bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Levels of Vascular Endothelial Growth Factor (VEGF) and Basic Fibroblast Growth Factor (bFGF) in Children with Acute Lymphoblastic Leukemia.
Authors: Palgan Izabela , Wysocki Mariusz , Palgan Krzysztof , Debski Robert , Odrowaz-Sypniewska Grazyna , Styczynski Jan 
Published: April 2020

Abstract
Angiogenesis is a process of blood vessel formation from the preexisting capillaries. It plays an essential role of growth and development of cancer. The aim of this study was to evaluate serum levels of the most important angiogenic stimulators, Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (bFGF) in children with acute lymphoblastic leukemia (ALL) and their relation to clinical manifestations of the disease, and in healthy controls. Although VEGF and bFGF have been suggested to be reliable prognostic indicators and important tools for treatment approach in hematopoietic malignancies and solid tumors, experience in childhood ALL has been limited. Patients and methods: 46 children with ALL (24 male, 22 female) aged 2-18 years (median 8 years) at the time of diagnosis and in remission and 70 healthy children (31 male, 39 female). For the quantitative determination of human VEGF and bFGF, the Quantikine (R&D Systems, Minneapolis, MN, USA), a solid phase enzyme-linked immunosorbent assay method was used. Elevated VEGF and bFGF were defined as being higher than the 95 percentile value in control group. Results: The range of VEGF serum levels in healthy controls was 24.73–467.7 pg/ml (median 168.9 pg/ml), 95 percentile was 431.85 pg/ml and the range of bFGF serum levels was 0–10.8 pg/ml (median 2.9 pg/ml), 95 percentile was 6.95 pg/ml. In children with ALL, the range of VEGF serum levels at the time of diagnosis was 0–532.3 pg/ml (median 91.18 pg/ml), and bFGF 0–64.48 pg/ml (median 5.11 pg/ml). In children in remission, the range of serum levels of VEGF was 53.15–962.67 pg/ml (median 209.73 pg/ml), and bFGF 0–32.5 pg/ml (median 5.98 pg/ml). The median level of VEGF at diagnosis was lower than those of the control group (p=0.006), and higher in remission, when compared to values obtained in children on diagnosis and in the control group (p=0.0005; p=0.01). Elevated level of VEGF was observed in 8.7% children at the time of diagnosis and in 24.4% of patients in remission. The median levels of bFGF at diagnosis and in remission were significantly higher than those in control group with 40% of children having elevated levels. A positive correlation between VEGF serum concentration and platelet number, and negative correlation between VEGF serum levels and WBC were observed, with no other correlations between growth factors (VEGF, bFGF) and age, type of lymphoblasts (FAB), risk group, and drug resistance. Conclusion: These results suggest that bFGF more than VEGF can play an important role in childhood ALL. The serum levels of angiogenic factors may be related to the activity of the disease, while both growth factors can possibly be a target of anti-angiogenic therapy.
Microarray Gene Expression Studies Reveal Potential Classifier Genes That Allow Prediction of Response to Interferon in Chronic Myeloid Leukemia Patients.
Authors: Barbany Gisela , Hagberg Anette , Strömberg Ulla Olsson , Isaksson Anders , Simonsson Bengt 
Published: April 2020

Abstract
Interferon has been extensively used to treat CML patients over the past years. However, not all patients respond and the reasons for this heterogeneity are largely unknown. Microarray-based gene expression analysis enables the study of thousands of genes in one single experiment and has been shown to be a useful tool to assign samples to specific categories. The goal of the study was to identify gene/s whose expression will permit prediction of response to interferon. Blood samples (n=9) or leukapheresis products (n=11) were collected from 20 CML chronic phase patients at diagnosis and all patients were subsequently treated with a-interferon. Responders were defined as patients achieving a complete or major cytogenetic response at 12 months or earlier after initiation of interferon (n=9) and patients with no cytogenetic response 5 to 18 months after interferon start were assigned to the non-responder group (n=11).
Mononuclear cells from two healthy blood donors were pooled and the RNA used as a reference sample. RNA was extracted from mononuclear or leukapheresis cells and gene expression profiles were analyzed using cDNA microarrays with approximately 7500 genes. Genes were organized according to the absolute difference in the median expression levels between the two groups and the top 20 genes were then used in an “all pair” selection procedure to identify the gene/s with the highest prediction accuracy. Six genes were selected by this procedure: RNAse2, PRG2, NRGN, LTF, JARID1A and DEFA4. These genes had an estimated error rate in predicting interferon response of 0,13 with a Fisher linear discriminant test.
Our results show that gene expression analysis may permit the identification of genes whose expression levels may be useful in the prediction of response to interferon in CML diagnostic samples.
Posttransplant Immunotherapy with a GM-CSF-Based Tumor Vaccine (GVAX®) Following Autologous Stem Cell Transplant (ASCT) for Acute Myeloid Leukemia (AML).
Authors: DeAngelo Daniel J. , Alyea Edwin P. , Borrello Ivan M. , Levitsky Hyam I. , Stock Wendy , Sher Dorie , Damon Lloyd E. , Linker Charles A. , Donnelly Amy , Hege Kristen M. 
Published: April 2020

Abstract
Background: Preclinical models have demonstrated the efficacy of GM-CSF secreting cancer vaccines accompanied by vaccine-primed lymphocyte infusion following ASCT.
Methods: Patients ≤ 60 years old with de novo AML (excluding M3) were enrolled. Leukemia cells were harvested at diagnosis followed by induction and consolidation chemotherapy and ASCT. A pretransplant vaccine composed of irradiated autologous leukemia cells mixed with GM-CSF gene-modified K562 cells (CG9962) was given followed by collection of vaccine-primed lymphocytes that were reinfused with the stem cell graft. Posttransplant vaccinations were initiated at week 6 (or upon platelet engraftment) and given every 3 weeks (10x107 tumor cells + 4x107 CG9962 cells) x 8 vaccinations.
Results: Leukemia cell harvest was successful in 51/54 patients (blood draw − 22, leukapheresis − 28, bone marrow aspirate − 4). To date, 44/54 patients (81%) have achieved a complete remission (CR) following induction chemotherapy, 27 have received the pretransplant vaccination, and 15 have initiated posttransplant vaccinations. Local vaccine injection site reactions developed in all patients. Delayed-type hypersensitivity (DTH) reactions to irradiated, autologous tumor were induced post vaccination in 4/11. Antibodies reactive against autologous tumor were induced in 5/11 and against CG9962 cells in 10/10. Minimal residual disease (MRD) is being monitored by quantitative analysis of peripheral blood (PB) and bone marrow (BM) for WT1, a leukemia-associated gene, by RT-PCR. All patients had detectable WT1 transcripts in PB and BM at diagnosis. Most patients in CR had persistently detectable WT1 transcripts in BM following induction (92%), consolidation (91%), and ASCT (63%), whereas, clearance of WT-1 in PB was more frequent (49% detectable post induction, 50% post consolidation, and 31% post ASCT). A decrease in WT1 was noted in 67% (12/18 in the BM and 10/15 in PB) following the pretransplant vaccination.
Conclusions: Collection of large quantities of autologous leukemia cells for vaccine production is feasible. Reduction in WT-1 transcript levels following the pre-transplant vaccine suggests anti-leukemic activity of this GVAX® vaccine platform.
The Comparative Analysis of Serum Proteomes for the Discovery of Biomarkers for Acute Myeloid Leukemia.
Authors: Kwak Jae-Yong , Lee Na-Ri , Kim So-Ri , Yim Chang-Yeol , Song Eun-Gi , Kwak Yong-Geun 
Published: April 2020

Abstract
Acute Myeloid Leukemia (AML) develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. However, the definitive diagnostic protein-biomarkers for AML are still unclear, and monitoring these markers has not yet been completely achieved. In our study, to identify the biomarkers for an initial diagnosis, detection of relapse and monitoring the minimal residual disease in acute myeloid leukemia (AML) by a lesser invasive method, serum proteins reflecting alteration in their proteomes were analyzed. We compared two-dimensional electrophoresis patterns of human sera of twelve patients with acute myeloid leukemia with that of normal twelve subjects. The differentially expressed spots were identified by matrix-assisted laser desorption/ionization-time-of flight (MALDI-TOF) and electrospray ionization quadupole time of flight (ESI-Q-TOF) mass spectrometry. Eight proteins that expressed differentially in AML group were found. The expression levels of alpha-2-HS-glycoprotein, complement-associated protein SP-40,40, RBP4 gene product, lipoprotein C-III and an unknown protein were down-regulated in serum of AML patients, whereas the other three proteins including immunoglobulin heavy chain variant, proteosome 26S ATPase subunit 1 and haptoglobin-1 up-regulated. These results suggest that these proteins can be used as less invasive diagnostic and monitoring biomarkers of AML if further studies were done.
Prognostic Significance of Molecular Remission Determined by Highly Specific PCR after Dose-Reduced Allogeneic Stem Cell Transplantation (SCT) in Patients with Multiple Myeloma.
Authors: Zagrivnaja Maria V. , Badbaran Anita , Corradini Paolo , Fehse Boris , Zander Axel R. , Kröger Nicolaus 
Published: April 2020

Abstract
Achieving molecular remission after standard allogeneic stem cell transplantation in multiple myeloma is associated with long term freedom of disease and possible cure. We recently reported a high rate of complete remission after an auto-allo tandem approach using fludarabine (150 mg/m²), melphalan (140 mg/m²) and anti-thymocyte globulin (ATG: 3 x 10–20mg/kg) three months after a cytoreductive autograft (melphalan 200 mg/m²). To determine the incidence of molecular remission we tried to develop allele-specific oligonucleotides (ASO) based upon the clonal rearrangement of immunoglobulin heavy chain genes and ASO - polymerase chain reaction (ASO-PCR) for each patient who achieved complete remission with negative immunofixation after SCT (n=27). The specificity of the ASO-PCR was tested using patient and control DNA. Patient DNA isolated from bone marrow (BM) samples obtained at diagnosis and after allografting at variable time points was used for further molecular analysis. For nine patients we were able to generate specific primers and MRD diagnostics have been performed for a median of two years after SCT. Molecular remission was strictly defined by the absence of any PCR-positivity. In 6 patients nested PCR remained negative after a median follow up of 22 months (range 10–24). Only one of these patients relapsed with extramedullary disease (14 months) still being PCR-negative in his bone marrow. In contrast, all those patients with complete remission but positive PCR (n=3) relapsed (at 11, 14 and 16 months after SCT, respectively) thus underlining the importance of achieving molecular remission after allo-SCT. We suppose that quantitative real-time PCR might be a useful tool to closely monitor MRD kinetics post allo-transplantation in order to verify efficiency of various treatment regimens, e.g. donor lymphocyte infusions.
Results of Conventional Cytogenetics and Interphase FISH (I-FISH) Analyses in Patients with a Clinical and Morphologic Diagnosis of CML: Analysis of 52 Cases.
Authors: Gupta Seema , Berman Ellin , Jhanwar Suresh 
Published: April 2020

Abstract
The presence of the Philadelphia chromosome (Ph), derived from a balanced translocation between chromosomes 9q and 22q, serves as a hallmark for the diagnosis of CML or Ph-positive ALL. In recent years, I-FISH has become the method of choice to detect Ph-positive clones at diagnosis and during treatment. In addition, I-FISH analysis is also able to identify variant translocations and loss of DNA sequences, some of which are known to be predictors of poor clinical outcome. To determine the contribution of I-FISH in detecting genetic alterations at diagnosis and during therapy, we summarized our experience in a series of patients with CML and Ph+ ALL studied in a single institution between 2000–2004. A total of 52 patients had both cytogenetic and I-FISH analyses available for review. The 52 patients included 30 patients in chronic phase, 10 patients in accelerated phase, 9 patients in blastic phase, and 3 patients with acute lymphoblastic leukemia (ALL). Sixteen of the 52 patients had newly diagnosed CML, and the remaining 36 patients had studies performed while on imatinib. Conventional cytogenetics detected the Ph-chromosome in 44 patients (85%), whereas I-FISH detected Ph chromosome positivity in all 52 patients (100%). In three of the 16 patients with newly diagnosed disease, I-FISH identified variant translocations in the setting of a normal karyotype. Two of these 3 patients were found to be RT-PCR negative for bcr/abl transcripts. Nineteen of 52 patients (37%) had additional abnormalities detected by karyotype. Nine of these 19 patients (47%) had more than one additional cytogenetic abnormality. The most common abnormalities in the Ph+ clone included: 6 patients with 2 copies of the Ph chromosome, 4 patients with trisomy 21, 2 patients with deletion (20q), 2 patients with isochromosome 17, and 2 patients with trisomy 8. Independent clones with trisomy 8 were noted in an additional 2 patients on imatinib therapy. A total of 12 of the 52 patients (23%) had variant signal patterns by I-FISH; loss of DNA sequences on chromosomes 9 and 22 occurred in 4 and 3 cases respectively and a variant signal pattern involving additional chromosomes was seen in 5 patients. While in general we found a good correlation between the proportion of Ph-positive cells detected by conventional cytogenetics and I-FISH, differences between the two types of analyses were observed in 8 patients. Six patients had a normal karyotype (20 cells analyzed) with positive I-FISH analysis (range 3.2–99%). Two of the 8 patients had a small percentage of Ph-positive metaphases with negative I-FISH. These results underscore the significance of utilizing both conventional cytogenetics and I-FISH in CML patients at diagnosis as well as during therapy. The biologic and clinical implications of the disparity between conventional cytogenetics, I-FISH, and in some cases RT-PCR results are not yet fully realized.
FLT3 Internal Tandem Duplications in Adults with De Novo Acute Myeloid Leukemia.
Authors: Xavier Sandra G. , Hassan Rocío , Clementino Nelma C.D. , Tabak Daniel G. , Spector Nelson , Zalcberg Ilana R. 
Published: April 2020

Abstract
FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. Recently, internal tandem duplication (ITD) mutations of the FLT3 gene have been described in patients with AML and associated with a poor prognosis. The aim of this study was to analyze the prevalence of FLT3-ITD in a series of 90 adults with de novo AML and correlate the presence of this mutation with biological characteristics and clinical response. We analyzed diagnostic peripheral blood or bone marrow specimens from 43 women and 47 men, with a median age of 38 years (16–83). Polymerase chain reaction was performed on genomic DNA using previously published primers for exons 11 and 12. An FLT3-ITD was found in 22/89 patients (25%). It was present in 37% (9/24) of the patients with acute promyelocytic leukemia (APL) and in only 20% (13/65) of the patients with non-M3-AML (p=0.07). The FLT3-ITD was not detected in patients with M6 (n=1) and M7-AML (n=3), nor in patients with the AML1-ETO (n=2) or with the CBFb-MYH11 (n=4) fusion genes. The median WBC counts were higher in FLT3-ITD patients than in those without the mutation (37 X 109/L vs. 27 X 109/L, p=0.43). In APL, FLT3-ITD was found in 5 out of 6 patients with the short PML-RARa isoform, but in only 4 out of 18 patients with the non-short isoform (p=0.01). Univariate analysis showed an association between the presence of FLT3-ITD and both a lower complete remission (CR) rate (41% vs. 64%; p=0.05) and a shorter overall survival (14% vs. 34%; p=0.03). However, FLT3-ITD was not associated with the CR rate (p=0.18) or the OS (p=0.07) in the multivariate analysis. The clinical significance of FLT3-ITD in adult AML remains uncertain, and further investigation is clearly warranted.
Toxicity of ALL Treatment in Adolescents as Compared to That in Younger Children.
Authors: Dijkema Tim , GrootLoonen Jacqueline , Bokkerink Jos , Hoogerbrugge Peter 
Published: April 2020

Abstract
Introduction: The results of therapy in young adults and adolescents with ALL has reported to be better if more aggressive pediatric treatment regimens were applied as compared to regimens more commonly used in adults (E.g. deBont, ASH 2003; Boissel, JCO 2003). A point of concern in applying pediatric regimens in young adults is the possible toxicity of these regimens. To address this, we retrospectively evaluated the toxicity of childhood ALL regimens in younger children as compared to older children and adolescents.
Patients: 90 patients treated for ALL in our hospital between 1985 and 2003 were included in the study. Treatment consisted of ‘classical’, multi-agent, pediatric regimens of the Dutch Childhood Oncology Group and the I-BFM, and included dexamethasos (n=47) or prednison (n=4) during induction and maintenance therapy in the majority of the patients. The survival and toxicity data of 66 children aged 3 to 9 years (mean 6 +/− 1 year) were compared with those in 24 children aged 13 to 17 (mean 15 +/− 1 year). Toxicity analysis included infectious complications, renal and liver function, bone density and occurrence of diabetes.
Results: As expected, as older age is a risk factor in childhood ALL, survival was better in the younger group (87% vs. 67%), although the survival in the older group is still better than in most adult-studies (Boissel, JCO 2003, deBont, ASH 2003). Older children showed more corticosteroid-related toxicity: Insulin-dependant hyperglycemia occurred in 25% of older patients, as compared to 0% in the younger group. Also, bone-density was significantly more reduced in patients treated with dexamethason-including maintenance treatment in older patients (Z-score of -2.8) as compared to the younger patients (Z-score of -1.5) at the end of treatment. No differences in renal and liver toxicities were seen between the two groups. Fever with neutropenia occurred more often in the younger patients (NS), and also treatment delay was more often necessary in the younger patients.
Conclusion: Childhood-ALL regimens are regarded as possible beneficial in older patients as compared to ‘adult regimens’. However, major concern is the possible toxicity of these pediatric regimens. Our data show that toxicity of these aggressive regimens is similar in older children/adolescents as compared to the toxicity in younger children. Only reversible corticosteroid-induced toxicity was more prominent in older patients, other toxicities were similar or even less in older patients. These data suggest that ‘pediatric regimens’ are well-tolerable in older patients with ALL.
Kringle IV Encoding Domains in the Apo(a) Gene and Serum Lipoprotein(a) Level Do Not Contribute to Avascular Necrosis of Bone (AVN) in Acute Lymphoblastic Leukemia.
Authors: Bezemer Désirée D.L. , van Beek Robert D. , Meijerink Jules P.P. , de Muinck Keizer-Schrama Sabine M.P.F. , Pieters Rob , van den Heuvel-Eibrink Marry M. 
Published: April 2020

Abstract
Introdution
Symptomatic AVN occurs as a serious complication of treatment in 4%–12.5% of pediatric cases with ALL. The final common pathway for the development of AVN involves a compromise in the blood flow, leading to infarction. The pathogenesis is multifactorial, including elevated intracortical pressure, vascular occlusion, altered lipid metabolism/fat emboli, hemostatic abnormalities and inhibition of angiogenesis. The difference in incidence of AVN in patients treated according to one and the same protocol suggests a genetic variation as a contribution to the biology of AVN. In one report, familial occurence of bone marrow edema syndrome (early phase of AVN) was associated with elevated levels of lipoprotein(a)[Lp(a)]. Lp(a) is a complex of low-density lipoprotein (LDL) and a high molecular weight glycoprotein called apolipoprotein(a)[apo(a)]. The Lp(a) level is inversely correlated with the kringle IV repeat number in apo(a), that is present as a naturally variation in the population.
Methods
We investigated the Lp(a) levels and the genetic variation in the Apo(a) gene in pediatric patients with and without AVN. DNA from mononuclear cells was isolated from 10 ALL patients with AVN (group I) and 12 patients without AVN (group II), all matched for age, gender and protocol. AVN is defined as pain of the extremities, not related to treatment with vincristine, confirmed by finding typical abnormalities on MRI. The control group consisted of 13 healthy Caucasian subjects (group III). To detect the number of kringle IV repeats pulsed field gel elctrophoresis (PFGE) and Southern blot of genomic DNA was performed. Serum Lp(a) levels were determined by immuno-nefelometric detection method.
Results
The median number of kringle IV repeats (mean of both alleles) did not significantly differ between the three groups: 25 (range 16–37, group I), 24 (range 13–32, group II), 21 (range 10–36, group III). The median Lp(a) levels in ALL patients with AVN versus ALL patients without AVN were respectively 0.085 g/L (range &lt;0.02–0.848) and 0.067 g/L (range &lt;0.02–0.362). Again the difference was not significant.
Conclusion Our results suggest that Lp(a) and genetic polymorphism of apo(a) do not play a mayor role in the pathogenesis of AVN in pediatric ALL.
Differential Expression of VEGF and Its Receptors in the Primary Cells of Various Risk Classified Acute Lymphoblastic Leukemia Patients.
Authors: Liang Aibin , Li Li , Gu Long-Jun , Jiang Hua , Ye Hui 
Published: April 2020

Abstract
Expression of VEGF and its receptors (Flt-1, KDR) were assayed by means of ELISA and RT-PCR on healthy donors (20 cases), patients under remission (20 cases), patients of standard risk (29 cases) and high-risk group cases (12 cases). Meanwhile, the clinical data of all the patients enrolled in this study were collected and then analysed with the detection of VEGF and its receptors. Results showed that expressions of VEGF and its receptors are diversely detected in 4 groups studied. VEGF and its receptors are expressed higher in high risk group than standard risk group, however, compared to remission group and healthy donors standard risk patients expressed higher VEGF and its receptors. Concordantly, the clinical data are in line with the expressions of VEGF and its receptors on all leukemia samples studied. Patients with higher expression of VEGF and its receptors often have higher peripheral white blood cell counts, severe liver infiltration, higher LDH value and poor treatment response. We also found that expression of VEGF and its receptors are not associated with age, sex, sample status and cytogenetic characteristics. This is demonstrated that ALL patients with highly expressed VEGF and its receptors are usually with higher tumor burden, especially in high-risk cases. Detection of VEGF and its receptors might be one of prognostic marker for ALL treatment.