bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Study of Low-Dose Decitabine for the Front-Line Treatment of Older Patients with Acute Myeloid Leukemia (AML).
Authors: Cashen Amanda , Schiller Gary J. , Larsen Julie S. , Cullen Michael T. , DiPersio John F. 
Published: October 2019

Abstract
Decitabine (Dacogen™) was recently approved for the treatment of patients with myelodysplastic syndromes (MDS). Response in MDS is associated with reversal of the hypermethylated phenotype of silenced genes. The prevalence of hypermethylated genes contributing to AML progression, coupled with the challenges involved in the treatment of AML in the elderly, is a basis for exploring the activity of decitabine in this patient population. The objective of this phase II trial was to estimate the rate of morphologic complete response (CR) in patients with AML. To be eligible for the study, patients had to be at least 60 years old with newly diagnosed, untreated AML with intermediate- or poor-risk cytogenetics, and they could not be candidates for standard induction chemotherapy. Decitabine was given at a dose of 20 mg/m2 over 1 hour for 5 consecutive days every 4 weeks. At the time of the analysis, 27 patients were enrolled in the trial (14 men, 13 women; median age = 69 years, range = 61–87) and received at least 1 cycle of treatment (median = 4, range = 1–10). Seventeen patients (63%) received 3 or more cycles of treatment. Seven of 27 patients (26%) responded, 2 patients (7%) with a morphologic CR, 1 patient (4%) with a complete cytogenetic response (CRc), and 4 patients (15%) with a morphologic CR with incomplete blood count recovery (CRi) according to AML response criteria (Cheson, JCO 2003). In addition to these defined responses, 11 other patients demonstrated clinical benefit by achieving stable disease, with 4 of these patients having a >25% reduction in bone marrow blasts. Median time to response was 3 treatment cycles. Of the 13 patients with a prior history of MDS, 6 patients had a response (CR, CRc, or CRi, 46%). Two of 2 patients with leukemia cutis exhibited complete resolution of skin lesions and responded (CR or CRi). Eight patients discontinued treatment prior to receiving 3 cycles because of death, progressive disease, or patient decision. All patients were evaluated for safety. Besides myelosuppression, the most commonly reported adverse events considered related to decitabine treatment were fatigue, nausea, febrile neutropenia, vomiting, and asthenia. Decitabine given daily for 5 days showed activity in patients with newly diagnosed AML, with a toxicity profile that was manageable in this older patient population. The results to date are comparable to those from previous studies in AML patients using a variety of decitabine schedules, which have reported CR rates from 14% to 33% (Blood2004;103:1635, Blood2005;106:527a, Cancer2006;106:1794). Updated response and adverse event data will be available at the time of presentation.
Homoharringtonine Based Triple-Drug Regimen as Induction Chemotherapy for De Novo Acute Myelogenous Leukemia.
Authors: Jin Jie , Qian Wenbin , Liu Hui , Jian Daozi , Mai Wenyuan , Tong Hongyan , Men Haitao 
Published: October 2019

Abstract
HAA regimen, consisting of homoharringtonine (HHT), aclarubicin and cytarabine (Ara-C), is an efficacious chemotherapy regimen for induction treatment of acute myelogenous leukemia (AML). HHT, a plant alkaloid that is derived from a Chinese evergreen tree, has been shown to inhibit protein, DNA, and RNA synthesis by inhibition of chain initiation. HAA regimen consists of HHT administered at a dose of 4 mg/m2/day by continuous infusion over 4 hours or 2 mg/m2 intramuscular injection twice daily on days 1–3, aclarubicin administered at a dose of 12 mg/m2/day by continuous infusion over 2 hours on days 1–7, and cytarabine (Ara-C) given at a dose of 75 mg/m2 twice daily on days 1–7. Granulocyte colony-stimulating factor (Lenograstim) 5 μg/kg/day subcutaneously was started from the day neutrophil count <0.5×109/l, and continued until the day neutrophil count >1.0×109/l on 3 successive days. For patients with partial remission (PR) after the evaluation of the first course of the therapy, another same induction HAA regimen was administered. Between May 1999 and June 2006, 80 patients consisted of 31 male and 49 female patients were enrolled. All patients had newly diagnosed with de novo AML and had not received any induction treatments before. Out of them, 3 were M1, 44 M2, 2 M4, and 31 M5 according to FAB classification criteria. The median age was 36 (14–59) years. Of all the 76 patients with cytogenetic analysis available, 13 had favorable karyotype, 58 intermediate karyotype, and 5 unfavorable karyotype. In all, 68 (85%) patients achieved complete remission (CR), and the first single course of this induction regimen resulted in a CR rate of 75%. The CR rate of 100%, 88% and 20% were achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. We also found that patients with M5 achieved a CR rate of 74% (23/31), while patients with M1 or M2 94% (44/47). The toxicities associated with this regimen were no more than those expected with standard chemotherapy, and the most common non-hematological toxicity was infection. This study suggested that HAA regimen is a safe regimen and it is efficacious, well-tolerable induction therapy for newly diagnosed de novo AML, the use of G-CSF (Lenograstim) appears to be safe, with little risk of accelerating leukemic relapse. A high CR rate can be achieved with only one or two courses of this regimen. Besides, cytogenetics is an important prognostic factor.
Impact of Pegfilgrastim on Hematological Reconstitution and Incidence of Neutropenic Fever after Consolidation Therapy with High-Dose Cytarabine in Acute Myeloid Leukemia: Comparative Analysis between AMLSG 07-04 and the German AML Intergroup Trial.
Authors: Schlenk Richard F. , Dohner Konstanze , Groner Silia , Hartmann Peer C. , Krauter Jürgen , Ganser Arnold , Dohner Hartmut 
Published: October 2019

Abstract
Therapy using high-dose cytarabine (HiDAC) according to the CALGB scheme (3g/m2 bid. days 1,3,5) is recognized as a standard consolidation treatment for younger adult patients with acute myeloid leukemia (AML). Pegfilgrastim has been shown to be effective in reducing the duration of neutropenia in the treatment of solid tumors and it seems to be even more effective than Filgrastim in reducing the incidence of neutropenic fever. The objective of the current study is to investigate the effect of pegfilgrastim given after HiDAC consolidation within our AMLSG 07-04 clinical trial. The AMLSG 07-04 trial was initiated in September 2004 (age 18–60 yrs). Consolidation therapy consists of 3 cycles of HiDAC (3g/m2 bid. days 1,3,5) with pegfilgrastim 6mg given at day 10 after start of chemotherapy. As a control group, patients randomized from AMLSG into the German AML Intergroup protocol using the same scheme for consolidation therapy with permitted interventional application of G-CSF were used. Data from 127 patients and a total of 285 cycles are available, including 104 patients of the AMLSG 07-04 trial and 23 patients of the German AML Intergroup trial. Data from all three cycles were pooled for the comparison between AMLSG 07-04 (prophylactic pegfilgrastim) and German AML Intergroup (interventional G-CSF) trials. The duration of leukopenia and neutropenia was significantly shorter in patients receiving prophylactic pegfilgrastim (p=0.01 and p=0.008, respectively) compared to patients with interventional G-CSF, which was given in 16% of the pts. This was paralleled by a lower incidence of neutropenic fever with 53% in patients receiving prophylactic pegfilgrastim compared to 77% in patients with interventional G-CSF (p=0.0004). Data from 12 patients and 23 cycles were available for pharmocokinetics of pegfilgrastim. The median peak G-CSF serum level was 221 ng/ml (range 57–553 ng/ml) measured between 24 and 48 hours after the administration of pegfilgrastim and median terminal half-life was 5 days (range 3–7 days). G-CSF serum levels returned to normal in all patients after neutrophil reconstitution. Multivariable regression analysis for longitudinal data on G-CSF serum levels revealed total leukocyte count (p=0.02) and presence of neutropenic fever (p=0.03) as statistically significant variables. In conclusion, the administration of pegfilgrastim shortened the duration of leuko- as well as neutropenia and reduced the rate of neutropenic fever in pts. with AML receiving consolidation therapy with high-dose cytarabine.
Gene Expression Profiling of Diffuse Large B-Cell Lymphomas Supervised by CD21 Expression.
Authors: Miyazaki Kana , Yamaguchi Motoko , Kimura Miho , Ogawa Shoko , Ueno Satoshi , Katayama Naoyuki , Shiku Hiroshi , Kobayashi Tohru 
Published: October 2019

Abstract
We have reported that CD21 expression in tumor cells is a favorable prognostic factor in diffuse large B-cell lymphomas (DLBCLs)(Ogawa S, et al. Br J Haematol, 2004; 125: 180–86). In the present study, we investigated the relationship between CD21 expression and the groups of germinal center B-cell-like (GCB) DLBCLs and activated B-cell-like (ABC) DLBCLs. The diagnosis of DLBCL was made according to the WHO Classification. CD21 in tumor cells was examined by means of immunohistochemistry using frozen sections. Forty cases of DLBCLs were investigated using Agilent 44K human oligo-microarrays (Agilent Technologies, Palo Alto, CA). GCB and ABC DLBCLs were identified based on Rosenwald’s gene set (Rosenwald A, et al. N Engl J Med, 2002; 346: 1937–47). Four cases (10 %) of 40 DLBCLs were found to be GCB DLBCLs, and 36 cases ABC DLBCLs. Incidence of CD21-positive cases was 50% (2/4) in GCB DLBCLs and 39% (14/36) in ABC DLBCLs. Overall survival of 36 patient with ABC DLBCLs were shown in Fig.1.
Fig. 1 Fig. 1.
Signature genes to distinguish between CD21-positive and CD21-negative DLBCLs were as follows; IgM (P=0.00017), CCR6 (P=0.0011), IL7 (P=0.0017), IgK (P=0.0037), EBI2 (P=0.0066), CD24 (P=0.0099) etc. were overexpressed in CD21-negative DLBCLs, and CR2 (CD21) (P=0.0010), MKNK2 (P=0.0028), LMO2 (P=0.00478), CDKN2A (P=0.0059), PDE8B (P=0.0066) etc. were overexpressed in CD21-positive DLBCLs. In 40 cases of DLBCLs, overall survival of patients with sIgM-positive DLBCL was significantly worse than that of patients with sIgM-negative DLBCL (P=0.023). Furthermore, in 216 consecutive cases of DLBCLs analyzed by immunohistochemistry using frozen sections from 1987 to 2004, overall survival according to sIgM expression was significantly different (P=0.013).
In conclusion,CD21 expression was a favorable prognostic factor in ABC DLBCLs.A top feature gene to distinguish between CD21-positive and CD21-negative DLBCLs was IgM. CD21 expression seemed to be related to the differentiation level of lymphoma cells.sIgM expression itself was a poor prognostic factor in ABC DLBCLs and in whole DLBCLs.
Spindle Checkpoint Insufficiency and Unscheduled APC-Dependent Proteolysis in Acute Myeloid Leukemia.
Authors: Schnerch Dominik , Felthaus Julia , Engelhardt Monika , Waesch Ralph M. 
Published: October 2019

Abstract
Genetic instability including aneuploidy is frequent in most cancers. The spindle assembly checkpoint (SAC) is a mitotic surveillance mechanism responsible for accurate chromosome segregation. Unattached chromosomes or lack of spindle tension are sensed by the SAC. The activated SAC inhibits the ubiquitin-ligase anaphase-promoting complex (APC), which prevents the proteolysis of cell cycle regulators in order to delay progression through mitosis and allow cells to recover from defective mitotic spindle attachment. Spindle checkpoint malfunction proved to favor the generation of aneuploidy. In our recent work we investigated the roles of essential SAC proteins in acute myeloid leukemia (AML). We found the SAC-protein Bub1 to be posttranscriptionally downregulated in all investigated AML cell lines. As a consequence, after exposure to the microtubule disrupting agent nocodazole we observed a defective mitotic delay mechanism in comparison to SAC-competent cell lines and increased apoptosis consistent with the effects of Bub1 downregulation by RNA interference. At the molecular level we found a dramatic decline in mitotic regulator levels such as cyclin B1 and securin despite lasting spindle disruption. Additional data showed that the levels of these regulator proteins can be efficiently restored by exposure to the proteasome inhibitor MG-132 indicating that APC-dependent proteolysis is directly involved in SAC insufficiency. Thus, continuous activation of the APC triggers degradation of essential regulator proteins even in leukemic cells faced to mitotic stress such as complete spindle disruption. Such defects can lead to establishment of aneuploidy in vivo. Our findings emphasize a role of SAC insufficiency and unscheduled proteolysis in rise and progression of AML with complex karyotype.
Array-CGH Based Genomic Profiling in B-Cell Chronic Lymphocytic Leukemia Reveals Specific Correlations of Genomic Imbalances and Prognostic Subgroups and Underlines the Consistency of Chromosomal Aberration Patterns within This Disease.
Authors: Schwaenen Carsten , Kienle Dirk , Krober Alexander , Ruf Sandra , Winkler Dirk , Kohlhammer Holger , Kestler Hans A. , Lichter Peter , Wessendorf Swen , Dohner Hartmut , Stilgenbauer Stephan 
Published: October 2019

Abstract
Chronic lymphocytic leukemia of B-cell type (B-CLL) is characterized by a number of typical genomic aberrations. In comparison to patients with normal karyotypes or 13q deletions patients with high risk imbalances such as deletions of 11q, 17p or unmutated IgVH status have a higher risk for advanced disease and a significantly shorter survival.
For a precise mapping of chromosomal imbalances as well as to verify the number of aberrations per case in different genetic subgroups of B-CLL (e.g. del11q, del13q, del17p, +12 or unmutated IgVH status) we performed high resolution genomic profiling using a genomic DNA-chip containing 2.800 probes. Target clones compriseda large genome-wide cluster of clones covering the genome at a distance of approx. 1.5Mb andclones mapping to genomic regions or genes of possible pathogenetic relevance in lymphoma.
This chip covers approximately 10% of the human genome.
In 93 (70%) of 133 analyzed B-CLL cases 171 genomic imbalances were identified (between 1–7 aberrations/case). Besides the confirmation of known recurrent chromosomal aberrations, previously unknown recurrent imbalances were detectable on 2p (8%), 4p (4%), 7p-q (5%), 10q (5%) and 20p (3%). Most of these imbalances were of larger extension (> 10 Mb) and therefore impeded a further delineation of minimal aberrant regions and the identification of possible candidate genes. The mean number of chromosomal aberrations per case (= genomic complexity) in IgVH unmutated CLLs was approx. 2 times higher than in mutated cases (0,77 vs. 1,58 per case). 84% of samples with > 2 aberrations showed an unmutated IgVH status. Moreover, most of the previously unknown imbalances were identified within this group. A higher genomic complexity was also shown for samples with gain on 2p vs. balanced 2p status (2.2 times higher; 2.5 vs. 1.2) and in samples with del17p vs. balanced 17p status (3.7 times higher; 3.52 vs. 0.95). 11q aberrations had no impact on the number of genomic aberrations per case (1.6 vs. 1.2). Moreover, we found a strong association of 2p gains and an unmutated IgVH status (100%).
Array based genomic profiling confirmes the chromosomal aberration structure and underlines the consistency of chromosomal aberration patterns of B-CLL. The biological and prognostic relevance of 2p gains and unmutated IgVH mutational status have to be further investigated.
Occurrence of Chromosomal Translocations as Independent Prognostic Factor in Chronic Lymphocytic Leukemia.
Authors: Mayr Christine , Schulz Cathrine , Stilgenbauer Stephan , Kröber Alexander , Döhner Hartmut , Jäger Ulrich , Kainz Birgit , Hopfinger Georg , Hoffmann Rüdiger , Wendtner Clemens , Hallek Michael , Speicher Michael R. 
Published: October 2019

Abstract
Background: The course of chronic lymphocytic leukemia (CLL) is highly variable. Therefore, there is a need for prognostic factors that are readily performed and have a high predictive power.
Methods: The occurrence of translocations, a recently identified prognostic factor in CLL (Blood2006;107:742–751), was studied in 148 previously untreated, mostly early-stage patients and compared with respect to treatment-free survival (TFS) to several prognostic factors (Binet stage, mutational status of immunoglobulin genes, CD38, thymidine kinase serum concentration and cytogenetic aberrations detected by interphase FISH). To investigate chromosomal translocations, we applied a new method, CpG oligodeoxynucleotide stimulation that allows efficient preparation of metaphase spreads from CLL cells.
Results: The occurrence of translocations classified the majority of patients with poor prognosis. If translocations were investigated in addition to the currently used prognostic factors they identified those patients who were classified to be in a low-risk group based on traditionally used criteria, who had in fact a high risk for progression. Vice versa, patients in the high-risk groups for progression who did not have translocations had a long TFS. There was a substantial overlap of patients who had translocations and additional risk factors. But when we omitted patients who had translocations in addition to a given risk factor, we found that the respective risk factor lost its prognostic significance for the remaining patients. The two factors that retained their prognostic power in these patients were translocations and the Binet stage. This could suggest that the prognostic significance of the currently used factors derives from their frequent co-occurrence with translocations. Finally, multivariate analyses demonstrated that Binet stage (p=0.02) and translocations (p=0.0005) are the factors with the highest impact on TFS in our study cohort.
Conclusion: We present a method for efficient preparation of metaphase spreads in CLL cells in order to investigate chromosomal translocations. The occurrence of translocations is an independent prognostic marker in CLL. Finally, translocations occur not as a late event in the course of the disease and may define a new biological subgroup in this disease entity.
Analysis of B-CLL Transcriptomic and Proteomic Profiles: Differences between Molecular Subgroups.
Authors: Lewintre Eloisa Jantus , Marin Miguel , Reinoso Cristina , Montaner David , Dopazo Joaquín , Calvete Juan Jose , Garcia-Conde Javier 
Published: October 2019

Abstract
INTRODUCTION: B cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder with a variable clinical course. Patients (pts) with unmutated (unmut) IgVH gene show a shorter progression free survival and overall survival than the patients with IgVH mutated (mut). To understand the differences between molecular subgroups of B-CLL we have studied transcriptomic and proteomic profiles on samples from 40 B-CLL pts (Binet stage A).
MATERIAL AND METHODS: 100 μg of total PBMC proteins were used for IEF followed by 2D electrophoresis. Image analysis of scanned gels was used to identify statistically differentially expressed proteins. Image acquisition and analysis were performed using the Ludesi software (http://www.ludesi.com). Selected spots were subjected to automatic digestion and the proteins were identified by MALDI-TOF (Voyager DE-Pro, Applied Biosystems) peptide mass fingerprint using the Protein Prospector software. To confirm the initial results, sequencing of selected peptide ions was carried out by collision-induced dissociation (CID) with a nESI-QTRAP mass spectrometer from Applied Biosystems. Eight proteins were validated by Western Blot.
Total RNA from B cells was used to analyze the expression profile by hybridization with Whole Human Genome U133 Plus 2.0 Array from Affymetrix. Normalization, differential gene expression and functional annotations were analyzed using the GEPAS suite (http://www.gepas.org). qPCR using TaqMan primers/probes was used for validation of the microarray data
RESULTS: When we compared IgVH mut vs unmut transcriptomic and proteomic profiles, we found more than 600 differentially expressed genes and 12 proteins ( fdr <0.05 adjusted for multiple test contrast and p<0.05, Mann-Whitney’s test, for gene and proteins, respectively). In tables 1 and 2 we show some of the most differentially expressed gene/proteins in each group of pts. Validation of results from microarrays and proteomic data using qPCR and Western blot are in progress. We obtained positive correlation between transcriptomic and proteomic profiles, (corr=0.21, p=0.04, Pearson’s correation test) suggesting that common features are found using both approximations.
CONCLUSION: We found a number of interesting gene/proteins that could be able to differentiate molecular subgroups of B-CLL pts. The study of these proteins and genes may lead to better understand the different clinical behaviour of IgVH mut and unmut B-CLL forms, but validation with a larger group of pts is still necessary.
Table 1: Genes differentially expressed
IgVH mut IgVH unmut Genes annotated using their gene symbol BCL11A MGC9913 DUSP22 RGS4 PDLIM5 CRY1 RDH13 GGT2 PHF15 DMD SVH TUBB6 ADAM29 LPL ITPKB ITGA9 RBKS BCL7A NFATC1 MYEOV RIN3 PPP1R9A Table 2: Proteins differentially expressed IgVH mut IgVH unmut Proteins were annotated according to their gene symbol VIM ERP29 COTL1 CCT2 S100A9 PSMB10 HSPD1