bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Factors in CBFB-MYH11 Positive AML: Trisomy 21, AGE, and t(16;16) Are Associated with Inferior Outcome.
Authors: Weisser Martin , Schnittger Susanne , Kern Wolfgang , Hiddemann Wolfgang , Haferllach Torsten , Schoch Claudia 
Published: April 2020

Abstract
The fusion transcript CBFB-MYH11 is the molecular correlate of inv(16)/t(16;16) and strictly associated with FAB subtype M4eo. This subgroup is associated with a favorable prognosis in AML. However, approximately 30% of the patients relapse. Our intention was to examine prognostic factors for the outcome within this subgroup. Therefore 153 CBFB-MYH11 positive AML patients were analyzed. The median age was 52 years (range 18–83), 80 patients were female, 73 were male. In 22 cases AML was therapy-related, in 131 cases a de novo AML was diagnosed. Inv(16) was detected in 138 and t(16;16) in 12 cases. In 3 cases neither inv(16) nor t(16;16) were detectable despite PCR and FISH positivity for CBFB-MYH11 suggesting cryptic rearrangements. The most frequent additional cytogenetic abnormalities were +8 (n=19), +9 (n=3), +21 (n=7), +22 (n=23). Cox regression analysis revealed that advanced age (OS: p=0.026; EFS: p=0.029) and increased CBFB-MYH11/ABL ratio at diagnosis (OS: 0.016, EFS: p=0.064) were associated with a worse prognosis. Using log rank test additional factors influencing survival were detected. These included: t(16;16) vs inv(16) (OS: n=8, censored 4, median 362 days vs n=118, censored 92, median not reached, p=0.018; EFS: n=8, censored 4, median 232 days vs n=118, censored 70, median 918 days, p=0.048) and trisomy 21 vs no additional aberrations (OS: n=6, censored 3, median 435 days vs n=74, censored 59, median not reached, p=0.024; EFS: n=6, censored 2, median 293 d vs n=74, censored 44, median 764 days, p=0.0047). Therapy related AML was associated with worse EFS than de novo AML (n=16, censored 6, median 371 days vs n=112, censored 70, median 1179 days, p=0.0167) and there was a trend towards worse OS (p=0.157 n=16, censored 10, median 764 days vs n=112, censored 88, median not reached). A multivariate analysis including t(16;16), age, CBFB-MYH11/ABL ratio, therapy related AML and +21 as covariates revealed t(16;16) and age as independent factor for OS (p=0.014 and p=0.015, respectively) and age, t(16;16), and +21 as independent factors for EFS (p=0.047, p=0.013, and p=0.016, respectively). There was no evidence that the additional aberrations +22 or +8 had an influence on survival. Taken together our data suggest that t(16;16) as compared to inv(16), trisomy 21 and age are associated with worse prognosis in patients with CBFB-MYH11 positive AML.
Successful Induction of Hematologic and Cytogenetic Remission with Gemtuzumab Ozogamicin (Mylotarg(R)) in Patients with Myeloid Blast Crisis of Chronic Myelogenous Leukemia in Refractory to Imatinib Mesylate and Chemotherapy.
Authors: Weng Jingyu , Du Xin , Wu Shuijing , Lu Zesheng , Huang Zilu , Lin Wei 
Published: April 2020

Abstract
Introduction The treatment options for patients with chronic myeloid leukaemia (CML) in blast crisis phase are limited, especially to those were refractory to imatinib mesylate. We report the achievement of hematologic and molecular completely remission after the use of gemtuzumab ozogamicin( mylotarg) in two patients with CD33-positive CML-BC who were refractory to chemotherapy and imatinib mesylate(Gleevec). Two patients(male,62yr; female, 40yr), Before received Mylotarg, they were administrated imatinib mesylate(600mg per day) more than three months and receiveed combination chemotherapy, but they were refractory and their disease progressed. Then, they received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m2, at 2-week intervals for three doses. One of the patient was treated with Mylotarg combinated MA(Mitoxantrone 5mg, d1–4; cytarabin 100mg/M2,d1–7). After the first cycle Mylotarg, two patients achieved a complete hematologic and molecular remission, bcr/abl fusion gene negative detected by FISH, real time PCR bcr/abl ratio 0.03. They have been alive and continuous complete remission.
CONCLUSION: Mylotarg alone or combinated with chemotherapy to patients with CD33-positive CML-BC in refractory to imatinib mesylate can obtain complete hematologic and molecular cytogenic remissions with what appears to be a favorable safety profile.
Serum Protein Profiling Distinguishes BCR-ABL+ CML from Normal and Neutrophilia Cases.
Authors: Mohamedali Azim M. , Sahu Satyaji , Thomas Nicholas Shaun B. , Mufti Ghulam J. 
Published: April 2020

Abstract
We sought to identify additional biomarkers for chronic myelogenous leukaemia (CML) that could be an aid to early diagnosis and also yield novel antigens for immunotherapy. To this end, we screened patient serum samples at presentation against hematologically normal controls as well as patients with neutrophilia using Surface Enhanced Laser Desorption/Ionization technology (SELDI; Ciphergen ProteinChip series 4000). A total of 84 retrospective and prospective serum samples were analysed: presentation −28, reactive neutrophilia (&gt;15x109 neutrophils/L) − 24 and hematopoietic normal controls − 33. Patients were initially screened by routine cytogenetics and in some cases with qPCR for the BCR-ABL breakpoint. The sera samples were evaluated on 4 different array surfaces and the Immobilised Metal Affinity (IMAC) array was chosen as it bound serum proteins that distinguished CML from normal controls. As little as 1 μl serum was sufficient for each analysis. Biomarker artefacts due to variations in sample collection procedures were ruled out by analysing sera (n=4) from each group at the time of collection and 3 and 6 hours post collection. There were no significant differences in any of the biomarkers at any of the time points. The spectrum of proteins obtained from each of the 84 serum samples was averaged from duplicate runs per experiment. Using the Ciphergen Express program, a panel of 5 proteins were significantly differentially expressed in CML versus the reactive neutrophilia and normal hematopoietic controls (p&lt;0.001). These proteins were identified by a combination of purification techniques using Q HyperD F columns, desalting using reverse phase C-18 beads and isolating the biomarker by 1D-SDS PAGE. The biomarkers were identified by peptide mass fingerprinting and confirmed by Tandem MS sequencing. These were
Albumin fragment − 2.8Kd (p&lt; 3.5 x 10−5, ROC=0.78), Fibrinogen fragments − 5.3Kd (p&lt; 6.25 x 10−10, ROC=0.07) and 5.9Kd (p&lt; 9.6 x 10−8, ROC=0.14), Complement 3a precursor fragment − 8.9Kd (p&lt; 0.0015, ROC= 0.70), Platelet basic protein precursor − 10.2Kd (p&lt; 1.5 x 10−4, ROC=0.73) and Lysozyme − 14.6Kd (p=0, ROC=0.92).
Biomarkers 3, 4 and 5 were also verified by antibody capture experiments using NP-20 arrays. In a blinded test set of sera, CML, normal and neutrophilia samples were correctly classified 27/28 (96%), 32/32 (100%), 20/24 (83%) respectively using a combination of the 5.3Kd, 10.2 Kd and the 14.6 Kd markers (Biomaker Pattern software). The algorithm correctly classified 21 new samples as CML (7/8) and control (10/13). The 1/8 CML was misclassified for technical reasons. Therefore, a small number of serum biomarkers in as little as 1 μl serum can be used to distinguish between patients with CML and neutrophilia or hematopoietic normal controls. Similar analyses may be applicable to other more heterogeneous hematological malignancies.
The Induction of Dendritic Cells with IFN-alpha and GM-CSF from Bone Marrow Mononuclear Cells from Patients with Chronic Myeloid Leukemia.
Authors: Zhen Shuier , Jin Jie , Tong Xiangmin 
Published: April 2020

Abstract
Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from the clonal expansion of a stem cell with the typical Philadelphia (Ph) chromosome cytogenetic abnormality. IFN-a has been proven to be effective for patients in the chronic phase of myelogenous leukemia (CML), yet the mechanisms of the antitumor action of these cytokines are still a matter of debate. Dendritc cells (DCs) are potent antigen-presenting cells that prime effective T-cell response aginst tumour antigens. Recent studies have shown that IFN-a can exert a variety of effects on dendritic cells (DCs), which may play an important role in the induction of an antitumor immunity. Human DCs can be generated in vitro from peripheral blood(PB) monocytes or from CD34+ haematopoietic precursor cells in culture medium containing human granulocyte macrophage-colony stimulating factor (GM-CSF), IL-4 and some other cytokines. Previous studies have shown a new effective protocol for the generation of human DCs from unseparated BM aspirate cells with excellent functional capacity of antigen uptake and of stimulating naive and memory T cell responses superior to that of DCs from peripheral blood(PB) monocytes. We, therefore, explored whether treatment with IFN-a may influence the CML bone marrow mononuclear cells(BMMNCs) derived DCs in vitro. Treatment BMMNCs of 12 patients with CML in chronic phase with IFN-a+rhGM-CSF(IFN-a-DC) generated DCs with more mature phenotype properties expressing higher of CD80,CD86,HLA-DR,CD83 compared to the CML- BMMNCs treated with rhGM-CSF+IL-4(IL-4-DC). And in parallel with phenotypes, IFN-a-DC also showed more effective than IL-4-DC in eliciting an allogeneic mixed lymphocyte reaction by MTT assay. FISH confirmed the DCs of both groups were leukemic origin. These findings demonstrate that IFN-a promotes the differentiation/maturation of DCs derived from BMMNCs of patients with CML in vitro, these studies also broaden the clinical scope of IFN-a as a promising agent in the immunotherapy of CML.
Effects of STI571 on the Development of Dendritic Cells Derived from Bone Marrow Mononuclear Cells from Patients with Chronic Myeloid Leukemia.
Authors: Jin Jie , Zheng Shuier , Tong Xiangmin 
Published: April 2020

Abstract
Mature dendritc cells(DCs) are potent antigen-presenting cells that prime effective T-cell response aginst tumour antigens. However, in the tumour microenviroment the differentiation and maturation of DCs is always suppressed by many factors, such as VEGF, IL-10,TGF-βet al. Though DC derived from CML patients have been shown to process and present endogenous BCR-ABL to CD4+ T cells, the function of DC may be abnormal in CML, which have been shown differences in cytoskeletal organisation and impaired migration, and a reduced capacity to capture and present nonleukaemic antigen, and less effective than normal DC in eliciting an allogeneic mixed lymphocyte reaction. STI571(trade name Glivec or Gleevec) is a specific inhibitor of Abl tyrosine kinase and has been a first- line agent for the treatment of chronic myelogenous leukemia (CML). Previous studies have found that defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and can be partially normalized by STI571. We, therefore, explored whether treatment with STI571 may influence the CML -derived DC in vitro. Treatment bone marrow mononuclear cells(BMMNCs) of 11 patients with CML in chronic phase with STI571+rhGM-CSF+IL-4(STI571-DC) generated DCs with more mature phenotype properties expressing higher of CD80,CD86,HLA-DR,CD83 compared to the CML- BMMNCs treated with rhGM-CSF+IL-4(IL-4-DC). And in parallel with phenotypes, STI571-DC also showed more effective than IL-DC in eliciting an allogeneic mixed lymphocyte reaction by MTT assay. FISH confirmed the DCs of both groups were leukemic origin. To explore whether the positive effects of STI571 on CML-DC may attributed to negative factors of DC differentiation/maturation suppressed by STI571, media were tested for VEGF concentrations by using the sandwich enzyme-linked immunosorbent assay (ELISA). As a result, the concentration of VEGF was dramatically reduced in STI571-DC. These findings demonstrate that treatment with STI571 promotes maturation and enhances the antigen-presenting capabilities of CML- BMMNCs derived DCs, these studies also offer a more comprehensive understanding of the role of STI571 in the immunotherapy of CML.
Sphingosine Kinase 1 Is Involved in Proliferation and Survival of Chronic Myeloid Leukemia Cells.
Authors: Ricci Clara , Onida Francesco , Soligo Davide , Lambertenghi-Deliliers Giorgio , Ghidoni Riccardo 
Published: April 2020

Abstract
Sphingosine Kinase 1 (SK1) is a key enzyme of the sphingolipid metabolism. By phosphorylating sphingosine (Sph), SK1 induces accumulation of sphingosine 1 phosphate (S1P). As a second messenger, S1P stimulates proliferation and survival and protects cells against ceramide-induced apoptosis. Although oncogenic activity of SK1 has been demonstrated in a variety of solid tumors, its role in leukemic cells growth remains unclear. Recently, SK1 overexpression has been reported to represent an oncogenic event during erythroleukemia progression (Lescolan E. et al, Blood 2005). We focused on Chronic Myeloid Leukemia (CML), a hematopoietic disorder characterized by the presence of the Philadelphia (Ph) chromosome that leads to the expression of the chimeric protein Bcr/Abl. Through its constitutive tyrosine kinase activity, Bcr/Abl is recognized as the pathogenetic event that causes CML and thus the basis for the development of specific inhibitors. Among these, Imatinib Mesylate (IM) represents the more successful drug for CML treatment. However, most patients who are treated in advanced stages of the disease relapse after an initial response to IM. Therefore, the existence of a functional link between Bcr/Abl and SK1 would provide new strategies to overcome acquired resistance to IM in CML. To test the hypothesis that SK1 contributes to the growth and survival of leukemic cells, we first verified that the kinase transcript is expressed in a panel of CML cell lines [AR230 (p230Bcr/Abl+), K562 and RWLeu4 (both p210Bcr/Abl+)], although at different levels. Then the effect of pharmacological inhibition of SK1 was assessed by using a competitive inhibitor (SKI, SK Inhibitor, Calbiochem) of the ATP-binding site of SK1. Cells were treated with increasing doses (1 to 50 μM) of SKI for up to 72 hrs and the WST-1 assay was performed. A dose- and time-dependent anti-proliferative and cytotoxic effect was observed (IC50: 7.02 μM for AR230, 7.06 μM for K562 and 35.8 μM for RWLeu4 cells). Surprisingly, up-regulation of SK1 transcript was detected. Finally, when the Eosinophilic Leukemia cell line Eol-1 (FIP1L1-PDGFRα+) was exposed to SKI under the same experimental conditions of CML cells, an even more potent anti-proliferative and cytotoxic effect was observed, indicating a higher sensitivity of these cells to SKI (IC50: 0.43 μM). Altogether our results suggest involvement of SK1 in the control of growth and survival of myeloid leukemia cells of different origin. To address the question whether a functional link between SK1 and Bcr/Abl occurs, we are now investigating if Bcr/Abl expression and phosphorylation status are modulated following treatment with SKI and conversely if SK1 expression and activity are affected by treatment with IM.
Chronic Myeloid Leukemia during Pregnancy: Report of Management and Outcome in Seven Patients.
Authors: Matias Kleber , Matias Carolina , Freire Ana Dulce , Azevedo Alita Andrade 
Published: April 2020

Abstract
The occurrence of leukemia during pregnancy is very rare with an estimated incidence of one per 100,000 pregnancies annually. It has been estimated that during pregnancy most leukemias are acute: two thirds are myeloid (AML) and one third are lymphoid (ALL). Chronic myeloid leukemia (CML) is found in less than 10% of leukemias during pregnancy and chronic lymphocytic leukemia (CLL) is extremely rare. The management of CML during pregnancy is a difficult problem because of the potential effects of the therapy on the mother and fetus. Since the disease has an initial chronic phase, it is usually managed conservatively during pregnancy, while an aggressive approach, such as bone marrow transplantation, may be considered after delivery. A limited number of cases described successful treatment modalities of CML during pregnancy including leukapheresis, hydroxyurea (HU) and interferon (IFN). We report nine cases of pregnancy in seven chronic myeloid leukemia patients, giving birth healthy children in a single institution from 1979 to 2005. In four cases the diagnosis of CML was made on prebirth period in routine blood testing, and five pregnancies developed during the course of disease. Four of the pregnancies were found in the first trimester, four in the second and one in the third. Median age of patients was 21 years (range 18–30years). All patients were Ph1 positive and the leucocyte count ranged between 45 to 336 x 109 /L. Table 1 shows treatment performed in patients before and during pregnancy. Patients 4 and 7 had a subsequent pregnancy despite the use of contraceptive methods, both diagnosed in the first trimester. Hydroxyurea was stopped during pregnancy. Delivery was performed by caesarean section in 5 cases and by spontaneous vaginal delivery in 4 cases. All infants’ examination and blood counts were normal and there were no perinatal or maternal complications. In june 2005, two new cases of pregnant CML patients were seen at our institution. One of them was being treated with imatinib, and the other without treatment at the moment of pregnancy. They will be managed only with leukapheresis. Our data suggest that exposure to IFN and HU during pregnancy is probably not associated with a significantly increased risk for malformations, however leukapheresis can be considered for treatment of CML during pregnancy because of the lack of teratogenic and other adverse effects in patients who tolerate and respond to the procedure.
Cases Age (years) CML diagnosis Pregnancy diagnosis Trimester of pregnancy Treatment before pregnancy Treatment during pregnancy 1 18 Sep/1993 Oct/1993 First None HU 2 30 Dec/1996 Jan/1997 Third None Leukapheresis 3 18 Dec/1993 Nov/1995 First IFN stopped IFN 4 21 Sep/1995 Sep/1995 Second None HU 5 21 Jul/1994 Aug/1994 Second HU stopped HU 6 27 Jan/1979 Jan/1979 Second None Busulphan - 2 months 7 18 Dec/1995 Oct/1996 Second HU HU
Study on the Burden of Abnormal Hematopoietic Clone of the Patients with Myelodysplastic Syndromes.
Authors: Shao Zonghong , Wang Huaquan , Shi Jun , Cao Yanran , Liu Hong , Bai Jie , Tu Meifeng , Xing Liming , Liu Shihe , Sun Juan , Jia Hairong 
Published: April 2020

Abstract
Background Myelodysplastic syndromes (MDS) is a group of clone haematopoietic stem cell diseases. The burden of abnormal hematopoietic clone plays key roles in the development of this disease and needs to be further studied quantitively. Methods The ratio of the counted bone marrow cells with abnormal chromosomes to the total counted bone marrow cells was regarded as the index of MDS clone burden. The disease severity related parameters including white cell count, hemoglobin, platelet count, lactate dehydrogenase level, bone marrow blast, myeloid differentiation index, the ratio of cFU-GM to CFU-GM, micromegakaryocyte, transfusion, IL-2, TNF, CD4+ and CD8+ T cells of MDS patients were assayed and the correlations between those parameters and MDS clone burden were also analysed. Results The clone burden of MDS patients was (67.4±36.2)%. MDS clone burden correlated positively with bone marrow blasts(r =0.483, P=0.012), negatively with hemoglobin level(r = −0.445, P= 0.023); The number of blasts, hemoglobin and erythocytes in high clone burden(&gt;50%) and low clone burden(≤50%) groups were (7.78±5.51)% and (3.45±3.34)%(P=0.035), (56.06±14.28)g/L and (76.40±24.44)g/L(P=0.013), (1.82±0.12)×1012/L and (2.32±0.21)×1012/L(P=0.034)respectively. CD4+ T lymphcytes of MDS patients and normal controls were (274.18±71.85)×106/L and (454.82±205.88)×106/L(P=0.012)respectively. CD8+ T lymphcytes of MDS patients and normal controls were (240.45±150.01)×106/L an (305.27±145.14)×106/L(P=0.317)respectively. The serum level of interleukin 2 of MDS patients and normal control group were (6.29±3.58)ng/ml and (3.11±1.40)ng/ml (P=0.002) respectively. The serum level of tumor necrosis factor of MDS patients and normal control group were (2.42±1.79)ng/ml and (1.68±0.69)ng/ml(P=0.124)respectively. The ratio of CD4 to CD8 in high clone burden MDS patients was (1.90±0.52), and that in low clone burden patients was (0.97±0.44)(P=0.022). Conclusion The quantitive clonal karyotype abnormalities and deficient T cell immunity are important parameters for evaluating MDS severeity and prediciting it’s progression.
Exisulind Selectively Induces Apoptosis Via C-Jun Kinase Activation in MDS and sAML/MDS.
Authors: Czibere Akos , Prall Wolf C. , Knipp Sabine , Kuendgen Andrea , Zerbini Luiz F. , Germing Ulrich , Haas Rainer , Libermann Towia A. , Gattermann Norbert , Aivado Manuel 
Published: April 2020

Abstract
Treatment of patients suffering from myelodysplastic syndromes (MDS) is difficult and frustrating, particularly when in progression or already progressed to secondary acute myeloid leukemia (sAML). In these cases, the bone marrow contains an increasing number of immature cells, which are characterized by reduced apoptotic and increased proliferative activity. Therefore, pro-apoptosis has recently been proposed as a novel therapeutic approach. Exisulind is a potentially pro-apoptotic agent, and therefore, we investigated its influence on proliferation, differentiation, cell cycle and apoptosis in peripheral blood-derived CD34+ stem cells (PBSC) obtained from 10 patients suffering from refractory anaemia with excess of blasts in transformation (RAEB-T), two sAML/MDS cell lines, one de-novo AML cell line and healthy CD34+ bone marrow cells. Incubation of sAML/MDS cells with Exisulind clearly inhibited colony formation in the CFU-assays. Interestingly, Exisulind did not alter the percentages of sAML/MDS cells in G1-, S-, G2-, M-phase, but reduced proliferation and induced apoptosis in this cell type. Likewise, in 8 out of 10 RAEB-T samples Exisulind significantly inhibited proliferation and increased the rate of apoptotic cells. Exisulind had no effect on de-novo AML or normal CD34+ cells. We detected increased c-Jun NH2-terminal kinase activity in sAML/MDS cells treated with Exisulind. Adding a specific JNK-inhibitor to Exisulind-treated sAML/MDS and RAEB-T cells partly abrogated apoptosis, thus proving that Exisulind-mediated apoptosis in sAML/MDS and RAEB-T cells is dependent on JNK activation. We conclude that JNK is one mediator of apoptosis in MDS cells treated with Exisulind. Moreover, our data strongly suggests to explore the potential use of Exisulind as a novel, pro-apoptotic therapy for patients with RAEB-T and sAML/MDS.