bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comorbidity Scoring Using the Hematopoetic Cell Transplantation Comorbidity Index (HCTCI) Is Predictive of Early Death Rate and Event Free Survival (EFS) in Patients over 60 Years of Age Receiving Induction Therapy for Acute Myeloid Leukemia (AML).
Authors: Giles Francis , Borthakur Gautam , Ravandi Farhad , Faderl Stefan , Verstovsek Srdan , Pierce Sherry , Jabbour Elias , Cortes Jorge , Kantarjian Hagop 
Published: October 2019

Abstract
The majority of patients diagnosed with AML who are 60 years of age or over are not offered specific anti-leukemia therapy. Outcomes in the minority who are offered standard induction are considerably inferior to those in younger patients. While a major factor is AML with inherently worse biology, comorbidity seen in the elderly which increases vulnerability to the adverse events of induction cytotoxic chemotherapy is also a major factor. The HCTCI is useful in predicting nonrelapse mortality and overall survival post stem cell transplantation (Sorror. Blood.2005;106:2912) As this scale represents a refinement of the Charlson Comorbidity Index, and was developed specifically in patients with hematologic malignancies, we investigated whether it might also be applicable to elderly patients receiving AML induction chemotherapy. Pre-therapy comorbidity scoring by the HCTCI was assessed in a cohort of 177 patients over 60 years of age with AML treated at MDACC with standard idarubicin and ara-C induction since 1990. Median patient age was 70 (60–89), 64% were male, 26% had PS 2 or above, 60% had an antecedent hematological malignancy, and 90% had non favorable cytogenetics (33% -5/-7). 22% of patients had HCTCI scores of 0, 30% had scores of 1–2, and 48% scores of 3 or more. Complete response rates in the 3 groups were 64%, 43%, and 42% respectively (p=0.051). Early death (defined as death within 28 days from time of commencing induction therapy) was 3%, 11%, and 29% respectively (p= <0.001). HCTCI score was also highly correlated with EFS with a score of 0 associated with a median EFS of 26 weeks in contrast to a median EFS of 6 weeks in those with a HCTCI score greater than 0 (p=0.03). Even in the probably highly selected subset of patients over 60 years of age currently deemed suitable for standard induction therapy for AML, scoring of pre-treatment comorbidity using the HCTCI is predictable of early death rates and EFS. The further investigation of HCTCI scoring in AML induction, including its value relative to other standard prognostic indicators, is warranted. Stratification of patients for current therapy or for protocol entry based on HCTCI scores seems reasonable.
Impact of Comorbidities on the Outcome of Elderly Patients with Acute Myeloid Leukemia.
Authors: Etienne Anne , Esterni Benjamin , Charbonnier Aude , Prébet Thomas , Coso Diane , Stoppa Anne-Marie , D’Incan Evelyne , Doglio Marie-Françoise , Sainty Danièle , Arnoulet Christine , Mozziconacci Marie-Joëlle , Gastaut Jean-Albert , Vey Norbert 
Published: October 2019

Abstract
Elderly patients with acute myeloid leukemia (AML) have a very poor prognosis, explained by the biologic characteristics of the disease but also by host-related factors including comorbidities. The objective of this study was to determine the prognostic role of comorbidities in this population. Between 1995 and 2004, 133 patients aged 70 years or older with newly diagnosed acute non promyelocytic leukemia, were treated with intensive induction chemotherapy (“3+7” regimen) at a single institution. Comorbidities at diagnosis were retrospectively evaluated using an adapted form of the Charlson Comorbidity index (CCI) (Sorror et al., Blood2004;104:961–968). Seventy-five patients achieved a complete response (CR) (56.4%) and 23 patients died during induction chemotherapy (17.3%). Comorbidity scores at diagnosis were 0 for 83 patients (68%), 1 for 16 patients (13.1%), and > 1 for 23 patients (18.7%). The median overall survival (OS) was 9 months (95% CI: 6–13) and was significantly poorly affected by high leukocyte count (≥ 30 G/l) and elevated serum creatinine level (>1.5 x upper normal limit). By multivariate analysis, we identified 4 adverse prongnostic factors for CR: unfavorable karyotype, leukocytosis ≥ 30 G/l, expression of CD34 on blast cells and a CCI > 1. Age was not found to be a significant prognosic factor for either CR or survival. When a score of 0 or 1 was affected to each prognostic variable, patients could be separated into a low-risk group (score= 0–1; 22% of patients), an intermediate-risk group (score= 2; 41% of patients) and a high-risk group (score≥3 ; 37% of patients), having 87%, 63% and 37% chance of achieving CR following conventional induction chemotherapy, an 8-week mortality rate of 9%, 22% and 34% (p=0.02), and a 2-year overall survival rate above 50%, less than 30% and 15%, respectively (p=0.01).
Our results show that comorbidity is an important prognostic factor for elderly patients with AML which may help the physicians’ decision making. Its capture at diagnosis should be prospectively evaluated in larger study for its future use for risk-stratification among elderly patients treated for AML.
VEGF-TRAP Exhibits Potent In Vivo Anti-Tumor Activity in Acute Myeloid Leukemia Xenograft Models.
Authors: Lal Deepika , Park Jennifer A. , Drake Allison S. , Hoelcle Brandon J. , Wang Eunice S. 
Published: October 2019

Abstract
Vascular endothelial growth factor (VEGF) is known to play a pivotal role in solid tumor angiogenesis, but its role in hematological cancers is less well established. Recent data have shown that subsets of acute leukemias express aberrant VEGF receptors (VEGFR) and rely on both autocrine and paracrine VEGF-VEGFR mechanisms for proliferation, migration, and extramedullary disease. We evaluated the efficacy of a soluble decoy receptor for VEGF-A (VEGF-TRAP, provided through collaboration with CTEP and Sanofi-Aventis/Regeneron Pharmaceuticals) in xenografts of human acute myeloid leukemia (AML) established in SCID mice. All three AML cell lines (ML-2, HEL, HL60/tVCR) used in these studies expressed VEGF isoforms and VEGFR by RT-PCR. The HL60/tVCR line has previously been shown to express Pgp glycoprotein conferring resistance to multiple chemotherapy agents. Mice bearing subcutaneous leukemia xenografts were treated with PBS (vehicle control) or VEGF-TRAP (5 or 25 mg/kg) twice a week for three weeks (for a total of six doses). We found that VEGF-TRAP therapy consistently reduced leukemia tumor volumes by an average of 76–93% versus controls in all three xenograft models. VEGF-TRAP treated tumors were visibly less vascular than control tumors and demonstrated large necrotic areas with only small islands of viable cells by immunohistochemistry. In vivo administration of VEGF-TRAP, which binds VEGF secreted both by tumor (human) and host (murine) cells, was significantly more effective in reducing leukemia tumor volumes (87%) than anti-human VEGF antibody (bevacizumab (Avastin)) treatment (5 mg/kg three times per week) (68% tumor reduction, p<0.05). Moreover, mice treated with VEGF-TRAP also demonstrated a marked elevation of murine VEGF levels (up to thousand fold higher than control or Avastin-treated animals), which persisted over the duration of therapy despite much smaller overall tumor volumes. These data show that the in vivo anti-VEGF effects mediated by VEGF-TRAP may result in significant feedback response loops in the host microenvironment as well as potential direct effects on tumor cells. Additional experiments investigating the effects of VEGF-TRAP in systemic leukemia mouse models are ongoing. Because VEGF-TRAP treatment alone was not curative, we further examined the effects of combination VEGF-TRAP and chemotherapy (cytarabine or doxorubicin) treatment on subcutaneous leukemia xenograft growth. Data in HL60/tVCR and ML-2 mouse models suggest a potential additive effect with concomitant VEGF-TRAP and doxorubicin (3 mg/kg 2x/week) therapy but not concomitant VEGF-TRAP and cytarabine (2.0 mg 5x/week) therapy.
CONCLUSIONS: These preclinical data demonstrate the potent in vivo tumor activity of VEGF-TRAP, a novel VEGF inhibitor, in AML. Our results support further clinical development of this agent in acute myeloid leukemia, particularly in combination with anthracycline chemotherapy.
ZM447439, a Novel Aurora Kinase Inhibitor, Induces Growth Arrest and Apoptosis of Human Leukemia Cells.
Authors: Ikezoe Takayuki , Nishioka Chie , Tasaka Taizo , Taniguchi Ayuko , Komatsu Naoki , Kuwayama Yoshio , Togitani Kazuto , Phillip Koeffler H. , Taguchi Hirokuni 
Published: October 2019

Abstract
The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases have been shown in solid tumors and considered to associate with aneuploidy and carcinogenesis. This study found that Aurora kinase A and B were aberrantly expressed in human leukemia cell lines (n=15, e.g., PALL-1, -2, HL-60, NB4, MV4-11, etc.) as well as freshly isolated leukemia cells from individuals with acute myeloid leukemia (n=44) compared to peripheral blood mononuclear cells from healthy volunteers (n=12), as measured by real-time PCR. In addition, ZM447439, a novel selective Aurora kinase inhibitor, induced growth inhibition, accumulation of cells with 4N DNA content and apoptosis in human leukemia cells as measured by thymidine-uptake, cell cycle analysis and annexin V staining, respectively. Especially, profound growth inhibition occurred in PALL-1 and -2 cells which possess wild-type p53 gene. Of note, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy volunteers. Taken together, inhibition of Aurora kinase may be a promising treatment strategy for the individuals with leukemia.
Sorafenib Potently Inhibits ETV6-PDGFRβ and FLT3 Mutants, and Shows Activity Against FLT3 Mutants That Are Resistant to Other Small Molecule Inhibitors.
Authors: Lierman Els , Lahortiga Idoya , Van Miegroet Helen , Mentens Nicole , Marynen Peter , Cools Jan 
Published: October 2019

Abstract
Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, Nexavar®) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma. Sorafenib also has activity against receptor tyrosine kinases from the PDGFR and VEGFR families. Here we show that sorafenib is a potent inhibitor of the ETV6-PDGFRβ tyrosine kinase that is associated with chronic myelomonocytic leukemia. Oncogenic FLT3 receptor tyrosine kinase mutants implicated in the pathogenesis of acute myeloid leukemia are also potently inhibited by sorafenib, including some of the resistant mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the AML cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication. In contrast, the imatinib resistant KIT(D816V) mutant that is associated with systemic mastocytosis was found to be resistant to sorafenib. These results suggest that sorafenib could be used for the treatment of myeloid leukemias expressing activated forms of PDGFRβ, FLT3, and some PKC412 resistant mutants, but not for leukemias expressing imatinib resistant KIT(D816V).
Induction of Bim Facilitates Apoptosis in Leukemia Cells Treated with HDAC Inhibitors.
Authors: Stubbs Matthew C. , Kim Teresa , Krivtsov Andrei , Atadja Peter , Armstrong Scott A. , Kung Andrew L. 
Published: October 2019

Abstract
Lymphoblastic leukemias containing chromosomal translocations involving the Mixed Lineage Leukemia (MLL, HRX, ALL-1) gene, as well as most acute myeloid leukemias (AMLs) have relatively poor clinical prognoses due in part to intrinsic drug resistance. Therefore, new avenues are being explored for treatment of MLL-rearranged ALL and AMLs. One possible new therapeutic class currently being investigated is the histone deacetylase (HDAC) inhibitors. We utilized the histone deacetylase inhibitor NVP-LAQ824 (Novartis, Basel, Switzerland) and analyzed its effects on MLL rearranged and other myeloid leukemias. We also made use of an MLL-AF9 expressing myeloid leukemia cell line (AKLG) derived from purified murine leukemia stem cells to perform gene expression analysis on NVP-LAQ824 treated cells in order to further understand the mechanism of action of HDAC inhibitors, and to potentially identify cooperating therapeutics. NVP-LAQ824 inhibits cell growth at similar concentrations for all cell lines and primary patient samples tested (~25–50nM) as determined by MTT assay 48 hours after treatment. NVP-LAQ824 does not appear to induce apoptosis solely through inhibition of the HSP90/FLT3-ITD complex as cell lines possessing FLT3-ITD (a HSP90-chaperoned protein) and cells without this mutation have similar drug sensitivities. In fact, in cells overexpressing FLT3-ITD that are treated with NVP-LAQ824, phospho-FLT3-ITD levels do not diminish. Microarray data indicated that NVP-LAQ824 induces the BH3-only family member bim. This finding was verified by Western blotting in all cell lines and patient samples tested. Further, shRNA-mediated knockdown of Bim induced relative resistance of cells to NVP-LAQ824. The expression profile also showed similarities to gene expression patterns of dexamethasone treated cells, namely, increased bim levels and decreased expression of c-myc, raising the possibility of synergy between the two drugs. Using MTT assays, we discovered that NVP-LAQ824 in low doses (25nM) induces sensitivity to dexamethasone in glucocorticoid resistant cell lines in a glucocorticoid receptor (GR) dependent manner. Therefore, our data indicate that NVP-LAQ824 may reverse glucocorticoid resistance and may provide insight into glucocorticoid resistance in MLL rearranged leukemias. The biochemistry behind HDAC inhibitors merits further study.
A Randomized Study with or without Intensified Maintenance Chemotherapy in Patients with Acute Promyelocytic Leukemia Who Had Become Negative for PML-RARα Transcript after Consolidation Therapy: The Japan Adult Leukemia Study Group (JALSG) APL97 Study.
Authors: Asou Norio , Kishimoto Yuji , Kiyoi Hitoshi , Okada Masaya , Kawai Yasukazu , Tsuzuki Motohiro , Horikawa Kentaro , Matsuda Mitsuhiro , Shinagawa Katsuji , Kobayashi Tohru , Ohtake Shigeki , Nishimura Miki , Takahashi Masatomo , Yagasaki Fumiharu , Takeshita Akihiro , Kimura Yukihiko , Iwanaga Masako , Naoe Tomoki , Ohno Ryuzo 
Published: October 2019

Abstract
The use of all-trans retinoic acid (ATRA) has markedly improved therapeutic outcome in patients with acute promyelocytic leukemia (APL). Non-cross resistance between ATRA and chemotherapeutic drugs has contributed to not only a high complete remission (CR) rate but also a decrease in the relapse rate, leading to the significant improvement in disease-free survival (DFS) and overall survival (OS) rates. However, it is not clear whether maintenance chemotherapy actually prevents relapse in APL patients treated with ATRA and chemotherapy. If short-term therapy without maintenance shows identical DFS rates as compared to long-term therapy with maintenance, it would be beneficial for quality of life of patients as well as to medical costs. In these aspects, to determine an efficacy of maintenance/intensification chemotherapy, this study was designed to compare the DFS and OS rates in previously untreated adult patients with APL who showed absence of PML-RARα fusion transcript at the end of consolidation therapy and were randomly allocated to either maintenance therapy or observation. Of 302 registered, 283 patients were assessable and 267 (94%) achieved a CR. Predicted 6-year OS and DFS rates were 83.7% and 69.2%, respectively. The PML-RARα fusion gene was amplified using bone marrow samples at the diagnosis and after consolidation therapy by the reverse transcriptase-polymerase chain reaction analysis. The detection limit of PML-RARα fusion transcript in this assay was 10-4. Among 235 patients who completed 3 courses of consolidation chemotherapy, five (2.1%) were positive for the PML-RARα fusion transcript. Three of them subsequently relapsed and another one patient received allogeneic hematopoietic stem cell transplantation. On the other hand, 230 patients (97.9%) showed no PML-RARα transcript in the bone marrow cells at the end of consolidation. Of these, 175 patients were randomly assigned to receive moderately intensive and intermittent maintenance chemotherapy (n=89) or to observation (n=86). Predicted 6-year DFS was 63.2% for the chemotherapy group and 81.8% for the observation group, showing no statistically significant difference (p=0.102). Predicted 6-year OS in patients assigned to observation was 98.7% and was significantly higher than 85.9% in those allocated to maintenance therapy (p=0.013). These results indicate no benefit from adding maintenance chemotherapy in APL patients who are negative for PML-RARα fusion transcript after 3 courses of intensive consolidation.
Prognostic Analysis of Aberrant Somatic Hypermutation of RhoH in Diffuse Large B Cell Lymphoma.
Authors: Katsumi Akira , Hiraga Junji , Iwasaki Toshihiro , Abe Akihiro , Kiyoi Hitoshi , Matsushita Tadashi , Kinoshita Tomohiro , Naoe Tomoki 
Published: October 2019

Abstract
The Rho family of small GTPases including Rho, Rac, Cdc42 has been well characterized as molecular switches to transduce signals from plasma membrane to the downstream effectors. RhoH, a member of the Rho family, is specifically expressed in hematopoietic cells, especially in T and B lymphocytes, and has been reported to downregulate Rac and LFA-1. As RhoH is GTPase deficient and constitutively active, GTP-bound form, the activity of RhoH is directly related to the level of expression. Aberrant somatic hypermutation (SHM) of RhoH gene has been reported in 43% of Diffuse Large B cell Lymphoma (DLBCL) patients (Pasqualucci L et.al., Nature.2001;412:341–346). Although several studies demonstrated the SHM of DLBCL and other lymphoid malignancy, few of the previous reports investigated the clinical significance of SHM. To definitively resolve this issue, we have screened for SHM of RhoH gene in the lymph node samples from 100 previously untreated DLBCL cases. These patients were diagnosed and treated at Nagoya University hospital since 1987 to 2002. Informed consent was obtained from all patients. Samples from 12 cases of reactive lymphadenopathy were also screened for negative control. Intron 1 of RhoH gene was amplified and screened by a denaturing HPLC technique (Transgenomic WAVE_). Mutant samples were confirmed by direct sequencing. We found 78 mutations (76 point mutations, 2 insertions) unique to individual tumor DNAs in 36 of 100 DLBCL cases (36%) in RhoH. Overall, 73 out of 78 were novel SHM, and five were same mutations as previously reported (Pasqualucci L et.al., Nature.2001;412:341–346). The number of mutation in one patient ranged from one to six, and 20 patients had more than one mutations. These mutations were distributed in a region throughout the first 1.6 kb of the RhoH gene. The presence of aberrant SHM in RhoH gene impacted neither on overall survival nor disease free survival (p=0.36 and 0.69, respectively). The absence of aberrant SHM correlated with advanced stage (stage III and IV, p<0.05). Taken together, our study demonstrated that although the SHM might contribute the lymphomagenesis through regulation of RhoH gene expression, it has less impacts on survival of DLBCL patients.
Association between Drug-Metabolizing Enzymes Polymorphisms and Diffuse Large B-Cell Lymphoma Risk in the Middle Eastern Population.
Authors: Siraj Abdul K. , Bu Rong , Al-Rasheed Maha , Ibrahim Muna , Bavi Prashant , Abubaker Jehad , Al-Jomah Naif , Mourad Walid , Al-Dayel Fouad , Ezzat Adnan , El-Solh Hassan , Uddin Shahab , Al-Kuraya Khawla 
Published: October 2019

Abstract
The last four decades have seen significant increase in the incidence of non-Hodgkin’s lymphoma (NHL) as a possible result of increasing environmental carcinogens exposure. Based on the increasing evidence for the association between carcinogens exposure related cancer risk and xenobiotic gene polymorphisms. We have undertaken a case control study on xenobiotic gene polymorphisms in Saudi individuals with a diagnosis of diffuse large B-cell lymphoma (DLBCL).
Polymorphisms in five genes (CYP1A1, GSTT1, GSTP1, GSTM1 and NQO1) were characterized in 187 individuals with DLBCL and 513 normal controls using polymerase chain reaction (PCR) based method. We chose the Saudi population as our study population because of its high consanguinity and its relative genetic homogeneity.
The CYP1A1*2C, GSTT1 null and GSTP1 TT genotype were all found to be significant predictors of DLBCL risk (odds ratio 6.62, 11.94 and 3.42 respectively). None of the other alleles tested for proved to be significant indicators of DLBCL risk. These results suggest that the risk of DLBCL may indeed be associated with xenobiotics - metabolism and thus with environmental exposures.
Table 1 Distribution of polymorphisms in healthy population and lymphoma patients. Polymorphism Genotype Control group Lymphoma patients p OR CYP1A1 −/− 384(76.5%) 104(78.8%) *2A −/2A 105(20.9%) 24(18.18%) 0.543 0.844 2A/2A 13(2.6%) 3(2.27%) 1.000 0.852 2A allele 13% 11.36% 0.659 0.839 CYP1A1 −/− 443(88.2%) 121(91.66%) *2B −/2B 50(10%) 10(7.58%) 0.505 0.732 2B/2B 9(1.8%) 1(0.76%) 0.697 0.407 2B allele 6.8% 4.55% 0.424 0.646 CYP1A1 −/− 497(99%) 125(94.7%) *2C −/2C 5(1%) 4(3.03%) 0.090 3.181 2C/2C 0 3(2.27%) 0.008 ND 2C allele 0.5% 3.8% 0.011 6.627 NQO1 C609T CC 295 (58.5%) 94 (62.7%) CT 177 (35.1%) 37 (24.7%) 0.051 0.656 TT 32 (6.4%) 19 (8.7%) 0.059 1.863 CT+TT 209 (41.5%) 56 (37.3%) 0.395 0.841 GSTP1 2293 CC 389 (76.3%) 113 (77.9%) CT 113 (22.2%) 24 (16.6%) 0.240 0.731 TT 8 (1.5%) 8 (5.5%) 0.017 3.422 CT+TT 121 (23.7%) 32 (22%) 0.739 0.910 GSTP1 A1578G AA 170 (33.5%) 56 (35%) AG 271 (53.5%) 96 (60%) 0.772 1.075 GG 66 (13%) 8 (5%) 0.013 0.368 AG+GG 337 (66.5%) 104 (65%) 0.774 0.937 GSTT1 P 385 (75%) 36 (20.1%) D 128 (25%) 143 (79.9%) <0.001 11.948 GSTM1 P 233 (45.4%) 91 (50%) D 280 (54.6%) 91 (50%) 0.300 0.832 Table 2 Distribution of combined GSTT1 and GSTM1 polymorphisms in case and control group. Genotype Control Case p OR Null: Complete deletion of GSTT1 and GSTM1 allele Present 423 (82.8%) 109 (60.9%) Double Null 88 (17.2%) 70 (39.1%) <0.001 3.087