bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk Factors Analyses for Outcomes after Unrelated Cord Blood Transplantation for Children with Myelodysplastic Syndromes. An Analysis on Behalf of EWOG-MDS and Eurocord Groups.
Authors: Moreno-Madureira Adrienne B. , Teira Pierre , Locatelli Franco , Piccardi Alessandra , Woolfrey Ann , Chan Ka-Wah , Socié Gérard , Vora Ajay J. , Bertrand Yves , Bonfim Carmem , Garnier Federico , Ionescu Irina , Gluckman Eliane , Niemeyer Charlotte M. , Rocha Vanderson 
Published: April 2020

Abstract
Myelodysplastic syndromes (MDS) are very rare diseases in children and hematopoietic stem cell transplantation remains the only curative treatment. This is a retrospective registry-based study of 42 children with MDS (refractory cytopenia n=21, refractory anemia with excess of blasts n=15, and refractory anemia with excess of blasts in transformation n=6), who underwent unrelated cord blood transplantation (UCBT). Both databases from Eurocord and EWOG-MDS group were used. Diagnosis of MDS was established by each reporting center based on the WHO classification modified for pediatric patients. Median age was 7.4 years, median cell dose infused was 4.2 × 107/Kg and median follow-up was 39 months. All patients received one cord blood unit, with 0 or 1 HLA disparity in 22, and 2 or more in 20. Twenty-five children received a Busulfan-based conditioning regimen. The association of Cyclosporine A and prednisone was used in 69% of patients. The 60-day cumulative incidence (CI) of engraftment was 69±7%, in a median time of 25 days. In multivariable analysis, ABO match (Hazard Ratio=2.94, 95% Confidence Interval=1.23–6.66, p=0.01) and refractory cytopenia (HR=2.38, 95% Confidence interval=1.01–5.55, p=0.05) were favorable factors associated with neutrophil recovery. Thirteen patients developed acute GVHD grades II–IV. Moreover, 16 children had skin, 5 liver, 6 gastrointestinal involvements (stages 2–4). The 100-day CI of aGVHD was 29±7%. Of 20 evaluable patients, 10 developed chronic GVHD and the 1-year CI of cGVHD was 24±7%. The 2-y CI for treatment-related mortality was 56±8%. In univariable analysis, recipient’s weight was the only statistical significant factor associated with TRM (47% for children weighting less than &lt; 38Kg versus 80% for remainders, p=0.05). In addition, there was a trend of higher TRM for patients who received CBU with 2 or more HLA disparities (p=0.09). The 2-y overall survival and disease-free survival were 37±8% and 32±8% respectively. In multivariable analysis, OS improved when recipient’s weight at UCBT was lower than 38kg (HR= 2.53, 95% confidence interval=1.16–5.55; p=0.02). In conclusion, since hematopoietic stem cell transplantation is the only treatment with curative potential, UCBT is a reasonable option for children without an identical sibling donor. Moreover, outcomes might be improved with better donor and patient’s selection.
GPVI Mutation and Absent Platelet Collagen Activation in a Patient with a Bleeding Disorder.
Authors: Freson Kathleen , Hermans Cedric , Thys Chantal , Van Geet Christel 
Published: April 2020

Abstract
The physiological relevance of the collagen GPVI receptor was known prior to its recognition as a platelet membrane receptor since several patients lacking GPVI as a consequence of autoantibody inhibition present with a mild bleeding diathesis. Remarkably, patients with a proven GPVI gene mutation could not yet been identified. We here describe a female patient with ecchymoses, epistaxis, several posttraumatic and postsurgery bleeding complications since her childhood and menorraghia. Coagulation and vWF studies were normal. The patient has a normal platelet count and electron microscopy showed no structural platelet abnormalities. All standard platelet aggregations were normal except for an absent response to Horm collagen, convulxin and the collagen-related peptide even at high concentrations of these agonists. Platelet ATP secretion was normal for ADP stimulation but absent for collagen. The mechanism of this dysfunction was further analyzed. Flow cytometric analysis of the different platelet membrane receptors showed a normal expression of integrin alphaIIb/beta3, integrin alpha2 and GPIbalpha but a completely absent membrane expression of GPVI. In contrast, immunoblot analysis of total platelet lysates showed a 50% reduced expression of both GPVI and its binding partner Fcgamma. Molecular analysis of the immunoreceptor GPVI/Fcgamma revealed no abnormalities in Fcgamma gene, except for the presence of Fcgamma mRNA with exon 2 skipping which could also be detected in control platelets. The patient was heterozygous for the known SKTQH/PEALN functional GPVI haplotype (Joutsi-Korhonen et al, Blood, 2003) but importantly also carried a heterozygous out-of-frame 16 bp deletion in exon 3 of GPVI gene. Subcloning and sequencing of the platelet GPVI mRNA resulted in only 25% of clones without the exon 3 deletion. The normal GPVI allele carried in addition to the SKTQH haplotype also 3 SNPs in the 3′UTR of the GPVI gene. The GPVI downstream intracellular signaling and collagen adhesion studies for this patient are ongoing. This study presents the first patient with a genetic GPVI defect with in contrast to patients with an autoantibody against GPVI a normal platelet count and ultrastructural morphology.
Long-Term Follow-Up of BEACOPPescalated Chemotherapy in Patients with Advanced-Stage Hodgkin Lymphoma on Behalf of the German Hodgkin Study Group.
Authors: Andreas Engert , Franklin Jeremy , Diehl Volker 
Published: April 2020

Abstract
The HD9 trial of the German Hodgkin Study Group (GHSG) compared two different doses (baseline and escalated) of the novel chemotherapy regimen BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) in patients with advanced-stage Hodgkin lymphoma (HL). The previous analysis with a median follow-up of 5 years showed improved tumor control (FFTF) and overall survival (OS) for BEACOPPescalated. Since BEACOPPescalated had been associated with more toxicity as compared with ABVD we report the results of long-term follow-up of 1196 patients enrolled and randomized in that study. The median follow-up was 112 months; a total of 370 centres contributed. Patients received one of three chemotherapy regimens: 8 cycles of COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) alternating with ABVD (doxorubicin, bleomycin, vinblastin, and dacarbazine), 8 cycles of standard-dose BEACOPP or 8 cycles of escalated-dose BEACOPP. At 10 years, FFTF rates were 64%, 70% and 82%, OS rates were 75%, 80%, and 86 for COPP-ABVD (arm A), BEACOPPbaseline (arm B), and BEACOPPescalated, respectively (p &lt; 0,001). Importantly, BEACOPPescalated was also significantly better than BEACOPPbaseline in terms of FFTF (p &lt; 0.0001) and OS (p = 0.0053). Death due to HL occurred in 11.5%, 8.1% and 2.8% in arms A, B, and C, respectively. 74 second malignancies were documented, including secondary acute myeloid leukaemias (1,7,14), Non-Hodgkin lymphoma (7,8,5), and solid tumors (7,16,9) in arms A, B, and C respectively. The corresponding overall secondary malignancy rates were 6.7%, 8.9% and 6.8%. Importantly, the risk of secondary AML (sAML), although increased in this study after BEACOPPescalated, amounts to 0.9% in our follow-up study with BEACOPPescalated (HD12) in 1502 advanced-stage HL patients randomized and four years median follow-up. Although the higher rate of secondary AML after BEACOPPescalated in HD9 most likely occurred by chance, interestingly, 70% of patients in this group had additional radiotherapy whereas only 39% were radiated in HD12. Taken together, the 10 years follow-up of BEACOPPescalated chemotherapy demonstrates a stabilized significant improvement in long-term FFTF and OS for advanced-stage HL. Although for formal prove the results of ongoing prospective randomized comparisons with 8 cycles of ABVD might be required, these results clearly challenge ABVD as standard of care for this patient population.
FDG-PET for Assessment of Residual Tissue after Completion of Chemotherapy in Hodgkin Lymphoma - Report on the 2nd Interim Analysis of the PET Investigation in the Trial HD15 of the GHSG.
Authors: Diehl Volker , Kobe Carsten , Haverkamp Heinz , Dietlein Markus , Engert Andreas 
Published: April 2020

Abstract
Introduction The prospectively randomized HD15 multicenter trial of the German Hodgkin Study Group (GHSG) included advanced-stage Hodgkin lymphoma patients comparing 8 cycles of BEACOPPescalated with 6 cycles or 8 cycles time-condensed BEACOPPbaseline. One other main study endpoint was the prognostic value of 18F-fluorodesoxyglucose (FDG) positron emission tomography (PET) following chemotherapy. The aim was to specify the negative predictive value of PET (NPV) in patients with residual tumour mass after chemotherapy.
Methods Entry criteria for the PET question were partial remission (PR) after the end of chemotherapy with at least one involved nodal site measuring more than 2.5 cm in diameter by computed tomography (CT). Exclusion criteria included diabetes, elevated blood sugar levels and skeletal involvement with risk of instability. Calculations were restricted to those cases with either progressive disease (PD) or relapse within 12 months after PET or at least 12 months of follow-up. A total of 275 patients were eligible for this analysis. The assessment was based on those patients confirmed by an expert panel as being PET-negative. CT verification was performed to identify false positive PET findings. The NPV was defined as the proportion of patients without progression or relapse within 12 months.
Results 9/216 patients with PET-negative residues and 9/59 patients with PET-positive residues had PD or relapse within one year of follow-up. The NPV was 0.958% (95% CI 0.931 – 0.985%). In 244/245 cases with PET-negative residual masses, no irradiation was given. In the 62/66 cases with PET-positive residues, additional radiotherapy was performed. Progression/relapse rates were significantly different between those patients with residual mass being PET-negative or PET-positive (p=0.0053). PET-negative patients, who were assessed as partial response by CT, had a prognosis similar to those in complete remission. There was no significant difference in the progression free survival in this trial and the prior GHSG trials HD12 (arms pooled) and HD9 (arm C) for advanced-stage HL (p=0.266). Importantly, the proportion of patients receiving radiotherapy decreased from 70% (HD9-C) to 39% (HD12) and 12% (HD15).
Discussion The high NPV of PET suggests that radiotherapy following 6 or 8 cycles of BEACOPP might be restricted to those patients who are PET-positive after chemotherapy.
FDG-PET Guided Consolidative Radiotherapy in Patients with Advanced Stage Hodgkin Lymphoma with Residual Abnormalities on Post Chemotherapy CT Scan.
Authors: Savage Kerry J. , Connors Joseph M. , Wilson Don , Klasa Richard , Shenkier Tamara , Hoskins Paul , Voss Nicholas , Sehn Laurie H. 
Published: April 2020

Abstract
Consolidative radiotherapy (RT) is often administered following chemotherapy for advanced stage Hodgkin lymphoma (HL) with bulky disease at diagnosis or for residual abnormalities on post-chemotherapy CT imaging. It is unknown whether RT is necessary for such patients if the residual mass is FDG-PET-negative (PET-neg) following chemotherapy (CHT). Further, it has been previously shown that a post-therapy PET-positive (PET-pos) scan is highly predictive of future relapse; however, it is unclear whether consolidative RT can be used to salvage these cases.
Methods Since July 2005, adult (&gt; 16 y) patients in British Columbia (BC) with advanced stage HL (stage III /IV and/or the presence B symptoms and/or bulky disease (&gt; 10cm)) have been treated with 6 cycles with ABVD followed by a PET scan for further treatment planning if residual abnormalities ≥2 cm were observed on CT imaging. Prior to this, post-treatment PET scans were obtained in some individuals by self-pay. If the PET scan was positive, RT was administered if feasible, otherwise, patients were observed. There were 68 eligible patients, including 7 self-pay patients, that were identified in the BC Lymphoid Cancer Database. 16 patients were excluded (PET not performed (5); palliative tx or refusal (3); composite lymphoma (1); progressive disease during CHT or at the time of PET scan (4); HIV + (1); PET mid-therapy (1); death due to unrelated cause prior to PET scan (n=1).), leaving a total of 52 patients who had a PET scan post-chemotherapy for a residual mass and who had adequate follow-up (median 19 m, 10–59 m). Patient characteristics include: M:F 1.1:1, Median age 29 (17–81); 55% stage II, 46% stage III/IV 44%; 49% bulky disease; 69% B symptoms; IPFP Prognostic score 0 8%; 1 39%; 2 26%; &gt;3 26%.
Results In total, 40/52 (77%) were PET-neg and 12/52 (23%) were PET-pos (SUV mean 4.4, 2.2–6.8). PET-pos patients had an inferior 2 y PFS compared to PET-neg patients (26% vs 91%, p=.001). In the PET-pos group, 10/12 received the planned RT and 5 have relapsed. In the PET-neg group, there was no difference in the 2 y PFS in patients with bulky (n=17) vs non-bulky disease (n=20) (86% vs 94%, p=.35).
Conclusions Advanced stage HL patients who achieve a post-CHT PET-neg status are at a low risk of relapse and do not require additional consolidative RT thus avoiding potential long-term side effects. The majority of patients with bulky disease who have a PET-neg scan following CHT also remain in remission, however, longer follow-up is still needed. Although some patients with a positive PET-scan may be salvaged by consolidative RT, a high proportion ultimately relapse.
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Analysis of Class I and II Histone Deacetylase Fails To Identify a Human Leukemia Specific Expression Profile.
Authors: Garcia-Manero Guillermo , Quesada Andy S. , Maddipoti Shirisha , Kuang Shaoqing , Tong Weigang , Wierda William G. , Bueso-Ramos Carlos M. , Yang Hui 
Published: April 2020

Abstract
Histone deacetylase (HDAC) inhibitors are being developed clinically for the treatment of leukemia. Because HDACs are composed of a large number of different proteins, and substrate specificity may differ among different HDAC inhibitors, it is important to understand if human leukemias are characterized by specific HDAC expression patterns. To study this, we have analyzed using real-time PCR and Western blots, all major class I and II HDACs in normal marrow controls (N=13, including 10 CD19+ B cell specimens), leukemia cell lines (N=25), samples from patients with AML (N=6), MDS (N=12), CLL (N=10) and human samples (N=6) obtained pretreatment and sequentially from patients with leukemia treated with two different phase I clinical trials of HDAC inhibitors: MGCD0103 and vorinostat. In general, normal controls were characterized by low levels of HDACs 1 to 10, although normal CD19+ B cells exhibited a significant increased expression of HDAC1 and 5. In leukemia cell lines, HDAC 1, 2 and 3 were expressed at higher levels than 4 to 10 but there were no differences between leukemia cell lines and normal controls or B cells. HDAC mRNA expression was not modified by cell proliferation or treatment with HDAC inhibitors. No specific HDAC expression profiles were detected in primary human AML or MDS samples. In contrast, CLL primary samples were characterized by an overexpression of HDAC 1,3,5 and 10, although this pattern was not significantly different than that of normal CD19+ B cells. Sequential analysis of human samples obtained from patients treated with two different HDAC inhibitors, vorinostat or MGCD0103 on two different clinical trials, did not affect expression profiles in patients with MDS or AML. Overall, mRNA expression results correlated with protein levels. In summary, our results indicate that AML or MDS are not characterized by a leukemia specific HDAC expression profile but that B cells and B cell leukemia are characterized by a significant overexpression of HDAC 1. This could explain the activity observed with HDAC inhibitors in B cell malignancies and serve as the bases for clinical studies of HDAC inhibitors in CLL.
Novel Function of FGFR1 in Hematopoietic Stem Cell Stress Response.
Authors: Ross Jason T. , Li Linheng 
Published: April 2020

Abstract
The hematopoietic stem cell (HSC) is one of the best characterized tissue-specific stem cells in adult mammals, yet a great deal remains to be learned about the signaling pathways involved in its regulation. Fibroblast growth factors (FGFs), a large family of cytokines, and their cell-surface receptors (FGFRs) are known to play key roles in regulating cell proliferation, differentiation, and migration, both during embryonic development and in the adult. Although HSCs are known to express certain FGF pathway components, the functional significance of this is not well understood. In order to investigate the contribution of FGF signaling to HSC regulation, we generated a conditional Mx1-Cre/FGFR1fx/fx knockout mouse line. Though lacking an overt phenotype within the hematopoietic system under homeostatic conditions, these mice displayed defects in mobilization of HSCs to the peripheral circulation and spleen after myelosuppression with the chemotherapeutic agent 5-fluorouracil (5-FU), as compared to littermate controls. We are currently exploring the mechanism of this defect by directly testing the migratory ability of a population of bone marrow cells containing stem and progenitor cells. Of interest are cells from FGFR1 knockout mice that displayed defective migration toward recombinant chemokine (C-X-C motif) ligand 12 (CXCL12), indicating a link between FGF signaling and CXCL12/CXCR4-mediated chemotaxis, a process with known roles in mobilization. We competitively transplanted LSK/Flk2- cells (a population highly enriched for HSCs) from FGFR1 knockout and control mice into lethally irradiated recipients to test their repopulation ability. Our findings indicate an important role for signaling through FGFR1 in the mobilization of HSCs in mice, knowledge which may enhance clinical mobilization protocols.
A Novel, Small Non-Peptidyl Butyzamide Activates Human Thrombopoietin Receptor and Promotes Megakaryopoiesis.
Authors: Nogami Wataru , Yoshida Hiroshi , Koizumi Kenzo , Yamada Hajime , Abe Kenji , Arimura Akinori , Yamane Noriko , Takahashi Koji , Tanaka Yoshikazu , Yamane Akiko , Takemoto Hiroshi , Ohnishi Yasuyuki , Ikeda Yasuo , Miyakawa Yoshitaka 
Published: April 2020

Abstract
Butyzamide is a novel non-peptidyl molecule which has agonistic activity to the thrombopoietin (TPO) receptor Mpl. Butyzamide promotes the proliferation of murine pro B cell line Ba/F3 expressing human Mpl (hMpl), and induces phosphorylation of JAK2, STAT3, STAT5 and MAPK. Interestingly, butyzamide does not promote the proliferation of Ba/F3 cells expressing murine Mpl (mMpl). To elucidate the mechanisms for this species specificity, we created stable transfectants such as Ba/F3-hMpl(H499L) and Ba/F3-mMpl(L490H) cells. Butyzamide induced the proliferation of Ba/F3-mMpl(L490H) but not Ba/F3-hMpl(H499L) cells, indicating that a histidine residue in the transmembrane domain of human Mpl is critical for butyzamide-induced signaling. Butyzamide induced the colony-forming unit-megakaryocyte and polyploid megakayocytes from human CD34+ hematopoietic progenitor cells, and its effects were comparable to those of thrombopoietin. When butyzamide was orally administered to immunodeficient NOD/Shi-scid/IL-2Rγcnull (NOG) mice transplanted with human fetal liver-derived CD34+ cells, the human platelet count increased by 6.2- and 22.9-fold at the doses of 10 and 50 mg/kg for 20 days, respectively. Butyzamide also increased the number of reticulated human platelets and human matured megakaryocytes in NOG mice. These results indicate that butyzamide is an orally bioavailable Mpl activator and suggest its potential for clinical development as a therapeutic agent in patients with thrombocytopenia.
GM1 Expression of Non-Hodgkins Lymphoma Determines Susceptibility to Rituximab Treatment.
Authors: Bueschenfelde Christian Meyer zum , Feuerstacke Yvonne , Goetze Katharina S. , Schlolze Kathrin , Peschel Christian 
Published: April 2020

Abstract
The monoclonal antibody rituximab directed against the cell surface molecule CD20 of mature B cells has been proven to be successful in the treatment in a variety of B cell malignancies. However, resistance against rituximab occurs and there is no prognostic marker to predict individual response. Rituximab has been shown to induce cell killing via antibody dependent cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) and the induction of apoptosis. However, the mechanism that renders rituximab so effective in vivo remains elusive as does the reason for treatment failure in a subgroup of patients. On the molecular level the function of rituximab has been associated with the partitioning of CD20 molecules to lipid microdomains. We now show that the extent of CD20 recruitment to lipid rafts correlates with response to rituximab. In addition, analyzing 11 different Non Hodgkin’s lymphoma cell lines we demonstrate that the expression of the raft associated sphingolipid GM1 on lymphoma cells is associated with the susceptibility to rituximab. Of note, lymphoma cells treated with the sphingolipid synthesis inhibitor PDMP exhibited reduced GM1 expression levels and showed impaired susceptibility to rituximab as compared to non treated lymphoma cells. Furthermore, analyzing the GM1 expression on lymphoma cells of 217 patients with various types of indolent Non-Hodgkin’s lymphoma, we demonstrate significantly different GM1 expression in various Non-Hodgkin’s lymphoma subtypes. Whereas chronic lymphocytic leukemia (CLL) cells have a low GM1 expression, marginal zone lymphoma (MZL) cells exhibit much higher levels. Differences were not only detected between various lymphoma subgroups but also within one lymphoma subtype. Interestingly, whereas CLL cells from patients with high GM1 expression responded to rituximab, patients with low GM1 expressing CLL cells did not. Similar results were observed analyzing lymphoma cells from patients with mantle cell lymphoma (MCL) suggesting that GM1 expression correlates with responsiveness to rituximab in further types of Non-Hodgkin’s lymphoma. Collectively, these data demonstrate the importance of membrane microdomains for the effect of rituximab and may offer a predictive factor for the responsiveness of lymphoma cells to rituximab.