bluuebunny/crossref_metadata_2025_split huggingface dataset:
Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma: Results of a Phase II Study.
Authors: Advani Ranjana , Hymes K. , Pohlman B. , Jacobsen E. , McDonnell J. , Belt R. , Lerner A. , Kim Y. , Mundis R. , Mansfield T. , Buhl-Jensen P. , Ooi C.E. , Duvic M. , Foss F. 
Published: October 2019

Abstract
Background: Belinostat (PXD101) is a hydroxamate pan-histone deacetylase inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. Phase I studies have shown that belinostat is well-tolerated.
Methods: This Phase II trial evaluated the activity of belinostat in patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Belinostat (1000 mg/m2) was administered as a 30-min IV infusion on Days 1–5 of a 3-wk cycle. The primary endpoint was objective response (OR) rate analyzed separately for PTCL and CTCL using the Cheson criteria and Severity Weighted Assessment Tool (SWAT), respectively. For each arm, a Simon 2-stage design was used based on target OR rate of 25%, with expansion to 34 pts if ≥ 2/13 OR were observed.
Results: In the PTCL arm, 12 pts (9 with stage III/IV disease) were enrolled; (7 PTCL-unspecified (PTCL-U), 2 anaplastic large cell lymphoma (ALCL), 2 angioimmunoblastic T-cell lymphoma and 1 NK-T-cell lymphoma), treated for a median of 2 cycles (range 1–8). Of 11 evaluable pts, 2 achieved a CR and 5 pts had SD. The two CR (11+ and 15+ wks) were both in pts with PTCL-U. A third pt with PTCL-U had SD lasting 14 wks and discontinued treatment due to an adverse event (AE). Both pts with ALCL had durable SD (20+ and 14 wks). In the CTCL arm, 16 pts were enrolled (9 Mycosis Fungoides (MF), 5 Sezary Syndrome (SS), 2 primary cutaneous ALCL) and treated for a median of 2 cycles (range 1–6). Four ORs were observed (25%): 1 CR (ALCL) and 3 PR (MF/SS). The median duration of the OR was 10 wks (range 7 to 39+ wks). Four additional pts had a 25 – 50% decrease in SWAT. Improvement in pruritus score by ≥ 3 on a visual analog scale was reported in 5/6 patients with significant pruritus at baseline. Overall in both study arms the drug was well-tolerated and most AE were grade 1/2 (nausea, fatigue, constipation, diarrhea, and vomiting). Grade 3 AE attributed to the study drug was reported in 7 pts and included peripheral edema, apraxia, adynamic ileus, pruritus, rash, and infections. Only 1 treatment related Grade 4 AE was noted (thrombocytopenia). One patient with progressive PTCL died 6 days after last belinostat dose with ventricular fibrillation and drug causality could not be excluded.
Conclusions: Belinostat (PXD101) is generally well tolerated and demonstrates encouraging clinical activity in recurrent or refractory PTCL and CTCL. The objective response rate in both arms has met the pre-defined criteria for study expansion to stage II of enrollment.
Unlike Imatinib, Dasatinib Uptake into Chronic Myeloid Leukaemia Cells Is Independent of hOCT1 Expression.
Authors: Giannoudis Athina , Davies Andrea , Lucas Claire M. , Harris Robert J. , Pirmohamed Munir , Clark Richard E. 
Published: October 2019

Abstract
In chronic myeloid leukaemia (CML), resistance to imatinib is an important clinical issue. We have previously shown that imatinib uptake into CML cells and cell lines is dependent on the uptake transporter human Organic Cation Transporter 1 (hOCT1; SLCA22). Furthermore, in clinical samples, low hOCT1 expression is an important mechanism of imatinib resistance (Wang L et al, Clinical Pharmacology and Therapeutics; epub June 13th 2007). Dasatinib is a second generation novel tyrosine kinase inhibitor that is effective in many imatinib-resistant patients. Its mechanism of transport into and out of CML cells has not been previously investigated. We hypothesised that dasatinib might be transported differently to imatinib, which might account for its favourable effects in imatinib-resistant patients. The CML cell line KCL22 was selected for transfection work as it has a particularly low basal level of hOCT1 expression. KCL22 cells were transfected with pcDNA3-hOCT1 plasmid (kind gift of D Gründemann, Germany) and stable lines were selected with high hOCT1 expression. The uptake of radiolabelled dasatinib (kind gift from Bristol Myers Squibb) was greater in high-hOCT1 expressing cells than in mock transfected cells (p=0.0149, n=3). However, prazosin and amantadine, both inhibitors of hOCT transport, did not decrease dasatinib uptake into mock transfected KCL22 cells, in sharp contrast to the block on imatinib uptake seen with both these inhibitors. Dasatinib decreased the level of phosphorylated CRKL (surrogate marker for BCR-ABL) by 49.9% in mock transfected KCL22 cells and 40.3% in high-hOCT1 expressing cells. The distribution coefficient (logD) of dasatinib between 1-octanol and HEPES medium was 2.05, compared with 0.81 for imatinib, demonstrating that dasatinib is more lipophilic. The efflux of dasatinib was investigated in confluent monolayers of Madin-Darby canine kidney (MDCKII) cells on a semipermeable membrane. These cells stably express ABCB1 (MDR1) on their apical but not their basal aspect. Both dasatinib and imatinib were transported from the basal to the apical layer, indicating ABCB1 transporter-mediated efflux of both drugs (p=0.001, p<0.0001, respectively). Addition of the ABCB1 inhibitor PSC833 blocked transport of both drugs (p=0.0013, p<0.0001 respectively). Taken together, the data are consistent with the view that dasatinib, unlike imatinib, may achieve adequate intracellular levels and BCR-ABL suppression even in cells with low or blocked hOCT1 function. However, in cells with high hOCT1 expression, dasatinib uptake may be augmented. Efflux of dasatinib and imatinib appear similar and via ABCB1. Dasatinib may be useful therapeutically in patients with imatinib resistance related to low hOCT1 expression.
Characterization of Acute Myeloid Leukemia with PTPN11 Mutation - The Mutation Is Closely Associated with NPM1 Mutation but Inversely Related to FLT3/ITD.
Authors: Hou Hsin-An , Chou Wen-Chien , Chen Chien-Yuan , Lin Liang-In , Tang Jih-Luh , Tseng Mei-Hsuan , Huang Chi-Fei , Chiou Rong-Jing , Lee Fen-Yu , Liu Ming-Chih , Tien Hwei-Fang 
Published: October 2019

Abstract
The development of acute myeloid leukemia (AML) is a multistep process. Recently, somatic mutations of PTPN11, the gene encoding non-receptor protein tyrosine phosphatase SHP-2, were observed in some hematological malignancies. However, the characteristics of adult AML with PTPN11 mutations have not been comprehensively studied, and the specific genetic alteration cooperative with a PTPN11 mutation in the leukemogenesis remains largely unknown. In this study, PTPN11 mutation and its association with other gene aberrations were analysed for 272 adult patients with de novo AML. Missense mutations were identified in 14 individuals (5.1%). The PTPN11 mutation was closely associated with old age (P=0.036), FAB M4/M5 subtypes (P=0.049), CD14 expression (P=0.026), a normal karyotype (P=0.044) and NPM1 mutation (P=0.037), but negatively associated with FLT3/ITD (P = 0.025). In addition, four patients revealed simultaneous mutations of PTPN11 and AML1 (n=3) or MLL (n=1). We observed a shorter overall survival for patients with PTPN11 mutation than those without amongst NPM1-wild patients (P=0.001), but not amongst NPM1-mutated patients (P=0.738). Our findings provide evidence that AML patients with PTPN11 mutations had some distinct biological and clinical characteristics, and the mutation may cooperate with other gene alterations to lead to AML in a subset of patients.
Prognostic Significance of FLT3/ITD Mutation in AML1/ETO-Associated Acute Myeloid Leukemia.
Authors: Kim Yeo-Kyeoung , Kim Hee-Nam , Lee Il-Kwon , Bang Soo-Mee , Jo Deog-Yeon , Won Jong-Ho , Yim Chang-Yeol , Yang Deok-Hwan , Lee Je-Jung , Kim Hyeoung-Joon 
Published: October 2019

Abstract
Background: AML1-ETO fusion gene in acute myeloid leukemia (AML) usually predicts a good response to chemotherapy with a high remission rate and a relatively long median survival. An internal tandem duplication of the FLT3 gene (FLT3/ITDs) is known to be associated with poor outcome after standard induction chemotherapy in AML patients with normal cytogenetics. However, this mutation is reported to be rarely found in cases with AML1/ETO positive and it remains a matter of debate as to whether these mutations play an independent role in the prognosis of AML patients with AML1/ETO fusion gene.
Aims: To determine the prevalence and the prognostic role of FLT3/ITD in patients with AML1/ETO positive AML.
Methods: FLT3/ITD and NPM1 mutation status was evaluated by performing DNA polymerase chain reaction assays on 39 bone marrow samples obtained at initial diagnosis from the patients with AML1/ETO fusion gene positive AML. GeneScan analysis was performed to confirm the FLT3/ITD mutation and to measure mutant levels.
Results: Of total 39 patients, 11 patients (28.2%) demonstrated the aberrant FLT3/ITD mutations. The median age of patients was 40 years (range, 17–75 years). There were 24 males (61.5%) and 15 females (38.5%). There was no statistically significant difference in age, gender, leukocyte count, hemoglobin level, platelet count and percentage of peripheral or bone marrow blasts between the patients with or without FLT3/ITD. No NPM1 mutation was found in these AML Patients. To analyze the response to or outcome of therapy, we evaluated 34 patients who received intensive induction chemotherapy containing cytarabine. In univariate analysis, there was no significant difference in complete response rate (FLT3/ITD+: 100% vs. FLT3/ITD−: 95.6%, p = 0.48). However, the presence of FLT3/ITD was associated with higher relapse rate in these patients (FLT3/ITD+: 72.7% vs. FLT3/ITD−: 27.3%, p = 0.01).Significant shorter leukemic-free survival (LFS) was observed in patients with FLT3/ITD compared with those without FLT3/ITD (6.9±1.0 ms vs. 18.9±10.9 ms, p = 0.01), but there was no statistical significance in overall survival (OS) (10.6±0.6 ms vs. 16.5± NA ms, p = 0.56).
Conclusions: This study demonstrates that the presence of FLT3/ITD mutations is a significantly higher relapse rate and shorter LFS in AML1/ETO positive patients. Therefore, a stratified treatment plan such as stem cell transplantation may be warranted for the AML1/ETO positive AML harvoring FLT3/ITD mutation.
In Vivo Effects of Zoledronic Acid on Bone Remodeling.
Authors: Pozzi Samantha , Hideshima Teru , Vallet Sonia , Mukherjee Siddhartha , Chhetri Shweta , Cirstea Diana , Vaghela Nileshwari , Thomas Clare , Rosa Dilani , Ikeda Hiroshi , Okawa Yutaka , Kiziltepe Tanyel , Schoonmaker Jesse , Schipani Ernestina , Bouxsein Mary , Anderson Kenneth C. , Raje Noopur 
Published: October 2019

Abstract
Zoledronic acid (ZA) is an amino-bisphosphonate with very potent antiresorptive activity widely used in the treatment of multiple myeloma (MM) bone disease. Recently, the increasing incidence of osteonecrosis of the jaw and its possible association with prolonged use of amino-bisphosphonates such as ZA has been reported. Therefore, we here studied the effects of ZA on bone remodeling in vitro and in vivo. Although ZA has been shown to inhibit osteoclastogenesis and increase bone mineralization, data on its effects on osteoblastic activity and on bone formation are conflicting. To study the effects of ZA on osteoblasts (OB), 5 week old C57BL/6 mice were treated with low and high doses of ZA intraperitoneally (IP) weekly. The dose ranged from 0.05-1mg/kg, with the highest dose recapitulating a lifetime dose of ZA over a 5 year period in an adult MM patient. Blood was collected at baseline and weekly thereafter. IP calcein injections were administered to study bone formation rates. Consistent with its known effects on bone mass and density, in vivo DXA scans in ZA-treated animals demonstrated an increase in whole body bone mineral density (BMD). ZA treatment was associated with a dose-related increase in trabecular bone at the distal femur, evaluated by microCT and confirmed by static histomorphometry. ELISA assays showed a decrease in TRACP5B (bone resorption), as expected due to the anti-osteoclastic activity of ZA. In addition to osteoclast (OC) inhibition, mice treated with ZA also showed alterations in OB activity. Specifically, serum osteocalcin (a marker for bone formation) levels were lower in ZA treated mice, and dynamic histomorphometry confirmed decreased bone formation rates. In order to study the mechanism of our in vivo observations, we tested the effects of ZA on OB, OC, and bone marrow stromal cells (BMSCs) treated in vitro with ZA (0.01μM to 100μM) for 7, 14, and 21 days. Decreased viability during differentiation of both OB and OC was observed, without any significant effects on BMSCs. This was associated with decreased alkaline phosphatase activity, suggesting functional impairment of OB activity. Our data therefore suggests that ZA impairs OB number and activity, in addition to effects on OC and may impair normal physiologic bone remodeling. Ongoing studies will determine the molecular mechanisms whereby ZA mediates these sequelae and inform future studies of ZA use in patients with MM bone disease.
Binding of TACI and APRIL to Syndecan-1 Confer on Them a Major Role in Multiple Myeloma.
Authors: Moreaux Jerome , Sprynski Anne-Catherine , Mahtouk Karene , Moine Philippe , Robert Nicolas , Rossi Jean-François , Klein Bernard 
Published: October 2019

Abstract
B-cell activating factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) are produced by the bone marrow microenvironment of patients with multiple myeloma (MM) and are growth factors of multiple myeloma cells (MMC). BAFF and APRIL share two receptors - TACI and BCMA - and BAFF binds to a third receptor, BAFF-R. We previously reported that TACI expression is a good indicator of a BAFF-binding receptor in human myeloma cell lines (HMCL), unlike BCMA that is expressed on all HMCL. BAFF-R is lacking. More recently, Ingold et al (J Exp Med; 2005) and Hendriks at al (Cell Death Differ; 2005) identified proteoglycans as the APRIL-specific binding partners. Bischof et al (Blood; 2006) demonstrated that TACI binds also heparan sulfate (HS) chains, in particular to syndecan-1, syndecan-2 and syndecan-4. Syndecan-1 is expressed by plasma cells and epithelial cells and is involved in several cellular processes relying on interactions with extra-cellular matrix proteins, growth factors, chemokines and adhesion molecules. We found a very large binding of APRIL (mean fluorescence activity ≥ 500), unlike BAFF, at the surface of all syndecan-1+ HMCL. These syndecan-1+ HMCL also highly bound TACI-Fc molecules, unlike BCMA-Fc or BAFF-R-Fc molecules. This large binding of APRIL or TACI-Fc molecules was abrogated by heparitinase pretreatment of MMC, removing the HS chains or by preincubation of APRIL and TACI-Fc with heparin. These data were extended to patients primary myeloma cells. In agreement with this large binding to MMC, APRIL was 15 to 40 fold more efficient than BAFF to stimulate the growth of HMCL. The APRIL growth factor activity could be inhibited using heparin, unlike that of BAFF. Our data establish that syndecan-1, by concentrating large levels of APRIL and TACI at MMC surface, can promote APRIL/TACI signaling that induces survival and proliferation of MMC. Heparan sulfate chain inhibitors could be helpful to synergize with BAFF/APRIL inhibitors in MM disease.
The Expression of CD56 Is Frequently Accompanied with the Expression of Neuronal Cell Markers and Its Down-Regulation Is Induced by IL-6 in Human Myeloma Cells.
Authors: Iqbal Mohd S. , Otsuyama Ken-ichiro , Shamsasenjan Karim , Abroun Saeid , Amin Jakia , Islam Abul , Kawano Michio M. 
Published: October 2019

Abstract
Human myeloma cells have the marked phenotypic heterogeneity of surface marker expressions, possibly because of loss of PAX-5 expression. Especially, ectopic expression of CD56, one of non-B cell lineage markers, is frequently detected on primary myeloma cells from more than 80% patients with overt myeloma. However, only 2 (NOP2 and AMO1) out of 10 myeloma cell lines were CD56(+). In primary myeloma cells as well as CD56(−) myeloma cell lines, the treatment with forskolin could induce the expression of CD56 in the in vitro culture. In most CD56(+) primary myeloma cells as well as myeloma cell lines, the expressions of neuronal cell markers such as neuron specific enolase (NSE), nestin, β-tubulin III or chromogranin A were found coincidentally. By gene expression profiling, CD56(+) myeloma cell lines showed the marked expressions of transcription factors involved in neuronal cell lineage. On the other hand, addition of IL-6 down-regulated the expression of CD56 in CD56(+) myeloma cell lines in the in vitro culture. In 13 out of 60 patients with overt myeloma, these myeloma cells showed CD56(−) and their values of plasma CRP were significantly increased and MPC-1(−)CD45(+) immature myeloma cells were also increased compared to those in CD56(+) myeloma cases. Therefore, these results indicate that the expression of CD56 is possibly due to phenotypic changes into neuronal cell lineage, and IL-6 can block these phenotypic changes, keeping PAX-5(−) myeloma cells being uncommitted cells to any lineage.
The JAK2 Kinase Inhibitor LS104 Induces Growth-Arrest and Apoptosis in JAK2V617F Positive Cells.
Authors: Lipka Daniel B. , Hoffmann Linda S. , Heidel Florian , Markova Boyka , Kasper Stefan , Breitenbuecher Frank , Kindler Thomas , Levine Ross , Elliot Joseph , Huber Christoph , Fischer Thomas 
Published: October 2019

Abstract
The JAK2V617F-mutation (V617F) is a novel, highly prevalent molecular marker in Ph-negative myeloproliferative disease (MPD). In vitro, the V617F mutation confers cytokine independent growth of Ba/F3 cells expressing erythropoietin receptor (EpoR) and constitutive activation of the JAK2 kinase and of the JAK-STAT pathway. In a murine bone-marrow transplant model the V617F-mutation alone is sufficient to induce a polycythemia vera-like phenotype. Therefore, mutant JAK2 kinase is a promising target for kinase inhibitor development. In this report, we characterize the small molecule LS104 (previously CR4; Grunberger et al., Blood 2003) as a novel non-ATP-competitive JAK2V617F kinase inhibitor. Ba/F3 cells stably transfected with EpoR and either the V617F-mutant (Ba/F3-EpoR-VF) or wildtype JAK2 (Ba/F3-EpoR-WT) were treated with LS104. Apoptosis assays as well as immunoblotting of JAK2 and of downstream signalling pathways were performed. The effects of LS104 on kinase activity were determined in an in vitro JAK2 kinase assay. A combination of LS104 with JAK-inhibitor I, which acts via the ATP-binding site, was tested in apoptosis assays. Finally, growth of endogenous erythroid colonies (EECs) obtained from patients with V617F-positive MPD was tested upon addition of LS104. LS104 selectively and dose dependently induced apoptosis in Ba/F3-EpoR-VF cells as compared to Ba/F3-EpoR-WT control cells. By immunoblotting we found inhibition of JAK2 autophosphorylation and of downstream targets as STAT5, AKT and ERK upon treatment with LS104. Activation of these targets by JAK2 was confirmed in experiments using JAK2 siRNA. The IC50 for JAK2 in an in vitro kinase assay using LS104 was <5μM, and this effect was not reversible using increased ATP-doses. Combination treatment of Ba/F3-EpoR-VF cells using LS104 plus JAK-inhibitor I lead to significantly increased apoptosis as compared to each substance alone. Furthermore, we observed 89% inhibition of in vitro formation of EECs at 10μM LS104 whereas growth of CFU-GM obtained from normal controls was virtually unaffected. Taken together, our data show that LS104 specifically inhibits JAK2 kinase activity and JAK2 downstream signals and thereby induces apoptosis in V617F-positive cells. Our data suggest, that LS104 either irreversibly binds to the ATP-binding site or acts as a substrate kinase inhibitor and may be combined with ATP-competitive JAK2 inhibitors to enhance treatment efficacy. Growth of EECs from patients with MPD is shown to be significantly suppressed by LS104. Based on these data, a phase I/II clinical trial of LS104 for patients with JAK2V617F-positive MPD has been initiated recently.
Choosing the Right Patients for Clinical Trials in Essential Thrombocythemia or Polycythemia Vera: Leukemic or Fibrotic Transformation Risk Assessment among 1061 Patients from a Single Institution.
Authors: Tefferi Ayalew , Gangat Naseema , Wolanskyj Alexandra P. , Schwager Susan M. , Pardanani Animesh , Mesa Ruben A. , McClure Rebecca F. , Li Chin-Yang , Hanson Curtis A. 
Published: October 2019

Abstract
Background: In both polycythemia vera (PV) and essential thrombocythemia (ET), aspirin and/or hydroxyurea therapy provide adequate protection from thrombosis but not from disease transformation into acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or myelofibrosis (MF). In designing clinical trials with new drugs, including the use of small molecule JAK2 inhibitors, in either ET or PV, it is important to identify patients who are at a higher risk of early transformation into AML/MDS/MF as well as those in whom the long-term risk of these complications is too low to justify exposure to experimental drugs with unknown short-term and long-term toxicity profile.
Methods: Information on an institutional database of 1061 patients with either PV (n=458) or ET (n=603) was updated in July of 2007. The World Health Organization criteria were used for diagnosis of PV, ET, AML, MDS, and MF. Two different approaches were used to assess both early and overall risk of AML/MDS/MF development in both ET and PV. In the first approach, three distinct groups were delineated and their presenting features compared; group A was comprised of patients who have remained AML/MDS/MF free after a minimum follow-up of 20 years whereas groups B and C included patients who developed either AML/MDS or MF, respectively, in the first decade of their disease. In the second approach, prognostic factors for AML/MDS/MF-free survival were examined among the entire cohort of 1061 patients.
Results : In ET, the number of patients that fulfilled the above-mentioned criteria for inclusion in groups A, B, and C were 40, 12, and 8; the three groups displayed significant differences in the prevalence, at diagnosis, of lower than normal hemoglobin level (8% vs. 58% vs. 38%; p=0.0004), male sex (18% vs. 58% vs. 50%; p=0.01), and arterial thrombosis at diagnosis (p=0.03), respectively. However, only the former two remained significant during multivariable analysis that included age as a covariate. In PV, the number of patients in groups A, B, and C were 23, 18, and 12; the only difference between the three groups was the association between group B and leukocytosis (p=0.02). Cox regression analysis of the entire 1061 ET/PV patients cohort, including 65 AML/MDS/MF events in ET and 36 AML/MDS events in PV, confirmed the inferior AML/MDS/MF-free survival in ET associated with lower than normal hemoglobin and AML/MDS-free survival in PV associated with leukocytosis (Figure).
Conclusion : The current study identifies PV patients with leukocytosis as being the most appropriate and ET patients without anemia as the least appropriate for consideration of participation in experimental drug treatment trials.
Figure Figure Figure Figure