bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excellent Results in Children and Adolescents with Isolated Mature B-Acute Lymphoblastic Leukemia (B-ALL) (Burkitt): Report from the French-American-British (FAB) International LMB Study FAB/LMB96.
Authors: Goldman Stan , Gerrard Mary , Sposto Richard , Davenport Ginny , Auperin Anne , Pinkerton Ross , Michon Jean , Weston Claire , Perkins Sherrie L. , Raphael Martine , McCarthy Keith , Patte Catherine , Cairo Mitchell S. 
Published: April 2020

Abstract
The prognosis for Burkitt leukemia has improved steadily over the past thirty years with short intensive therapy utilizing high dose methotrexate and fractionated cyclophosphamide (Cairo et al Br J Haem, 2003, Patte et al Blood, 2001, Reiter et al Blood, 2005). The presence of CNS involvement at diagnosis with B-ALL is, however, associated with a poorer survival (3yr EFS 60%) as demonstrated previously in 235 children and adolescents with B-ALL (≥25% L3 cells) with or without CNS involvement randomized to standard intensity FAB/LMB therapy vs adjusted (decreased) intensity and maintenance therapy demonstrating an advantage to standard intensity therapy (Cairo et al ASH, 2004). We now analyze the results in 110 children and adolescents with B-ALL and no evidence of CNS involvement at diagnosis treated on FAB/LMB96 (4–6 mo TX). 110 patients, 18% 0–4, 47% 5–9, 29% 10–14 and 6% 15–20yrs of age, 77% male; 109/110 Burkitt histology (one Burkitt-like); 89% ≥2 LDH upper limits, 90% ≥ 70% L3 BM involvement. 44% were treated in COG, 38% SFOP and 18% in UKCCSG. The 4yr EFS and OS was 88±3.1% and 89±3.0%, respectively. Patients randomized to standard vs adjusted (decreased) intensity had a 4 yr EFS of 94±3.8% vs 88±4.8%, respectively (p=0.26). Overall, readjusted for randomized intensity of therapy, the 4 yr EFS was 91±3.1%. Response to reduction therapy with COP (cyclophosphamide, vincristine, prednisone) was assessed at day 7. Patients with a complete response (M1) vs incomplete response (20–99% reduction of BM L3 cells) had a similar outcome; (4yr EFS) CR vs IR (93±5 vs 88±2.9%) (p=0.51). Patients with a higher percentage of L3 blasts, (≥70% vs 25–69% bone marrow involvement), had an improved 4 yr EFS. 4 yr EFS was 90±3.0 vs 70±15% (p&lt;0.06) and 4 yr OS 91±3.0 vs 70±15% (p&lt;0.03). Elevated LDH ≥ 2NL at diagnosis had no impact on prognosis. Furthermore, there was a dismal outcome for patients who relapsed (10% 2 yr PFS). In summary, children and adolescents with isolated B-ALL have an excellent (&gt;90% 4 yr EFS) prognosis with 6 months of standard intensity FAB/LMB therapy. Mature B-acute lymphoblastic leukemia (Burkitt) (B-ALL) should now be considered one of the most curable forms of childhood ALL. Furthermore, as therapy reduction has been unsuccessful in this patient group with B-ALL, future strategies should consider whether substitution of targeted immunotherapy might allow for chemotherapy intensity reduction (with reduced morbidity) in this population. The outcome is poor for the few patients who relapse and new therapeutic strategies are required for this small subgroup.
Tinzaparine in the Management of Painful Vaso-Occlusive Crisis of Sickle Cell Anaemia.
Authors: Qari Mohamad H. , Mousa Shaker , Alsaigh Mohamad A. , Zografos Panagiotis , Aljaouni Suad K. , Fatani Huda , Alalfi Adnan , Alsayes Fatin M. , Beirouti Basim T. , Alamin Mohamad A. , Gadi Abdulilah 
Published: April 2020

Abstract
Introduction
Several components of the haemostatic system are altered in sickle cell anaemia(SCA). The sum of these alterations is manifested as a state of hypercoagulability. Many therapeutic approaches including anticoagulants has been tried in managing the acute painful crisis of SCA along with the analgesics.
Aim
This trial aimed at assessing the efficacy and safety of low molecular weight heparin Tinzaparine (innohep®) as an adjuvant therapy in the management of acute painful vaso-occlusive crisis.
Material and Methods
This two arm pilot, randomised multi-centre controlled prospective trial has incorporated 253 patients admitted through emergency in acute painful crisis, with no other complications of SCA. Subjects were consecutively randomized to the study or control group. In the study group 127 patients (mean age 22,83 years) received tinzaparine 175 i.u, s.c once daily along with analgesics, while in the control group 126 patients (mean age 21,64 years) received placebo and the same analgesics. Subjects were followed for improvement using the numerical pain scale (NMS), assessing the number of days in which the patient experienced the severest degree of pain on the NMS, the hospitalization period, the duration of painful crisis, and the rate at which the pain intensity declined over time. The maximal treatment period was seven days. The complications encountered are treated and estimated in both groups. The results were analysed using “SSPS-V10” statistical tests
Results
The results displayed in the table.1 showed statistically significant reduction in the duration of morbidity in the study group. The drop in the pain intensity is sharper, and the complications experienced in the study group were two events of minor bleeding treated conservatively.
Patient Control No. of days with severest pain score on the NMS (Days) 1,28 1,74 Duration of painful crisis(Days) 2,57 4,35 Total duration of hospitalization(Days) 7.08 12,06
Conclusion
The results indicate a favourable outcome in the study group compared to the control group. The use of tinzaparine in the acute painful crisis of SCA as an adjuvant to the strong analgesics is recommended due to its proven efficacy and safety in shortening the period of the agonizing pain at presentation, the period of painful crisis and the hospital stay.
Early Predictors of Fetal Hemoglobin Response to Hydroxyurea in Sickle Cell Disease.
Authors: Partovi Kristine , Martyr Sabrina , McGowan Vicki , Machado Roberto , Taylor James , Kato Gregory , Gladwin Mark , Little Jane 
Published: April 2020

Abstract
We investigated the kinetics of hematologic change in patients with sickle cell disease (SCD, HbSS, n=6) or SC disease (HbSC, n=1) who had been newly started on hydroxyurea (HU), with the intention of identifying early correlates to fetal hemoglobin (HbF) responsiveness. We found that HbF increased in all patients on HU, and that the half-maximal degree of HbF response could be estimated by 2 months, in patients’ whose MCVs had risen ≥ 10% above baseline.
All 7 patients were treated with HU and followed closely for 6 months or more, until hematologic stability. Hematologic stability was apparent by ≥ 5 months. White blood cell count (WBC), absolute neutrophil count (ANC), reticulocyte (retic) count, % HbF, and mean corpuscular volume (MCV) were examined at bi-weekly intervals. Baseline values (1 or 2 values averaged) were compared with mean values obtained during weeks 2 to 8 (3 or 4 values averaged). As expected, by 2 months WBC and ANC had fallen 30 +/− 8% and 26 +/− 8%, respectively. Change in total hemoglobin (5.8 +/−6.7%), total platelet count (less 11 +/− 10.8%), and LDH (5.3 +/− 8.7%) was not consistent during this two month interval. By eight weeks after initiation of HU, retic counts had dropped in all six SS patients, from 15 to 52% less than baseline while MCV rose 9–21% above baseline; in general, rise in MCV preceded the rise in HbF. Overall, by the time of hematologic stability, all patients had increased their percent HbF, at between 3–8.5-fold relative to baseline; baseline percent HbF of total hemoglobin (Hgb) ranged from 0.7 to 8.3% and, after stabilization, from 5.2% to 24.9%. Maximal percentage of Hgb that was accounted for by HbF at stabilization was arbitrarily set at 100; at 8 weeks, all patients had achieved ≥ 42% of their maximal HbF level, mean 55 +/− 9.4% of maximum HbF. Two additional patients in whom extensive lab data were available, but who were suspected to be non-compliant or sub-therapeutically treated, had a &gt;10% rise in MCV that was temporally associated with an inflection upward for HbF. Patient 8 had mean bi-weekly MCVs of 94, 91, 93, and, after a family conference, 102 (p=.003); Concurrent HbF was 7, 6, 6 and then 10 (p=.046). Patient 9 had mean bi-weekly MCVs on low-dose HU of 97, 96, and, after dose adjustment, 109(p=.003); HbF was 2%, 3%, and then 5 (p=.0094).
We speculate that, in many patients, an increase in MCV above baseline of ≥ 10% is a marker of adequate HU dosing, and that HbF levels at that time approximate half-maximal response. A larger series will be necessary to confirm this relationship; a predictive model, correlating MCV and HbF responsiveness, could be used to determine sufficiency of, and compliance to, HU therapy, and to early identify patients who are at high-risk from SCD (e.g. with pulmonary hypertension) whose HbF responsiveness may not be adequate from HU alone.
Figure Figure
Inactivation of the Suv39h1 Histone Methyltransferase Accelerates Myc-Driven B-Cell Lymphomagenesis and Compromises Drug-Inducible Cellular Senescence.
Authors: Lee Soyoung , Tabor Vedrana , Loddenkemper Christoph , Peters Antoine H.F.M. , Stein Harald , Dorken Bernd , Jenuwein Thomas , Schmitt Clemens A. 
Published: April 2020

Abstract
Activation of the myc oncogene is a frequent finding in human lymphomas. Acute induction of Myc in primary cells initiates massive apoptosis via the ARF/p53 pathway. In turn, apoptotic defects strongly collaborate with Myc in tumor formation. Previous work in a transgenic mouse model demonstrated that DNA damaging drugs can force apoptotically-compromised Myc-lymphomas to enter a terminal cell-cycle arrest, termed cellular senescence, which prolonged overall survival of the tumor-bearing animals. Recently, we identified the histone H3 lysine 9 (H3K9) methyltransferase Suv39h1 as a critical mediator of cellular senescence that acts as an early barrier against Ras-initiated lymphomagenesis, raising the question whether Myc-driven formation of lymphomas and their treatment sensitivity may depend on Suv39h1 function.
Eμ-myc transgenic mice were intercrossed to mice harboring targeted deletions in the Suv39h1 locus. Myc transgenic mice with no additional defined genetic lesions - hereafter referred to as controls - developed B-cell lymphomas with a median onset of more than 100 days, while mice lacking one or both Suv39h1 alleles produced lymphomas significantly earlier, i.e. at a median age of less than 60 days. Importantly, lymphomas arising in female myc transgenic Suv39h1+/− mice invariably lost expression of the X-linked Suv39h1 gene. TUNEL staining in situ and short-term cytotoxicity assays in response to the DNA damaging compound adriamycin in vitro expectedly demonstrated no overt difference in spontaneous or drug-inducible apoptosis in control versus Suv39h1-deficient Myc-lymphomas. However, when the fractions of Myc-driven lymphoma cells in cycle where assessed by Ki67 staining in situ, absence of Suv39h1 allowed Myc to keep nearly all cells in cycle, while a substantial fraction of non-apoptotic control lymphoma cells apparently had exited the cycle. Accordingly, adriamycin-treatment in vitro produced a strong senescent phenotype in control cells in the presence of Bcl2, while no senescence response could be provoked in Suv39h1-deficient cells.
Our findings provide novel insights into Myc-related deregulation of cellular growth control and senescence as a tumor suppressor mechanism, and have important ramifications for the therapeutic utilization of DNA-damage effector programs such as apoptosis and cellular senescence. Whether Suv39h1 inactivation impacts on the long-term outcome of cancer therapy in vivo is currently under investigation and will be reported at the meeting.
Postremission Therapy with an Allogeneic Transplantation from an HLA-Matched Family Donor Seems To Overcome the Negative Prognostic Impact of FLT3-ITD in Younger Patients with Acute Myeloid Leukemia Exhibiting a Normal Karyotype.
Authors: Schlenk Richard F. , Krauter Jürgen , Fröhling Stefan , Späth Daniela , Schäfer Irina , Hein Stefan , Döhner Hartmut , Ganser Arnold , Döhner Konstanze ,   for the German-Austrian AML Study Group (AMLSG)
Published: April 2020

Abstract
Internal tandem duplications (ITD) of the FLT3 gene have been identified as negative prognostic marker in patients with acute myeloid leukemia (AML) exhibiting a normal karyotype. To evaluate the impact of different postremission strategies, such as high-dose cytarabine based chemotherapy (chemo), autologous (auto-SCT) or allogeneic stem cell transplantation (allo-SCT), in patients with normal karyotype and FLT3-ITD, we initiated a pooled data analysis within the prospective treatment trials AML-2/95, AML-1/99, AMLHD93, and AMLHD98A.
Methods: All patients (age 16–60 years) received two cycles of induction therapy with standard-dose cytarabine combined with etoposide and idarubicin. After a first consolidation therapy, patients were assigned to allo-SCT if an HLA-identical sibling donor was available in all four trials. In the AML-2/95 and AMLHD93 trials, all other patients were assigned to chemo, whereas in the AML-1/99 and AMLHD98A trials patients were randomized between chemo and auto-SCT. Patients were analyzed for the presence of FLT3-ITD by genomic DNA PCR and conventional gel electrophoresis. All statistical tests were stratified for the variable “study group”.
Results: Between 1993 and 2004 872 patients exhibiting a normal karyotype were registered. To date, results of FLT3 mutation analysis are available for 620 patients, and 182 (29%) exhibited an ITD. Response to induction therapy was 72% and 79% in the FLT3-ITD positive group and the FLT3-ITD negative group, respectively. After a median follow-up of 41 months, relapse-free (RFS) and overall survival (OS) were 33% versus 51% (p&lt;0.0001) and 27% versus 46% (p&lt;0.0001) in the FLT3-ITD positive and the FLT3-ITD negative groups, respectively. Analysis based on the availability of an HLA-matched family donor revealed a significantly better RFS (p=0.007) of 60% for patients with a donor (n=26) versus 21% for patients without a donor (n=102).
Conclusion: In AML patients with normal karyotype exhibiting a FLT3-ITD mutation who achieve CR after induction therapy, consolidation with allo-SCT seems to overcome the negative impact of FLT3-ITD on outcome.
Prognostic Impact of Anti-Apoptotic and Multidrug Resistance Phenotypes in Elderly Acute Myeloid Leukemia Patients.
Authors: Vidriales María-Belén , Suarez Lilia E. , García-Laraña Jose , García-Boyero Raimundo , Moreno María-José , Bernal Teresa , Reina Vicencia Martín , González-San Miguel Jose D. , Pérez José J. , Fernández-Abellán Pascual , García-Suarez Julio , San Miguel Jesús F. , Orfao Alberto ,   for the Pethema Cooperative Group
Published: April 2020

Abstract
Elderly patients with acute myeloid leukemia (AML) have an unfavorable outcome, which has been related to both the poor performance status of many of these patients and the biological characteristics of the malignant clone, including the expression of multidrug resistance (MDR) phenotypes. We have quantitatively analyzed by flow cytometry the expression of apoptosis- (bcl-2, bax, APO2.7) and MDR- (P-gp, MRP, LRP) associated proteins in a group of 117 elderly (&gt;65 years) uniformly treated de novo AML patients according to the Pethema LMA-98 protocol. Upon analyzing factors influencing the response to induction therapy, as expected, patients with good and intermediate cytogenetics (n=76) more frequently achieved morphological complete remission (mCR) (63%) than patients having poor cytogenetics (n=23) (mCR: 30%). In addition, CD34 expression also influenced response; thus, 81% (21/26) of CD34-negative patients achieved mCR vs only 46% (42/91) of CD34-positive cases (p=0,008). Neither age nor WBC counts showed a significant influence in response rate. As far as apoptosis and MRD proteins is concerned, interestingly, responding cases showed a lower expression of the bcl-2, MRP and LRP proteins (bcl-2 RFI (relative fluorescence intensity) 10±5.5 vs 13±6, p=0.02; MRP RFI 1.9±0.8 vs 2.7±1.8, p=0.008; LRP RFI 6.2±4.9 vs 8.7±7.5, p=0.01 in responding vs non-responding patients). By contrast, expression of APO 2.7, Bax, and MDR-1 did not influenced response. Analysis of relapse free survival showed that only the number of cycles of chemotherapy required to achieve mCR had prognostic influence (p=0.008), with no significant influence for age, WBC counts, CD34 expression, or cytogenetics. In turn, a high percentage of early apoptotic cells in bone marrow at diagnosis (p=0.01), as well as a low bcl-2/bax ratio (p=0.05), and low MRP expression (p=0.04) were associated with a prolonged RFS. Moreover, upon grouping AML patients according to the expression of MRP and the bcl-2/bax ratio (&gt; and &lt; of the mean of both parameters), only patients with both low MRP expression and low bcl-2/bax ratio (n=16) achieved a plateau phase in the RFS curve after 20 months of follow-up, while the remaining patients showed a continuous relapse trend.
In summary, our results show that, in addition to high bcl-2 and bcl-2/bax ratio, a high expression of the LRP and MRP multidrug resistant proteins have an adverse prognostic influence in elderly AML patients. The combination of these parameters contribute to identify distinct groups of patients at a different risk of relapse.
Clinical Characteristics and Prognostic Implications of NPM1 Mutations in Acute Myeloid Leukemia.
Authors: Suzuki Tatsuya , Kiyoi Hitoshi , Ozeki Kazutaka , Tomita Akihiro , Suzuki Ritsuro , Kodera Yoshihisa , Miyawaki Shuichi , Asou Norio , Kuriyama Kazutaka , Yagasaki Fumiharu , Shimazaki Chihiro , Akiyama Hideki , Nishimura Miki , Motoji Toshiko , Shinagawa Katsuji , Takeshita Akihiro , Ueda Ryuzo , Naoe Tomoki 
Published: April 2020

Abstract
Nucleophosmin (NPM) is a nucleolar protein with multi-functions including centromere duplication, nuclear-cytoplasmic shuttling, ribosomal biogenesis, p53 stability. NPM1 mutations were found in a large number of patients with acute myeloid leukemia (AML) especially with normal karyotype. The mutations lead to the aberrant subcellular localization of NPM protein. However, their impacts on clinical outcome remain controversial. We screened the mutations of NPM1 in 257 AML patients and analyzed the clinical significance. NPM1 mutations were found in 64 of 257 patients (24.9%). Seven types of mutations, including four novel mutations, were identified. NPM1 mutations were associated with normal karyotype, FLT3 mutations (both FLT3-ITD and D835 mutation) but not with other gene alterations such as N-RAS, p53 mutations and partial tandem duplication of the MLL gene. In 190 patients except the M3 subgroup, who were treated according to the protocol of Japan Adult Leukemia Study Group, the multivariate analysis revealed that NPM1 mutation was a favorable factor for achieving complete remission, but significantly associated with relapse. A sequential analysis, using paired samples obtained at diagnosis and relapse in 39 patients, revealed that NPM1 mutations were lost at relapse in 2 of the seventeen patients who had NPM1 mutations at diagnosis and none of the patients, who did not have NPM1 mutations at diagnosis, gained NPM1 mutations at relapse.
Our results suggest that NPM-mutated AML should be a distinct subgroup with specific clinical characteristics and outcome. Loss of NPM mutations at relapse implies that NPM mutation is not necessarily a primary genetic alteration and that these leukemic clones could be sensitive to chemotherapy.
Multivariate Analysis of Prognostic Impact of Flow Cytometrically Determined Minimal Residual Disease in Patients with Acute Myeloid Leukemia.
Authors: Kern Wolfgang , Voskova Daniela , Schoch Claudia , Schnittger Susanne , Haferlach Torsten 
Published: April 2020

Abstract
Treatment of acute myeloid leukemia (AML) is adapted according to individual risk profiles. The assessment of levels of minimal residual disease (MRD) is feasible in the vast majority of patients with AML and may significantly improve prognostication. We applied multiparameter flow cytometry to highly sensitively quantify MRD in patients with AML and analyzed its prognostic impact in a multivariate analysis. A total of 356 patients receiving standardized intensive antileukemic treatment was analyzed at different checkpoints: CP1 (up to day 28, n=156), CP2 (day 28–60, n=122), CP3 (day 61–120, n=195), CP4 (day 121–365, n=172), and CP5 (after day 365, n=73). Leukemic cells were identified by their individually defined leukemia-associated aberrant immunophenotypes (LAIPs). MRD levels were calculated as the logarithmic difference (LD) between LAIP-positive cells at diagnosis and LAIP-positive cells at follow-up assessment. The median LD amounted to 2.18 (range, −0.14 to 4.20) at CP1, 2.31 (−0.03 to 4.17) at CP2, 2.49 (0.11 to 4.17) at CP3, 2.58 (−0.28 to 4.28) at CP4, and 2.87 (0.46 to 4.02) at CP5. A higher LD (continuous variable) was related to a better event-free survival (EFS; CP1, p=0.0002; CP2, p=0.00001; CP3, p=0.0002; CP4, p&lt;0.00001; CP5, p=0.00007) and to a better overall survival (OS; CP1, p=0.004; CP2, p=0.001; CP3, p=0.021; CP4, p=0.00006). Other parameters related to EFS and OS were age and cytogenetics in the present series. The prognostic impact of MRD levels on outcome was idependent of cytogenetics and age for EFS (CP2 to CP5) and OS (CP2 and CP4). MRD was the most important prognostic parameter at CP4 and CP5. Separation of patients into two groups, respectively, by the median LD resulted in significant differences in EFS at all CPs and in OS at CP1 to CP4. The largest difference was observed at CP4: median EFS, 57.1 vs. 13.7 months, p&lt;0.00001; 3-year-OS, 95% vs. 65%, p=0.0003. Determination of MRD levels by multiparameter flow cytometry provides a highly powerful and independent prognostic parameter which is applicable to the total of an AML population. It should be evaluated as a stratification parameter in clinical trials.