bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of New Method for Measuring Plasma Myeloperoxidase with Clinical Behavior in Acute Myeloid Leukemia and Myelodysplastic Syndrome.
Authors: Abdool Adam , Wang Xiugiang , Jilani Iman , Zhou Weidong , Kantargian Hagop , Estey Elihu , Giles Francis , Albitar Maher 
Published: October 2019

Abstract
We previously reported that levels of myeloperoxidase (MPO) enzyme in plasma of patients with acute myeloid leukemia (AML) may correlate with aggressive disease. However, we found poor reproducibility and significant variability from lot to lot when commercially available kits are used. We developed a cytometric beads assay (CBA) for measuring plasma MPO that shows high reproducibility (CV<10%) with no significant variability with time. More importantly, MPO levels as measured using this CBA assay showed better correlation with clinical behavior in AML and myelodysplastic syndrome (MDS). Based on studying plasma levels of MPO in 98 patients with AML and 50 patients with advanced stage MDS, we found no significant difference in plasma MPO between AML and MDS patients. As expected MPO levels were significantly lower in patients with ALL (N=48) than in AML patient (P=0.04) and MDS (P=0.02). While MPO levels were significantly higher in patients with good cytogenetic abnormalities (P=0.004) in AML patients, MPO levels did not differ between intermediate and poor cytogenetic groups in patients with AML or MDS. Unexpectedly we found a difference between AML and MDS in their correlation with MPO levels and clinical outcome. Patients with advanced stage MDS and high levels of MPO (<300 ng/ml) had significantly longer survival than patients with lower levels (P=0.01). Multivariate analysis showed that this correlation with better survival in this group of MDS patients was independent of cytogenetic grouping. In contrast in AML, higher levels of MPO (>70 ng/ml) correlated with shorter survival (P=0.04). Similarly, patients with acute lymphoblastic leukemia (ALL) and high levels of MPO (>70 ng/ml) had shorter survival (P=0.05). Despite there was a correlation between the commercially available kit for measuring MPO and our CBA method (r=0.71, P<0.0001), the commercial kit did not provide robust data for clinical correlation. This data confirms that confirms that plasma levels of MPO play a role in the biology of the leukemia. Further studies are needed to establish if this role is a reflection of an inflammatory process or a reflection of disease load, although the finding of clinical relevance in ALL suggests that it is more likely reflecting an inflammatory process.
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Efficacy of Imatinib-Based Therapy in a Patient with Resistant NUP214-ABL1 T-Cell Acute Lymphoblastic Leukemia.
Authors: Delaunay Jacques , Abdelali Raouf Ben , Touzeau Cyrille , Chevallier Patrice , Thierry Guillaume , Le Gouill Steven , Ayari Sameh , Harousseau Jean-Luc , Macintyre Elisabeth , Loiseau Herve Avet , Dombret Herve , Talmant Pascaline 
Published: October 2019

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease which represents 25% of adult ALL. In T-ALL, many cryptic abnormalities can only be detected by FISH or RQ-PCR. Herein, we describe the case of a 25 year-old man presenting with a NUP214-ABL1 T-ALL. This rearrangement is observed in about 5% of adult T-ALL, results in ABL1 amplification and has been associated with sensitivity to imatinib in vitro At diagnosis, the patient presented with multiple lymphadenopathies and a high WBC (120 G/L). Blast cells expressed T (CD3, CD5, CD7, and CD8) and myeloid (CD13 and CD33) markers. Karyotype was normal, while FISH analysis revealed HOX11L2 rearrangement and extrachromosomal ABL amplification. Presence of NUP214 exon32-ABL1 exon2 transcript and overexpression of HOX11L2 were both confirmed by RT-PCR. Treatment induction according to the GRAALL-2003 protocol, consisted of a corticosteroïd prephase (d1–7) followed by 5-drug induction (doxorubicin, cyclophosphamide, vincristine, corticosteroid and asparaginase) (d8–21). Because of ALL resistance and presence of severe infection, treatment was stopped at d21 and salvage therapy associating imatinib (400 mg, bid), vincristine (2 mg d1,d8,d15,d21) and dexamethasone (30 mg/m2 d1–2,d8–9,d15–16,d21–22) was initiated at d25. At d50, the patient had reached complete hematological response. He then received monthly consolidation courses combining imatinib (400 mg bid d1–28), vincristine (2 mg d1) and prednisolone (40mg/m2 d1–7). After the second course, he reached major molecular response at d120 (NUP214/ABL1 = 1x10-3 by RQ-PCR) but relapsed at d150. Karyotype was still normal and FISH analysis showed persistance of HOX11L2 rearrangement but loss of extrachromosomal ABL amplification and presence of a third ABL signal (cryptic rearrangement) in the majority of metaphases. Quantitative RT-PCR analysis detected a low level of NUP214/ABL1. We initiated a second salvage combining dasatinib (70 mg bid) and Hyper-CVAD, with achievement of a second hematological CR. After two consolidation courses, the patient is still in hematological CR (8 months) and complete molecular response. He will receive a double cord blood transplant In conclusion, we report here the first case of transitory imatinib efficacy in a patient with NUP214/ABL1 T-ALL, followed by achievement of a secondary remission with dasatinib, despite the partial loss of NUP214-ABL1, in favor of the use of ABL inhibitors in this specific T-ALL subset. We also raise the hypothesis that NUP214/ABL1 may be a secondary oncogenic event.
Adaptation of Augmented Berlin-Frankfurt-Munster (ABFM) Therapy in Adolescents and Young Adults with Acute Lymphoblastic Leukemia (ALL).
Authors: Rytting Michael , Thomas Deborah , Kantarjian Hagop , Cortes Jorge , Borthakur Gautam , Wierda William , Nunez Cesar , Kornblau Steven , Ravandi Farhad , Wells Robert , Brenda Muriera , Anna Franklin , O’Brien Susan 
Published: October 2019

Abstract
Comparisons of survival of adolescents up to age 21 years of age treated on either pediatric or adult ALL protocols so far show improved survival for patients (pts) treated with pediatric therapies. ABFM therapy has been shown to be effective therapy for teen-aged pts up to age 21, and is the standard therapy arm of the current Children’s Oncology Group high-risk ALL trial. We have initiated a trial of ABFM based therapy for pts up to the age of 30 with lymphoblastic leukemia. Pts receive four drug induction with prednisone 60 mg/m2 daily for 28 days, daunorubicin 25 mg/m2 weekly for four doses, vincristine 2 mg weekly for four doses, and a single dose of intravenous pegylated asparaginase (PEG-asp) in week one of therapy. Intrathecal (IT) cytarabine is given on day one, and IT methotrexate is given on days 8 and 29. IT therapy is intensified depending on the presence of spinal fluid blasts. Induction is extended by two weeks for patients who do not acheive a bone marrow morphologic remission (MR) by day 29. Pts that are in MR by day 15 are rapid early responders; they receive one phase of delayed intensification. Pts who are not in MR by day 15 but enter MR by day 29 or 42 are slow early responders; they receive two delayed intensifications. Upon completion of induction, pts continue with intensive phases of chemotherapy for approximately 6 months. They then start 24 months of maintenance therapy. 13 patients with newly diagnosed ALL have been enrolled with a planned enrollment of 80. The median age is 20 (range 14–28). 10(77%) have pre-B ALL and 3(23%) have T-ALL. 12(92%) are rapid early responders. All pts are in MR by day 29. Minimal residual disease (MRD) status is evaluated at day 29 and day 84 by four-color flow cytometry. 8(62%)pts are MRD negative by day 29. All pts so far are MRD negative by day 84. One pt has relapsed. There are no treatment related deaths. Treatment delays for bone marrow suppression are common. There has been 1 allergic reaction to PEG-asp and 2 cases of clinical pancreatitis. 2 pts have had stroke-like symptoms with MRI findings compatible with treatment toxicity; complete clinical resolution has occurred in both. 4 pts have had grade (Gr) 3–4 hyperglycemia. 2 pts have had Gr 3–4 hyperbilirubinemia. 2 patients have been non-compliant. One pt has had Gr 4 sepsis. Other infectious complications are not common. Early evaluation indicates that ABFM therapy is effective in inducing rapid MR in young adults with ALL. The regimen appears tolerable, but morbidity is frequent. Gr 3–4 toxicity occurs more often than recently reported for similar therapy in adults with ALL (Douer D, et al. Blood, 1 Apr2007, 2744050).
Potentiation of Reactive Oxygen Species Is a Marker for Synergistic Cytotoxicity of MS-275 and 5-Azacytidine in Leukemic Cells.
Authors: Gao Shan , Miller Claudia , Boklan Jessica , Chandra Joya 
Published: October 2019

Abstract
Epigenetic therapy, the reversal of aberrant epigenetic changes in tumor cells such as the silencing of tumor suppressor genes through means of DNA hypomethylation and histone deacetylation, has become a successful new mode for cancer treatment. Classes of drugs such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors are currently being used to target these epigenetic changes. Recently, numerous studies supporting the combination of HDACi and DNA methyltransferase inhibitors have emerged, encouraging early clinical trials of these agents together. MS-275 is a novel and highly active benzamide derivative HDACi that has exhibited in vivo and in vitro anti-proliferative activity toward pancreatic, gastric, lung, and ovarian cancer cells. In addition, MS-275 has been evaluated in Phase I/II clinical trials to treat acute leukemias and solid tumors. 5-azacytidine (Vidaza), a DNA methyltransferase inhibitor, has been shown to reactivate tumor suppressor and DNA repair genes through the hypomethylation of cytosines and is used for treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Here we show that MS-275 and 5-azacytidine display synergistic cytotoxicity in AML and ALL (acute lymphocyctic leukemia) cells. Loss of cell viability was increased in a synergistic manner in Jurkat and ML-1 cells treated with the combination of MS-275 and 5-azacytidine. Synergy was assessed using isobologram analysis employed by Calcusyn software. Quantitation of several distinct biochemical apoptotic events, such as DNA fragmentation, phosphotidylserine exposure and caspase-3 activity, also indicated synergistic interactions between MS-275 and 5-azacytidine. Hyperacetylation of histone H3 was also measurably stronger in cells treated with the combination versus either drug alone. Interestingly, intracellular production of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, also increased in a dose dependent and synergistic manner. Since this is a novel marker for this synergism in ALL cells, our data suggest that assessment of oxidative stress can serve as a marker of the concerted action of MS-275 and 5-azacytidine. Recent results from a clinical trial combining MS-275 and 5-azacytidine suggest that the hypomethylation of certain tumor suppressor genes, such as p15, CDH-1, DAPK-1 and SOCS-1, did not correlate with clinical response in myeloid malignancy patients. Thus, identifying new biological markers for clinical activity of these compounds will assist the development of these epigenetic strategies.
Microvesicle Information Transfer from Lung to Marrow Cells.
Authors: Aliotta Jason , Faradyan Sam , Dooner Mark , Dooner Gerri , Quesenberry Peter J. 
Published: October 2019

Abstract
A body of work in the literature has shown that after marrow transplantation into irradiated mice, there appear cells in the lung with an epithelial lung cell phenotype, but with markers of the donor marrow cells. After transplantation of green-fluorescent protein positive marrow cells into lethally irradiated mice, we have previously shown that there are from 3–5% non-hematopoietic cells bearing the donor marrow markers in the lung, most of these being cytokeratin positive (Aliotta et al., Exp Hematol., 34(2):230–41, 2006). We have utilized a cell impermeable double culture chamber to co-culture irradiated and non-irradiated lung across from marrow cells. With 2 or 7 days of co-culture, the marrow cells express the lung-specific mRNAs surfactant proteins B and C and Clara Cell specific protein at high levels. This phenomenon is most pronounced when the lung has been exposed to 500 cGy 5 days prior to initiating co-culture, although it is also seen with non-irradiated lung. Conditioned media from lung exerts the same effects and RNase treatment of the conditioned media markedly decreased this effect. Ultracentrifugation of the conditioned media pellets the converting activity, which appears to reside in microvesicles. These microvesicles were demonstrated to enter marrow stem cells and to enhance their capacity to convert to lung epithelial cells after transplantation. Most recently, we have also shown that the capacity to enter marrow cells varies both with the cell cycle status of lineage negative Sca-1+ murine marrow cells and with the source of the microvesicles, either from irradiated or normal lung. Altogether, these data indicate that microvesicle transfer from damaged tissue may be the basis of some forms of marrow plasticity, which have been previously reported.
Ubenimex Enhances the Gemtuzumab Ozogamicin-Induced Cytotoxicity Against Myeloid Leukemia Cells.
Authors: Takamatsu Yasushi , Jimi Shiro , Yoshimura Yuka , Suzumiya Junji , Tamura Kazuo 
Published: October 2019

Abstract
Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody conjugated to a derivative of a tumoricidal antibiotic calicheamicin. GO alone induces complete remission in 26% of AML patients in first relapse. One way to improve the response rate is to combine GO with other agents. A quantitative relationship has been shown between rates and degrees of CD33 expression and GO-induced cytotoxicity in vitro by using gene transfer to manipulate CD33 expression in myeloid cell lines. We first studied CD33 expression on myeloid leukemia cells by stimulating with several agents in vitro, and found that ubenimex, but not G-CSF, M-CSF, or ATRA, increased CD33 expression on both HL-60 and K562 cells. Ubenimex is an aminopeptidase inhibitor isolated from Streptomyces olivoreticuli and commercially available as an oral agent for clinical use for AML treatment. To investigate whether ubenimex enhances the cytotoxicity of GO, HL-60 and K562 cells were cultured with GO and/or ubenimex for 3 days. When GO was administered, cell viabilities of HL-60 and K562 were reduced to 31.5% and 90.3% as compared with control, respectively. Treatment with ubenimex alone did not influence viabilities of either HL-60 or K562. However, when cells were preincubated with ubenimex and then cultured with GO, cell viabilities decreased to 18.5% and 81.4% for HL-60 and K562, respectively, indicating that pretreatment with ubenimex enhanced GO-induced myeloid leukemia cell death in vitro. We next assessed the mechanism of cell death. The treatment with GO alone and ubenimex alone induced apoptosis in 39.2% and 2.9% of HL-60 cells, respectively. When HL-60 cells were preincubated with ubenimex and then cultured with GO, the number of apoptotic cells increased to 62.9%, demonstrating that ubenimex augments GO-induced apoptosis. Our data suggest that the priming of AML cells with ubenimex should improve the clinical efficacy of GO.
Epstein-Barr Virus Status Correlates with Poor Outcome and Is an Independent Prognostic Variable in De Novo Nodal Diffuse Large B Cell Lymphoma in Peru.
Authors: Beltran Brady , Morales Domingo , Riva Luis , de Mendoza Fernando Hurtado , Quinones Pilar , Yabar Alejandro , Carrasco-Yalan Antonio A. 
Published: October 2019

Abstract
BACKGROUND: Epstein Barr Virus (EBV) positive status is associated with poor survival in Hodgkin lymphoma and T cell NHL.
AIM: In order to define the prognostic impact of Epstein Barr Virus (EBV) infection in newly diagnostic nodal diffuse large B cell lymphoma (DLBCL), we investigated the EBV status in Peruvian DLBCL patients.
PATIENTS AND METHODS: Between January 2002 and December 2004, seventy-four patients, diagnosed with nodal DLBCL, were included in the analysis. Tissues from patients were analyzed for the presence of EBV encoded RNA (EBER) using the in situ hybridization (ISH)
RESULTS: Of the 74 cases, 53 cases (71.6%) were of the non Germinal Center DLBCL type (non GC). This group had a higher IPI than the Germinal Center DLBCL type (GC). Also the non GC DLBCL type had an inferior overall survival compared with GC DLBCL type, but the difference was not significant (p=0.171). Eleven cases (14.9%) were identified as EBER-positive. EBER positive was associated with an advanced age (> 60 years), poorer performance status, more advanced stage, higher IPI and poorer outcome to initial treatment. The EBER+ DLBCL patients demonstrated substantially poorer overall survival (EBER+ vs. EBER−): 1.1 months (95% CI, 0.0–2.6 months) vs. 15.5 months (1.0–30.0 months) respectively, (p=0.001). Most of the cases EBER (+) were of the non GC group. At the multivariable level, EBER status is an independent variable compared with the International Prognostic Index (IPI) (p=0.001) with a 3.2-fold (95% CI, 1.5–7.2) risk for death for positive cases.
CONCLUSION: EBV positive status in de novo, nodal DLBCL was present in 11/74 cases and is a powerful prognostic factor in this Peruvian population. EBV positive status correlated with advanced age, poor performance status, more advanced stage, non-GC group and short survival. New therapeutic strategies should be investigated in this poor prognostic subgroup.
Figure Figure
HAEMACARE Project: Reclassifing Hematologic Neoplasias According Morphological Data.
Authors: Giraldo Pilar , Latre Paz , Franco-García Esther , Alvarez Ramiro , Pascual Mar , Castilla Tomas , Sants Milena , Martos Carmen 
Published: October 2019

Abstract
Aims: The European Project HAEMACARE (VI Frame Research Program), is working in the reclassification of hematological neoplasias included in population based Cancer Registries of 13 European countries with the objective to improve and standardize morphological data validation.
Patients and methods: a multidisciplinary research group of the I+CS integrated by epidemiologists, hematologists, pathologists is working in the reclassification of Hodgkin disease (HD) included in the population based Cancer Registry of Zaragoza (CRZ) in order to reclassify according to WHO and ICD-O classifications and identify the non other specification (NOS) cases. From January 1995 to December 2000, a total of 141 patients diagnosed as Hodgkin disease are included. The sources of data were: Zaragoza population based Cancer Registry, Aragon hematological malignancies Registry (FEHHA) and from the records of public Hospitals and the National Deaths Index. All cases were identified from the CRZ and 35 cases (24.8%) NOS were re-studied by the hematologists and pathologists and reclassified according histological and morphological subtypes of WHO classification. Diagnostic criteria were set for LRCHD: scattered Hodgkin-Reed-Sternberg cells with a classical immunophenotype in a background of small lymphocytes without admixture of eosinophils and neutrophils and without sclerosis nodular lymphocyte predominant HD (NLPHD), mixed cellular (MCD) and lymphocyte-rich classical HD (LRCHD). In 24.8% of cases were necessary to process the samples again or review smears and applied immunochemistry techniques in order to establish accurate diagnosis according the new sub-classification in NLPHD or CHD and distinguish some cases of T-cell rich large B-cell lymphoma. In addition we have calculated the estimated survival according specific morphological subtypes.
Results:
Hodgkin Disease. Histological distribution ICD-0-3 No % males females mean age(y) mean surv(y) No deaths (%) *non other specification NOS* 35 24.8 15 20 43.7 5.8 13 (34.3) CHD 64 45.4 39 25 39.3 7.6 19 (29.7) MCD 21 14.9 15 6 46.3 7.7 4 (19.0) LRCHD 11 7.8 9 2 51.1 6.7 5 (45.5) NLPHD 10 7.0 6 4 51.2 8.3 2 (20.0) Total 141 84 57 43.2 7.1 43 (30.5)
The estimated survival analysis showed a mean of 7.6 years (95% CI: 6.7–8.4) for all cases, median not reached.
Comments: In our study has been necessary to reclassify the 24.8% of cases according WHO criteria. The incidence peaks are classical. The overall survival is similar to describe previously.
The Effects of Zoledronic Acid on Serum Lipids in Multiple Myeloma Patients.
Authors: Gozzetti Alessandro , Martini Giuseppe , Avanzati Annalisa , Franci Beatrice , Marchini Elena , Nuti Ranuccio , Lauria Francesco 
Published: October 2019

Abstract
Nitrogen-containing bisphosphonates (N-BPs) inhibit osteoclast-mediated bone resorption and they are widely used for the treatment of postmenopausal osteoporosis, Paget’s disease and tumor-associated osteolysis. The mechanism of action of these drugs has not been completely clarified but it has been observed that N-BPs may inhibit squalene synthase, as ibandronate, or farnesyl pyrophosphate synthase, as alendronate or pamidronate, inducing also a reduction of cholesterol biosynthesis. Zoledronic acid (ZA) represents a novel N-BPs which has also antitumor activity. To explore the effects of ZA on serum lipids, twenty-six untreated consecutive patients (14 males/12 females; median age 71.4 ± 7.8, range 49–82 years) with SMM (14 IgG/k, 2 IgG/λ, 8 IgA/k 2 IgA/λ) were recruited between October 2004 and March 2005 from the Department of Hematology of the University of Siena. In particular, enrollment criteria were marrow plasmacytosis between 10–30%, no lytic bone lesions, no myeloma related symptoms. In order to enter the study, patients had not to be on treatment for hypercholesterolemia. Patients gave an informed consent before the enrollment. After baseline evaluation, SMM patients were sequentially assigned to receive no treatment (10 patients) or ZA (16 patients), 4 mg administered as a 15 min i.v. infusion at baseline and after 1, 2, 4 and 6 months. Data distribution was expressed as mean ± SD. Two-Sample T-test for independent data were used to evaluate the differences between groups. To test the effect of treatment, we used the Repeated Measures ANOVA Procedure. p value of less than 0.05 were considered significant. Analysis were performed using SPSS software for Windows, version 10.0 (SPSS ltd., Chicago, IL, USA). In all subjects, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and C-terminal telopeptide of Type I collagen (CTX) were measured at baseline and after 1, 3 and 6 months. In the control group no significant changes were observed throughout the study period for any of the biochemical variables. As expected, CTX decreased significantly by 40–50% after ZA administration. In treated patients, we observed a progressive and significant reduction of TC with a maximum decrease of 13% at 6 months; moreover LDL-C decreased by 21% at 6 months while no significant differences were appreciated in HDL-C and TG. Also the indexes of cardiovascular risk improved after ZA administration: TC/HDL-C ratio progressively decreased by 17% and HDL-C/LDL-C ratio increased by 36% showing an effect that appears to be cumulative. In conclusion ZA is able to alter lipid profile more than older N-BPs as pamidronate or neridronate. This effect can be due to the potency of ZA to inhibit FPP synthase that is about 70-fold than pamidronate.