bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute Lymphoblastic Leukaemia Has a Poor Outcome in Children with Down Syndrome Due to Infective Death in Remission (Results of UK MRC ALL 97 Trial).
Authors: de la Fuente Josu , Richards Sue , Webb David K. , Hann Ian M. , Mitchell Christopher D. , Vora Ajay J. , Kinsey Sally E. , Eden Osborn B. , Ancliff Phil ,   On Behalf of the UK Childhood Leukaemia Working Party
Published: April 2020

Abstract
Acute lymphoblastic leukaemia (ALL) has a poorer outcome in children with Down syndrome (DS) which has been attributed in the past to a higher incidence of infective death in remission and late relapses. We report on the outcome of children with DS enrolled on the UK Medical Research Council trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Thirty seven children had DS (2%), of whom three were treated on the high risk protocol (HR1). Thirty-three (89%) achieved complete remission at the end of induction, 3 died during induction (8%), and one died later without remission. The median follow up was 4.9 years (2.4–7.8). The 5-year event free survival (EFS: 48.0%, SD 8.9) was not an improvement on the previous MRC UKALL XI trial (57.9%, SD 8.0, p=0.2) and was significantly worse than for children without DS (p&lt;0.00005). At the time of follow up, 46% of the children had died (n=17). Five patients suffered relapse, and the relapse rate was not significantly different from those without DS. One patient known to have cardiac disease died during maintenance due to arrhythmia and 8 died of infection, resulting in a significantly higher rate of death in remission (28%) than in children without DS (3%, p&lt;0.00005). Infective deaths were associated with intensification therapy, except in one child who died during interim maintenance. It was possible to isolate a microorganism in 50% of the cases (two cases of Pseudomonas, one Staphylococcus aureus, one Staphylococcus epidermidis and yeast) plus Rhinovirus was found in a nasopharyngeal aspirate of a fifth case with clinical evidence of bacterial sepsis. For the randomised comparisons (prednisolone versus dexamethasone n=30, mercaptopurine versus thioguanine n=23), results within the DS patients were not significantly different from those in all patients, with benefit for dexamethasone. The increase in remission deaths with DS was greater with prednisolone, and with mercaptopurine (p for interaction = 0.0002, &lt;0.00005, respectively). The revision of the trial in 1999 which adopted the template of CCG 1952 which improved EFS, did so for DS patients also, with no change in the DS remission death rate. In conclusion, children with DS may benefit from increased treatment intensity but still have an unacceptably high rate of infective death in remission.
Thrombotic and Hemorrhagic Events for Patients on Pediatric Oncology Group (POG) Protocols 9201, 9605, 9406.
Authors: Rice Megan A. , Bell Beverly A. , Chauvenet Allen , Kurtzberg Joanne , Abish Sharon B. , Pullen Jeanette , Devidas Meenakshi , Camitta Bruce M. 
Published: April 2020

Abstract
Thromboembolism (TE) and hemorrhage are known complications following L-asparaginase (L-asp) therapy, but the incidence and epidemiology of these events in children are not clearly defined. POG protocols 9201, 9605, and 9406 were phase III studies for low, standard, and higher risk patients with acute lymphoblastic leukemia (ALL). Protocol 9201 enrolled 649 patients, 9605: 1087, and 9406: 911. All 3 studies used a common 4 week induction protocol (POG 9400) of native L-asp (6000 IU/m2 IM x 6 doses), weekly vincristine, and daily prednisone. Doxorubicin was added for patients meeting higher risk criteria based on age, initial white blood cell count, and CNS/testicular status. Patients on 9201 and 9605 received no L-asp after induction. 9406 patients received 3 doses of PEG L-asp (1000 or 2500 IU/m2 IM) during consolidation. The incidence of TE and hemorrhage on 9201 was 2.2% (14/649), on 9605 1.9% (21/1087) and on 9406 5.3% (48/911). In all three protocols, TE was more common than hemorrhage. Hemorrhages were more frequent in POG 9406.
# Patients # Thromboses # Hemorrhages # Total Events # in Induction 9201 649 13 1 14 6 9605 1087 17 4 21 10 9406 911 34 14 48 27 Total 2647 64 19 83 43
The largest proportion of events occurred during the month of induction therapy. 70% of induction events (30/43) occurred in patients who received 4 drug therapy. Of the 43 induction events, 21/26 patients with reported coagulation studies had abnormal fibrinogen levels &lt;100mg/dL, 7 of those were &lt;50mg/dL. Antithrombin levels were not reported. 28 of 64 TE were likely central venous line (CVL) related [6 tip of catheter, 16 axillary/subclavian vein, 2 superior vena cava, 2 atrium, 1 internal jugular vein, 1 basilic vein]. Locations of remaining TE included: 13 CNS [4 venous sinus, 9 cerebral]; 10 lower extremity; 4 upper extremity; 1 pulmonary embolism; 8 site not specified. Locations of hemorrhages included: 8 CNS [7 intracranial, 1 subdural]; 2 GI [1 gastric, 1 esophageal perforation]; 2 acute epistaxis; 2 site not specified; and 1 of each of the following: CVL site, pulmonary, splenic, vitreous eye, and hemothorax. Statistical analyses correlating number of L-asp doses to induction events and correlates with gender, age, race, and congenital abnormality are being evaluated.
Figure Figure
Forodesine (FodosineTM), a PNP Inhibitor Active in Relapsed or Refractory T-Cell Leukemia Patients (Phase II Study).
Authors: Furman Richard R. , Iosava Genadi , Isola Luis , Ravandi Farhad , Zodelava Mamia , Bennett J. Claude , Kilpatrick J. Michael , Bantia Shanta ,   Fodosine Development Group
Published: April 2020

Abstract
Inherited deficiency of purine nucleoside phosphorylase (PNP) is associated with a profound loss of T-cells. This rare clinical condition provides a model for developing specific inhibitors of PNP as therapy for T-cell malignancies. Forodesine is a specific PNP inhibitor that raises plasma 2′-deoxyguanosine (dGuo) and intracellular dGTP levels, leading to T-cell apoptosis. The objective of this study was to determine the efficacy and safety of forodesine in patients with relapsed or refractory T-cell leukemia. Patients received IV forodesine 40 mg/m2 5 days each week (1 cycle) for a total of 6 cycles (8 cycles if dose escalation needed after cycle 2). To date, 21 patients have been treated, 19 of which are T-ALL. Results are based on available data from 13 T-ALL patients. Median number of prior regimens was 4 (range: 1–6). Overall response rate was 38%, including 3 patients with complete response (CR) (23%) and 2 patients with partial response (PR) (15%). Three patients had stable disease and 5 patients had disease progression. Time to progression (TTP) for the 3 CR patients was 80, 119, and 160+ days. One CR patient continues to receive treatment. TTP for the 2 PR patients was 89 and 40 days. Plasma dGuo was elevated in all patients (range: 3.4 to 88.5 μM; predose levels ≤0.004 μM). Treatment was well tolerated. One serious adverse event possibly drug related was CMV pneumonitis in 1 patient. The most common adverse events possibly drug related were nausea (33%), headache (26%), anemia (20%), thrombocytopenia (20%), and weakness (20%). In 1 patient, after 2 doses of forodesine, WBC count dropped dramatically, requiring interruption of treatment for 2 weeks because of tumor lysis syndrome (Figure). After 2 cycles of treatment, the patient achieved a CR. By week 3, platelets and neutrophils recovered, indicating a specificity of forodesine for leukemic cell populations. These study results show that forodesine is active, with minimal toxicity, as a single agent in relapsed or refractory T-cell leukemia. Additional clinical efficacy and safety data will be presented.
Effect of Forodesine on Blood Components in One T-All Patient Effect of Forodesine on Blood Components in One T-All Patient
Long-Term Results of the GIMEMA LAP AIDA 0493 Amended Protocol in Elderly Patients with Acute Promyelocytic Leukemia (APL).
Authors: Latagliata R. , Breccia M. , Fazi P. , Vignetti M. , Cupri A. , Sborgia M. , Vincelli D. , Candoni A. , Salvi F. , Rupoli S. , Martinelli G. , Kropp M.G. , Di Rienzo N. , Zampaglione V. , Venditti A. , Melillo L. , Cimino G. , Petti M.C. , Avvisati G. , Coco F. Lo , Mandelli F. 
Published: April 2020

Abstract
In order to reduce toxicity in elderly patients with newly diagnosed APL, since 3/1997 the Italian cooperative group GIMEMA evaluated an amended AIDA protocol for patients aged &gt; 60 years, consisting of the same induction with ATRA and Idarubicin but only 1st consolidation course (Idarubicin + Cytarabine), followed by 2 years maintenance with ATRA alone. Up to now, 56 patients (25 males and 31 females, median age 66.2 years, 46 with PS 0-1 and 10 with PS 2) are fully evaluable. At onset, according to GIMEMA-PETHEMA risk score, 18 were low-risk(32.5%), 31 intermediate risk (55%) and 7 high risk (12.5%). After induction treatment, 54 patients (96.4%) achieved CR and 2 (3.6%) died from haemorrhage (1) and infection (1). ATRA syndrome was documented in 5 patients (9.3%): 13/56 patients (23.2%) showed during induction other toxicities (WHO 3 – 4) not related to ATRA. After CR achievement, 2 patients died in CR from haemorrhage (1) and infection (1) and 52 received the consolidation course: on the whole, during consolidation 4 patients (7.6%) had a toxicity WHO 3 – 4 and 2 of them (3.8%) died from haemorrhage (1) and infection (1). The remaining 50 patients started maintenance treatment: up to now, 12 patients (22.2%) relapsed, after a median time from morphological CR of 19 months (range 7 – 86). Overall survival (OS) was 76.1% and 73.3% at 3 and 5 years, respectively. Disease free survival (DFS) was 64.5% and 61.3% at 3 and 5 years, respectively. At the univariate analysis, PS =2 (p=0.0019), WBC count &gt; 3 x 109 /l (p=0.018) and male gender (p=0.03) had a bad prognostic impact on DFS, while only PS=2 (p=0.05) did it on OS. Age, PLTS count, WBC count &gt; 10 x 109 /l, and risk score did not affect both OS and DFS. At the multivariate analysis on DFS, only PS =2 retained prognostic significance (HR = 3.8). In conclusion, the amended GIMEMA protocol has shown to be effective and safe in elderly APL patients, as the rate of death in CR was reduced when compared with previous results in not amended GIMEMA LAP AIDA 0493: however, to face with a relapse rate &gt; 20%, future strategies might be designed which exploit the use of more targeted approaches including combinations of ATRA, arsenic trioxide, and anti-CD33 monoclonal antibodies.
Influence of Perceived Risk Factors for Bleeding on Venous Thromboembolism Prophylaxis Practices in Acutely Ill Medical Patients: Findings from IMPROVE.
Authors: Monreal Manuel , Zotz Rainer B. , Decousus Hervé , Chong Beng H. , Merli Geno , Pavanello Ricardo , Pini Mario , Turpie Alexander G.G. , Huang Wei , Anderson Frederick A. ,   for the IMPROVE Investigators
Published: April 2020

Abstract
Background Acutely ill medical patients at risk for venous thromboembolism (VTE) should receive VTE prophylaxis. However, factors perceived by physicians to increase patients’ risk of bleeding may influence VTE prophylaxis practices. In this analysis from The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE), we examined whether perceived risk factors for bleeding had a significant influence on physicians’ prescribing of in-hospital prophylaxis in acutely ill medical patients.
Methods Patients aged ≥18 years and hospitalized ≥3 days with an acute medical illness have been enrolled consecutively since July 2002. Risk factors considered were: severe renal failure, known bleeding disorder, hemorrhagic stroke, thrombocytopenia, bacterial endocarditis, active gastroduodenal ulcer, NSAID use, hepatic failure, age, immobility and alcoholism. Factors associated with different prescription rates of prophylaxis compared with rates in patients without these factors were identified and included in a multiple logistic regression model (significance at p&lt;0.05).
Results Up to 31 March 2005, 6946 patients were enrolled in 49 hospitals in 12 countries. Pharmacologic prophylaxis was received by 42%, 25%, 16%, and 14% of patients with a platelet count at admission &gt;100, 50–100, 20–50 and &lt;20x109/L, respectively (p&lt;0.0001), and 43%, 39%, 30% and 32% of patients with none, 1, 2 and 3 risk factors for bleeding (p&lt;0.0001). Factors independently associated with a lower/higher prescription rate of heparin-based prophylaxis compared with the risk in patients without these factors are shown in the Table.
Conclusions The likelihood that hospitalized acutely ill medical patients receive in-hospital pharmacologic prophylaxis decreases as their platelet count at admission decreases, or their cumulative number of perceived risk factors for bleeding increases. Further studies are needed to determine whether the changes in prophylaxis practices observed in this study are justified.
Table. Factors Independently Associated with a Higher/lower Rate of Heparin-based VTE Prophylaxis Factor Odds Ratio 95% Confidence Interval Age (per 10-year increase) 1.19 1.66–1.22 Immobility (per 10-day increase) 1.03 1.02–1.05 Alcoholism 0.62 0.46–0.83 Thrombocytopenia 0.60 0.48–0.74 Active duodenal ulcer 0.36 0.26–0.52 Hepatic failure 0.34 0.21–0.54
Murine Modeling of Human Severe Congenital Neutropenia and Non-Immune Chronic Idopathic Neutropenia.
Authors: Zarebski Adrian P. , Pawlak Wojciech , Baktula Avinash M. , Basu Sudeep , Trent John , Grimes H. Leighton 
Published: April 2020

Abstract
Severe Congenital Neutropenia (SCN) is a rare hematological disease manifested by a complete block in the maturation of neutrophils. The lack of neutrophils leads to recurrent bacterial and fungal infections. Most SCN patients have mutations in Ela2, the gene encoding neutrophil elastase; however, introduction of SCN-patient mutations into murine Ela2 or disruption of murine Ela2 does not recapitulate neutropenia in mice. Thus, there are no mouse models of SCN. Gfi1 is a transcriptional repressor leukemia oncoprotein involved in HSC maintenance as well as proper lymphoid and myeloid development. Mice lacking Gfi1 have profound neutropenia. We recently described four patients in which Ela2 was intact but mutant for Gfi1. The heterozygous single aminoacid substitutions were found in zinc finger 5 (N382S) and zinc finger 6 (K403R) correlating to either SCN or Non-immune Chronic Idiopathic Neutropenia of Adults (NICINA) respectively. Given that Gfi1 null mice lack neutrophils, and that people with Gfi1 mutations display SCN or NICINA, we asked whether the human mutations when introduced into murine Gfi1 are sufficient to model neutropenia in mice. To this end, we constructed murine Gfi1 cDNAs containing the SCN and NICINA patient mutations, retrovirally overexpressed them in murine Lin- bone marrow cells, then analyzed them by in vitro differentiation assays. Strikingly, cells overexpressing Gfi1-N382S produced no granulocytic colonies (similar to the profound phenotype of SCN). Whereas, the expression of Gfi1-K403R mutation resulted in a moderate reduction in granulocytic colonies (corresponding to the mild phenotype of NICINA). We have constructed a virtual model of Gfi1 zinc finger/DNA interaction to explore the molecular defect engendered by the N382S mutation. At the meeting, we will discuss the molecular basis of the profound phenotype engendered by Gfi1-N382S expression. These data demonstrate for the first time that human neutropenia can be modeled in murine cultures through the introduction of mutations in Gfi1 found in SCN and NICINA patients.
Neutrophil Elastase, but Not Myeloperoxidase, Depends on Serglycin Proteoglycan for Granule Localization in Neutrophils.
Authors: Niemann Carsten U. , Åbrink Magnus , Pejler Gunnar , Christensen Erik I. , Knight Stefan D. , Borregaard Niels 
Published: April 2020

Abstract
Granule proteins play a major role for the bactericidal activity of neutrophils. The mechanisms for sorting of proteins to granules in neutrophils remain unknown. Serglycin proteoglycan with glycosaminoglycan side chains is the major intracellular proteoglycan of hematopoietic cells. Neutrophil elastase, a resident of primary (azurophilic) granules, binds glycosaminoglycans. Serglycin has been proposed to play a major role in sorting and packaging of granule proteins in neutrophils and other cells.
Figure Figure
We have investigated the expression and localization of granule proteins in neutrophils from a serglycin knock out mouse. We found neutrophil elastase absent from neutrophils of serglycin knock out mice as shown by activity assay (fig. 1), Western blotting (fig. 2), and immunocytochemistry. Northern blotting (fig. 1) demonstrated the presence of neutrophil elastase mRNA both in serglycin knock out mice and in wild type mice. No other granule proteins tested (myeloperoxidase, cathepsin G, proteinase 3, bacterial permeability increasing protein (primary granules), lactoferrin, 24p3 (secondary (specific) granules), MMP-9/gelatinase B (tertiary (gelatinase) granules)) showed differences in expression or localization in neutrophils from wild type mice compared to serglycin knock out mice. Three-dimensional models of neutrophil elastase revealed a cluster of positively charged amino acids around the active site of the enzyme. This cluster may be engaged in binding the negatively charged glycosaminoglycan side chains of serglycin and thus forms the basis for serglycin mediated sorting of elastase to primary (azurophilic) granules. No counts for both bone marrow cells and peripheral blood are similar for the wild type and serglycin −/− genotypes; indicating that the lack of sorting of elastase to granules does not induce neutropenia itself. These findings disclose an important role for serglycin proteoglycan in targeting neutrophil elastase to neutrophil primary granules. This is in accordance with the recently published significance for serglycin in granule formation of mast cells. Our results also indicate that different mechanisms are responsible for sorting of different granule proteins to the same neutrophil granule subset, as none of the other tested granule proteins showed differences in localization between wild type and serglycin knock out neutrophils.
Cytokine Gene Expression Profile Distinguishes CD4+/CD57+ T-Cells of Nodular Lymphocyte Predominance Type of Hodgkin Lymphoma from Their Tonsillar Counterparts.
Authors: van den Berg Anke , Atayar Cigdem , Visser Lydia , Poppema Sibrand 
Published: April 2020

Abstract
Little is known about the cytokine profile of nodular lymphocyte predominance Hodgkin lymphoma (NLPHL) and the significance of the characteristic rosetting CD4+/CD57+ T-cells. We analyzed the T-lymphocyte populations isolated from lymph node suspensions of 5 patients with NLPHL, 2 with follicular hyperplasia and progressive transformation of germinal centres (PTGC), 3 with classical Hodgkin lymphoma (CHL) and 5 with hyperplasia of the tonsil. We sorted the T-cells based on expression of CD3, CD4 and CD57 by flow cytometry and evaluated the cytokine mRNA profiles of the T-cells with quantitative RT-PCR. NLPHL cases were as rich in T-cells as the CHL cases, but all NLPHL cases with a much higher frequency of CD4+/CD57+ T-cells. In contrast to the CD4+/CD57+ T-cells from tonsils, IL2 and IL4 mRNA was consistently absent from the CD4+/CD57+ T-cells of NLPHL. Even after stimulation, no IL4 transcripts could be detected in the CD4+/CD57+ T-cells of NLPHL. On the other hand, IFNγ transcripts were elevated in NLPHL and PTGC T-cell subsets as compared to tonsillar T-cell subsets. IL13 mRNA was exclusively produced by the T-cells of CHL cases, indicating that IL13 may be a key cytokine in CHL. In conclusion, elevated levels of CD4+/CD57+ T-cells are characteristic for NLPHL and these T-cells display a distinct cytokine mRNA profile.
6q Deletion in Waldenström Macroglobulinemia Is the Most Common Cytogenetic Abnormality and Is Associated with Aggressive Disease with a Trend towards Worse Survival.
Authors: Schop Roelandt F.J. , Ocio Enrique M. , Gonzalez Belen , Gutierrez Norma C. , Moro Maria Jesus , Aguilera Carmen , Hernández Jose , García-Sanz Ramon , Xu Ruifang , Hernandez-Rivas Jesus M. , Greipp Philip R. , Dispenzieri Angela , Jalal Syed M. , Lacy Martha Q. , Gonzalez-Paz Natalia , Gertz Morie A. , San Miguel Jesús F. , Fonseca Rafael 
Published: April 2020

Abstract
Fluorescence in situ hybridization (FISH) is an effective alternative for the analysis of cytogenetic abnormalities of low proliferative entities such as Waldenström macroglobulinemia (WM) but, to date, no studies have been carried out to explore the potential impact of molecular cytogenetics on disease evolution. Deletion of the long arm of chromosome 6 (6q-) is the most frequent cytogenetic abnormality in WM. In this study we have analyzed the incidence of this aberration (using both conventional cytogenetics and FISH analysis) in 102 WM patients, and we have correlated it with disease characteristics. Deletion of 6q21 was detected in 6% of patients by conventional cytogenetics, while FISH studies increased this incidence up to 39%. Moreover, in those patients analyzed by cIgM-FISH, the incidence of 6q- was higher (54%). Interestingly, 6q- patients displayed features associated with adverse prognosis (higher levels of ESR, CRP and beta-2 microglobulin), and a greater tendency to display anemia and hypoalbuminemia. Other differentiating variables without reaching statistical significance were a tendency of displaying a higher bone marrow lymphoplasmacytoid infiltration and the amount of monoclonal component in 6q- patients (table). In addition, patients with 6q- displayed shorter survival from time of diagnose (log-rank; p=0.09). In summary, our results show that 6q deletion in WM patients is currently the most frequently found cytogenetic abnormality. Patients with this deletion also shows a trend towards an aggressive disease and poorer outcome in WM. Further studies should focus on possible tumor suppressor genes in the minimal area of deletion at 6q and to determine their role in disease progression.
table del6q present del6q absent p-value n 40 (39%) 62 (61%) β2M ≥4mg/dL 48% 16% 0.005 CRP ≥3.5 mg/dL 47% 11% 0.006 Albumin &lt;4mg/dL 86% 55% 0.006 ESR ≥100 mm/h 73% 44% 0.02 Hb &lt;11 g/dL 63% 40% 0.02 serum IgM &gt;20 g/L 86% 73% 0.10 BM infiltration &gt;40% 44% 31% 0.20