bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal Heterogeneity in TEL/AML1+ Acute Lymphoblastic Leukemia (ALL): A Clinical Appraisal
Authors: Papadhimitriou Stefanos I , Paisiou Anna , Tsagarakis Nikolaos , Papadakis Vassilios , Kentrou Nektaria , Paterakis Georgios , Parcharidou Agapi , Tsakiridou Anastasia A , Tsitsikas Konstantinos , Kostopoulos Ioannis , Pavlidis Dimitrios , Georgiakaki Maria , Polychronopoulou Sophia 
Published: April 2020

Abstract
Introduction: In TEL/AML1+ ALL, the formation of the fusion gene is frequently followed by clonal evolution, with the acquisition of additional aberrations, some involving the TEL and AML1 genes. The resulting variant subclones often coexist at diagnosis, but the clinical significance of this heterogeneity is unclear.
Patients and Methods: The study included a group of 28 children with ALL, found TEL/AML1+ on interphase FISH. In all cases, 500 nuclei were assessed and all signal patterns indicative of a typical t(12;21) or any deviation were recorded. The patients were treated according to the BFM-95 protocol and followed-up for 5,3 to 101,10 (median 66,40) months.
Results: In 19 cases, a single clone was found. In 12 of them (Group A), the typical pattern was obtained, while in 7 (Group B) there were additional aberrations (deletion of the non-rearranged TEL in 4; fusion duplication in 1; both in 2). In the rest 9 cases (Group C), we found coexistence of two (7) or three subclones (1). Certain variations (i.e. fusion triplication or AML1 deletion) were not seen in cases with a single clone, typical or variant. Epidemiological and biological variables and outcome were comparable between the three groups. However, 8 of the 9 children in Group C had residual disease detectable by flow cytometry on D15, versus only 2 and 1 patients in Group A and B respectively (p&lt; 0,05). One patient in Group A relapsed and subsequently died with the same signal pattern as in diagnosis. There was another relapse in Group C, but the patient entered a second remission on re-induction. Interestingly, in this latter case, involving the only patient with three subclones seen on diagnosis, all three were also present on relapse, at comparable percentages as in diagnosis.
Conclusions: Clonal heterogeneity is frequent in TEL/AML1+ ALL. It is associated with a slower clearance of the marrow on induction but not with the long-term outcome. However, this is unlikely to reflect the presence of a more resistant subclone with regard to additional aberrations of TEL and AML1 genes, since the presence of residual disease on day 15 was seen in similar frequency in patients with a typical t(12;21) and in those with a single variant clone. It is possible that patients with clonal heterogeneity may harbor other cytogenetic abnormalities involving other genes or chromosomes. Further study will be necessary to endorse this hypothesis and, perhaps, identify new pathways in the development of TEL/AML1+ ALL.
Veno-Occlusive Disease of the Liver during Induction Therapy for Acute Lymphoblastic Leukemia
Authors: Papadopoulos Athanasios , Ntaios George , Kaiafa Georgia , Girtovitis Fotios I , Saouli Zoi , Kontoninas Zisis , Diamantidis Michael D. , Andreadis Charalambos , Savopoulos Christos , Hatzitolios Apostolos 
Published: April 2020

Abstract
Veno-occlusive disease (VOD) of the liver constitutes a well known complication of high-dose chemotherapy during hematopoietic stem cell transplantation. We present a fatal case of VOD during conventional induction chemotherapy for acute lymphoblastic leukemia. A 51-year-old woman was admitted in our department due to fatigue and malaise since 2 weeks. She was diagnosed with T-acute lymphoblastic leukemia. Liver and lymph nodes were not palpable. Routine biochemistry was within normal range, except a slightly increased lactate dehydrogenase. Induction therapy was started with vincristine, daunorubicin, prednisone, L-asparaginase and methotrexate. On day 12, the patient became slightly icteric (total bilirubin 2.87mg/dl) and complained of epigastric and right upper quadrant pain, vomiting and flatulence. On physical examination, her liver was now palpable and tender. Within the next two days, her clinical status progressively deteriorated with further increase in bilirubin levels, significant hepatomegaly and ascites. As a result, we had to interrupt treatment on day 14 and start antibiotics and parenteral fluid administration. However, on day 17 her clinical status was further aggravated with low-grade fever and increase of body weight by 5kgs, which makes 9% of her original weight. We aspirated 1500cc of ascitic fluid. Laboratory tests revealed pancytopenia, hyperbilirubinemia, mild transaminasaemia and slightly impaired renal function. Coagulation status was normal. Serologic tests for infectious hepatitis (HBV, HCV) were negative. Ultrasound and computed tomography scan of the abdomen revealed hepatomegaly, ascites, patent splenic and portal veins, no mass lesions of the liver and normal appearance of the gallbladder and bile ducts. We administered recombinant tissue plasminogen activator at a dose of 1mg/kg over four days. On day 22, the clinical status of the patient was critical with high fever, and central nervous system involvement with drowsiness, paresis of the hypoglossal and facial nerves, right hemiparesis and hypaesthesia. On day 25, the patient became stuporous, with large abdominal distention and deep jaundice (total/direct bilirubin 34/20mg/dl) and she finally died the next day. To our knowledge, this is the first fatal case of hepatic VOD during induction therapy for acute lymphoblastic leukemia.
Outcomes of Children with Acute Lymphoblastic Leukemia Treated with 2 Consecutive Protocols: Ramathibodi Hospital Experience
Authors: Surapolchai Pacharapan , Pakakasama Samart , Sirachainan Nongnuch , Anurathapan Usanarat , Chuansumrit Ampaiwan , Hongeng Suradej 
Published: April 2020

Abstract
We determined the outcomes and prognostic factors of children (age, 0.8 to 14.8 years) with acute lymphoblastic leukemia (ALL) treated with 2 consecutive protocols between 1997 and 2008. The risk classification was followed NCI criteria. One hundred and one patients, (60 males and 41 females), were enrolled to the first protocol (modified St Jude Total XIII) (1997–2003). Ninety seven patients (96%) of these 101 patients achieved remission after induction. The event free survival (EFS) rates were 90.1 ± 3%, 85 ± 3.6%, and 83.8 ± 3.7%, and the cumulative risk of CNS relapse were 2.1 ± 1.5%, 3.2 ± 1.8%, and 3.2 ± 1.8%, at 3, 5, and 10 years, respectively. The median follow-up time for patients remaining free of adverse events was 6.8 years (4.2–10.3 years). The adverse prognostic factors included obesity (p =0.013), high risk group (p= 0.012), minimal residual leukemia (MRD) presence (&gt; 0.01%) on day 15 of induction (p &lt;0.001) and sepsis during treatment (p= 0.003). For the second protocol (modified St Jude Total XV) (2004–2008), 80 patients, 43 males and 37 females, were enrolled. Seventy nine (98.8%) of these 80 patients achieved remission after induction. The EFS rates were 92.1 ± 3.1% and 88.9 ± 3.7% at 1 and 3 years, respectively. The median follow-up time was 2.6 years (0.1–4.3 years) without evidence of CNS relapse. The adverse prognostic factor included mucositis during treatmenrt (p = 0.014). The EFS rates up to 85% in childhood ALL treated with two consecutive protocols attest the effectiveness of risk-adaptive therapy and multidisciplinary approach. Regarding to the second protocol, the efficacy of intensive systemic and intrathecal chemotherapy further supports the probability of eliminating cranial radiation and early therapeutic intervention on patients with persistent MRD leading to improve outcome overall, irrespective of patient’s risk groups. Further studies on pharmacogenetic, genetic and proteomic profiles of leukemic cells ascertain the precise risk classification and treatment regimen of childhood ALL in the future.
Hyper-CVAD Plus Nelarabine: A Pilot Study for Patients with Newly Diagnosed T Cell Acute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LL)
Authors: Faderl Stefan , Thomas Deborah A. , Koller Charles A. , Ravandi Farhad , Burger Jan , O’Brien Susan , Dara Samuel , Kantarjian Hagop M. 
Published: April 2020

Abstract
Despite improvement in the prognosis of patients (pts) with T-ALL/LL relapses remain frequent and prognosis of relapsed patients is poor. New drugs specific for T-cell lymphoproliferative disorders and treatment programs combining successful strategies of the past with new agents remain critical. Nelarabine is the water-soluble prodrug of the deoxyguanosine analogue guanosine arabinoside (ara-G) and has activity in pts with relapsed/refractory T cell hematologic malignancies. Here we combine hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine for a total of 8 courses, Kantarjian et al. JCO 18:547, 2000) with nelarabine to try and improve response duration and survival of patients with T-ALL/LL. Nelarabine was given at 650 mg/m2 i.v. daily × 5 days q 28 days for two courses following completion of the hyper-CVAD sequence and prior to the POMP maintenance (vincristine, prednisone, 6-mercaptopurin, methotrexate). CNS prophylaxis consisted of 8 intrathecal (IT) treatments (2 with each of the first 4 cycles of hyper-CVAD, but not concomitant with nelarabine) alternating IT methotrexate with IT cytarabine. Starting in August 2007, 7 pts with pre-T ALL/LL have been enrolled. Three pts were in CR at study start following prior therapy with hyper-CVAD for a maximum of 3 cycles. Median age was 38 yrs (range 21–76). All pts had a pre-T immunophenotype. One pt had nodal-based disease only, 6 pts had marrow involvement and 4 pts presented with mediastinal masses. No patient had CNS involvement. Cytogenetics were diploid in 6 pts and abnormal in 1 [translocation t(1;14), del(13)]. All patients achieved or maintained a complete remission. Three patients completed the nelarabine consolidations (too early for the remaining pts). The dose of nelarabine had to be reduced to 650 mg/m2 on alternate days (1,3, 5) in one pt because of grade 2 toxicity from previous vincristine. No exacerbation of neurotoxicity was noted in any of the patients following nelarabine. The study continues to accrue. Hyper-CVAD achieves a high CR rate in T-ALL/LL. Administration of nelarabine is feasible following the hyper-CVAD induction. Assessment of impact of the nelarabine consolidation on DFS and survival requires higher patient numbers and longer follow up.
N-Terminal-ProB-Type Natriuretic Peptide as a Marker for Anthracycline Cardiotoxicity in Children with Acute Lymphoblastic Leukaemia
Authors: Jackowska Teresa , Golabek Malgorzata 
Published: April 2020

Abstract
Background: Anthracyclines (ANTR) are very effective agents in treatment of acute lymphoblastic leukaemia (ALL). However, a potential heart damage caused by ANTR in patients who have been cured of ALL may lessen the success of this cure. Plasma brain B-type natriuretic peptide (BNP) levels are highly sensitive biochemical markers for myocardial damage.
Objectives of the study: Our purpose was to evaluate N-terminal proBNP (Nt-proBNP) as a screening test for detecting cardiac dysfunction in children with ALL.
Subjects: 156 asymptomatic children (72 girls and 84 boys) who had received ANTR during treatment for ALL were evaluated. They had received ANTR doses of 180 to 480mg/m2 (according to the protocol treatment) at median age of 6.6 years at diagnosis. 47 healthy children constituted the control group.
Methods: Concentration of plasma N-terminal proBNP was measured in 420 samples by enzyme immunoassay (Biomedica) before treatment, after 6 months, 2 and 4 years and longer than 5 years after ANTR therapy. 261 echocardiograms (ECHO) were performed in 128 children. Nt-proBNP was measured at the same time. Shortening fraction (%SF) and ejection fraction (%EF) were determined as systolic left ventricular function.
Results: Mean Nt-proBNP plasma levels in children with ALL were higher in comparison with the control group (90.7 and 66.2pg/ml respectively) but the difference was not significant (p=0.2). The levels of Nt-proBNP before ALL treatment were significantly the lowest (51.5pg/ml). Later, they were respectively: 108.3pg/ml after 6 months, 97.4pg/ml after 2 years and 92.9pg/ml after 4 years (p=0.0019). The highest levels of NT-proBNP were observed in children with cumulative ANTR doses of 240, 330 and 480mg/m2 (98.8pg/ml, 102.8pg/ml, 86.1pg/ml respectively) (p=0.0008). The lowest levels were observed with the cumulative doses of 180mg/m2 and 300mg/m2 (60.7pg/ml and 58.8pg/ml respectively). The average value of %SF in children with ALL was 39.4% (26 to 52%) and the average value of %EF was 69.95% (51.1 do 83.4%). In children with %SF and %EF lower than the average in both study and control group Nt-proBNP was insignificantly higher than in children whose %SF and %EF were higher than the average in both groups (respectively for %SF: 107.1pg/ml and 97.3pg/ml and for %EF: 106.3pg/ml and 98.8pg/ml).
Conclusion: Increased Nt-proBNP levels were observed more often in children who received higher doses of ANTR and in all children after the end of treatment. Independently of ECHO assessment of the left ventricular function, the Nt-proBNP is of value in the detection of subclinical left ventricular dysfunction in children with ALL who were treated with ANTR therapy.
Is It Better to Treat Adolescents with Acute Lymphoblastic Leukemia as Old Children or as Young Adults?
Authors: Alves Marta , Daudt Liane , Mazzucco Karina L. M. , Taniguchi Adriano , Nava Tiago , Moreno Fabio L. , Gonzalez Alice , Silla Lucia 
Published: April 2020

Abstract
PURPOSE: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents.
PATIENTS AND METHODS: From January 1997 to December 2007, 34 and 11 adolescents (10 to 20 years of age) were treated according to German pediatric BFM 90 and 95 and adult BFM 84 protocols, respectively. Age, B/T lineage, WBC count, complete remission, cytogenetics, and response to steroids were analyzed. Age, B/T lineage and WBC count were similar. Poor risk-cytogenetics (t (9;22),t(4;11) and hypodiploidy less than 45 chromosomes were present only in BFM 90 and 95 group. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving overall survival (OS) and event-free survival (EFS).
RESULTS: OS in 10 years and EFS was, respectively, 68.6% and 68.7% for the pediatric protocol and 31.4% and 21.6% for the adult protocol.
CONCLUSION: This study’s findings were similar to others in USA, UK, France, Italy and Holland that clearly demonstrate that current pediatric regimens are more effective for adolescents and may contribute to indicate that adolescents should be included in intensive pediatric protocols. Keywords: leukemia, survival, adolescent.
A Cross-Sectional Study Comparing Variation in Body Surface Area and Chemotherapy Dosing in Pediatric Oncology Using Two Different Methods
Authors: Jastaniah Wasil , Aseeri Mohammed 
Published: April 2020

Abstract
Abstract: Standardizing Body Surface Area (BSA) determination is essential for avoiding variation in chemotherapy dosage calculations. In this study we compared variation in BSA calculation using weight and height by the Mosteller formula with weight alone using recently adapted table at the Princess Norah Oncology Center (PNOC).
Methods: Cross-sectional study of pediatric oncology patients presenting to the pediatric oncology clinic at PNOC over a week period of time.
Results: One hundred consecutive pediatric oncology patients presented to the clinic. The mean BSA calculated by the Mosteller formula was 0.83m2 (Standard Deviation = 0.24) and the mean BSA determined by the table (based on weight alone) was 0.82m2 (Standard Deviation = 0.25). The mean variation in dosing between the two methods was 1.64% (Standard Deviation = 3.4). Only 13 out of 100 patients (13%) had equal dosing using both methods and 21 out of 100 patients (21%) had dosing variation greater than 5%. When comparing both methods, using paired t-test, the difference was statistically significant (t(99) = 3.99 and P &lt; 0.001).
Conclusion: Significant differences in BSA-based chemotherapy dosing exist in our center. The Mosteller method should remain the standard until prospective studies are performed to determine the significance of this dosing variability on toxicity and survival outcome.
Elevated Vanin1 and Advillin Expression Is Associated with Progression to Chronic ITP in Children
Authors: Zhang Bing , Sood Ruchira , Jones Carol , Wong Wendy , Jeng Michael , Zehnder James L. 
Published: April 2020

Abstract
The majority of pediatric ITP patients recover spontaneously within 6 months (acute ITP), while about 20% of the patients develop chronic ITP. The ability to distinguish patients at higher risk of developing chronic disease during the acute phase of the illness could give prognostic information and serve as a basis for clinical trials to study earlier or more aggressive interventions to prevent morbidity associated with long-term immunosuppression. We have previously described the gene expression pattern of pediatric ITP patients. This data set was used to search for genes which would predict progression to chronic ITP. We identified 8 samples from patients with acute self-limited ITP and 4 samples from patients who progressed to chronic ITP, all tested during the acute phase of the disease. At a false discovery rate of 0, two genes—VNN1 (vanin1) and AVIL (advillin) were the most significantly different between the groups. To validate these findings from microarray analysis, real-time PCR experiments were performed using unamplified whole blood RNA from the original cohort, with 4 additional patients (for a total of 9 samples in self-limited acute ITP group and 7 samples in progressed to chronic ITP group), and a control group of 5 normal children. All real-time data was normalized to housekeeping gene (GADPH) expression. Both VNN1 and AVIL expression were significantly increased in the group which developed chronic ITP compared to patients with acute self-limited ITP (VNN1 p=0.008, AVIL p=0.006) and normal controls (VNN1 p=0.044, AVIL p=0.009). Table 1 shows the medians and ranges of the normalized real-time PCR results of the three groups. The mechanism of these over-expressed genes in pediatric ITP patients who progress to chronic ITP is currently being investigated. VNN1 is a GPI anchored protein involved in T cell trafficking and has a pro-inflammatory role as an oxidative-stress response gene. AVIL, whose gene product is a member of the gelsolin/villin family of actin regulatory proteins, is involved in monocyte/macrophage phagocytosis and cytoskeletal remodeling. Thus both of these genes have functions consistent with recent reports implicating T cell regulation and trafficking as well as immune-mediated destruction of platelets in chronic ITP. These findings represent the first candidate biomarkers in predicting prognosis in pediatric ITP and at the same time open the door for further investigation of the molecular mechanism underlying the clinical transition from acute to chronic ITP. A prospective study to validate these findings is in progress.
Table1:
Normalized VNN1 (Vanin1) Normalized AVIL (Advillin) Median Range Median Range Self-limited Acute ITP group 0.461 0.170~0.813 8.535 0.953~17.395 Progress to chronic ITP group 1.827 0.326~4.723 25.601 6.031~44.296 Normal control group 0.350 0.202~1.029 5.491 1.449~8.585
BCL2 Gene Polymorphism Could Predict the Treatment Outcomes in Patients with De Novo Acute Myeloid Leukemia
Authors: Kim Kyoung Ha , Kim Dong Hwan , Lee Su Jin , Moon Joon Ho , Chang Myung Hee , Lee Myung Hoon , Jung Chul Won , Sohn Sang Kyun 
Published: April 2020

Abstract
The bcl-2 protein inhibits apoptosis (programmed cell death) of hematopoietic stem cells induced by a variety of noxious stimuli, thus mediate chemoresistance and decrease chemosensitivity. Higher bcl-2 expression was demonstrated to correlate with an adverse outcome in acute myeloid leukemia (AML). The current study attempted to determine whether BCL2 gene single nucleotide polymorphism (SNP) could affect treatment outcomes of 109 AML patients. Two genotypes were tested including BCL2 −938 C&gt;A (rs2279115) and +21 A&gt;G (rs1801018) using Light cycler-assisted analyses. Neither −938 C&gt;A nor +21 A&gt;G BLC2 genotype was not associated with the difference of the probability to achieve complete remission (CR) after chemotherapy. While −938 A&gt;C BCL2 genotype did not affect leukemia free survival (LFS), event free survival (EFS) or overall survival (OS), of interest, BCL2 +21 A&gt;G genotype correlated with LFS and EFS significantly. The group with +21 AA genotype had a significantly longer median LFS (p&lt;0.001) or EFS (p=0.014), and marginally better OS (p=0.08). The multivariate analyses confirmed that BCL2 gene SNP is independent prognostic factor for LFS (p=0.05, HR 2.57, 95% C.I. [1.02–6.62]) and EFS (p=0.02, HR 2.38, 95% C.I. [1.11–5.13]), but not for OS (p=0.3) considering previously known risk factors. These data indicate that chemotherapy resistance may involve the bcl-2 mediated mechanism in AML.
Characterization of Leukemic Stem Cells in a Newly Established Acute Myeloid Leukemia (AML) Cell Line 2006-5
Authors: Zhong Rui-kun , Lane Thomas A. , Ball Edward D 
Published: April 2020

Abstract
AML cell line 2006-5 was established by serial culture of an AML patients’ PBMC (M5).
Compared to primary AML cells, this line expresses CD13, CD33, CD15, CD4, CD86, CD54 but lost CD34, CD64, CD123 and HLA-Dr. A group of CD13−/CD33− cells was detected consisting of 0.2% of total cells, but no significant CD34, CD90 or CD123 expression cells could be detected by FACS. After depleting of CD13+/CD33+ cells by magnetic beads, the CD13−/CD33− cells were enriched to 95%. Significant CD34+, CD90+ or CD123+ cells (0.2–0.5%) appeared in the CD13−/CD33− enriched fraction of AML cells. Leukemia colony forming (LCF) cell assay analyzed at day 14 demonstrated CD34+, CD90+ or CD123+ cells selected by magnetic beads formed typical compact large colonies of more than 1000 cells representing 40–60% of total colonies (Fig left panel). The CD13−/CD33− enriched fraction formed medium colonies with a dense center surrounded by a halo of migrating cells (80–90% of total colonies) (Fig right). Untreated 2006-5 cells formed small diffuse colonies (70–80%). Re-plating of compact colonies selected from CD34+, CD90+ or CD123+ cell LCF assays formed the above 3 type of colonies in one culture dish. Although a daughter line can be generated from a single colony formed by CD13-CD33− cells, no compact colonies could be observed in re-plating experiment. After 14 days of culture, immature erythroid cell clusters were observed in the area surrounding compact colonies suggesting that the progenitors of the colony forming leukemia cells were at the GEMM stage. Small colonies of untreated cells gradually became apoptotic and necrotic after 10 days. These results support the theory that AML is organized as a hierarchy similar to the normal hematopoietic system. CD34+, CD90+ or CD123+ cells with very low frequency of 1–2 in 1×105 2006-5 line cells demonstrated high proliferation and differentiation potential, and may represent leukemia stem cells. CD13−/CD33− cells with lower proliferation rate may belong to more differentiated leukemia progenitors without self renew potential. If additional experiments support the notion that cells forming compact colonies are leukemia stem cells, they may serve as a useful resource to test the biology of leukemia and its therapy.
Figure Figure Figure Figure