt;1; 51% elevated LDH; 31% &gt;1 extranodal site. IPI risk factors: 10% 0; 42% 1–2; 48% 3–5. In addition to higher stage and greater extranodal involvement, pts with a positive BM were more likely to have a higher LDH and a poorer PS than pts with a negative BM. Compared to pts with Con-BM, pts with Dis-BM were more likely to be elderly, but otherwise exhibited a similar distribution of clinical prognostic factors. The Kaplan-Meier 4-year PFS was significantly worse for pts with both Dis-BM (32%) and Con-BM (46%) involvement compared to pts with a negative BM (75%) (p&lt;0.0001) (see Figure). Similarly, 4-year overall survival was significantly worse for pts with Dis-BM and Con-BM involvement (53% and 54%) compared to pts with a negative BM (74%) (p=0.005). All patients with Dis-BM involvement who developed progressive or relapsed disease were believed to have progression of their aggressive lymphoma based on clinical behavior or biopsy proof. In a multivariate analysis controlling for the IPI, BM involvement (Dis-BM and Con-BM) remained an independent predictor of PFS (p=0.03).
Conclusions: In DLBCL pts treated with R-CHOP, both discordant and concordant BM involvement predict for a poorer outcome independent of the IPI. It is possible that pts with DLBCL and discordant BM involvement represent a subset of pts with transformed disease which is inherently less treatment-sensitive.
Figure Figure
NK and T-Cell Status as Well as Their Perforin Expression Is Related to Clinical Severity and Outcome in Difuse Large Cell Lymphoma.
Authors: Gutierrez Antonio , Rodriguez Jose , Martinez Jordi , Ballester Carmen , Crespi Catalina , Bea Maria Dolores , Amat Juan Carlos , Villavicencio Roberto , Morey Miguel , Duran Maria Antonia , Linares Cristina , Rifa Julio , Bautista Antonia , Voegler Oliver , Alemany Regina , Sampol Antonia , Besalduch Joan 
Published: April 2020

Abstract
A variable degree of immune impairment is present in lymphomas, either as a cause or a consequence of the disease. There is preliminary evidence that this immune status is related to disease control and survival. Our objective was to analyze the relationship of the immune status with the main clinical prognostic variables in DLCL. Seventeen patients with DLCL de novo were prospectively included in the study, receiving an homogenous induction treatment based on CHOP-R regimen. Median age was 60 (29–74); ECOG PS &gt; 1 in 65%; Ann-Arbor stage &gt; II in 53%; B-symptoms in 47%; more than one extranodal site in 47%; bulky mass present in 59%; high LDH in 65%; high beta-2-microglobulin in 56%. Levels of B, T and NK subpopulations were assessed at diagnosis by flow cytometry, including general populations as well as cytotoxicity, costimulation and adhesion phenomena. This was compared with main clinical prognostic variables included in the adjusted-IPI (a-IPI) and MD. Anderson Tumor Score (TS) by U of Mann-Whitney non parametric test or Kaplan Meier survival analysis. Worst a-IPI patients (2–3 scores) (59%) showed significant lower levels of total lymphocytes as well as of the following populations:
General T lymphoid markers (CD2 and CD3); expression of adhesion molecules (CD3+CD11a+, CD4+CD11a+ and CD8+CD11a+); expression of costimulatory molecules (CD4+CD28+ and CD8+CD28+); cytotoxicity in CD56+ cells (CD56+ Perforin+).
Worst TS patients (3–4 scores) (59%) showed significant lower levels of the following populations:
Activated or regulatory lymphoid subsets (CD3+CD25+); expression of costimulatory molecules (CD4+CD152+ and CD8+CD152+); cytotoxicity in CD56+ cells (CD56+ Perforin+).
With a median follow-up of 16 months we observed a better overall survival and progression-free survival data in patients with levels above median of CD56+ and expression of perforin by T and NK cells. We conclude that worst prognostic groups of a-IPI and TS in DLCL are associated with a worst immune status, based on T and NK immune phenomena analysis. Perforin expression by NK and T CD56+ cells was associated with outcome in DLCL.
Role of C-MYC Rearrangement in Survival Status of HIV Positive and HIV Negative Patients with Diffuse Large B-Cells Lymphoma.
Authors: Zhang Ling , Luu Hung , Mirocha James , Lill Michael , Alsabeh Randa 
Published: April 2020

Abstract
Background: Diffuse large B-cell lymphomas (DLBCL) are the most common type of lymphomas and have heterogeneous clinical behavior. Three commonly dysregulated genes (BCL-2, BCL-6 and C-MYC) have been recognized in DLBCL based on molecular gene profile studies. The 8q24 C-MYC rearrangement is found in 10–15% of patients with DLBCL. C-MYC status in HIV+ and HIV− population with DLBCL is not well studied and the role of C-MYC in the survival status of these two group is worthy of exploration.
Design: Ninety-one patients with DLBCL diagnosed between 01/2005– 04/2007 were included in this study. Atypical Burkitt lymphoma according to WHO classification was excluded. Patients were divided into HIV+ (26 cases, average 44.5 ± 10.7 y/o) and HIV− (65 cases, average 65 ± 17.2 y/o) groups. Eight plasmablastic lymphomas (PBL) (7 HIV+ and 1 HIV−) were diagnosed. FISH (Vysis, Des Plaines, IL) break-apart for the 8q24 C-MYC rearrangement (91 cases), immunohistochemical stains for CD20, CD3, BCl-2, CD10, BCl-6, EBER in all cases, p53 (available for 78 cases), and proliferation rate by Ki-67 (available for 89 cases) were performed. Categorical variables were compared with the Fisher exact test. Numerical variables were compared by either the t test or the Wilcoxon rank sum test, as appropriate. The Kaplan-Meier method was used to estimate survival. The Log-Rank test was used to compare survival in the following groups: HIV+ vs. HIV−, C-MYC+ vs. C-MYC−, Ki-67 proliferation ≥ 90% vs. &lt;90%, and various combined profiles.
Results: C-MYC rearrangement was detected in 13/26 (50%) HIV+ DLBCL and 9/65 (14%) HIV− DLBCL (P&lt;0.001). Excluding the 8 PBL cases, C-MYC was found in 7/19 (37%) HIV+ DLBCL and 9/64 (14%) HIV− DLBCL (P=0.04). High Ki-67(≥ 90%) and p53 positivity were more often found in HIV+ DLBCL than in HIV− DLBCL (P=0.02 and P=0.001, respectively). A Kaplan-Meier Survival Curve demonstrated that patients with C-MYC+ DLBCL had worse survival than C-MYC− patient, regardless of their HIV status (P=0.031); HIV+ DLBCL patients have poorer survival than HIV− DLBCL ones (P=0.0007). The proliferation rate by Ki-67 (≥90% or &lt;90%) did not affect survival (P=0.65). Survival was superior in the HIV−/C-MYC− group compared to the combined group of patients who were HIV+/C-MYC +, HIV−/C-MYC+ or HIV+/C-MYC− (P&lt;0.0001, Figure 1).
Conclusion: high frequency of C-MYC rearrangement is identified in HIV+ patients with DLBCL in comparison to HIV− patients with the same disease. C-MYC rearrangement plays a critical role in survival regardless of HIV status. Although high Ki-67 proliferation was more often noted in HIV+ than in HIV− DLBCL, higher Ki-67(≥ 90%) did not correlate with a shorter survival in HIV+ DLBCL.
Survival by HIV and C-MYC Status Survival by HIV and C-MYC Status
Vaccination of Acute Myeloid Leukemia Patients with Dendritic Cells Electroporated with mRNA Encoding the Wilms’ Tumor Protein WT1: A Phase I/II Trial.
Authors: Berneman Zwi N. , Van Driessche Ann , Van de Velde Ann , Nijs Griet , Braeckman Tessa , Stein Barbara , Vermeulen Katrien , Pieters Katrien , Gadisseur Alain P. , Schroyens Wilfried A. , de Vries I. Jolanda , Price David A. , Van Tendeloo Viggo F. 
Published: April 2020

Abstract
To date, Wilms’ tumor protein (WT1) is acknowledged as a valuable target for active specific immunotherapy in several solid and hematological malignancies, such as leukemia. Preclinical data from our laboratory and that of Hans Stauss have already shown that WT1 RNA-electroporated dendritic cells (DC) stimulate WT1-specific T cells in vitro (Van Driessche A et al. Leukemia2005;19:1863–1871). Therefore, we started a phase I/II dose-escalation trial in which patients with acute myeloid leukemia (AML) in remission received intradermal injections with WT1 RNA-loaded DC. Feasibility, safety and immunogenicity of the vaccine were investigated. Seven patients received four biweekly DC vaccines. A delayed-type hypersensitivity (DTH) test was performed 2 weeks following the last vaccination. Patients underwent an apheresis and monocytes were isolated using CD14-labeled magnetic beads by CliniMACS. DC were generated in 6-day cultures in clinical-grade medium supplemented with serum, GM-CSF and IL-4 and maturated with PGE2 and TNF-a. Keyhole limpet hemocyanin (KLH) was added during maturation as a CD4+ helper antigen. Mature DC were harvested, electroporated with WT1 mRNA and used as vaccines. Patients were monitored for minimal residual disease (MRD) by analyzing WT1 RNA expression in peripheral blood by qRT-PCR. When the patient was HLA-A2+, tetramer staining was performed to detect WT1-specific CD8+ T cells. Before and after the vaccination cycle, peripheral blood was collected for immunomonitoring purposes. There was successful DC generation and vaccine production in all patients selected. No serious adverse events or toxicity was seen and all vaccinations were well tolerated. A decrease in WT1 RNA expression was observed during the course of the vaccination in 3/5 patients who had an increased WT1 mRNA level in peripheral blood at the start of DC vaccination. A vaccine-specific immune response was demonstrated in 7/7 patients by an in vivo DTH reaction both to KLH as well as to WT1. By tetramer analysis, detectable levels of WT1-specific CD8+ T cells could be demonstrated during the course of the vaccination both in the peripheral blood as well as in the expanded DTH-infiltrating T cells from the skin biopsies. Preliminary data from immunomonitoring in pre- and post-vaccination T cell samples from 3 patients show a mixed T helper (Th)1/Th2 response towards the KLH and the WT1 protein following vaccination. We conclude that vaccination of AML remission patients with WT1 RNA-loaded DC is feasible and safe. Furthermore, the vaccine elicits anti-vaccine T-cell responses in vivo and a decrease in WT1 RNA expression levels was observed during MRD monitoring in some vaccinated patients.
SB939: A Potent and Orally Active HDAC Inhibitor for the Treatment of Hematological Malignancies.
Authors: Sangthongpitag Kanda , Stunkel Walter , Bonday Zahid Q. , Goh Kee C. , Wang Xukun , Wu Xiaofeng , Hu Changyong , Wang Haishan , Yu Niefang , Sun Eric , Entzeroth Michael , Kantharaj Ethirajulu , Chen Chien-Shing , Wood Jeanette M. 
Published: April 2020

Abstract
Histone deacetylases (HDACs) are emerging new molecular targets for cancer therapy. Small-molecule HDAC inhibitors have been developed and shown to induce tumor cell cytostasis, differentiation and apoptosis in experimental models and efficacy in clinical trials in various hematological malignancies following intravenous and/or oral administration. SB939 is a novel HDAC inhibitor with improved metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors currently in clinical trials1. The objective of this study was to characterize the anti-tumor efficacy of SB939 in preclinical models of hematological malignancies. SB939 selectively inhibits HDAC class I and II isozymes, with Ki values ranging from 16 to 247 nM. It inhibited the proliferation of cell lines from various haematological malignancies, including leukemia, lymphoma and multiple myeloma with IC50 values ranging from 80 nM to 200 nM. It induced cell cycle arrest leading to apoptotic cell death in tumor cell lines as well as primary cells isolated from patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). SB939 has excellent pharmacokinetic properties and tolerability after oral administration in mice1. The oral anti-tumor efficacy of SB939 was evaluated in models of AML (MV4-11) and lymphoma (Ramos) with the tumors grown subcutaneously in nude mice. After daily oral treatment at 50mg/kg (21 days for MV4-11; 14 days for Ramos), SB939 significantly reduced tumor growth in both models (%TGI values were 116% and 100% respectively in MV4-11 and Ramos). In the MV4-11 model, SB939 induced complete tumor regression, in 6/10 mice. In conclusion, our data demonstrate that SB939 is a potent, orally active anti-tumor drug with potential for the treatment of various types of hematological malignancies. 1Kanda Sangthongpitag, Haishang Wang, Pauline Yeo, Liu Xin, Evelyn Goh, Lee Sun New, Peizi Zeng, Xiaofeng Wu, Changyong Hu, Tony Ng and Kantharaj Ethirajulu. ADME attributes of SB939, a best-in-class HDAC Inhibitor, and its PK/PD correlation in the Pharmacological Species. EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics Prague Congress Centre, 2006, Nov 7–10; Prague, Czech Republic, Abstract number 166
Activity and Mechanism of Action of AS1411 in Acute Myeloid Leukemia Cells.
Authors: Chen Weiwei , Sridharan Vijayalakshmi , Soundararajan Sridharan , Otake Yoko , Stuart Robert , Jones David , Fernandes Daniel 
Published: April 2020

Abstract
AS1411 is a 26 base unmodified DNA aptamer which is currently in a Phase II clinical trial for the treatment of acute myeloid leukemia (AML) and will shortly enter a Phase II trial in renal cell carcinoma (RCC). AS1411 has previously been shown to have cytostatic (a result of arrest in S phase of the cell cycle) and cytotoxic effects on tumor cells, but not normal cells. AS1411 binds to nucleolin, which is overexpressed in the cytoplasm and on the surface of tumor cells. Treatment of MV4-11 cells (an AML-derived cell line) with low micromolar concentrations of AS1411 results in cell growth inhibition and a reduction in viability; this effect becomes apparent after 48 hours incubation. Co-immunoprecipitation of nucleolin and AS1411 from MV4-11 cells treated with radiolabeled AS1411 confirmed previous work that AS1411 binds to nucleolin. In addition, confocal microscopy showed that nucleolin is present in the cytoplasm and the plasma membrane of MV4-11 cells. Incubation of these cells with AS1411 decreased nucleolin mRNA levels, and nucleolin protein was decreased in both cytoplasm and nucleus to approximately 10% of control levels after 96 hours. The reduction in nucleolin levels started to appear at around 48 hours and may reflect cells arresting in S phase of the cell cycle. Nucleolin binds to an ARE sequence in the 3′-untranslated region of Bcl-2 mRNA resulting in stabilization of the mRNA. Using gel shift assays with a radiolabeled fragment of Bcl-2 mRNA we show here that AS1411 interferes with this binding. In addition, levels of Bcl-2 mRNA in MV4-11 cells decrease to 10% of control levels after 48 hours incubation with AS1411 and the level of Bcl-2 protein also decreases in comparison to control cells. Finally, mononuclear cells isolated from blood samples of AML patients were incubated with AS1411 for 96 hours and viability determined. In all samples, AS1411 caused a reduction in cell viability at low micromolar concentrations, similar to those required to kill cell lines. This work therefore demonstrates that AS1411 has both cytostatic and cytotoxic effects on AML cells and underpins the dosing regime of AS1411 in the ongoing AML clinical trial.
Role of Microparticles in Thrombin Generation in Patients at Risk for Atherothrombosis.
Authors: Kaufmann Viktoria , Mager Jutta , Graf Markus , Geiter Sabine , Vetr Helga , Laemmle Bernhard , Redondo Maurice , Binder Bernd R. 
Published: April 2020

Abstract
We have shown recently (Hron et al. JAMA 2006) that measuring thrombin generation can identify patients at low risk for recurrent venous thromboembolism and that peak thrombin is a suitable parameter to differentiate low risk from high risk patients. In this study we used the same assay (Technothrombin®TGA) to analyze patients at high risk of atherothrombosis (a swiss study of patients with a history of myocardial infarction). Moreover, we investigated the influence of microparticles on thrombin generation in these patients. Thrombin generation was measured using Technothrombin®TGA. The reagent used contained low levels of phospholipid and 5 pM tissue factor. Platelet poor plasma from 178 patients (n=178, age =55±8 ys, male/female = 157/21) who had a previous myocardial infarction and 79 normal age and sex matched controls. (n=79, age = 55±8 ys, male/female = 70/9) was analyzed. Microparticle-free plasma was generated from PPP plasma by filtration through a membrane (0.2 μm pore size) using a standardized filtration device (Ceveron®MFU 500, Technoclone). In the control group the mean value for peak thrombin in platelet poor plasma was 252±7.7 nM (mean±SD). A significantly higher (p&lt; 0,05) peak thrombin was found in the group of patients (355±49 nM) when patients without medication were analyzed. In patients on aspirin (n=109) the peak thrombin was not significantly different from untreated patients (297±10 nM) while in patients on oral anticoagulation (n=34) peak thrombin was significantly lower (225±27 nM). In the group of patients on oral anticoagulation also the lag period was significantly longer as compared to controls or patients without medication (21.9±2 minutes versus 14.8±0.2 minutes) whereas aspirin treatment did not affect the lag period significantly. After removing microparticles from the samples, the peak thrombin values between patient and control group were no longer significantly different. The difference between microparticle free plasma and platelet poor plasma was significantly higher (p&lt;0.05) in the patient groups without therapy (304±39nM) and in patients on Aspirin therapy (257±23nM) as compared to the normal controls(182.6±10.4nM). These data indicate that thrombin generation is significantly increased in patients with previous myocardial infarction and that this increased thrombin generation is likely due to microparticles contained in these samples.