bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Randomized Trial Investigating an Exercise Program to Prevent Osteoporosis and Motor Problems during Treatment for Childhood Acute Lymphoblastic Leukemia.
Authors: te Winkel Mariel L. , Hartman Annelies , van Beek Robert D. , de Muinck Keizer-Schrama Sabine M.P.F. , Kemper Han C.G. , Hop Wim C.J. , van den Heuvel-Eibrink Marry M. , Pieters Rob 
Published: October 2019

Abstract
Reduction in bone mineral density (BMD), fractures, altered body composition, deteriorated motor performance and impaired passive ankle dorsiflexion are side-effects of chemotherapy during childhood acute lymphoblastic leukemia (ALL). Because only scarce information is available on the value of regular exercise to prevent these side-effects, we performed a randomized trial to investigate the effects of intervention with an exercise program. At diagnosis 51 ALL patients (median age: 5.4 years) were randomized into a group receiving intervention (including twice-daily high-intensity weight-bearing activities throughout the two-year during treatment period), or a control group receiving standard care. BMD of total body (BMDTB) and lumbar spine (BMDLS) and body composition parameters were measured using dual energy X-ray absorptiometry (DEXA). We measured motor performance with the Bayley Scales of Infant Development and the Movement-ABC, and passive ankle dorsiflexion with a goniometer. The investigators were blinded to the randomization. Repeated measurements analysis (ANOVA) was used. BMD decreased equally in the intervention and control group during treatment (delta-BMDTB: −0.75 SDS vs −0.96 SDS, p=0.65 and delta-BMDLS: −0.15 SDS vs −0.04 SDS, p=0.83), and increased equally during the year after treatment (delta-BMDTB: 0.42 SDS vs 0.35 SDS, p=0.70 and delta-BMDLS: 0.10 SDS vs 0.14 SDS, p=0.84). Body-fat increased during treatment in both groups (delta-fat: 1.04 SDS vs 1.56 SDS, p=0.25). In the intervention group a more rapid decline of body-fat was observed during the year after completion of therapy than in the control group (delta-fat: −1.08 SDS vs −0.49 SDS, p=0.01). Lean body mass (LBM) of both groups decreased equally during treatment (delta-LBM: −0.61 SDS vs −0.12 SDS, p=0.16) and increased equally the year after stop of treatment (delta-LBM: 0.29 SDS vs 0.22 SDS, p=0.66). Both groups showed similar changes in passive ankle dorsiflexion mobility (−5.2º vs −4.6º, p=0.76) and motor performance (0.37 SDS vs 0.68 SDS, p=0.44) during treatment. Adherence to the exercise program varied considerably: 11% of the patients performed exercises daily, 37% more than once a week, 16% once weekly and 36% less than once a week. The exercise program was not more beneficial in preventing reduction in BMD, motor performance and passive ankle dorsiflexion than standard care, most likely due to unsatisfactory compliance. However, the faster recovery after stop of treatment of the excess of body-fat in the intervention group than in the control group may be due to the educational effect of the intervention program.
Relapse in Childhood “Very High Risk” Acute Lymphoblastic Leukemia Treated with BFM Chemotherapy Has a Dismal Outcome Even When Treated with Transplantation.
Authors: Balduzzi Adriana , Valsecchi Maria Grazia , Schrauder André , Silvestri Daniela , Buldini Barbara , von Stackelberg Arend , Testi Anna Maria , Klingebiel Thomas , Peters Christina , Rizzari Carmelo , Barisone Elena , Schrappe Martin 
Published: October 2019

Abstract
The definition “very-high risk” (VHR) in the setting of childhood acute lymphoblastic leukaemia (ALL) is usually adopted to identify children eligible for transplantation in first complete remission (CR1). The endpoint of this study is to assess whether, how many, and how VHR ALL children achieving CR1 and not transplanted in CR1 can be rescued in case of relapse. Eligiblity criteria to transplantation in AIEOP-BFM ALL 2000 study slightly changed overtime and differed between the BFM (Berlin Frankfurt Muenster) and AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) Groups.. For this analysis VHR ALL was defined by one or more of the following criteria:
induction failure (IF), high levels (≥ 1x10−3) of minimal residual disease at day 78 (VHR-MRD), clonal abnormality t(4;11), prednisone poor response associated (PPR+) with one or more of the followings: hyperleukocytosis, T-immunophenotype, ≥ 25% marrow blasts at day 15, pro-B immunophenotype.
Patients carrying clonal abnormality t(9;22) were not included here since allocated in a specific study protocol since 2004. Out of 571 VHR patients, distributed among the four criteria (17%, 45%, 3%, 35%, as hierarchically listed), 249 (43%) were transplanted in CR1 (80%, 48%, 47%, 25% in each category) and 322 (57%) were not. Of the 322 patients treated with chemotherapy [5-year-EFS 53.5% (SE 3.1), 5-year-survival 66.6% (SE 2.9)], 19 died in CR1, 6 presented with a second malignancy, and 113 (35%) relapsed at a median of 15 months after diagnosis, mostly in the bone marrow (81%: 66% isolated, 15% combined) or in an extramedullary site (19%, 15% in the central nervous system) at a median time of 9 ms after diagnosis. The 3-year-survival after relapse was only 26.0% (SE 5.1) for the 113 patients overall, 38.7% (SE 7.8) for the 55 who underwent transplantation in CR2 and 16.2% (SE 5.3) for the 58 who were not transplanted in CR2. Interestingly the 3-year-survival after relapse by VHR criteria was only 7.1% (SE 9.3) in the IF, 28.6% (SE 7.1) in the VHR-MRD and 33.1% (SE 6.7) in the PPR+ subgroups. In conclusion very few VHR-ALL children could be rescued after relapse, particularly among those carrying most unfavourable criteria at the onset (IF and VHR MRD), confirming that transplantation should be performed in CR1. Transplantation in CR2 was feasible in only half of the patients and presumably their outcome was influenced by MRD response after relapse; this aspect is under investigation. New strategies are needed for this dismal subset of patients.
AML1-ETO Collaborates with the Homeobox Gene Meis1 in Inducing Acute Leukemia in the Mouse Bone Marrow Transplantation Model.
Authors: Naidu Vegi M. , Rawat Vijay P.S. , Schessl Christina , Petropoulus Konstantin , Cusan Monica , Deshpande Aniruddha J , Martinez Leticia Quintanilla , Hiddemann Wolfgang , Buske Michaela Feuring , Buske Christian 
Published: October 2019

Abstract
AML1-ETO is the most frequent fusion gene in human AML. Previously, we and others have demonstrated that the fusion is not able to cause leukaemia on its own in experimental murine models, but that it needs collaborative partners. However, although mutations such as the FLT3-length mutation and C-KIT mutations were defined as important collaborative genetic events in AML1-ETO positive AML, most human AML1-ETO cases do not carry these mutations, indicating the presence of unkown collaborative partners in these patients. On the other hand Meis1, a HOX gene co-factor, belonging to the TALE family of homeodomain proteins, has a well established function as a protooncogene with a strong collaborative potential in Hox gene associated AML in mice. First we confirmed expression of MEIS1 in some patients with AML1-ETO positive AML by real-time PCR. Based on this we sought to determine if AML1-ETO can collaborate with Meis1 in inducing acute leukemias: single constructs or both genes were co-transfected in 5-FU treated primary murine bone marrow cells by retroviral gene transfer, using MSCV retroviral constructs with an IRES–GFP or YFP cassette. Mice were transplanted with BM cells expressing Meis1 alone (n=10), with BM cells solely expressing the fusion gene (n=10) or EGFP (n=7, control) or with BM expressing both genetic alterations (n=14). None of the mice in the Meis1 and AML1-ETO as well as in the control group developed disease. In contrast, 14 mice transplanted with BM co-expressing AML1-ETO and Meis1 developed lethal disease after a median latency of 102 days. Three mice succumbed to a myeloproliferative syndrome and nine mice died by acute leukemia (6 mice developed AML, 3 mice ALL), which was serially transplantable into secondary recipients (median = 57 days). Immunohistochemistry of various organs of leukemic mice showed massive infiltration with blast cells. In MPS and AML 85 ± 9.3 % of the blast cells co-expressed Gr-1+ and Mac1+. In ALL cases 40 ± 19.9 % of the malignant cells co-expressed Mac1 and the lymphoid-associated B220 antigen. Analysis of retroviral integration did not reveal recurrent integration sites as an indication for insertional mutagenesis. In summary, our data demonstrate for the first time that AML1-ETO can collaborate with Meis1 and identify a novel collaborative partner in t(8;21) positive AML. Furthermore, our analyses demonstrate that Meis1 can collaborate with non-homeobox genes in inducing acute leukemia.
Results of a Randomized Phase 2 Study of Clofarabine Plus Cytarabine (CA) Vs Clofarabine Plus Idarubicin (CI) Vs Clofarabine, Idarubicin, Plus Cytarabine (CIA) as Salvage Therapy in Acute Myeloid Leukemia (AML).
Authors: Faderl Stefan , Borthakur Gautam , Ravandi Farhad , Huang Xuelin , Beran Miloslav , Ferrajoli Alessandra , Koller Charles A. , Thomas Deborah A. , Verstovsek Srdan , Kwari Monica , Kantarjian Hagop M. 
Published: October 2019

Abstract
Clofarabine is a second-generation deoxyadenosine analog with activity in adult AML. To improve single agent activity, various combinations of clofarabine are being studied. In two dose-finding phase I studies, we have previously established the MTD and DLT of the CI and CIA combinations in AML salvage (Blood2006; 108: 51a). Here we report the outcome of a subsequent adaptively (Bayesian) randomized phase 2 study comparing the two anthracycline-containing combinations CI and CIA with CA. Eligible were patients (pts) for first salvage therapy with first relapse or primary refractory AML. Drug doses and schedules were as follows: CI - clofarabine 22.5 mg/m2 iv d 1–5 and idarubicin 10 mg/m2 iv d 1–3; CIA – clofarabine 22.5 mg/m2 iv d 1–5, idarubicin 6 mg/m2 iv d 1–3, cytarabine 0.75 g/m2 d 1–5; CA - clofarabine 40 mg/m2 iv d 1–5 and cytarabine 1g/m2 iv d 1–5. Up to 2 induction and 4 consolidation cycles were allowed. Eighty-five patients were enrolled of whom 80 are evaluable. Pretreatment characteristics were similar with respect to median age (CI 57 yrs [range 25–73], CIA 56 [21–81], CA 55 [39–73]), proportion of pts with secondary AML (CI 33%, CIA 28%, CA 29%), proportion of pts with primary refractory disease (CI 31%, CIA 50%, CA 41%), prior median CR duration (CI 6 mos [1–108], CIA 6 [1–18], CA 10 [2–27]), prior exposure to at least intermediate doses of cytarabine (CI 78%, CIA 63%, CA 65%), and proportion of pts with FLT3/ITD abnormalities (CI 25%, CIA 17%, CA 18%). Thirty-three pts received CI, 31 CIA, and 16 CA. Overall, 31 (39%) pts responded (28% CR, 9% CRp). No difference in response was observed according to treatment arm (CI - CR 27%, CRp 12%; CIA - CR 29%, CRp 13%; CA - CR 25%, CRp 6%). Median CR duration was 6.4 mos (0.2–18) with CI, and not reached (1–12+) with CIA and CA (0.3–24) (p=0.07). Overall survival was 5.5 mos (0.3–25.5+) for CI, 5.1 mos (0.4– 13.4+) for CIA, and 5.1 mos (0.4–27+) for CA (p=0.94). Adverse events were comparable to the preceding phase 1 studies and as have been described with clofarabine in the past. Induction deaths occurred in 6% (CI), 16% (CIA), and 25% (CA), respectively (p>.05), and were due to myelosuppression-associated infectious complications. In summary, the response rate of the clofarabine combinations in AML salvage is 39% (CR+CRp). Response duration and overall survival are not significantly different between the treatment arms.
Phase 1 Clinical Trial of Prion-Filtered Red Cell Concentrates (pfRCC) in Patients Requiring Allogeneic Blood Transfusion.
Authors: Murphy Tracy , Cahill Mary R , Fagan Jim , Harry Croxon , Khan Mohammed , Gilligan Oonagh , McGrath Stephen , Murphy William G 
Published: October 2019

Abstract
Background; Transmission of vCJD by blood transfusion from pre-symptomatic blood donors has occurred in 4 reported cases to date. Screening blood donors for infectivity is unlikely to be feasible for several years. Removing infectivity from blood using selective filtration may provide a useful degree of protection from transfusion transmission of the disease. A filter that may remove infectivity from red cell concentrates has been developed and trialed in volunteers receiving autologous blood. No studies have been carried out to date of pfRCC in allogeneic transfusions in the clinical setting.
Aims; To establish safety and tolerability of transfusion of prion filtered red cell concentrates.
Methods; Twenty patients scheduled to receive transfusion were recruited following ethical approval and with informed consent. Prion filtered units were prepared by the Irish Blood Transfusion Service. A mean loss of 9 gm of haemoglobin per unit of RCC occurred during the filtration process. Each patient received one unit of pfRCC, and a median of 2 units overall (range 1 to 4 units) per transfusion episode. A cross-match sample, full blood count (FBC), renal and liver profile was taken from each patient prior to transfusion. Patients were observed for adverse reactions. After 24 hours, FBC, renal and liver profile were repeated. Six weeks after the transfusion a further sample was tested for red cell antibodies. Six of these patients have consented to undergo re-transfusion with pfRCC. Two re-infusions have taken place uneventfully six months after the first exposure to pfRCC and 4 more are planned. Results No serious adverse events were encountered during the study, or at 24 hour and 6 week follow up after the initial transfusion episode. Mean haemoglobin increment per unit transfused was 0.68g (SD 0.45g; range −0.5 to 1.35g ). Recruitment and follow-up is ongoing in patients exposed to repeat transfusion challenge. Summary The first clinical transfusions of pfRCC were well tolerated. Two patients were rechallenged with transfusions of pfRCC without adverse effect. Further studies with transfusions of prion filtered red cells are now warranted to extend the safety data and to determine whether efficacy is comparable to standard transfusions in adult and paediatric populations.
Human Adenylate Kinase 2 Deficiency Causes a Profound Haematopoietic Defect Associated with Sensorineural Deafness
Authors: Cavazzana-Calvo Marina , Lagresle-Peyrou Chantal , Six Emmanuelle M , Picard Capucine , Rieux-Laucat Frederic , Michel Vincent , Ditadi Andrea , Demerens-de-Chappedelaine Corinne , Morillon Estelle , Valensi Françoise , Simon-Stoos Karen L , Mullikin James C , Noroski Lenora M , Besse Céline , Wulffraat Nicolas , Ferster Alina , Abecasis Manuel M , Calvo Fabien , Petit Christine , Candotti Fabio , Abel Laurent , Fischer Alain 
Published: October 2019

Abstract
Human adenylate kinase 2 deficiency causes the most profound human haematopoietic defect associated with sensorineural deafness. Reticular dysgenesis (RD) is an autosomal recessive form of human severe combined immunodeficiency (SCID) characterized by an early differentiation block in the myeloid lineage and a profound impairment in lymphoid maturation associated with bilateral sensorineural deafness. The lack of polymorphonuclear neutrophils in affected newborns is responsible for the occurrence of severe infections earlier than usually observed in the other forms of SCID. Furthermore, RD associated neutropenia is characterized by the lack of responsiveness to G-CSF. We have identified bi-allelic mutations in the adenylate kinase 2 (AK2) gene is seven patients affected with RD. These mutations resulted in the absence or a strong decrease in protein expression. Restoration of AK2 expression in the bone marrow cells of RD patients overcomes the neutrophil differentiation arrest, underlying its specific requirement in the development of a restricted set of haematopoietic lineages. Lastly, we established that AK2 is specifically expressed in the stria vascularis region of the inner ear. The function of this gene in the differentiation of a given set of cell lineages is rapidly in progress, showing that studies of primary immunodeficiencies continue to provide key information on human lympho-haematopoietic development. Moreover the AK2 enzyme seems a key molecule in different biological systems such as the lympho-haematopoiesis and the brain development.
The Role of GM-CSF Signaling and CREB in Myeloid Proliferation and Survival.
Authors: Sakamoto Kathleen M. 
Published: October 2019

Abstract
Normal myelopoiesis is regulated by the delicate interplay between hematopoietic stem cells (HSCs) and the bone marrow microenvironment. Through the action of hematopoietic growth factors and their receptors, alterations of transcriptional regulation result in myeloid progenitor cell proliferation and survival. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Interleukin-3 (IL-3) are cytokines that regulate myelopoiesis. GMCSF and IL-3 induce signaling pathways that activate serine threonine kinases, including MEK, ERK, and pp90RSK, leading to expression of immediate early genes such as early growth response gene-1 (egr-1). Analysis of promoter regions of egr-1 demonstrated that the cAMP response element, CRE, was necessary and sufficient for egr-1 expression in myeloid cells. We previously demonstrated that the transcription factor, CREB (cAMP Response Element Binding Protein), recognizes the CRE in the egr-1 promoter and is phosphorylated at serine 133 in response to GM-CSF and IL-3 through a MEK-dependent, protein kinase A-independent pathways. CREB is a leucine zipper transcription factor that regulates proliferation, differentiation, and survival of neuronal cells and lymphocytes. The majority of patients with acute lymphoid and myeloid leukemias express higher levels of CREB in their bone marrow. Therefore, we hypothesized that CREB plays a critical role in the regulation of normal hematopoiesis. To this end, we studied the biological and molecular effects of CREB in myeloid cells. CREB overexpression results in increased proliferation and survival through induction of cyclin A1 and other target genes. Transgenic mice that overexpress CREB in Gr-1/Mac-1+ cells develop myeloproliferative disease after one year. Knockdown of CREB using shRNAs leads to decreased proliferation and differentiation of myeloid progenitor cells and increased apoptosis of HSCs. Cell cycle analysis demonstrate that CREB downregulation in HSCs leads to greater numbers of cells in G1 and fewer cells in S phase. Both cyclin D1 and A1 levels are decreased in CREB shRNA-transduced HSCs. However, CREB knockdown of bone marrow progenitors did not affect long-term engraftment in transplantation assays. Recent findings on downstream pathways of CREB and potential target genes will be presented.
CD28 Costimulation of Effector T Cells During An Anti-Tumor Attack Sustains Its Repression by Regulatory T Cells Which Can Be Overcome by Preventing Lck Activation.
Authors: Kofler David M , Chmielewski Markus , Riet Tobias , Hombach Andreas , Hallek Michael , Wendtner Clemens M , Abken Hinrich 
Published: October 2019

Abstract
Abstract 3569
Poster Board III-506

Background
Massive infiltrations of the tumor tissue with CD4+CD25highFoxP3+ regulatory T (Treg) cells render a productive T cell anti-tumor response ineffective resulting in unrestricted tumor growth despite the presence of tumor-specific, cytolytic T cells.

Methods
Using a human/CD1-deficient mouse model we investigated the impact of human regulatory T cells on redirected effector T cells expressing a tumor-specific chimeric antigen receptor. The chimeric antigen receptor consists of an antibody derived binding domain for antigens in the extracellular part and of the TCR/CD3zeta or the combined CD3zeta-CD28 signaling domain in the intracellular part. Upon antigen binding the chimeric antigen receptor transmits an activation signal via the CD3zeta or CD3zeta-CD28 domain to drive T cell activation, resulting in cytokine secretion, T cell proliferation, and cytolytic activity.

Results
We revealed that effector T cells redirected by a tumor-specific chimeric antigen receptor are more effectively repressed by Treg cells when they are activated through a combined CD3zeta-CD28 signal compared to a CD3zeta signal without CD28 costimulation. Mutations in the CD28 signaling domain of the chimeric antigen receptors resulted in abolished IL-2 secretion by prevention of CD28 mediated lck activation. Abolished IL-2 induction in redirected effector T cells expressing the modified CD3zetaCD28delta antigen receptor increased their in vivo efficacy in an anti-tumor response by reduced sustaining of Treg cell suppression.

Conclusions
While data indicate the dichotomy of CD28 costimulation in inducing full effector T cell activation and sustaining Treg repression, our findings provide a strategy to improve the efficacy of the T cell anti-tumor attack in the presence of Treg cells for use in adoptive immunotherapy of cancer.

Disclosures:
No relevant conflicts of interest to declare.
Establishment and Characterization of A New Leukemia Mouse Model Induced by MLL/AF4 Fusion Protein.
Authors: Tamai Hayato , Miyake Koichi , Miyake Noriko , Yamaguchi Hiroki , Dan Kazuo , Shimada Takashi , Inokuchi Koiti 
Published: October 2019

Abstract
Abstract 3573
Poster Board III-510

Background
MLL/AF4 fusion is the most common abnormality in infant leukemia and is associated with a poor prognosis. Although further study and treatment should be groped for acute lymphoblastic leukemia (ALL) with MLL/AF4, the lack of a proper animal model has impeded understanding of the molecular mechanism of leukemia associated with the MLL/AF4 fusion gene. Previous mouse models suggest that the tumorigenesis capacity of MLL/AF4 alone is insufficient for development mixed-lineage leukemia. MLL/AF4 is capable of inducing lymphoid malignancy with long latency, which is very different from aggressive pro-B ALL in humans. Recently, we have reported that enhancement of S100A6 (calcyclin) expression played an important role in MLL/AF4-leukemogenesis using murine 32Dc cell line. In this study, we tried to make improved MLL/AF4 transgenic (Tg) mice which reflect human leukemogenicity and analyzed molecular mechanism of MLL/AF4 fusion gene.

Methods
To get high and sustained expression of MLL/AF4 in hematological lineage, we used MSCV promoter to express MLL/AF4 fusion gene. After MLL/AF4 expression plasmids were injected into fertilized eggs of mice (C57BL/6), the manipulated embryos were transferred into the oviducts of pseudopregnant females to make MLL/AF4 Tg mice. Finally we characterized MLL/AF4 Tg mice and analyzed molecular mechanism of MLL/AF4-leukemogenesis.

Results
Our new established MLL/AF4 Tg mice had lymphoma earlier than previous MLL/AF4 knock-in mice (median 12M vs 17M). Infiltration of lymphoid cells was located in liver, lung, kidney, and spleen and they consist of pro B-cell (CD45R+CD43+CD19-) lineage. Leukemic change developed two months (median 14M) after appearance of lymphoma. More than 30% of abnormal lymphocytes and severe anemia (RBC: 276×104 ml, Hb: 4.9 g/ml) were found in peripheral blood in MLL/AF4 Tg mice. Western blot analysis showed that up-regulation of HoxA9 and S100A6 was detected in MLL/AF4 Tg mouse compared to wild type C57BL/6.

Conclusion
We succeeded in establishment of improved more aggressive MLL/AF4 Tg mice which reflect MLL/AF4 leukemogenicity of humans. Appearance of lymphoma in our MLL/AF4 Tg mice needed short er latency than those of the previous knock-in mice. Enhancement of HoxA9 and S100A6 expression was involved in MLL/AF4-associated leukemogenesis. We believe that this new MLL/AF4 Tg mouse is useful for study of the molecular mechanisms of MLL/AF4 leukemogenesis and development of new therapy for mixed-lineage leukemia.

Disclosures:
No relevant conflicts of interest to declare.