bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relapse Patterns and Subsequent Outcomes of Patients Treated on the NCIC CTG HD.6 (ECOG JHD06) Randomized Trial Evaluating ABVD Alone in Patients with Limited Stage Hodgkin Lymphoma (HL).
Authors: Macdonald David A. , Gospodarowicz Mary K. , Wells Woodrow A. , Pearcey Robert G. , Connors Joseph M. , Winter Jane N. , Horning Sandra J. , Djurfeldt Marina S. , Ding Keyue , Shepherd Lois E. , Meyer Ralph M. 
Published: April 2020

Abstract
Background: We completed a randomized trial comparing ABVD alone with treatment that included extended field (EF) radiation therapy (RT) in 399 patients with limited stage HL. Patients allocated to EF RT received this as a single modality if categorized as favourable risk or preceded by 2 cycles of ABVD if unfavourable risk. The 5-year FFP was superior in patients receiving RT but no difference in overall survival was detected as the difference in FFP has been offset by deaths due to other causes (Meyer, J Clin Oncol2005; 23: 4634 42). Overall, 34 patients had progressive disease (PD) and 15 patients died (4 from HL, 2 from treatment-related toxicity and 9 from other causes). To better understand the implications of treatment with ABVD alone, we compared the patterns of PD and outcomes with secondary therapy of the two randomized groups. We were particularly interested in assessing how frequently sites of PD observed in patients assigned to ABVD alone occurred within the EF of RT that was prescribed in the HD.6 trial, or within a hypothetical involved field (IF) of RT that constitutes an accepted current practice.
Methods: Two expert reviewers, blinded to treatment allocation, were provided a list of disease sites at diagnosis and at PD. Sites of PD were categorized as ’within field only’, ’out of field only’ and ’in + out of field’. Two analyses were performed by considering both EF and IF RT fields. A third blinded reviewer adjudicated disagreements.
Results: Inter-observer agreement was excellent for both the EF (kappa 0.87) and IF (kappa = 1.0) analyses. More cases of PD were observed in patients allocated to ABVD alone (24 vs. 10). More within field only PD was observed in patients allocated to ABVD alone when assessed according to both the EF (88% vs 30%; P = 0.002) and IF (71% vs. 20%; P = 0.01) analyses. Individual investigators determined the actual choice of therapy for PD; among patients allocated to ABVD alone, secondary therapy included chemotherapy alone (2), RT alone (8), combined modality therapy (6) and autologous stem cell transplantation (8). No difference in the proportion of patients alive without second progression was detected between patients allocated to ABVD alone (18 /24; 75%) or treatment that included RT (8 /10; 80%) (P = 1.0).
Conclusion: For patients with limited stage HL, treatment with ABVD alone is associated with a greater risk of PD at disease sites that would be included in an IF of RT. Secondary therapy is often successful and further testing is required to determine the optimum choice of therapy for these patients.
Dendritic Cell Deficiencies in Pediatric Acute Lymphoblastic Leukemia Patients.
Authors: Maecker Britta , Mougiakakos Dimitrios , Zimmermann Martin , Behrens Mirja , Hollander Sophia , Schrauder Andre , Schrappe Martin , Welte Karl , Klein Christoph 
Published: April 2020

Abstract
Acute lymphoblastic leukemia (ALL) cells are particularly poor at generating anti-leukemia immunity, despite residing in lymphoid organs. The mechanisms accounting for this phenomenon of immunoevasion are poorly understood. To assess a potential role of dendritic cells (DC) in poor anti-leukemia immunity, we analyzed peripheral blood DC in 55 pediatric ALL patients at the time of initial diagnosis and 44 age-matched healthy controls. DC were identified by their expression of HLA-DR, lack of B-, T-, NK-, and monocyte-markers, and expression of CD11c (myeloid DC) or BDCA-2 (plasmacytoid DC) using flow cytometry. T-lineage ALL patients showed normal plasmacytoid DC and significantly elevated myeloid DC (p=0.003) levels with normal expression of HLA-DR and co-stimulatory molecules. Preliminary data suggest that these DC may be less capable of stimulating allogeneic T cell responses than DC from healthy volunteers. In contrast, we found that in children with B-lineage ALL, numbers of both myeloid and plasmacytoid DC were significantly reduced (p=0.0001) as compared to healthy controls. A decrease in DC could not be explained by impaired bone marrow function, since we could not demonstrate a correlation of DC numbers with granulocyte or monocyte counts, hemoglobin levels, or platelet counts in patients with B-lineage ALL. Interestingly, in univariate analysis there was a significant correlation of lack of myeloid DC with aberrant expression of myeloid surface marker CD13 on B-lineage ALL blasts. This unexpected finding raises the hypothesis that in some cases of B-lineage ALL the physiological differentiation of a common myeloid progenitor cell might be blocked and differentiation might be skewed towards leukemia-development. No correlation of DC numbers with subtype of ALL (proB, common, preB ALL) could be demonstrated. Furthermore, in a subgroup of B-lineage ALL patients, a complete lack of plasmacytoid DCs correlated with prednisone poor response, a surrogate marker of poor prognosis. It remains currently unclear, whether lack of myeloid or plasmacytoid DC directly correlates with long-term survival. Thus, depletion of DC in B-lineage ALL patients may contribute to poor anti-leukemia immune responses in pediatric patients with ALL. Further investigations will prove whether these deficiencies may impact on patient survival and may support the concept of immunosurveillance in lymphatic malignancies.
Induction of CD33 Expression in B-Precursor ALL by E2A-HLF Fusion Transcription Factor Derived from t(17;19).
Authors: Akahane Koshi , Inukai Takeshi , Inaba Toshiya , Kurosawa Hidemitsu , Endo Mikiya , Goto Hiroaki , Kiyokawa Nobutaka , Look A. Thomas , Goi Kumiko , Sugita Kanji , Nakazawa Shinpei 
Published: April 2020

Abstract
CD33 (Siglec-3), one of myeloid-specific antigens, belongs to a family of sialic acid-binding, immunoglobulin-like lectins (Siglecs), which is adhesion receptor for sialic-acid bearing ligands and regulates a signal transduction through its cytoplasmic tyrosine residues designated immunoreceptor tyrosine-based inhibitory motif (ITIM) as representatively well-characterized in CD22 (Siglec-2). CD33 is ectopically expressed in 5–20% of B-precursor ALL, and has been reported to be potentially associated with poor prognosis. This myeloid-specific antigen expression in B-precursor ALL is considered as lineage promiscuity or lineage infidelity, but underlying mechanism remains totally unknown. We have recently found that B-precursor childhood ALL with t(17;19), which has extremely poor prognosis, is principally CD33 positive, suggesting that CD33 expression might be regulated by E2A-HLF fusion transcription factor generated by t(17;19). To test this hypothesis, using zinc inducible expression vector, we have introduced E2A-HLF into Reh cells, which is a CD33-negative B-precursor ALL cell line. In flow cytometric analysis, by the addition of zinc, CD33 expression was gradually induced in Reh cells transfected with E2A-HLF but not in control cells, and returned to baseline after deprivation of zinc. Of note, mutant of E2A-HLF defective in its DNA-binding domain did not induce CD33 expression. Induction of CD33 expression was not due to “myeloid differentiation”, since upregulation of other myeloid markers including CD11b, CD13, CD14, CD15 and cytoplasmic myeloperoxidase was not observed. In real-time PCR analysis, despite the immediate expression of E2A-HLF protein after addition of zinc, the CD33 mRNA was slowly induced and progressively upregulated to the level approximately 20 times higher than baseline at 5 days after addition of zinc. In promoter region of the CD33 gene, there was no authentic HLF-binding consensus sequence. These observations suggest an indirect induction of CD33 transcription by E2A-HLF. As reported in myeloid cells, when CD33-positive t(17;19)-ALL cell lines were treated with a phosphatase inhibitor pervanadate and analyzed with immunoprecipitaions and Western blotting assay using anti-CD33 antibody, CD33 was confirmed to be tyrosine-phospholyrated and recruit both the protein-tyrosine phosphatases, SHP-1 and SHP-2. This is a first report indicating that an oncogenic fusion transcription factor is evidenced to be associated with ectopic expression of CD33 in B-precursor ALL and that CD33 might play some roles in signal transduction in B-precursor ALL cells.
Upregulation of FLIPs upon CD40 Stimulation - A Novel Inhibititory Mechanism of CD95-Induced Apoptosis in Precursor B-ALL Blasts in Children.
Authors: Troeger Anja , Schmitz Ingo , Glouchkova Ludmila , Siepermann Meinolf , Janka-Schaub Gritta , Schulze-Osthoff Klaus , Dilloo Dagmar 
Published: April 2020

Abstract
The influence of the microenvironment on the activation status and behaviour of ALL blasts is critical for interactions with the immune system in vivo. The capacity of B cells to respond to CD40-ligand (CD40L) stimulation is critical for their sensitisation to immunological control mechanisms and susceptibility to apoptotic signals. Primary precursor B-ALL blasts (BCP-ALL; n=32) lack CD95-expression (mean±SE; 4.2±0.6% positive cells) and are resistant to apoptosis while significant up-regulation of CD95 is apparent upon CD40-stimulation in BCP-ALL blasts that reaches a plateau after 72 h. Yet, in spite of equivalent CD95-upregulation in ALL blasts (58.3±6.5%; n=17) and normal B cells (59.3±13.1%) specific apoptosis is markedly lower in ALL compared to mature B cells (19.1±3% vs 36.7±5.5%). Resistance to apoptosis in ALL blasts and its reversibility after cycloheximid treatment suggest that anti-apoptotic mechanisms prevent induction of cell death via CD95 ligation in CD40 activated blasts. In accordance, in CD40-activated ALL blasts caspase 8 and 3 activity is not enhanced upon CD95 ligation in contrast to an 1.8±0.3 and 1.7±0.3 fold increase in caspase activity in stimulated normal B cells (n=7), suggesting a block of the apoptotic cascade in BCP-ALLrelatively close to the receptor level. CD40L-activated ALL blasts and normal B cells were submitted to western blot analysis with respect to the molecules associated to the death-inducing signalling complex (DISC). FADD and the zymogen form of caspase-8 are constitutively expressed in both malignant and non malignant B cells with no modulation following CD40 ligation. In contrast, the anti-apoptotic short isoform of the c-FLICE inhibitory protein FLIPS is weakly expressed in naïve blasts and B cells, but strongly up-regulated upon 72h CD40-ligation in ALL with only barely detectable levels in CD40-activated normal B cells. We therefore propose, that prolonged induction of the FLIPS expression inhibits the onset of apoptosis despite high CD95 surface expression levels in BCP-ALL blasts. As an additional anti-apoptotic mechanism inhibiting the downstream effector caspases we demonstrated significant upregulation of the inhibitor of apoptosis protein (IAP) survivin in CD40-activated BCP-ALL (n=6) compared to the unstimulated control (632pg/ml±200pg/ml vs 180pg/ml±52pg/ml). Thus, we identified FLIPS as a CD40-regulated upstream anti-apoptotic element and concomitant downstream upregulation of survivin protein expression as critical mechanisms contributing to blast cell resistance to apoptosis.
Acute Lymphoblastic Leukemia in Children with Associated Genetic Conditions Other Than Down Syndrome. The AIEOP Experience.
Authors: Ziino Ottavio , Rondelli Roberto , Porta Fulvio , Mura Rossella , Micalizzi Concetta , Conter Valentino , Boccalatte Marie France Pinta , Messina Chiara , Luciani Matteo , Barisone Elena , Locatelli Franco , Pession Andrea , Basso Giuseppe , Biondi Andrea , Masera Giuseppe , Aricò Maurizio 
Published: April 2020

Abstract
Background and Objectives. Constitutional molecular defects are known to play a role in oncogenesis, as shown by the increased incidence of embryonic cancers in children with Beckwith-Wiedemann syndrome or of leukemia in children with Down syndrome. The association between acute lymphoblastic leukemia (ALL) and genetic diseases other than Down syndrome has been less widely investigated. The aim of this study was to address this issue in a large series of childhood ALL patients prospectively treated in the AIEOP-ALL studies.
Design and Methods. We retrospectively reviewed the data-bases of AIEOP studies ALL-79, 82, 87, 88, 91, 95, and 2000 to identify all patients in whom an associated genetic disease, other than DS, had been reported.
Results. Out of the total of 6.695 patients, 42 (0.62%) were reported to have an associated genetic condition, including b-thalassemia (n=10), ataxia-telangiectasia (n=5), neurofibromatosis (n=3), Sotos syndrome (n=2) and a number of other individual conditions. Complete remission was achieved after induction therapy in 37 patients (1 died, 2 were resistant, 2 were not evaluable), of whom 10 had an adverse event, either death during remission (n=1), leukemia relapse (n=8), or went off-study (n=1). In the two largest groups, while patients with b-thalassemia had an outcome comparable to that of the general population, those with ataxia-telangiectasia, all with T-cell ALL, had a higher frequency of adverse events.
Interpretations and Conclusions. In the AIEOP experience, 0.62% of the patients enrolled in the childhood ALL studies have an associated genetic disorder; due to the reasonable risk of underestimation, this should be taken as a minimal rate. Although such patients should have access to contemporary ALL-directed therapy, those with ataxia-telangiectasia are more likely to deserve treatment modifications. Childhood leukemia specialists should pay special attention for screening of clinical signs or symptoms, as well as personal and family history, which may be relevant for identification of a possible associated condition. Study of such associations may provide additional clues for studying leukemogenesis in humans. Given the high probability of cure, for most patients leukemia will be only one part of their medical history. Thus, a correct diagnosis of the underlying genetic condition may be particularly useful for the patients and their families in order to tailor the future medical follow-up also during adulthood.
VEGF Regulates Leukemia Migration Via FLT-1, Involving Pi3 Kinase, RhoA and Rac1 Activation and Lipid Rafts Formation.
Authors: Fragoso Rita , Casalou Cristina , Dias Sergio 
Published: April 2020

Abstract
Vascular endothelial growth factor (VEGF) and its receptors play a crucial role in malignancy and in disease, regulating the survival, proliferation, and migration of several cell types, such as endothelium and also leukemia cells. We previously demonstrated crucial roles for VEGFR-2 in acute myeloid leukemia, where its blockade showed clinical potential in murine models, by affecting leukemia survival and proliferation. In the present study we focused on a different VEGF receptor, FLT-1, and studied the molecular mechanisms whereby it modulates acute leukemia cell migration in response to VEGF/Placental Growth Factor (PLGF). First, we observed the formation of cell protrusions on ALL cells after VEGF/PLGF stimulation, with evidence for polimerized actin and FLT-1 co-localization (as determined by phalloidin, immunofluorescence staining, and confocal microscopy). Western blot analysis revealed that PLGF/VEGF stimulation resulted in increased RhoA and Rac1 GTPases expression. Co-treatment with LY200942 significantly decreased RhoA and Rac1 induction and cell migration by PLGF/VEGF, demonstrating this effect is modulated via Pi3 kinase. Next, we investigated the mechanisms whereby FLT-1 and actin co-localize at the cell “leading edge” (protrusions), after VEGF/PLGF stimulation, and the relevance of such co-localization for cell migration. We addressed this question using a drug (nystantin) that impairs the formation of lipid rafts, cholesterol and sphingolipid rich membrane domains that modulate the interaction of several proteins (Rho GTPases) with downstream effectors, an event essential to cell migration. Accordingly, co-treatment of leukemia cells with nystantin and PLGF/VEGF blocked cell migration, an effect that was associated with a decrease in FLT-1 polarization and co-localization with actin filaments. Instead, FLT-1 was now found mostly in the cell cytosol (possibly undergoing lysosomal degradation). Taken together, we hypothesize that FLT-1 localization in lipid raft-rich membrane domains allows interaction with the actin cytoskeleton and downstream effectors, resulting in cell migration. Our data reveal for the first time some of the molecular mechanisms involved in VEGF-mediated leukemia migration, which may be crucial for determining the onset of extramedullary disease (the exit of leukemia cells from the bone marrow).
Outcome of the ALL-96 Protocol for Childhood ALL from the Kyushu-Yamaguchi Children’s Cancer Study Group.
Authors: Nagatoshi Yoshihisa , Suminoe Aiko , Matsuzaki Akinobu , Ueda Koichiro , Inada Hiroko , Kawakami Kiyoshi , Yanai Fumio , Nakayama Hideki , Moritake Hiroshi , Itonaga Nobuyoshi , Ayukawa Hiroshi , Fujita Kyoko , Kawano Yoshifumi , Okamura Jun 
Published: April 2020

Abstract
Objective: We conducted a randomized study to compare the effectiveness of two maintenance regimens, namely the 6-MP/MTX-based regimen (A-arm) and the LSA2L2 type regimen (B-arm).
Patients and Methods: A total of 218 newly diagnosed patients between 1 and 15 years of age were enrolled from August 1996 to August 2002. The patients characteristics was as follows: median age, 5; T-cell/B-cell precursor phenotype, 22/196; median WBC, 8,100/μl (range, 600–809, 200). The high-risk group (HR) was defined as having a WBC of over 50,000/μl, a T-cell precursor phenotype, CNS disease, hepatosplenomegaly of more than 5 cm under the costal margin while the standard-risk group (SR) was defined as having no HR features. Any cases with t(9;22) and t(4;11) were excluded from the present protocol. After successful induction treatment, the patients received early intensification, consolidation and late intensification treatment. Before late intensification, the patients were randomly assigned to receive one of two maintenance regimens: the A-arm consisted of daily 6-MP with weekly MTX pulsed with DEX and VCR for 2 weeks irrespective of the risk group. The B-arm consisted of 4 blocks of 6-MP with CPM, 6-MP with CA, 6-MP with VCR and PSL, and intermediate-dose (ID)-MTX in the SR group, while in the HR group, high-dose CA was substituted for ID-MTX. The total treatment duration was 3 years. Eleven cases with t(9:22) and t(4;11), 5 with a disagreement to randomization, while the other 6 did not meet the eligibility criteria and thus were excluded from the protocol. As a result, 196 cases were evaluable (98 cases for each risk-group). Of these, 95 and 94 cases, excluding 7 who developed relapses before randomization, were assigned to the A and B-arms, respectively.
Results: CR was successfully achieved in 195 of 196 patients (99%). Relapse occurred in 36 cases (isolated BM, 30; others, 6). No toxic death was observed during the entire treatment period. The event-free survival (EFS) rates in all 196 eligible cases, SR and HR cases were 75.5±5.1 (SE) %, 88.1±3.6% and 62.5±7.5% (p=.0004), respectively. The EFS rates for SR were 86.8±5.6% in the A-arm and 90.6±4.6% in the B-arm (p=ns). In the HR cases, the EFS rate in the A-arm was tended to be superior to that in the B-arm (81.2±5.6% and 52.3±13.1%, p=.13).
Conclusion: No significant difference was observed in the EFS rates between the two maintenance regimens. However, the late adverse effects of each regimen should be carefully evaluated by a long-term follow-up of the patients.
Treatment Outcome of Discontinued L-Asparaginase in Children with Standard-Risk Acute Lymphoblastic Leukemia: Tokyo Children’s Cancer Study Group (TCCSG) Study L99-15.
Authors: Ogawa Chitose , Ohara Akira , Manabe Atsushi , Hanada Ryoji , Takahashi Hiroyuki , Koh Katsuyoshi , Kajiwara Michiko , Maeda Miho , Sugita Kenichi , Kikuchi Akira , Isoyama Keiichi , Noguchi Yasushi , Saito Masahiro , Ota Setsuo , Fukushima Takashi , Yabe Hiromasa , Toyoda Yasunori , Saito Tomohiro , Tsuchida Mahiro 
Published: April 2020

Abstract
BACKGROUND: L-asparaginase (L-asp) is one of the key drugs in the treatment of acute lymphoblastic leukemia (ALL) in children. However, L-asp often produces severe adverse effects including anaphylaxis resulting in its discontinuation.
OBJECTIVE: To evaluate retrospectively the outcome of discontinuation of L-asp in patients with ALL.
PATIENTS AND METHODS: Children newly diagnosed as ALL between 1999 and 2003 were consecutively enrolled on the TCCSG L99-15 study. Risk stratification was based on the age, initial white blood cell count, immunophenotype, cytogenetics and the response to prednisolone monotherapy. Totally, 267 (35%) out of 770 children were categorized into a standard-risk group (SR), 317 (41%) into a high-risk group (HR) and 186 (24%) into a very high-risk group (HEX). Allogeneic stem cell transplantation was indicated approximately in 50% of the HEX patients. L-asp was used 9 times in the induction phase in all the risk groups. The total number of L-asp administration all through the treatment was 19 in SR, 20 in HR and at least 10 in HEX. Patients were divided into two groups in the analysis: group A patients who received at least 50% of scheduled doses of L-asp and group B patients who received less than 50%.
RESULTS: Remission was obtained in 259 (97%) patients in SR, 311 (98%) in HR and 171(92%) in HEX. In the patients who achieved remission and were analyzed, 195 (83.7%) in SR, 223 (78.8%) in HR and 123 (83.7%) in HEX received all the scheduled doses of L-asp. Event-free survival (EFS) (SE) and overall survival (OS) (SE) at 5 years for all the risk groups are shown in the table. Notably, EFS in group A (92.9%) and in group B (74.1%) in SR was significantly different (p=0.025).
CONCLUSION: The outcome in patients who received less than 50% of scheduled dose of L-asp was inferior to that in the patients who received more than 50% of the scheduled dose. This suggests that modification or intensification of the treatment should be considered for the patients who discontinued L-asp in SR.
EFS and OS in each group Risk group EFS ± SE(%) OS ± SE(%) (No. in A /B) group A group B p value group A group B p value SR (223 /10) 92.9±2.4 74.1±16.1 0.025 97.8±1.1 88.9±10.5 0.066 HR (269 /14) 78.5±3.2 66.7±19.2 0.969 88.9±2.6 50.0±25.0 0.158 HEX (142 /5) 58.2±5.5 75.5±21.7 0.514 75.6±4.3 80.0±17.9 0.873