bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigations on the Importance and Prevalence of the Acquired von Willebrand Syndrome in Patients with Myeloproliferative Disease.
Authors: Scharrer Inge , Flick Caroline 
Published: October 2019

Abstract
The acquired von Willebrand syndrome (AVWS) is a bleeding disorder, which is amongst others associated with myeloproliferative diseases. Its prevalence varies from 0,04–0,13% in literature. Typical laboratory findings such as a low VWF:RCo/VWF:Ag- Ratio, a prolonged aPTT, PFA and bleeding time, a decrease of VWF:RCo, FactorVIII:, VWF:Ag, typical VWF multimeric structure and the absence of a family history of bleeding are the basis for the diagnosis of AVWS. Bleeding episodes are typical for AVWS and are mostly of the mucocutaneous type (epistaxis, heavy menstrual bleeding, gingival and postoperative bleedings). Myeloproliferative diseases, particularily essential thrombocythemia, are with 15–18% the third most frequent observed comorbidity of patients with AVWS, but the prevalence of AVWS in patients with MPS is -at our knowledge- still unknown. We investigated 54 patients with the diagnosis of myeloproliferative disease (44 ET, 9 PV, 1 IMF), which was established according to the WHO-criteria over a period of 6 years (2000–2006). By analysing the typical laboratory parameters for AVWS, the VWF multimeric structure and the own and family history of bleeding we detected that 67% (36/45) of these patients had an AVWS: 27/44 ET (61%), 8/9 PV (89%), 1/1 IMF. The two most sensitive parameters in this context were VWF:RC/vWF:Ag- Ratio and VWF:RCo. It is well known that AVWS can disappear by treating the MPD. We could also show that treating the MPD with Hydroxycarbamid platelets, VWF multimeric structure, VWF:RCo/VWF:Ag-Ratio and VWF:RCo and the bleeding tendency were normalized. The JAK2-V617F mutation is frequently found in myeloproliferative disorders (MPD): Up to 97% patients with polycythemia vera (PV) and about 50% of patients with essential thrombocythemia (ET) carry this mutation. A further goal in this investigation was to find out a correlation between JAK2-V617F mutation, MPD and AVWS. JAK2-V617F diagnosis was performed in 27 of the 54 patients with MPD. 10 of these 27 patients carried a mutated JAK2-allele. However we observed no significant difference between mutated and unmutated patients in correlation to AVWS. In our investigation the high prevalence of 67% AVWS in patients with MPD confirm the hypothesis that until now AVWS is an underdiagnosed disease. Because of this high prevalence, the possibility of regression by treating MPD and the importance of early diagnosis for prevention of unexpected, sometimes letal bleeding complications, it would be benefical to introduce the AVWS- diagnosis-procedure as a routine step for patients with MPD.
Risk-Adapted Treatment of Acute Promyelocytic Leukemia: Updated Results of the Spanish PETHEMA LPA99 Trial Using ATRA and Anthracycline Monochemotherapy.
Authors: Sanz Miguel A. , Montesinos Pau , Vellenga Edo , Rayon Chelo , Parody Ricardo , de la Serna Javier , Bergua Juan , Leon Angel , Negri Silvia , Rivas Concha , Brunet Salut , Gonzalez Marcos , Esteve Jordi , Lowenberg Bob 
Published: October 2019

Abstract
Background: A first report of the PETHEMA LPA99 trial in acute promyelocytic leukemia (APL) showed that a risk-adapted treatment strategy combining ATRA and anthracycline alone for induction and consolidation results in high antileukemic efficacy and low toxicity. We report here an updated analysis of this trial including a significantly higher number of patients and longer follow-up.
Methods: From November 1999 to July 2005, 564 patients (median age 40 years, range 2–83) with APL received induction with ATRA (45 mg/m2/d) until CR and idarubicin (12 mg/m2/d) on days 2, 4, 6 and 8. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows:
“low-risk” patients (WBC <10×109/l and platelets >40×109/l), idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); “intermediate-risk “ (WBC <10×109/l and platelet <40×109/l) and “high-risk” (WBC >10×109/l) patients received ATRA (45 mg/m2/d × 15) in combination with reinforced chemotherapy (Idarubicin 7 mg/m2/d in the course #1 and two days instead of one in the course #3).
Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 45 mg/m2/d ATRA for 15 days every 3 months.
Results: CR was achieved in 511 patients (91%). Except for three cases labelled as resistant, of the remaining 50 patients 56%, 24%, 16% and 4% died due to hemorrhage, infection, retinoic acid syndrome, and acute myocardial infarction, respectively. Multivariate analysis showed that WBC >10×109/l, age >60 years, male gender, and serum creatinine >1.4 mg/dl at presentation had independent predictive value of death during induction. The median follow-up of the cohort was 57 months (range 20–94 months). Thirteen patients (median age 72 years, range 4–81) died in remission and 99% of patients completed the entire assigned therapy. Thirty-six patients presented haematological relapse, 16 molecular relapse, and 8 secondary myelodysplastic syndrome or acute myeloid leukemia. Overall, the 5-year cumulative incidence of relapse (CIR), disease-free survival, and overall survival were 11%, 85%, and 84%, respectively. The 5-year CIR for low-, intermediate- and high-risk patients were 4%, 7% and 28%, respectively.
Conclusions: A risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation therapy results in high antileukemic efficacy, low toxicity and a high degree of compliance in newly diagnosed APL.
An 86-Probe Gene Expression Signature Can Predict Survival in AML with Normal Karyotype Independently of FLT3 ITD and NPM1 Mutation Status - A Collaborative Study from the AMLCG and CALGB Study Groups.
Authors: Metzeler Klaus H. , Hummel Manuela , Bloomfield Clara D. , Spiekermann Karsten , Sauerland Maria C. , Heinecke Achim , Radmacher Michael , Marcucci Guido , Whitman Susan P. , Maharry Kati , Paschka Peter , Larson Richard A. , Berdel Wolfgang E. , Büchner Thomas , Wörmann Bernhard , Mansmann Ulrich , Hiddemann Wolfgang , Bohlander Stefan K. , Buske Christian 
Published: October 2019

Abstract
Patients with acute myeloid leukemia and a normal karyotype (NK AML) comprise 50% of all AML cases and show heterogeneous treatment outcomes and survival. We used gene expression profiling to develop a prognostic gene signature that predicts survival in this clinically relevant AML subgroup. Our analysis was based on data from 163 patients with newly diagnosed NK AML treated in the German multicenter AMLCG 2000 trial, for whom pretreatment gene expression profiles were obtained using Affymetrix HG-U133 microarrays. We used supervised principal component analysis to identify 86 oligonucleotide probesets (corresponding to 66 different genes and ESTs) that were correlated with overall survival (OS), and to define a prognostic score based on these probesets. When applied to an independent test cohort of 79 NK AML cases from the same AMLCG trial, the continuous prognostic score was predictive of OS (P=0.002, hazard ratio [HR] for a change in prognostic score equal to the difference between the 75th and 25th percentiles of the score = 1.94) and event-free survival (EFS) (P = 0.001, HR=1.70). The score based on our gene signature showed a strong correlation with the presence of the FLT3 internal tandem duplication (ITD), but retained its prognostic value for OS in the test cohort even after adjustment for FLT3 ITD, NPM1 status and age (P=0.037, HR=1.65). When we defined a cut-off value in the training population and used it to dichotomize the gene expression score values in the test cohort, the resulting two subgroups had significantly different OS (median, 259 days vs. not reached, P=0.002) and event-free survival (EFS) (median, 72 vs. 300 days, P = 0.015). We subsequently confirmed our findings in a group of 64 NK AML patients (Blood2006;108:1677–83) treated on CALGB 9621. In this validation cohort, our continuous gene expression score was predictive of OS (P < 0.001, HR=4.11) and EFS (P < 0.001, HR=2.90). In multivariate analyses that adjusted for age, NPM1 and FLT3 ITD status, the gene expression score remained significant for OS (P = 0.007, HR=3.40). When we used the prognostic score to split the CALGB validation cohort into two groups, based on the same cut-off value as in the AMLCG test population, the two resulting subgroups differed in their OS (median, 375 days vs. not reached, P < 0.001) and EFS (median, 258 vs. 728 days, P = 0.027). In summary, we present a novel and robust gene expression signature that offers independent prognostic information for patients with normal karyotype AML.
Constitutive Activation of STAT5a in Myeloid Progenitors of Severe Congenital Neutropenia Patients Leads to Downregulation of LEF-1.
Authors: Skokowa Julia , Gupta Kshama , Brechlin Annette Mueller , Meyer Johann , Moore Malcolm A.S. , Welte Karl 
Published: October 2019

Abstract
Severe congenital neutropenia (CN) is a hematological disorder characterized by an early stage maturation arrest of granulopoiesis in bone marrow at promyelocytic stage. Previously we found that LEF-1 and its target gene C/EBPα are severely abrogated in promyelocytes of CN patients, which plays a decisive role in the pathomechanism of defective granulopoiesis (Skokowa J., et al., Nat. Med.2006;12:1191). Recently it has been shown that constitutively activated STAT5a inhibits myeloid differentiation of human CD34+ cells by downregulation of C/EBPα (Moore MA, et al., Exp. Hematol.2007;35:105). Therefore, we investigated whether the presence of constitutive activated STAT5a in CD34+ cells of healthy individuals leads to downregulation of LEF-1 and whether STAT5a is activated in myeloid progenitors of CN patients. A screen of the 10kb upstream region of LEF-1 gene revealed two putative STAT5a binding sites (−3913 bp to −3894 bp and −3728 bp to −3709 bp) and specificity of the STAT5a binding to the LEF-1 promoter in nuclear extracts of CD34+ cells was confirmed in a chromatin immunoprecipitation (ChIP) assay. Additionally, our data demonstrated that introduction of retroviral constructs expressing IRES-GFP and cDNA of constitutively activated STAT5a (mutant of STAT5a, (STAT5A[1*6]) into CD34+ cells of healthy individuals resulted in 20-fold downregulation of LEF-1 mRNA expression. To compare G-CSF- dependent phosphorylation of STAT5 in CD33+ bone marrow myeloid progenitors of CN patients and healthy individuals, we treated these cells with G-CSF in vitro and measured phosphorylation of STAT5 by intracellular staining of cells with phosphoSTAT5 (Y694) antibody. We found that G-CSF stimulation resulted in a significantly higher phosphorylation of STAT5 in myeloid progenitors of four CN patients, as compared to four healthy volunteers (mean fluorescence intensity (MFI) 436 ± 57 in CN patients vs 212 ± 30 in healthy controls). Interestingly, augmented phosphorylation of STAT5 has been observed in both groups of CN patients carrying either ELA2 or HAX1 mutations. These data confirm the hypothesis that downregulation of LEF-1 and LEF-1 target gene C/EBPα is at least in part a consequence of increased activation of STAT5a in both CD34+ cells of healthy individuals and in patients with CN.
Increased Risks of Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF) among 24577 First-Degree Relatives of 11039 Patients with Chronic Myeloproliferative Disorders (MPD) in Sweden.
Authors: Landgren Ola , Goldin Lynn R. , Kristinsson Sigurdur Y. , Samuelsson Jan , Bjorkholm Magnus 
Published: October 2019

Abstract
Background. Familial clustering of PV, ET, MF, and chronic myeloid leukemia (CML) has been reported through case reports and smaller case series. Recently, several studies reported that in families with multiple MPD patients, the JAK2 mutation is not an early germ line predisposing factor for MPD but rather a facilitator of proliferative advantages. However, the degree of familial clustering in the population has not been defined. We have conducted the first large population-based study to quantify risks of developing MPD and related malignancies in first-degree relatives of MPD patients.
Methods. Using high-quality central population-based registries, we identified 6217 PV, 2838 ET, and 1984 MF patients diagnosed in Swedish hospitals 1958–2005 (Cancer and local hospital-based registries), with linkable relatives; 43550 frequency-matched controls (Population registry); and first-degree relatives of cases (n=24577) and controls (n=99542) (Multigenerational registry). Relatives of MPD patients and controls were linked with the Cancer and local hospital-based registries to define occurrence of MPD and other related neoplasms. We used a marginal survival model to calculate relative risks (RR) and 95% confidence intervals (CI) as measures of familial aggregation.
Results. Compared with controls, relatives of MPD patients had significantly increased risks of PV (RR=5.70; 95% CI 3.55–9.14), ET (RR=7.37; 95% CI 3.67–14.81), and MF (RR=3.53; 95% CI 1.59–7.85). Risks were similar when we restricted the analyses to relatives of patients with the same MPD (PV-PV, ET-ET, and MF-MF) Also, risk-estimates were virtually the same for various types of first-degree relatives (parents, siblings, offspring); the same was true when we calculated risks by age at MPD of cases (above vs. below 65 yrs), and sex of relatives. Age at diagnosis of MPD was not different for case and control relatives. Furthermore, relatives of MPD patients (vs. controls) had a borderline increased risk of CML (RR=1.86; 95% CI 0.90–3.74; p=0.07). As expected, we found excess of subsequent acute myeloid leukemia (AML) (n=271; 2.5%) and myelodysplastic syndrome (MDS) (n=27; 0.2%) among MPD patients; however, there were no increased risks of AML or MDS among relatives of MPD patients.
Conclusions. In this first large population-based study including more than 11000 MPD patients and their almost 25000 linkable first-degree relatives, we found 3- to 7-fold elevated risks of developing MPDs among first-degree relatives of MPD patients. Our results support the hypothesis that there are common, strong, shared susceptibility genes that predispose to PV, ET, MF, and possibly CML.
NF1 Microdeletions in Pediatric MLL-Rearranged AML and T-ALL: A Novel Mechanism for RAS Activation.
Authors: Balgobind Brian V. , Van Vlierberghe Pieter , Hollink Iris H. , van den Ouweland Ans M.W. , Beverloo H. Berna , Terlouw-Kromosoeto Joan N.R. , van Wering Elisabeth R. , Kaspers Gertjan J.L. , Reinhardt Dirk , Horstmann Martin , Hahlen Karel , Pieters Rob , Zwaan Christian M. , Meijerink Jules P.P. , van den Heuvel-Eibrink Marry M. 
Published: October 2019

Abstract
Oligo array-comparative genomic hybridization (CGH) is a technique to detect DNA copy number changes (amplifications and/or deletions), and can be used to identify novel genetic abnormalities in cancer. Searching for such abnormalities in specific selected subgroups of pediatric leukemia, we analyzed array-CGH data obtained on 212 samples (71 with MLL-rearranged acute myeloid leukemia (AML), 38 with normal karyotype (NK) AML, and 103 with T-cell- acute lymphoblastic leukemia (T-ALL). Cryptic deletions involving the neurofibromatosis type 1 (NF1) locus, del(17)(q11.2), were identified in 2/71 MLL-rearranged AML and 3/103 T-cell ALL samples, all cases without clinical evidence of NF1, but were not observed in the NK AML samples. The single copy loss of the NF1 locus was confirmed by NF1 specific MLPA assay. Subsequent mutation analysis revealed mutations in the remaining NF1 allele in 3 patients, confirming its role as a tumor-suppressor gene in cancer, since both were restricted to the leukemic cells. Furthermore, NF1 expression in the del(17)(q11.2)-positive leukemias was significantly lower in the patients tested compared to the other patient samples without this deletion. NF1 is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. A small proportion of NF1 patients show germline NF1 gene deletions, in contrast to the confirmed somatic deletions described here in our leukemia patients. Other mutations in NF1, such as inactivation of both alleles by point mutations, or loss of one wild-type allele as an effect of uniparental disomy for the affected chromosome 17 has been observed in NF1 patients with JMML, may have been missed in our cohort. NF1 is a negative regulator of the RAS pathway (RAS-RAF-MEK-ERK pathway). Other mutations in this pathway have previously been associated with myeloid malignancies, and result in RAS activation, apoptotic resistance and proliferation of leukemic cells. We identified 22% N- and K-RAS and 1.4% PTPN11 mutations in our MLL-rearranged AML subgroup. RAS activation may therefore play an important biological role in at least 25% of MLL-rearranged AML samples. In conclusion, our data show that NF1 microdeletions are involved in leukemogenesis in pediatric leukemias, and that RAS-activation may be especially involved in the underlying biology of MLL-rearranged AML.
Limited-Stage Diffuse Large B-Cell Lymphoma (DLBCL) Patients with a Negative Pet Scan Following Three Cycles of R-CHOP Can Be Effectively Treated with Abbreviated Chemoimmunotherapy Alone.
Authors: Sehn Laurie H. , Savage Kerry J. , Hoskins Paul , Klasa Richard , Shenkier Tamara , Voss Nicholas , Wilson Don , Connors Joseph M. 
Published: October 2019

Abstract
Four cycles of CHOP chemotherapy has been shown to be sufficient treatment for low-risk elderly patients with limited-stage DLBCL, eliminating the need for radiation therapy (Bonnet et al, JCO 2007). FDG-PET scanning is an effective prognostic tool that may identify chemo-sensitive patients (regardless of age or clinical risk factors) who can appropriately be treated with abbreviated chemoimmunotherapy alone. Patients: Beginning in 2005, we have recommended that all prospective patients with limited-stage DLBCL (stage I/II, no B-symptoms, mass < 10cm) treated in British Columbia (BC) undergo a PET scan following 3 cycles of R-CHOP; PET-negative patients should then receive one additional cycle of R-CHOP (total 4 cycles R-CHOP), while PET-positive patients receive involved-field radiation therapy (IFRT). Clinical characteristics of the first 50 patients are as follows: median age 67 y (range 31–88); 56% male; 62% stage I, 38% stage II; 4% PS>1; 6% elevated LDH; 58% at least 1 extranodal site, 10% >1 extranodal site. Stage-modified IPI risk factors: 22% 0; 70% 1–2; 8% 3–4. Median follow-up is 17 mos (range 4–26).
Results: 37 patients (74%) were PET-negative and 13 patients (26%) were PET-positive after 3 cycles of R-CHOP. No clinical factors were found to be predictive of PET status. Of the 37 PET-negative patients, 35 completed treatment with one additional cycle of chemoimmunotherapy, 1 received IFRT due to poor chemotherapy tolerance, and 1 died of toxicity before receiving any more treatment. Only 1/37 PET-negative patients has relapsed (alive with lymphoma after salvage therapy). All 13 PET-positive patients received IFRT, with 3 relapses and 2 deaths from lymphoma to date. Although longer follow-up is necessary, the 2-year estimated Kaplan-Meier progression-free survival is 91% overall (97% and 75% for PET-negative and PET-positive patients, respectively, p=0.09). (see figure) The 2-year estimated Kaplan-Meier overall survival is 97% for PET-negative and 69% for PET-positive patients, p=0.1.
Conclusion: Patients with limited-stage DLBCL who are PET-negative after 3 cycles of R-CHOP can be effectively treated with abbreviated chemoimmunotherapy alone (4 cycles R-CHOP), avoiding the long-term toxicity of radiation while preserving excellent lymphoma control.
Figure Figure
Novel Spliced MLL Fusions Have Been Identified Involving the MLL Partner Genes ELL, EPS15, MLLT3, and SEPT5.
Authors: Meyer Claus , Kowarz Eric , Brahim Wajih , Grümayer Renate , Ben-Abdelali Raouf , De Braekeleer Etienne , De Braekeleer Marc , Macintyre Elizabeth A. , Delabesse Eric , Dingermann Theo , Klingebiel Thomas , Marschalek Rolf 
Published: October 2019

Abstract
Chromosomal rearrangements of the human MLL gene are a genetic hallmark for aggressive acute leukemias. More than 60 partner genes have been characterized at the molecular level until now. The observed recombination mechanisms between MLL and its many recombination partner genes include reciprocal chromosomal translocations, insertions, and intrachromosomal 11q deletions and inversion. “Spliced MLL fusions”, have recently been described as a novel mechanism to generate functional chimeric fusion transcripts for 50% of t(11;19)(q23;p13.3) leukemia patients where the MLL gene is fused to the MLLT1 (ENL) gene and for two single leukemia patients. One patient had a t(11;15) involving the ZFYVE19 gene and the other patient had a 11q interstitial deletion involving the DCPS gene. Within these cases the disrupted MLL gene is fused only on RNA level to a functional transcription unit located in the vicinity of the breakpoint. Here we describe eight novel “spliced MLL fusions” involving the MLL partner genes ELL (1x), EPS15 (3x), MLLT3 (1x), and SEPT5 (1x). For ELL, MLLT3 and SEPT5 the identified spliced fusion seems to be a single or rare event. However 1/3 of the t(1;11)(p32;q23) leukemia cases exhibit “spliced MLL fusions”. I.e. approximately 1/3 of all breakpoints are located upstream of the EPS15 gene. Further studies will help to investigate the remaining question whether these two groups of t(1;11)(p32;q23) leukemia patients have any significant difference in outcome. Interestingly, for the t(11;22)(q23;q11.2) leukemia the major identified fusion transcript has an additional 57 bp exon derived from the 2 kb area up-stream of the SEPT5 gene. Furthermore this patient has a T-ALL and thus differs from all other cases where the patients show myeloid markers when the MLL gene is fused to one of the five members of the septine family. This is leading to the question whether or not this 57 bp big exon can be made responsible for the lineage shift. With these results the number of genes involved in „spliced MLL fusions” has increased from three to seven. Supported in part by grants Ma 1876/7-1, /8-1 and /9-1 from the DFG, grant N1KR-S12T13 from the BMBF and grant 102362 from the Deutsche Krebshilfe.