bluuebunny/crossref_metadata_2025_split huggingface dataset:
Successful Unrelated Umbilical Cord Blood Transplantation for Shwachman-Diamond Syndrome.
Authors: Vibhakar Rajeev , Rumelhart Stephen L. , Tatman David J. , Radhi Mohamed A. , Goldman Frederick D. 
Published: April 2020

Abstract
Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic insufficiency and variable degrees of neutropenia. Additional clinical features include short stature, skeletal abnormalities and bone marrow dysfunction. SDS patients are at increased risk of developing myelodysplasia, aplastic anemia and leukemic transformation. The role and timing of allogeneic hematopoietic stem cell transplantation (HSCT) in SDS remains controversial due to a poorly defined predisposition toward peri-transplant complications and overall poor survival. Here we report three SDS patients (age 13 mo, 16 mo and 8 yr) with severe aplasia successfully transplanted using 5/6 HLA matched unrelated umbilical cord blood. All patients received a previously described “cardiac sparing” conditioning regimen consisting of Melphalan (180 mg/m2), Etoposide (1200 mg/m2), anti-thymocyte globulin (90 mg/kg), and low dose total lymphoid irradiation (500 cGy) with graft versus host disease (GVHD) prophylaxis consisting of cyclosporine and prednisone. Patients received grafts containing 6.7 – 9.1 x 105 CD34+ cells/kg. Myeloid engraftment occurred promptly with the ANC &gt; 500 cells/mm3 on day 15 ± 5. Platelet recovery (&gt;20k without transfusion) occurred on day 20, 30 and 140 days post transplant. All patients displayed 100% donor chimerism by 2 months post transplant. Patients were discharged between 25 – 60 days post transplant without severe complications, though all patients displayed grade II or III acute GVHD, and one developed chronic GVHD. The patients are alive 85, 390 and 850 days post transplant. Factors that may be important in HSCT outcome for SDS include transplantation at a relatively young age prior to malignant transformation, avoidance of cyclophosphamide in the preparative regimen, and adequate GVHD prophylaxis. Importantly, these cases also suggest that unrelated umbilical cord blood, in the absence of a matched family member, should be considered as the preferred source of donor stem cells in SDS patients undergoing HSCT.
Gene Expression Analysis of Leukemic Blasts Persisting at Day 8 of Induction Therapy in Childhood ALL.
Authors: Rhein Peter , Ratei Richard , Scheid Stefanie , Hagemeier Christian , Seeger Karl , Kirschner Renate , Schrappe Martin , Spang Rainer , Ludwig Wolf-Dieter , Karawajew Leonid 
Published: April 2020

Abstract
In childhood acute lymphoblastic leukemia (ALL), early response to therapy is of crucial prognostic significance. In the frontline ALL-BFM (Berlin-Frankfurt-Münster) trial, treatment stratification is based on blast count estimation in peripheral blood at day 8 of induction prephase with prednisone and one dose of intrathecal methotrexate at day 1. To approach yet unknown mechanisms of therapy resistance and to characterize cells persisting under therapy on molecular level, we investigated gene expression profiles of leukemic blasts at day 8 of therapy (“day 8” cells) and their changes as compared with blast cells at initial diagnosis (“day 0” cells). To this end, an experimental procedure has been established including flow sorting of leukemic cells by their leukemia-associated immunophenotype and preparation of cRNA, starting from a small number of cells and using an additional amplification step. Experiments have shown that flow sorting procedure does not affect RNA quality, and this experimental approach facilitates investigation of patient samples with blast cell counts as low as 50 blast cells/μl. Blast cells from ten patients with B-cell precursor ALL were investigated using Affymetrix HG U133A microarrays, and gene expression data were processed by normalization procedure on probe level by variance stabilization. Genes commonly up- or downregulated in blast cells under therapy were identified in matched pairs of day 8 and day 0 samples using Significance Analysis of Microarrays (SAM) and a filtering criterion of at least two-fold mean change. By this procedure a group of 84 genes with a false discovery rate of less than 10 % was identified. In this group, 24 genes, reportedly involved at different levels of the cell cycle regulation, including cell cycle progression (CDC2, cyclin B2), DNA replication (e.g. thymidylate synthetase TYMS, ribonucleotide reductase RRM2, proteins MCM 4 and 6) and execution of mitosis (e.g. cell cycle checkpoint kinases CHEK1 and BUB1B, kinesin-like proteins 1 and 7, and MAD2L1), were found to be downregulated in the day 8 cells. In contrast, genes (n=7) encoding for proteins involved in survival signaling (e.g. IL-4/IL-13 common receptor chain, membrane-spanning 4-domains MS4A1 and CD20) showed increased expression in day 8 blasts. Taken together, the described experimental approach enabled gene expression analysis of ALL cells persisting under therapy and pointed to increased survival signaling in day 8 blasts and their preferential positioning in the G1 cell cycle phase.
CD11b Is a Therapy-Induced Marker for Monitoring Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia.
Authors: Rhein Peter , Ratei Richard , Mitlohner Rita , Schrappe Martin , Ludwig Wolf-Dieter , Karawajew Leonid 
Published: April 2020

Abstract
Assessment of minimal residual disease (MRD) has become central to the clinical management of patients with acute lymphoblastic leukemia (ALL). Among the methods available for MRD monitoring, flow cytometry (FCM), which relies on the presence of leukemia-associated aberrant immunophenotype, holds great promise for clinical application. However, the major antigens used for FCM-MRD identification (CD10, CD34, CD45, CD20, CD19, TdT) undergo expression changes during therapy. Moreover, the presence of normal hematopoietic progenitors, in particular in the regenerating bone marrow after treatment, negatively impacts the sensitivity and specificity of MRD detection. Recently, we analysed genome-wide gene expression in blasts isolated from peripheral blood of pediatric precursor B-cell (PBC)-ALL patients after one week of therapy (day 8 cells). Expression changes observed in the day 8 cells pointed to several cell surface molecules, whose expression has not been characteristic for B-lineage hematopoiesis. In particular CD11b surface antigen has been frequently up-regulated in the day 8 cells. In the present study, we addressed expression dynamics of CD11b in PBC-ALL at clinically significant MRD timepoints during induction therapy (days 15, 33 and 78; ALL-BFM protocol). To this end, a CD11b specific antibody has been included into a nine-color, single-tube panel (antibodies to CD19, CD20, CD10, CD34, CD45, CD58, CD3, and a nuclear stain Syto16), which has been applied in order to detect residual blasts among 106 cells in bone marrow specimens from patients with PBC-ALL. At day 15, mean expression of CD11b (in MESF units) has been significantly increased if compared with leukemic cells at diagnosis (9600+/−2800 vs 850+/−140; p=0.005). The up-regulation by more than 10-fold has been found in 8 of 24 cases (33%), and has reached, in part, very high levels (eg, 450 MESF vs 49500 MESF at diagnosis and day 15, respectively). This indicates that CD11b expression changes are due to a therapy-induced gene up-regulation rather than to a clonal selection during clinical treatment. At the later timepoints of induction therapy, 7 of 22 patients (day 33) and 2 of 18 patients (day 78) were MRD positive. CD11b expression, if increased at day 15, retained its high values on day 33 (7900+/− 3200 MESF, 6 patients) and on day 78 (15100 MESF, 1 patient). Importantly, in contrast to leukemic cells, their normal CD19+CD10+ counterparts in both, non-leukemic and ALL bone marrow samples, remained CD11b negative. This difference has facilitated a reliable discrimination of normal and leukemic blasts in the MRD positive cases with regenerating bone marrow at day 78. In conclusion, treatment-induced up-regulation of CD11b in PBC-ALL has a promising potential as a novel marker, which may considerably improve specificity of FCM-MRD detection in bone marrow samples with a complex hematopoietic background.
Late Relapses of Childhood T-ALL Are Frequently Second T-ALL.
Authors: Szczepanski Tomasz , van der Velden Vincent H.J. , Van Vlierberghe Pieter , Gruhn Bernd , Panzer-Grumayer Renate , Spinelli Monica , Cave Helene , Stadt Udo zur , Campana Dario , Schrauder Andre , van Wering Elisabeth , Meijerink Jules P.P. , van Dongen Jacques J.M. 
Published: April 2020

Abstract
The vast majority of relapses in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients occur relatively early, usually within 2 years from diagnosis. Our previous comparative molecular analyses between diagnosis and relapse in all such “classical” T-ALL showed totally or at least partly identical T-cell receptor (TCR) gene rearrangement patterns at both disease phases. These results confirm that the relapse clone in these patients originated from the original diagnosis clone, which became resistant to the applied treatment. In contrast to these “classical” T-ALL, two patients experienced very late T-ALL recurrences and displayed completely different TCR gene rearrangement sequences between diagnosis and relapse. We hypothesized that such late “relapses” of T-ALL in fact might represent second malignancies in genetically predisposed persons. We investigated 16 T-ALL patients with late relapses, i.e. at least 2.5 years from initial diagnosis. The studies at the DNA level involved detailed comparison of TCR gene rearrangements between diagnosis and relapse (PCR-heteroduplex, sequencing and/or Southern blot analyses), the detection of gene fusions involving the TAL1 gene and/or TCR genes and comparative genomic hybridization (CGH) using high-resolution Agilent arrays. We found evidence of a common clonal origin between diagnosis and relapse in ten of the 16 patients. In one case, no clonal TCR rearrangements were detected neither at diagnosis nor at relapse. In the other five patients TCR gene rearrangement sequences had completely changed between diagnosis and relapse, suggesting a second T-ALL rather than a relapse. Moreover, three of these five patients remained in complete remission after second-line treatment, which is unusual for relapsed T-ALL. In three of the five patients with presumed second T-ALL, CGH arrays showed completely different patterns of genomic aberrations between diagnosis and relapse, while in the remaining two patients the patterns of genomic changes were vastly different, but some aberrations were similar at both disease phases. In eight patients with evidence of a common clonal origin between diagnosis and relapse at least 50% of genomic events revealed by CGH arrays were identical between diagnosis and relapse of T-ALL. We conclude that approximately one-third of late T-ALL “relapses” in fact represent second malignancies. We are currently performing further genomic analyses to identify common genetic events or common genomic features which might be related to predisposition for development of T-ALL.
Outcomes of MDS Patients with Chromosome 7 Abnormalities Treated with 5-Azacytidine.
Authors: Lim ZiYi , Ho Aloysius Y.L. , Samuel Jonathon , Hayden Janet , Garcia-Manero Guillermo , Mufti Ghulam J. 
Published: April 2020

Abstract
Chromosome 7 abnormalities occurring in isolation or as part of complex cytogenetics confer an adverse prognosis in patients with myelodysplastic syndromes (MDS). Preliminary clinical data from various groups has suggested that the use of 5-azacytidine, a DNA methyl transferase inhibitor, in this sub-group of poor risk patients may be associated with an improved clinical response. We report on a retrospective analysis on the outcomes of 31 MDS patients with chromosome 7 abnormalities treated with 5-azacytidine. 5-azacytidine was administered subcutaneously at 75mg/m2 daily for 7 days and each cycle was repeated every 28 days. The median age of the cohort was 61 years (range: 17–80). Based on the WHO classification, 4 patients (13%) were RCMD/RCMD-RS, 17 were RAEB I/II (55%), 8 patients had acute myeloid leukemia transformed from MDS (26%), an additional 2 patients had secondary MDS. The IPSS of the cohort was Int-1(n=1), Int-2(n=12), high-risk(n=18). 13(42%) patients had isolated chromosome 7 abnormalities, 8(58%) had chromosome 7 abnormalities as part of a more complex cytogenetic profile. 10 patients(33%) had previously been treated prior to therapy with 5 azacytidine. 5 patients were withdrawn from treatment after 1 cycle due to drug intolerance or disease progression and were excluded from further analysis. The remaining 26 patients received a median of 6 cycles of treatment (range: 2–28 cycles). Response criteria was based on the modified IWG response criteria for MDS (Cheson et al Blood 2007). 7 patients achieved a complete response (CR), 3 partial response (PR), with haematological improvement (HI) in a further patient. The median cycles of treatment before response was 2, with median response duration of 10.5 months (range: 4–20 months). Overall response rate (CR+PR+HI) was 6/12 (50%) for patients with isolated chromosome 7 abnormalities as compared with 5/14 (36%) for patients with complex cytogenetics (p=0.15). 7 patients had a complete cytogenetic response, with a further 2 patients achieving a partial cytogenetic response. These cytogenetic responses were observed in 4/12 patients with isolated chromosome 7, and 5/16 patients with complex cytogenetics. The median survival of the cohort was 19.8 months (95%CI: 16.3–23.3). Patients with isolated chromosome 7 abnormalities had median survival of 24.8 months (95%CI: 17.8–31.8) compared with those with complex cytogenetics (17.3 months, 95%CI: 8.3–26.3, p=0.10). In addition, patients achieving cytogenetic remission (complete or partial) had an improved overall survival when compared with non-responders (median OS: 24.8 vs 19.8 months, p=0.05). WHO classification, IPSS, patient age, and history of prior therapy were all not significant predictors of response or overall survival in this cohort. In summary, 5-azacytidine is able to induce high remission rates in a cohort of high risk MDS patients with chromosome 7 abnormalities.
Therapy of Myelodysplastic Syndrome (MDS) with Azacitidine Given in Combination with Etanercept: A Phase II Study.
Authors: Holsinger Aaron L. , Ramakrishnan Aravind , Storer Barry , Becker Pamela S. , Petersdorf Stephen , Deeg H. Joachim , Scott Bart L. 
Published: April 2020

Abstract
The heterogeneity of Myelodysplastic Syndrome (MDS) has spurred interest in combining agents with different mechanisms of action in an attempt to improve the frequency and robustness of responses. Laboratory studies in patients with MDS have shown a shift in the relative levels of TNF-α receptor 1 and 2 in favor of receptor 2 in patients with more advanced MDS. Receptor 2 conveys only proliferative (not apoptotic) signals, and blockade of TNF-α may thus interfere with disease progression, while possibly protecting normal hematopoietic precursors. Therefore, we combined an established regimen of azacitidine with administration of the soluble TNF receptor antagonist etanercept in patients with advanced MDS. Twenty-three patients were treated with azacitidine, 75mg/m2/day for 7 days combined with etanercept, 25mg sc twice a week for two weeks every 28 days. Eighteen patients with MDS (4 RAEB-1, 11 RAEB-2, 1 CMML-1, and 2 CMML-2) have completed at least 3 months of therapy and were considered evaluable. Five of these patients had intermediate-1 risk, seven intermediate-2 and six high risk MDS by IPSS. Using the revised International Working Group (IWG) criteria for MDS, 14 patients (78%) responded: 5 patients (28%) had complete remissions (CR), 8 patients (44%) had partial remissions (PR) and 1 patient (6%) had hematologic improvement of neutrophils. Three patients have been on therapy for two years with sustained responses. Two patients developed pneumonias. The most common grade ¾ adverse events were hematological toxicity (78%). This therapeutic combination may be superior to treatment with azacitidine alone and warrants further study.
XBP-1 Levels Predict Sensitivity of Myelomas to Proteasome Inhibitor Bortezomib.
Authors: Ling Silvia C. , Lau Edwin , Ho Lye L. , Ho Joy , Joshua Douglas E. , Allen John 
Published: April 2020

Abstract
Background: Proteasome inhibitors (PI) are remarkably effective in relapsed and refractory myeloma but the origin of this peculiar sensitivity remains unclear. Myeloma is dependent on the unfolded protein response (UPR) and its regulator, transcription factor XBP-1. PI perturbs the unfolded protein response (UPR) by inhibition of the 26S proteasome-the main pathway for protein degradation. We hypothesize that the dependence on the UPR and XBP-1 mediates sensitivity to PI and the level of XBP-1 correlates with sensitivity to PI. The aim of this study is to correlate Bortezomib sensitivity with XBP-1 in vitro and in myeloma patients; to check the effect of manipulating XBP-1 on Bortezomib sensitivity and develop Bortezomib-resistant myeloma cell lines to ascertain the effects on XBP-1 and the UPR.
Methods and Results: Sensitivity to Bortezomib was measured by growth inhibition assay. XBP-1 mRNA levels and its isoforms were measured by a two-step quantitative QPCR assay, in 6 myeloma cell lines and 17 other cancer cell lines. There is a strong inverse correlation in myeloma cell lines between total or unspliced XBP-1 with Bortezomib sensitivity (r = −0.9) but not in other cancer cell lines. 23 marrow biopsies from 11 Bortezomib-treated myeloma patients were analysed for XBP-1 expression. Myeloma cells (CD38 hi, CD14 lo, kappa or lambda light chain +ve) were purified by flow cytometry. XBP-1 levels in myeloma cell lines were manipulated by shRNA-mediated knockdown and overexpression by retroviral transduction and had little effect on Bortezomib sensitivity. Bortezomib-resistant myeloma lines were developed. The mechanism of resistance was elucidated (XBP-1, ATF6, P-EIF2a, P58 INK and immunogloblin production). Marked downregulation of XBP-1 was demonstrated.
Conclusion: XBP-1 is a surrogate marker of Bortezomib sensitivity and its clinical utility is being tested now. Sensitivity to PI is related to the dependence on the UPR, reflected in the level of XBP-1. Bortezomib resistance is mediated by downregulation of the UPR.
Gene Expression Profiling of Myeloma Cells To Predict Response to Primary Therapy with Thalidomide-Dexamethasone for Newly Diagnosed Multilple Myeloma.
Authors: Abdelkefi Abderrahman , de Vos John , Assou Said , Othman Tarek Ben , Rossi Jean-Francois , Ladeb Saloua , Safra Ines , Galai Yosr , Ahmed Malika Ben , Benkahla Alia , Jenhani Faouzi , Nasr Moufida Ben , Torjman Lamia , Lakhal Amel , Louzir Hechmi , Abdeladhim Abdeladhim Ben 
Published: April 2020

Abstract
Background: Thalidomide which represents an effective treatment strategy for relapsed/refractory multiple myeloma, actually represents a standard of care also for newly diagnosed multiple myeloma patients.
Methods: In the present study, we adopted a gene expression profiling (GEP) strategy in an attempt to predict response (&gt; 50% reduction in serum M protein) to primary therapy with thalidomide-dexamethasone for newly diagnosed multiple myeloma. Plasma cells (CD138+) were purified from bone marrow aspirates from 17 patients at diagnosis, before initiation of treatment with thalidomide-dexamethasone. GEP was performed using the Affymetrix U133 Plus_2 microarray platform. The Affymetrix output (CEL files) was imported into Genespring 7.3 (Agilent technologies) microarray analysis software, where data files were normalized across chips using GCRMA and to the 50th percentile, followed by per gene normalization to median. Criteria of response were those established by Bladè et al.
Results: After sufficient follow-up, responders (n=9) and nonresponders (n=8) were identified, and gene expression differences in baselines samples were examined. Of the 11000 genes surveyed, Wilcoxon rank sum test identified 149 genes that distinguished response from non response. A multivariate step-wise discriminant analysis (MSDA) revealed that 14 of the 149 genes could be used in a response predictor model (see table). Of interest, the gene list encompasses WXSC1, known to be involved in the chromosomal translocation t(4;14) (p16.3;q32.3) in multiple myeloma.
Conclusion: These results could be the first step to adopt microfluidic cards, in an attempt to select at diagnosis patients who will respond favourably to a particular treatment strategy.
List of 14 genes able to predict response to primary therapy with thalidomide-dexamethasone for newly diagnosed multiple myeloma. Gene ID Gene Name Chromosomal location 212771_at C10orf38 10p13 229874_x_at LOC400741 1p36.13 219690_at U2AF1L4 19q13.12 202207_at ARL7 2q37.1 243819_at GNG2 14q21 203753_at TCF4 18q21.1 235400_at FCRLM1 1q23.3 211474_s_at SERPINB6 6p25 226785_at ATP11C Xq27.1 215440_s_at BEXL1 Xq22.1–q22.3 209054_s_at WXSC1 4p16.3 227168_at FLJ25967 22p12.1 213355_at ST3GAL6 3q12.1 223218_s_at NFKBIZ 3p12–q12