bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Sensitive Risk Score for Directing Treatment in Younger Patients with AML.
Authors: Burnett Alan K. , Hills Robert K. , Wheatley Keith , Goldstone Anthony H. , Prentice Archie G. , Milligan Donald 
Published: October 2019

Abstract
Treatment strategies for younger patients (<60 years) with AML who enter complete remission (CR) are frequently decided on a risk assessment based on cytogenetic characterisation. Most collaborative groups have devised prognostic cytogenetic groupings of favourable, intermediate or poor risk which have relapse risks of 25–35%, 50–60%, and 80–85% respectively. The precise lesions in each group might vary by study group, but the overall discrimination is consistent. Favourable and possibly intermediate risk cases may not receive transplantation, whereas poor risk cases will. Outcomes for poor risk cases have failed to improve over the years, and if not transplanted these patients are candidates for experimental therapy. There is concern that cytogenetic segregation may not on its own be sufficiently sensitive on an individual patient level, and the inclusion of other factors may better customise risk. We performed a Cox regression analysis on 1937 non-APL cases with complete data who entered CR in the MRC AML10 and 12 trials. Increasing age, cytogenetic risk group higher WBC, male sex, secondary disease, and incomplete response to course 1 were all identified as significantly (p= 0.05) associated with poorer survival. These respectively contributed 0.013 per year, 0.651 per cytogenetic group, 0.002 per WBC unit (/nl), 0.170 for males, 0.221 for secondary disease, and 0.195 for PR/ 0.390 for resistant disease following course 1 to an individual’s total risk score. The groups were separated into scores of <2.00 (good risk), 2.00–2.667 (standard) and >2.667 (poor risk) which gave excellent discrimination for survival from CR at 5 years of 63%, 47% and 24% (p<0.00001). The score was prospectively validated in 897 patients who entered the MRC AML15 trial and was confirmed to be predictive with survivals from CR of 69%, 61% and 42% (p<0.00001). The value of the new score was to move patients out of the old cytogenetic category. The major effect was to move 274 patients from intermediate risk to poor risk and 42 poor risk patients to intermediate risk (table). This score has implications for treatment approach since, relatively, 60% more patients were identified as high risk and are therefore candidates for experimental therapy, or may, from Mantel-Byar analysis, benefit from transplantation.
MRC Risk Group Total Good Standard Poor Crosstabulation of old and new risk group classification New Risk Classification Good 309 28 0 337 (14%) Standard 51 1288 42 1381 (59%) Poor 2 274 353 629 (27%) Total 362 (15%) 1590 (68%) 395 (17%) 2347
Critical Role of CIB1 in Endothelial Cell Function and In Vivo Ischemia-Induced Angiogenesis.
Authors: Zayed Mohamed A. , McFadden Andrew , Yuan Weiping , Hartnett Mary E. , Chalothorn Dan , Faber James , Parise Leslie V. 
Published: October 2019

Abstract
CIB1, a 22kDa EF-hand containing calcium binding protein, was originally identified in a yeast two-hybrid screen as a binding partner for the cytoplasmic tail of the platelet integrin αIIb. CIB1 also associates with a number of kinases and modulates their activity, suggesting that CIB1 is an important regulatory molecule. Recently, we found that CIB1 is expressed in multiple endothelial cell (EC) types. We therefore tested the role of CIB1 in EC function in vitro, and in angiogenesis both ex vivo and in vivo. To test the role of CIB1 in EC function in vitro, we reduced endogenous CIB1 levels in ECs by RNA interference with an shRNA-delivered by lentivirus. CIB1 depletion significantly decreased EC haptotaxis on fibronectin and EC vascular tube formation on growth factor-reduced Matrigel. Treatment with FGF-2, an angiogenic factor, did not counter the observed inhibition of haptotaxis and tube formation by shRNA against CIB1. However, CIB1 overexpression enhanced FGF-2-induced EC haptotaxis relative to control cells. Similarly, ECs derived from CIB1 null mice exhibited a significant decrease in haptotaxis, tube formation, and proliferation compared to ECs isolated from wild-type littermate controls. In ex vivo aortic ring and tibialis anterior muscle culture assays, CIB1 null cultures supplemented with serum or FGF-2 demonstrated reduced blood vessel sprouting compared to wild-type littermate control cultures. Finally, in vivo assays for hyperoxic retinal angiogenesis and hind-limb induced-ischemia revealed a decrease in post-ischemia retinal neovascularization and Doppler hind-limb blood perfusion recovery, although developmental retinal angiogenesis in CIB1 null mice appeared normal. In conclusion, these findings support a critical role for CIB1 in EC function that appears to be important for ischemia-induced angiogenesis.
Identification of Genomic Classifiers That Distinguish Induction Failure in T-Lineage Acute Lymphoblastic Leukemia in COG Study 9404.
Authors: Winter Stuart S. , Khawaja Hadya , Jiang Zeyu , Griffin Timothy , Asselin Barbara , Larson Richard S. 
Published: October 2019

Abstract
The clinical features of age, white count, and presence of extramedullary disease cannot predict risk for induction failure (IF) in patients who present with T-cell acute lymphoblastic leukemia (T-ALL). On the basis of recent observations that gene expression profiles can distinguish clinicopathologic cohorts of patients with acute leukemia, we hypothesized that microarray analyses performed on diagnostic T-ALL bone marrow samples might identify a genomic classifier for IF patients. Using a case-control study design for children and young adults treated for T-ALL on Children’s Oncology Group Study 9404, we analyzed 50 cryopreserved T-ALL samples using Affymetrix U133A Plus 2 genechips, which have 54,000 genes, ESTs and genomic classifiers. Following RMA normalization, we used Prognostic Multi-array Analysis (PAM) to identify a 116-member genomic classifier that could accurately identify all 6 IF cases from the 44 patients who achieved remission. Within the IF cohort, 37 genes were up-regulated and 79 were down-regulated in comparison to other outcome groups. To further investigate the genetic mechanisms governing IF, we developed four cell lines with acquired drug resistance: Jurkat and Sup T1; each having resistance to daunorubicin (DNR) and asparaginase (ASP). Using a comparative analysis for fold-change in gene expression among 6 IF patients and the T-ALL DNR and ASP-resistant cell lines, we identified seven genes that were up-regulated, and another set of seven genes that were commonly down-regulated. To validate the potential use of our 116-member gene set in predicting IF in T-ALL, we tested our genomic classifier in 42 cases which were treated on COG study 8704 and hybridized to the Affymetrix U133Av.2 chip. Because only 85 probes were shared between U133A Plus 2 and U133Av. 2 chips, we employed shrunken class centroids to constrain our classifier to 25 rank-ordered probes. This smaller classifier correctly identified the single IF case in 8704, as well as another patient who was an early treatment failure, indicating that similar genomic classifiers may identify IF patients in different clinical trials. These results indicate that genetic profiling may be useful in prospectively identifying IF patients in T-ALL. In addition, we identified genes that were commonly upregulated in IF patients and T-ALL cell lines with intrinsic drug resistance.
Bcl2 Accelerates Onset but Not Progression of MYC-Induced T-Cell Leukemia in Transgenic Zebrafish.
Authors: Feng Hui , Langenau David M. , Kilgore Jennifer A. , Quinkertz Andre , Jette Cicely A. , Neuberg Donna S. , Campos-Ortega Jose A. , Kanki John P. , Look Thomas 
Published: October 2019

Abstract
MYC is a potent proto-oncogene aberrantly expressed in over 70% of human cancers. Our laboratory has previously generated transgenic zebrafish models that overexpress the mouse c-Myc gene fused to green fluorescent protein and develop T-cell Acute Lymphoblastic Leukemia (T-ALL) that recapitulates the human disease both molecularly and pathologically. These previous models have been limited by the inability to breed non-conditional transgenic animals due to disease onset prior to sexual maturity and by the low disease penetrance when conditional transgenic embryos are injected with Cre RNA. In order to improve these zebrafish T-ALL models to make modifier screens feasible, we have generated a new stable Cre transgenic line in which Cre expression is regulated by a heat-shock promoter, and have established a conditional compound transgenic zebrafish model by breeding this pzhsp70-Cre line with conditional rag2-lox-dsRED2-lox-EGFP-mMyc transgenic fish. Upon heat-shock treatment, 81% of compound transgenic fish developed tumor by 197 days of life (mean latency: 120 ± 43 days). Using this model, we showed that overexpression of zebrafish Bcl-2 strikingly accelerates the disease onset, suggesting that suppression of apoptosis is critical for zebrafish Myc-induced tumorigenesis and serving as a proof of principle for subsequent modifier screens. Paradoxically, overexpression of Bcl-2 delays the progression of T-ALL, implying functional roles for Bcl-2 in addition to the inhibition of apoptosis.
Clinical Significance of Free Circulating CD4 and CD8 in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome.
Authors: Abdool Adam , Giles Francis , Hodge Menna , O’Brien Susan , Keating Michael , Jilani Iman , Kantarjian Hagop , Estey Elihu , Albitar Maher 
Published: October 2019

Abstract
CD4 is a 55-kDa glycoprotein expressed mainly on the surface of helper/inducer T-cells and monocyte-derived cells. CD4 responds to antigen associated with MHC class II. CD8 is a disulfide-linked dimer of either an alpha- and a beta-chain or two alpha-chains (34 kDa each). CD8 is expressed on T-cytotoxic/suppressor cells and binds to antigen associated with MHC class I. Since leukemias are known to elicit an immune response we speculated that, owing to turnover of the responding T-cells, free circulating CD4 (cCD4) and CD8 (cCD8) could be detected in the plasma of patients with leukemias. We have developed a bead-based sandwich immunoassay to measure cCD4 and cCD8 in the plasma. Using this assay, we measured cCD4 and cCD8 in the plasma of 98 patients with AML and 50 patients with MDS and assessed associations with clinical behavior. Whereas cCD4 levels did not differ significantly between AML (median, 918 U/μl; range, 0–30038 U/μl) and MDS (median, 1029 U/μl; range, 0–48338 U/μl in MDS), cCD8 levels were significantly higher in AML (median, 120390 U/μl; range, 0–694820 U/μl) than in MDS (median, 105340 U/μl; range, 0–810110 U/μl) (P=0.03). The ratio of cCD4 to cCD8 was significantly higher in AML and MDS than in 51 normal controls (P <0.01). There was no correlation between cCD4 or cCD8 and clinical response or survival in AML patients. In MDS, Cox regression analysis showed that higher levels of cCD4 correlated with longer survival when considered as a continuous variable (P = 0.03) and when the median was considered as a cut-point (P = 0.04). MDS patients with high levels of cCD4 (>929 U/μl) also had longer remission duration (P = 0.01); there was no correlation between cCD8 levels and clinical behavior. These findings confirm that the immune system plays a significant role in the clinical behavior of MDS and shows that CD4 cells are more important immunomodulator in MDS.
Figure Figure
Structure-Based Drug Design of c-Kit Inhibitors for Use in the Treatment of Acute Myeloid Leukemia.
Authors: Maxwell David S. , Pal Ashutosh , Peng Zhenghong , Shavrin Alexandr , Faderl Stefan , Harris David , Van Quin , Liu Zhiming , Verstovsek Srdan , Manshouri Taghi , Ferrajoli Alessandra , Kantarjian Hagop M. , Estrov Zeev , Bornmann William G. 
Published: October 2019

Abstract
Inhibitors of c-Kit kinase have shown clinical relevance in various myeloid disorders, including acute myeloid leukemia (AML). Research in our lab has been oriented towards structure-based drug design of c-Kit inhibitors based on the available crystal structure. We describe the design, synthesis, and preliminary results from the in-vitro testing of several c-Kit kinase inhibitors in both enzymatic and cell-based assays. The design resulted from in-silico screening of several targeted libraries via docking to the crystal structure of c-Kit, followed by aggressive post-filtering by several criteria to significantly bias synthesis efforts towards candidate compounds with best chance for success. This led to 128 structures built from 8 common structural cores, from which 2 cores were initially selected based on the synthetic feasibility. Five compounds were initially synthesized, and were immediately followed by 60 compounds with variations to probe local structure-activity relationships. The initial set of compounds, designated APCKxxx, was tested in a c-Kit kinase assay; two compounds were found to have an IC50 in the high nM to low uM range. These compounds have been tested in a MTT-based assay using OCIM2 and OCI/AML3 cell lines. In the c-Kit expressing OCI/AML3 cell line, all five compounds possessed an EC50 < 500 nM and two had and EC50 ~100 nM. Our most recent results show that these compounds also show efficacy in some imatinib-resistant cell lines. We will discuss these results and our strategies for the second generation of compounds that are optimized for better activity, selectivity, and ADME properties.
Expression of Glucocorticoid-Induced TNF Receptor Ligand on Acute Myeloid Leukemia Cells Mediates the Release of Immunosuppressive Cytokines and Impairs NK Cell-Mediated Immune Surveillance.
Authors: Krusch Matthias , Baltz Katrin M. , Baessler Tina , Kloss Mercedes , Kumbier Ingrid , Peterfi Andrea , Kanz Lothar , Salih Helmut R. 
Published: October 2019

Abstract
NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance of hematological malignancies including acute myeloid leukemia (AML). Among the molecules influencing host-tumor interaction are many members of the TNF superfamily, which mediate multiple cellular functions including cellular proliferation, differentiation and cell death. The TNF family member Glucocorticoid-induced TNF Receptor (GITR) costimulates effector T cells, modulates apoptosis and nuclear factor kappa B and abrogates suppression of murine but not human regulatory T cells. Its cognate ligand GITRL has been found in various healthy tissues. Recently we reported that NK cells express GITR, while solid tumors express GITR ligand (GITRL), and GITR/GITRL interaction downregulates NK cell cytotoxicity and IFN-γ production. Here we analyzed the role of GITR and its ligand in AML. We report for the first time that GITRL is expressed on primary AML cells in 18 of 30 patients as determined by FACS and RT-PCR analysis. Reverse signaling through GITRL using a recombinant GITR-Ig fusion protein induces the release of the immunoregulatory cytokines IL-10 and TNF as determined by ELISA. GITRL-mediated cytokine production of AML cells is abrogated by inhibition of mitogen activated protein kinase (MAPK) pathways as demonstrated by addition of the specific p38 MAPK inhibitor SB202190, the specific JNK inhibitor SP600125 and the specific ERK Inhibitor II. Furthermore, binding of AML-expressed GITRL to GITR on NK cells downregulates cellular cytotoxicity and IFN-γ production in AML-NK cell cocultures, which can be overcome by addition of GITR-blocking antibodies as determined by cytotoxicity assays and ELISA. Thus, our data indicate that GITRL expression in AML substantially influences tumor immunoediting and enables the escape of leukemia cells from NK cell-mediated immunosurveillance.
A Phase I Study of the Farnesyltransferase Inhibitor Tipifarnib in a Week- on Week-Off Dose Schedule in Acute Myelogenous Leukemia.
Authors: Kirschbaum Mark , Selwyn Stein Anthony , Tuscano Joseph , Zain Jasmine M. , Popplewell Leslie , O’Donnell Margaret R. , Karanes Chatchada , Krishnan Amrita , Wright John J. , Pulone Bernadette , Rincon Amalia , Frankel Paul , Forman Stephen J. , Edward Newman 
Published: October 2019

Abstract
Tipifarnib (R115777, Zarnestra®) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 30 patients have been accrued. with 27 patients evaluable for toxicity. Median age is 64.5 (range 33–75). Grade 3 toxicities were seen at dose levels 1 (400 mg bid)- metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy, and level 5 (1200 mg bid)- grade 3 creatinine elevation. Other grade 1 and 2 toxicities included fatigue, nausea, anorexia, elevated liver enzymes, increased bilirubin, and renal insufficiency. The maximum target treatment dose, 1600 mg PO bid was attained. There were 3 complete responses (CR) out of 9 patients treated at the 1000–1200 mg bid dose level- after cycle 1 in a 47 year old woman with relapsed AML after autologous transplant, with a 10 month continuing remission as of 8/06 (she underwent successful allogeneic transplant); after 2 cycles in a 69 year old man with relapsed AML, who relapsed after 5 months, (with response after retreatment with tipifarnib), and in a 67 year old man with relapsed AML who achieved PR after one cycle and CR after five cycles. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts.
In AML patients, greater than two fold increase in tipifarnib dosing can be tolerated on this dosing schedule with efficacy perhaps enhanced. Based on these promising results a monotherapy phase 2 or tipifarnib combination study in AML appears warranted.
Phase II Study of Clofarabine and Cytosine Arabinoside in Adult Patients with Relapsed AML and in Elderly Patients with Untreated AML Who Are at High Risk of Anthracycline Toxicity.
Authors: Agura Edward , Brian Berryman R. , Brougher Laura , Cooper Barry , De Leon Andrew , Fay Joseph , Holmes Houston , Maisel Christopher , Molina Arturo , Pineiro Luis , Saracino Giovanna , Tadic-Ovcina Mirjana , Vance Estil 
Published: October 2019

Abstract
PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in adult patients with refractory or relapsed acute myeloid leukemia and in selected elderly patients with untreated AML and heart disease.
PATIENTS AND METHODS: In a phase II, open-label trial, 23 patients with de-novo AML, AML evolved from MDS or relapsed AML received a 5 day regimen consisting of clofarabine 40 mg/m2 intravenously over 1 hour followed within 4 hours by Ara-C 1000 mg/m2. The median age was 68 years (range 39–79 years). Fifteen (65%) had received at least one prior cytotoxic regimen (excluding 5-AZA). Significant cardiovascular disease (history of myocardial infarction, bypass grafting, cardiomyopathy) was present in 52% (12/23) prior to therapy.
RESULTS: 22/23 received at least one cycle of therapy and 5 received 2 cycles. One early death was due to disease progression. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 20 patients are evaluable for response. The histologic response rate (defined as marrow blasts <5%) is 60% (12/20) consisting of 10 (50%) complete remissions and 2 (10%) partial responses. Complete cytogenetic remissions occurred in 9 patients. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation.
CONCLUSION: Clofarabine (40mg/m2) and Ara-C (1000mg/m2) x 5 days is an active and well tolerated regimen in myeloid malignancies including “elderly AML”—a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are being explored for use in allogeneic transplant regimens and with other high-risk patient groups.
Phase I Study of XL-119, a Rebeccamycin Analog, in Patients with Refractory Hematological Malignancies.
Authors: Giles Francis J. , Ravandi Farhad , Cortes Jorge , Estrov Zeev , Faderl Stefan , Ferrajoli Alessandra , Garcia-Manero Guillermo , Thomas Deborah , Wierda William , Verstovsek Srdan 
Published: October 2019

Abstract
XL-119, a water soluble analog of the antibiotic agent rebeccamycin, has demonstrated broad spectrum antitumor activity in preclinical studies, including P388 and L1210 leukemia in murine models. XL-119 intercalates DNA, and inhibits topo II activity by a unique highly potent mechanism which renders it active in etoposide-resistant A549 and HCT 116 leukemia cell lines. On a Phase I study in patients with refractory hematological malignancies XL 119 was given as a 60 minute IV infusion, on D1–5 of 21 day cycles. The starting dose for the initial cohort was 140 mg/m2/d with planned escalation by 20% increments in the setting of a standard 3+3 design. A total of 28 patients (pts) have been treated to date. Three, 5, 3, 6, 3, and 8 have been enrolled to dose levels (DL) of 140, 160, 180, 200, 220 and 240 mg/m2/d, respectively. Median age was 57 years (range 19–82). Median ECOG status 1 (range, 0–2). Diagnoses included: AML (22 pts), MDS (1 pt) and ALL (5pts). AML was either primary refractory or at an advanced relapse state and had failed a median of 3 prior salvage treatments (range 1–10). The pt with MDS had received 4 prior therapies. Pts with ALL had received a median of 3 prior therapies. Dose limiting toxicities (DLTs) were observed in evaluable patients at the following dose levels: 1 patient at 200 mg/m2 experienced DLTs: grade 3 hand-foot syndrome and grade 4 mucositis. An expansion of this dose level yielded no further incidences of DLT. 1 patient at 240mg/m2 experienced DLT with grade 3 mucositis. The cohort was expanded without observation of additional DLTs. Dose level 260 mg/m2 is currently being explored with 2 patients too early for full evaluation. Two patients with refractory AML achieved a significant elimination of marrow blasts and received a second cycle of therapy. Twenty-four of 28 patients had transient reductions in peripheral blood blasts. XL 119 is a well-tolerated myelosuppressive agent which warrants further study in patients with hematological malignancies.