bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stem Cell Transplantation in Remission Improves Survival in Acute Myelogenous Leukemia Associated with FLT3 Mutations
Authors: Borthakur Gautam , de Lima Marcos , Kantarjian Hagop , Xiao Lianchun , de Padua Silva Leandro , Garcia-Manero Guillermo , Giralt Sergio , Ravandi-Kashani Farhad , Pierce Sherry , Champlin Richard 
Published: October 2019

Abstract
Background: Mutations in fms-like tyrosine kinase 3 are thought to be relevant to leukemogenesis. Two types of mutations are described; internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), which mostly affects asparate 835 (D835). ITD mutation is present in 20–30% of patients with acute myelogenous leukemia (AML) and is associated with poor outcome (Yanada, M. et al. Leukemia. 2005 ;19:1345–9). The role of stem cell transplant (SCT) is not established in patients with AML and FLT3 mutation.
Patients and Method: 125 patients (59% male) with AML and FLT3 mutation treated at M.D. Anderson Cancer Center between the years 2003 to 2007 were included in this analysis of predictors for survival. Age, PS, WBC, platelet count, hemoglobin level, bilirubin, creatinine, albumin, beta 2 microglobulin (B2M), response (CR/CRp vs others), transplant recipient status (yes/no) were included in uni and multi-variate analysis.
Results: Seventy-seven percent patients had ITD mutation and fourteen patients (11%) had both ITD and D835 mutation. Median age was 59 years (range, 17–84), WBC count 17.3 x 106/ml (range, 1–300.5), platelet count 50 x 109/ml (range, 7–313) and hemoglobin 8.1 gm/dL (range, 4.2–13.9). Most (98%) had a performance status of 0–2 (median=1) and cytogenetic was diploid in 72%. All patients underwent cytarabine based induction chemotherapy.
Fifty-seven percent patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and induction related death rate was 9%. Eighty-six (69%) patients died and median overall survival (OS) was 10.4 months (95% CI of 7.62 to 14.08 months). There was no difference in OS between ITD mutation and D835 mutation. Twenty-seven patients (22%) underwent stem cell transplantation; 13 in CR1, 7 with bone marrow blast ≥ 10%). On univariate analysis transplant recipient status, PS, response, age, creatinine, albumin and B2M were significantly associated with OS. Patients who underwent transplant had a better OS (median = 15.7 months versus 7.6 months, p=.007) (Fig.1). On multi-variate analysis transplant recipient status, PS, ITD mutation and creatinine impacted OS. Age was a marginally significant predictor for OS.
Conclusion: Stem cell transplantation in CR/CRp appears to improve OS in patients with AML and FLT3 mutation. Results of trials incorporating FLT3 inhibitors into induction/consolidation regimens are eagerly awaited.
Fig.1: Survival by transplant status in patient with AML and FLT3 mutation Fig.1:. Survival by transplant status in patient with AML and FLT3 mutation
Impact of Comorbidity Index on Outcome with Allogeneic Hematopoetic Stem Cell Transplantation for Chronic Lymphocytic Leukemia
Authors: Toze Cynthia L. , Sangara Rauvynne N , Connors Joseph M. , Nevill Thomas J. , Shepherd John D. , Lavoie Julye , Barnett Michael J , Nantel Stephen H. , Voss Nicholas , Hogge Donna E. , Sutherland Heather J. , Forrest Donna L , Song Kevin W , Mourad Yasser Abou , Power Maryse M , Narayanan Sujaatha , Brinkman Ryan , Smith Clayton 
Published: October 2019

Abstract
Chronic lymphocytic leukemia, a disease that is not curable with standard therapy, is an attractive target for allogeneic (allo) hematopoetic stem cell transplant (HSCT) with demonstrated strong graft vs. leukemia effect. However, optimal selection of patients (pts) in order to maximize outcome and minimize toxicity is still under study. We hypothesized that patient co morbidity, as measured by the HSCT adapted Charlson co morbidity index (CCI) would have a strong effect in this group of patients with older median age. At the Leukemia/BMT Program of BC the CCI has been prospectively calculated for HSCT pts since 2006, and we performed chart review to calculate scores retrospectively for the remaining CLL allo HSCT patients in order to evaluate the impact of this factor on outcome following allo HSCT. Transplant specific data was collected prospectively and entered into an electronic database. Forty pts with CLL proceeded to allo HSCT between Jan 91 and Dec 07, with myeloablative (MA) (n=21) or non-myeloablative/reduced-intensity (NMA/RIC) (n=12/7) conditioning regimen. Median (range) number of prior therapies was 4 (1–7). Twenty-four pts were refractory to fludarabine. Donors were related in 25 cases, unrelated in 15. Median age (range) was 49 yrs (32–57) (MA) and 57 yrs (52–64) (NMA/RIC), with 3 and 13 patients greater than age 55 in the 2 groups respectively. Interval from dx to HSCT was 60 months (range 7–135) (MA) and 90 months (range 18–350) (NMA/RIC). Five yr OS is 55% for the whole group; 51% for the MA group at a median follow-up (med FU) of 7.2 yrs (range 2.8–14.6) and 62% for the NMA/RIC group with med FU of 4.2 yrs (range 0.1–6.8). OS did not differ between the 2 groups (p=0.56). Related and unrelated donors had similar 5yr OS at 60.6 vs. 47.1%, p=0.23. Cumulative incidence of non-relapse mortality at 100 days and 2 years is 10 and 32% for the whole group, 14 and 38% for the MA and 6 and 26% for the NMA/RIC groups. CCI was 0, 1, 2, and 3 or greater for 21, 5, 7, and 7 patients. OS by CCI 0–2 vs. >=3 was 63 vs.18% for the whole group (p=0.01), 56 vs. 0% for the MA (p=0.03), and 74 vs. 27% for the NMA/RIC groups (p=0.06). Further analyses will explore the relationship between CCI and NRM, acute and chronic graft vs. host disease, and relapse. Patient numbers in this series are insufficient to evaluate the impact of specific co morbidities. In conclusion, for patients with CLL, who are in general of older age, and who may have other therapeutic options, allo SCT is optimally performed in those with a low co morbidity score. Patients with a CCI of 3 or greater may be preferential candidates for alternate less toxic therapies.
Outcome of Allogeneic Stem Cell Transplantation in Patients with Low Ventricular Ejection Fraction
Authors: Khan Ziad U. , Saliba Rima M , Qureshi Suhail , Hosing Chitra , Giralt Sergio A , De Lima M. J , Yusuf S. W , Popat Uday R , Champlin Richard E , Qazilbash Muzaffar H. 
Published: October 2019

Abstract
BACKGROUND: High-dose therapy and Allogeneic stem cell transplantation (allo SCT) is a potentially curative treatment for patients with hematologic malignancies. A high risk of regimen-related toxicity limits this treatment only for patients with excellent organ-system function. A low left ventricular ejection fraction (LVEF) of ≤ 45% is considered to be a major risk factor for post-transplant cardiac toxicity and nonrelapse mortality (NRM). However, several patients with advanced hematologic malignancies and low LVEF can potentially benefit from this therapy. To address this issue, we evaluated the frequency of cardiac toxicity and NRM in 56 patients with low LVEF undergoing allo SCT.
METHODS: We performed a retrospective analysis on 56 patients with baseline low LVEF who received allo SCT between January 2000 and February 2006 at our institution. Pre-transplant evaluation included an electrocardiogram and bidimensional echocardiogram or gated cardiac scan. Cardiac toxicity was defined as congestive heart failure (CHF), atrial/ventricular arrhythmia or an acute coronary syndrome. Of the 56 patients, 22 received a myeloablative regimen (16 busulfan-based, 6 total body irradiation-based) while 34 patients received a fludarabine-based reduced intensity conditioning regimen.
RESULTS: Twenty-three patients (41%) received allo SCT from an unrelated donor. Acute leukemia was the reason for allo SCT in 32 (57%) patients. Baseline LVEF within 30 days pre-transplant ranged 20 to 45%. At their 6 month follow-up, cardiac toxicity was seen in 7 (12%) patients. Toxicity included congestive heart failure (CHF) in 4 (7%) and atrial fibrillation (AF) in 4 (7%). One patient had both CHF and AF. There were no documented episodes of acute coronary syndrome. Cumulative incidence of NRM at 100 days was 12%; none of the deaths were attributable to cardiac causes. These results were comparable to allo SCT performed in patients with normal LVEF. Variables such as age, LVEF, type of transplant, or the underlying disease did not emerge as significant predictors of post-transplant cardiac toxicity or NRM.
CONCLUSION: Patients with low LVEF (<45%) are acceptable candidates for allo SCT. A prospective study with stratification of cardiac risk factors is warranted in patients with low LVEF.
Identification of the JAK/STAT Signaling Pathway as a Valid Therapeutic Target of T(8;21) Acute Myeloid Leukemia Using Combined Gene Expression and Promoter Occupancy Profiling.
Authors: Lo Miao-Chia , Peterson Luke F. , Yan Ming , Ahn Eun-Young , Ommen Hans B. , Chen I-Ming , Hokland Peter , Willman Cheryl L. , Zhang Dong-Er 
Published: October 2019

Abstract
t(8;21) is one of the most common chromosomal abnormalities associated with acute myeloid leukemia (AML). The resulting AML1-ETO fusion protein is directly involved in the pathogenesis of AML but is not able to cause leukemia on its own. We have shown previously that a C-terminal splice variant of t(8;21), AML1-ETO9a (AE9a), is sufficient to promote AML in mice. Here we show that the leukemia-initiating cells reside in the Lin-/Sca1-/cKit+ population. To identify molecular targets directly modulated by AE9a, we compared the gene expression profile to the promoter occupancy (ChIP-on-chip) profile of this population. We identified 1485 genes deregulated by AE9a, among which 544 genes are also ChIP-on-chip targets. CD45, a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, was greatly down-regulated in AE9a leukemia cells. We further show that t(8;21) AML-M2 patient samples have lower CD45 levels compared to non-t(8;21) AML-M2 samples. Interestingly, JAK1 and JAK2 were upregulated by AE9a and both CD45 and JAK1 are ChIP-on-chip targets. In addition we show that JAK/STAT signaling was enhanced in the leukemia cells. Consequently, the leukemia cells are more susceptible to JAK2 inhibitors than wild type cells. Our results indicate that AE9a enhances JAK/STAT signaling by directly modulating regulators of this signaling pathway, which provides a potential novel approach to treating t(8;21) AML.
E2a-Pbx1 Direct Targets and Secondary Mutations in Leukemogenesis.
Authors: Diakos Christofer , Xiao Yuanyuan , Hofmann Jerry , Zheng Shichun , Kang Michelle , Zhou Mi , Wiencke John , Zhong Sheng L. , Wiemels Joseph L. 
Published: October 2019

Abstract
E2a-Pbx1 is expressed as a result of the t(1;19) chromosomal translocation in nearly 5% of cases of acute lymphoblastic leukemia. The E2a-Pbx1 chimeric transcription factor contains the N-terminal transactivation domain of E2A fused to the C-terminal DNAbinding homeodomain of Pbx1. Previews studies indicate that additional genetic events may be required for E2A-Pbx1-leukemic transformation, based on long incubation times and monoclonal nature of tumors observed in mouse models. While there is no doubt of its oncogenic potential, the mechanisms of E2a-Pbx1-mediated pre-B cell transformation and the nature of direct E2a-Pbx1 target genes and additional events that complement the fusion oncogene to create full-blown leukemia are still unclear. Herein we used chromatin immunoprecipitation (ChIP-chip) assays to identify direct targets of E2a-Pbx1, and we used gene and miRNA expression arrays of siRNA E2a-Pbx1-silenced cells to evaluate changes in expression induced by the fusion protein. To identify complementary genetic rearrangements, analyses of primary E2a-Pbx1 leukemias were performed to copy number changes and loss of heterozygosity which might identify mutations that synergize with the direct/functional E2a-Pbx1 targets to produce the leukemic phenotype. These arrays were analyzed in comparison to high-density gene promoter methylation arrays. Our data identified members of the WNT pathway as direct targets of E2a-Pbx1. Expression data from E2a-Pbx1 silenced cells support this finding as they demonstrate a functional regulation of this pathway. We further show a differential impact of E2a-Pbx1 silencing on the miRNA profile and identify E2a-Pbx1 dependent miRNAs. Using CGH arrays on primary E2a-Pbx1 samples we were able to pinpoint candidate secondary mutations as well as broad genetic categories: cases with 1q+, 1q+ combined with 9p-, and, separately, cases with +8. In summary we present direct and functional E2a-Pbx1 targets as well as candidate secondary mutations. We propose a model were direct and functional E2a- Pbx1 driven pathways that might include both genes and miRNAs might collaborate with identified auxiliary events to produce the E2a-Pbx1 leukemia.
A Poor Response to Desmopressin Is Observed in Patients with Mild Hemophilia a and No Detectable FVIII Mutation.
Authors: Castaman Giancarlo , Giacomelli Sofia , Santagostino Elena , Tosetto Alberto , Mancuso MariaElisa , Mannucci Pier M. , Rodeghiero Francesco 
Published: October 2019

Abstract
Background. Desmopressin is the treatment of choice for patients with mild hemophilia A (FVIII:C 3; 5 %). However, the range of response is wide and patients with similar basal FVIII:C may respond in a significantly different way. Several clinical studies have demonstrated the clinical efficacy and safety of desmopressin, but few data are available on the relationship of biological response with a given FVIII mutation and physiological characteristics (such as age and blood group, or von Willebrand factor levels). Aim of the study. To evaluate the relationship between type of FVIII mutation, physiological caharacteristics and response to desmopressin
Methods. The biological response to subcutaneous desmopressin was assessed in a group of 51 consecutive patients with FVIII:C 3 5%. Blood samples were taken at 0, 30, 60, 120 240, 480 minutes and 24 hours after injection. FVIII mutation search strategy was based on DHPLC and gene sequencing.
Results Mean basal FVIII:C was 18 ± 9 U/dL (range 5 – 37) and the median increase at peak was 2.5-fold (range 1.1 – 7.1). Twelve patients with low FVIII:C and normal or increased FVIII:Ag (type II defect) had similar basal and fold increase compared to the remaining patients. By multivariate regression, VWF:Ag peak level reached after desmopressin infusion and patient age were positively related with the FVIII:C half-life (p=0.003 and p=0.002 respectively), but not with FVIII:C peak or AUC. A total of 28 different gene mutations were identified (10 novel) in 42 patients, while 9 had no detectable gene mutations even after two different complete gene sequencing with 2 different sets of primers. No mutations in exons 18–22, 24 and 27 of VWF were identified. Patients with no mutations had similar basal median FVIII:C (15 vs 19 U/dL) and VWF:Ag levels (109.1 ± 31.7 vs 133.1 ± 57.5 U/dL) compared with patients carrying missense mutations. However, the peak of FVIII:C was significantly lower in patients without mutations (median FVIII:C 26 vs 56 U/dL; P < 0.001), with only a 2-fold increase (range 1.1 – 2.7) vs 2.92-fold (range 1.6 – 7.1) in patients with mutations (P < 0.001 by ANOVA).
Conclusions. A poor biological response to desmopressin was associated with the absence of an evident FVIII mutation.
Relevance of Chloride Binding to Von Willebrand Factor in Type 2B Von Willebrand Disease Patients.
Authors: Baronciani Luciano , Peyvandi Flora , Punzo Margherita , Canciani Maria T. , Di Stasio Enrico , Federici Augusto B. , Mannucci Pier M. , De Cristofaro Raimondo 
Published: October 2019

Abstract
Background: In von Willebrand disease type 2B (VWD2B) the abnormal VWF spontaneously binds to circulating platelets, usually resulting into loss of high molecular weight multimers (HMWM) and thrombocytopenia. In these patients VWF:RCo/Ag ratio is indicative of reduced HMWM and roughly correlated with the severity of VWD2B defect. Physiological concentrations of Chloride ions (Cl−) inhibit the hydrolysis of VWF by ADAMTS-13. Cl− acts as an allosteric effector and its specific binding to VWF A1 domain results into a reduced availability of A2 to be proteolised by ADAMTS-13. Type 2B VWF R1306W showed a reduced affinity to Cl− (>KdCl−) and an increased (>kcat/Km) susceptibility to proteolysis by ADAMTS13 (De Cristofaro, R. et al Molecular mapping of the chloride-binding site in VWF. J Biol Chem2007; 281: 30400–11).
Aim: To determine if other VWD2B mutations affect Cl– binding by changing the proteolysis of mutant VWF by ADAMTS-13.
Methods: Five distinct mutant recombinant (r)A1-A2-A3 proteins (Table), have been prepared along with the WT. Determination of KdCl− of each rA1- A2-A3 was achieved by intrinsic protein fluorescence, performed as a function of both Cl− concentrations and temperature. Study on the kinetic rates of hydrolysis of each rA1- A2-A3 by ADAMTS-13 was evaluated using HPLC methods.
Results and Conclusions: The results (Table) confirmed that affinity of Cl− (KdCl−) was decreased in all mutant rA1-A2-A3s compared to the WT at different extent, with an inverse correlation to the catalytic specificity (kcat/Km) of ADAMTS-13 interaction. Higher VWF:RCo/Ag ratios were found associated with lower values of kcat/Km in our studied patients. This finding strongly support that the reduced affinity of type 2B VWF to Cl− might contribute to the depletion of HMWM.
Table (patients) WT --- R1341Q (4) R1341W (3) H1268D (1) V1316M (4) R1306W (15) KdCl− (mM) 156 191 359 481 526 540 kcat/Km (M−1s−1) 7.25x104 8.8x104 1.2x105 1.39x105 1.6x105 1.95x105 VWF:RCo/Ag ratio (range) 0.7 – 1.2 0.8 (0.77–0.84) 0.7 (0.6–0,8) 0.5 0.3 (0.2–0.7) 0.5 (0.25–1.0)
Thromboembolic Events among Adult Patients with Idiopathic Thrombocytopenic Purpura in the United Kingdom General Practice Research Database.
Authors: Sarpatwari Ameet , Bennett Dimitri , Logie John W , Shukla Amit , Beach Kathleen J , Newland Adrian , Sanderson Simon , Provan Drew 
Published: October 2019

Abstract
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterised by elevated peripheral platelet destruction and inadequate platelet production. Little published epidemiological data exists concerning the risk of thromboembolic events (TE) among adult patients with ITP.
The objective of our investigation was to estimate the risk of TE among adult patients with and without ITP in the United Kingdom (UK) General Practice Research Database (GPRD), which contains patient data from 6.4 million patients from more than 480 representative medical practices across the UK.
Using read [2871C] or Oxford Medical Information System (OXMIS) [D3130000, D313012, 42P2.11, D313.12] codes to define cases, incidence rates (IRs) per 10,000 patient-years of observation (PYO) with 95% confidence intervals (CIs) were estimated. Hazard ratios (HRs) of venous, arterial, and combined (venous and arterial) TE were modelled using Cox proportional hazards regression adjusting for history of prior TE, hypertension, splenectomy status, oral corticosteroids and intravenous immunoglobulin exposure.
840 adults (≥ 18 years) with codes for ITP first referenced between January 1, 1992 and September 30, 2005 and having at least one year pre-diagnosis and three months of post-diagnosis medical history were matched with 3,360 non-ITP patients by age, gender, primary care practice and pre-study follow-up time. Over a median 52 months of follow-up (range: 3–182 months), the cumulative incidence of TE among thromboembolic-free patients at baseline was higher within the ITP cohort [47 (6.7%) v. 172 (5.7%)]. As shown in the table below, the IRs of venous, arterial, and combined TE were additionally elevated among patients with ITP.
Outcome Incidence Rate/10,000 PYO 95% CI Adult Patients with ITP Adult Patients without ITP Venous TE 70.83 (46.67–103.05) 47.53 (37.39–59.58) Arterial TE 82.02 (55.73–116.42) 71.50 (58.87–86.04) Combined TE 134.74 (99–179.18) 116.32 (99.59–135.06)
Adjusted HRs of 1.58 (95% CI, 0.98–2.53), 1.02 (95% CI, 0.65–1.59), and 1.17 (95% CI, 0.82–1.66) were found for venous, arterial, and combined TE respectively. Further event categorisation revealed elevated HRs for each venous thromboembolic subtype [deep vein thrombosis 1.49 (95% CI, 0.62–3.61), pulmonary embolism 3.52 (95% CI, 1.23–10.04), and other TE 1.17 (95% CI, 0.64– 2.16)].
This study provides evidence of an increased risk in venous TE in adult patients with ITP relative to the general adult non-ITP population.
The Feature of TCR Vγ And TCR Vδ Repertoire Distribution and Clonality in Patients with Immune Thrombocytopeinc Purpura.
Authors: Zhang Xueli , Chen Shaohua , Yang Lijian , Zhu Kanger , Li Yangqiu 
Published: October 2019

Abstract
Chronic idiopathic/immune thrombocytopenic purpura (ITP) is an autoimmune disorder in which anti-platelet antibodies induce platelets destruction due to an imbalanced immune response. Recently, data indicated the γδ+T cells may play an important role in mediated autoimmune disease. Our previous study has showed the restricted expression of TCR Vβ subfamilies and the alteration of peripheral TCR Vβ repertoire pattern in the majority of ITP patients. In the present study, we farther analyze the feature of TCR Vγ and TCR Vδ repertoire distribution and clonality in patients with ITP. The CDR3 size of three TCR Vγ and eight TCR Vδ subfamily genes were analyzed in peripheral blood mononuclear cells (PBMCs) from 8 cases with ITP and 10 healthy individuals, using RT-PCR and genescan technique. To determine the expression level of TCR Vγ subfamily genes, quantitative analysis of TCR Vγ I–III subfamilies was performed by real-time PCR. TCR Vγ I to III subfamilies could be detected in the most samples from ITP as well as in healthy control. However, oligoclonal expansion of TCR Vγ I was identified in 3 cases with ITP, which display polyclonality in all of samples from healthy control. The expression level of all TCR Vγ I–III subfamilies in PBMCs from ITP was significant lower than that from healthy control (P=0.003,P=0.000,P=0.005 respectively). the pattern of TCR Vγ I–III repertoire in ITP was TCR VγI> TCR VγIII> TCR VγII, in contrast, TCR VγII> TCR VγI> TCR VγII was found in healthy control. TCR Vδ1 and TCR Vδ2 could be detected in most samples from ITP as well as in healthy control, whereas TCR Vδ3 could be detected only in 2 out of 8 cases with ITP, which could be found in 90% of healthy controls (p=0.02), TCR Vδ8 could not be identified in all of samples from ITP, which could be found in 30% of healthy control. Oligoclonal expanded TCR Vδ1and TCR Vδ2 T cells could be identified in the half of samples from ITP, similar results were found in healthy control. In conclusions, the alteration of peripheral TCR Vγ and TCR Vδ repertoire pattern might be important in the pathogenesis of immune-mediated platelet destruction in some cases with ITP. Our report is the first description of feature of TCR Vγ and TCR Vδ repertoire pattern in ITP patients.