bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoablative Therapy with Autologous Stem Cell Transplantation in the Treatment of Poor Risk Multiple Sclerosis.
Authors: Kozak Tomas , Havrdova Eva , Pitha Jiri , Mayerova Karolina , Evzen Gregora , Petr Kobylka , Sarka Vodvarkova , Jan Pachl , Marek Trneny , David Dolezil , Jiri Fiedler , Vladimir Koza 
Published: October 2019

Abstract
The immunoablative therapy with hematopoietic stem cell transplantation is tested in patients with intractable form of autoimmune diseases including multiple sclerosis (MS). Thirty one patients with secondary rapidly progressive MS were included in the phase I/II clinical trial involving the high dose chemotherapy with autologous peripheral blood progenitor cell (PBPC) support. Twenty seven patients underwent high dose conditioning BEAM. T cell depletion in vitro was performed in 18 grafts. Nine patients with not purged graft received in vivo ATG 4mg/kg i.v. D+1, D+2 after transplantation. Median follow-up is 48 months (24–72). Median EDSS (Expanded Disability Status Scale) of grafted patients at the time of inclusion was 6.5 (5.0–7.5), median EDSS of grafted patients at the last follow up was 7,0 (5.5–10.0). Two patients out of 27 (7 %) remain improved significantly (by ≥ 1.0 point on EDSS), 3 patients (11 %) are improved not significantly (by 0.5 point). Five patients (19 %) are stable in their EDSS. Seven patients (26 %) gained their disability significantly (by ≥ 1.0 point on EDSS) despite the treatment, one of them died 31 months after the transplantation from disease progression (EDSS 10.0). Ten patients (37 %) worsened not significantly (by 0.5 point) on their EDSS. Patients who clearly stabilized their disability or remain improved represent 37 %. The increase of EDSS at the 48 months (m) of the follow up is significatnt (Wicoxon’s, repeated measure ANOVA, t-test), however, is not at 36, 60 and 72 m respectively. The development of disability between the group that was grafted with in vitro purged graft and the group with ATG i.v. was not significant (Wilcoxon’s, Mann-Whitney). 20 patients stabilized their MRI finding, in 2 patients decreased number and size of lesions, 5 patients worsened their MRI. No mortality has been observed in this cohort. However, the toxicity of the transplantation differed in each individual; two serious events involving respiratory tract have been observed. Changes in lymphocyte subsets in peripheral blood were followed before and after the treatment. The percentage and absolute count of CD4+ cells and CD4+CD45 as well as IRI were significantly decreased 12 months after the transplantation
Conclusion: Almost 40 % of patients with otherwise intractable rapidly progressive MS remained stable or improved in their disability with median follow up 48 months after immunoablative therapy. The value of this type of therapy should be investigated in the randomized trial. The study was sponsored by Grant IGA No NF/6560-3 from Ministry of Health of the Czech Republic.
Voriconazole Replacing Liposomal Amphotericin B as First-Line Therapy in Suspected or Proven Fungal Infection in Acute Leukemia Patients: A Retrospective Audit of Clinical and Financial Outcomes in a UK District Hospital.
Authors: Hybnerova Jindrinska , Bahn Amit , Pocock Christopher 
Published: October 2019

Abstract
Background: In most centres in the United Kingdom, systemic antifungal therapy (AFT) is used as third-line therapy for fever complicating profound, prolonged neutropenia (PPN) during the treatment of acute leukemia. Voriconazole has been recommended as first-line AFT at the Kent and Canterbury Hospital (KCH) since October 2002; liposomal amphotericin B was the previous treatment of choice. The aim of the audit was to identify numbers of episodes of PPN and the numbers of suspected fungal infections in a 2-year period following the policy change. Subsequently the clinical and financial outcomes were examined. In addition, the impact on cost of AFT following centralisation of leukemia treatment from two district hospitals onto one site was examined.
Methods: A retrospective audit was conducted on data from hematology inpatients undergoing remission induction or consolidation therapy for acute leukemia at KCH between January 2003 and December 2004. The costs of voriconazole and liposomal amphotericin B treatment from 2002 to 2004, and 8 months prior and post centralisation of inpatient care (April 2004, which increased the population from 400,000 to 600,000), were examined.
Results: 84 episodes of PPN were identified in 41 patients undergoing treatment for acute leukemia; mostly acute myeloid leukemia (AML). Itraconazole prophylaxis from d1 of therapy and GCSF from d+5 was used in the majority of cases. 18 cases of suspected or radiologically proven fungal infection were identified. High-resolution computed tomography of the chest was performed in 10 cases and suspicious lesions identified in three. Voriconazole was used as first-line therapy in 17/18 cases. In 7 cases, treatment was switched to liposomal amphotericin B. Reasons for switching were rising C-reactive protein (1 patient), persistent fever (2 patients), radiological progression (1 patient) and side effects (3 patients). Of the 3 patients with radiological evidence of fungal infection, two had a complete resolution (1 voriconazole, 1 voriconazole/liposomal amphotericin B) and 1 patient died of refractory leukemia. There was a fall in total antifungal spend from £263K in 2002/3 to £229K in 2003 and a further 68% fall to £73K in 2004. We suspect this was due to increasing adherence to the new antifungal protocol and to improved practices following centralisation: in the 8 months pre-centralisation the antifungal spend across all hospitals was £102K falling by 74% to £26K in the 8 months on the single site.
Conclusion: Since introducing voriconazole as first-line AFT, centralising inpatient services, and adopting common policies for antimicrobial prophylaxis, there has been considerable financial benefit with no increase in morbidity and/or mortality.
Estimating the Total Cost of Infused Iron Chelation Therapy.
Authors: Desrosiers Marie-Pierre , Payne Krista A. , Baladi Jean-Francois 
Published: October 2019

Abstract
Background: Patients suffering from β-thalassemia or sickle cell disease require on-going blood transfusions. Chronic transfusion, however, results in iron overload, which if not removed by iron chelation therapy (ICT), causes organ damage. Deferoxamine (DFO) is currently the standard of care for ICT, but many patients do not adhere to therapy possibly because of the need for almost daily infusions lasting 8 to 10 hours each.
Rationale: While the impact of current care on clinical and patient outcomes is generally understood, less is known about the total cost of DFO therapy.
Objectives: To identify a complete set of cost items to inform the development of an ICT related Resource Use Questionnaire (RUQ) for administration in an international cohort study of the actual cost of ICT in practice; and to obtain a preliminary, literature-based estimate of total annual per patient costs of ICT.
Methods: A search of the literature (EMB Reviews; Scirus and Ovid Medline (1996+); PubMed (1995+) was performed using the following key words: thalassemia, sickle cell disease, myelodysplastic syndrome, cost, iron chelation, Desferal, deferoxamine, resource use, reimbursement and compliance. Cost items were extracted from eligible studies to create an aggregated, composite set of ICT-related variables to which unit costs (2004/2005 USD) were applied.
Results: Of 396 abstracts obtained, all but 96 were excluded because ICT cost data were lacking. Of those retained, only 4 studies (1 Israël;1 US;2 UK) reported ICT-related costs (1 lifetime;3 annual). Cost variables differed markedly among studies each focusing on some specific aspect. The application of unit costs to the composite list of ICT-related variables and associated resource use profiles reveal that total annual per patient ICT costs may be as high as $7,487 to $15,836 (£4,191 to £8,865) depending on age. The cost of DFO accounts for only 16%–31% of these estimated total costs, with the balance accounted for by other annual ancillary expenditures such as equipment and supplies, monitoring, and home health care services. Total costs could well be underestimated given that component lifetime costs such as DFO treatment complications, the clinical sequelae of poor adherence to DFO, and the indirect costs of lost productivity were not included. Cost estimates will be supplemented and validated at the time of abstract presentation by the resource use and unit cost data generated by the RUQ employed in the aforementioned international cohort study.
Conclusions: Estimated total costs of ICT are substantial and well exceed the cost of DFO alone. A paucity of published data related to the total costs of ICT underscores the need for additional ICT cost data from actual practice to better understand the economic impact of novel ICT agents.
SGN-35, an Anti-CD30 Antibody-Drug Conjugate, Exhibits Potent Antitumor Activity for the Treatment of CD30+ Malignancies.
Authors: Hamblett Kevin J. , Barton Jeremy , Cerveny Charles G. , Andreyka Jamie B. , Kissler Kim M. , Okeley Nicole M. , Stone Ivan , Sutherland May K. , Sun Michael M. , Senter Peter D. , Wahl Alan F. , Ihle Nathan C. 
Published: October 2019

Abstract
Hodgkin/Reed-Sternberg (H-RS) and anaplastic large cell lymphoma (ALCL) cells express high levels of the cell surface receptor CD30, a member of the TNF receptor superfamily. To augment the antitumor activity of anti-CD30 based therapies, a novel synthetic anti-mitotic agent, monomethyl auristatin E (MMAE), has been conjugated to the anti-CD30 antibody cAC10. MMAE was synthetically modified to include a maleimide for conjugation to an antibody and a protease cleavable Val-Cit peptide linker to release the drug from the antibody. The in vitro and in vivo activity of SGN-35, the resulting antibody-drug conjugate, is outlined. SGN-35 has an average of four MMAE molecules per antibody. Cell surface binding, internalization and intracellular release of MMAE were monitored by immunofluoresence and isotope labeling methods. The H-RS cell line L540cy translocates SGN-35 to lysosomes within 16 hours. Analysis of the cellular contents demonstrated that MMAE is rapidly and efficiently liberated from the antibody, and MMAE accumulates inside the cells. After treating L540cy cells with 200 ng/mL of SGN-35 (6 nM MMAE), the intracellular concentration of MMAE reaches 800 nM after 24 hours, rising to nearly 1000 nM after 72 hours. From 24 to 72 hours, about 70% of the intracellular drug is liberated MMAE, while 30% is still bound to the antibody. In vitro potency of SGN-35 was measured by incubating various concentrations of SGN-35 with CD30+ tumor cells and measuring cell viability in culture. SGN-35 had potent, selective in vitro activity with IC50s ranging from 4 to 35 ng/mL for CD30+ cell lines, and an IC50 > 1000 ng/mL for the CD30− line WSU-NHL. This demonstrates that the conjugation of the novel cytotoxic agent MMAE to an antibody can be accomplished without compromising the antibody’s specific binding and internalization. SCID mice were implanted with L540cy and treated with intravenous doses of SGN-35. In mice bearing L540cy xenografts, complete tumor regressions were achieved at doses as low as 2 mg/kg q4dx4. SGN-35 is also highly effective in treating mice with disseminated L540cy implants, at well tolerated doses. Based on the potent cytotoxicity, efficacy in xenograft models, and tolerability, SGN-35 is being advanced toward clinical development in CD30-positive hematologic malignancies.
Very Low Prevalence of Hyperhomocysteinemia among US Children with Personal/Family History of Thrombosis. Towards Reconsideration of the Recommendation for Routine Testing.
Authors: Manco-Johnson Marilyn J. , Goldenberg Neil A. , Stabler Sally 
Published: October 2019

Abstract
Background: Comprehensive thrombophilia laboratory testing is recommended for the evaluation of children with thrombosis by the Perinatal and Pediatric Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH). The C677T thermolabile variant of the methylene tetrahydrofolate reductase (MTHFR) gene is highly prevalent in Caucasians, carried in heterozygous form in 45% and homozygously in 10%. The thrombogenicity of the MTHFR C667T mutation is mediated via elevation in plasma homocysteine concentration. However, in the U.S., folate fortification of food products may circumvent the impact of this mutation upon plasma homocysteine.
Objective: To determine the prevalence of hyperhomocysteinemia among U.S. children with a personal history of thrombosis (thrombosis group) or a first-degree family history of thrombosis or thrombophilia (familial risk group).
Methods: All children comprising the two study groups had been referred to the Thrombosis/Thrombophilia Program at The Children’s Hospital, Denver, and were consecutively recruited for participation in collection of laboratory and clinical data for this research. Plasma homocysteine, performed clinically as part of the ISTH recommended thrombophilia laboratory assessment, was determined by gas chromatograph mass spectroscopy.
Results: Homocysteine concentration was normally distributed within the study population, and did not vary with age or differ significantly between the two study groups. Table 1 displays the results relative to age and study group. In 100% of subjects, homocysteine level was either low or normal with respect to the previously-established reference range for healthy individuals.
Conclusions: Despite a high historical prevalence of the MTHFR C677T mutation in Caucasians, the prevalence of hyperhomocysteinemia among U.S. children with thrombosis or a familial risk of thrombosis is extremely low, being absent among nearly 200 children studied. Because other mutations that do result in hyperhomocysteinemia and thrombosis occur rarely, homocysteine testing as part of a comprehensive thrombophilia assessment in U.S. children should be targeted to those patients in whom metabolic disease is suspected clinically.
Plasma Homocysteine Levels (UMl/L) in Children. Category Total < 1 year 1 - < 7 years 7 - < 13 years 13 - < 24 years + Thrombosis − Thrombosis N 193 25 48 44 76 128 65 Mean 5.6 4.4 5.0 5.3 6.6 5.6 5.6 Median 5.6 4.8 5.0 5.3 6.2 5.8 5.4 Std. Dev. 2.4 2.2 2.3 2.6 2.1 2.6 1.9
The Wilms’ Tumor Suppressor Wt1 Activates Transcription of the Erythropoietin-Receptor in Hematopoietic Progenitor Cells.
Authors: Dame Christof , Kirschner Karin M. , Hagen Patricia , Hussels Christiane S. , Scholz Holger 
Published: October 2019

Abstract
The Wilms’ tumor suppressor, Wt1, has been implicated in the stage-specific quiescence and differentiation of hematopoietic progenitor cells. Since Wt1 deficiency compromises the proliferation and differentiation of erythroid blast-forming units (BFU-E) and colony-forming units (CFU-E), we analyzed the potential role of the transcriptionally active Wt1 isoform, Wt1(-KTS), in regulating the expression of the erythropoietin receptor (EpoR). CD117-positive hematopoietic progenitor cells isolated from the liver of Wt1-deficient murine embryos (Wt1−/−) at 11.5 dpc exhibited a 10-fold lower proliferative responsiveness to recombinant erythropoietin than CD117-positive cells from wild-type embryos (Wt1+/+), or embryos with heterozygous Wt1-deletion (Wt1+/−). Benzidine staining revealed a reduced fraction of hemoglobin-containing cells in Wt1-deficient cells in comparison to Wt1+/+ cells after 48 hrs of culture of CD117-positive cells in the presence of 6 U rhEpo/ml medium. Consistently, expression of the EpoR was significantly reduced in hematopoietic progenitor cells that lack Wt1 compared to Wt1+/+ cells. The decrease of EpoR mRNA was not due to a general down-regulation of gene expression in Wt1−/− CD117-positive cells, since levels of c-kit and c-mpl expression were normal. In the heart of wild-type and Wt1−/− embryos, which was analyzed as a non-hematopoietic tissue expressing both EpoR und Wt1, no difference in Epo-R expression was found. Transient transfection of Wt1(-KTS) into human hepatoma-derived HepG2 cells increased EpoR transcripts approximately 2-fold. A luciferase reporter plasmid carrying 309 bp of the proximal human EpoR promoter was stimulated 8-fold by co-transfection with Wt1(-KTS). The responsible cis-element in the EpoR promoter was identified by mutation analysis, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. In summary, we identified the EpoR gene to be the first downstream target of Wt1 within the hematopoietic cytokine receptor superfamily. Our data indicate that activation of the EpoR gene by Wt1 is a critical mechanism in normal murine hematopoiesis. However, our data do not support a role for Wt1 in EpoR expression in non-erythoid tissues, such as the heart.
Influence of Mannose Binding Lectin (MBL) Gene Polymorphisms on Infectious Complications during Treatment for Childhood Malignancy.
Authors: Dommett Rachel M. , Bajaj-Elliott Mona , Chisholm Julia , Klein Nigel 
Published: October 2019

Abstract
Infection remains a major cause of morbidity and hospitalisation in children receiving chemotherapy. At present clinical parameters provide a guide to risk of severe infection but it has become increasingly apparent that, among patients with the same diagnosis and treatment regimen, not all suffer equally from infectious complications. Mannose binding lectin is a pattern recognition molecule of the innate immune system which, upon binding to a wide range of microorganisms, activates the lectin pathway of complement. Polymorphisms in the MBL2 gene result in low levels of MBL protein and are frequently associated with increased susceptibility to infection. Studies investigating the role of MBL in defence against infection following chemotherapy have reported conflicting findings to date. MBL replacement therapy is a potential treatment option in the future and we consider it imperative that we clarify the role of MBL in this clinical setting. Clinical data from episodes of febrile neutropenia (FN) in children aged 0−16 receiving chemotherapy for childhood cancer was recorded prospectively from April 2004−March 2005, including clinical and microbiological evidence of infection, antibiotic days and duration of admission. MBL genotyping was performed using a reverse hybridisation technique and results were analysed against FN outcome. 269 children were recruited into the study. A total of 513 episodes of FN were captured over the study period from 211 patients. 58 patients had no recorded episodes of FN. There was no association between age, sex, ethnicity or diagnosis and MBL genotype. 75% of subjects had a haematological malignancy and of these 84% had acute lymphoblastic leukaemia (ALL). Overall, patients with MBL2 polymorphisms experienced more episodes of FN than wildtype individuals (median 2 and 1, respectively, p=0.074). Analysis of episodes with documented clinical/microbiological infection revealed that the proportion of patients with ≥ 3 episodes was 14.6% in those with polymorphisms and 8% in wildtype, p=0.045. This trend was also true for the supgroup of patients with ALL. The duration of inpatient stay for FN, used as a surrogate measure of severity, was influenced by MBL genotype in some groups of patients. Longer inpatient stays and antibiotic days were most apparent in the MBL deficient patients with high risk diagnoses e.g. AML and B NHL who spent up to 4.5 days longer/per episode in hospital than high risk wildtype patients. These results suggest that MBL deficiency influences both susceptibility to FN and outcome of FN episodes in this study cohort. The effect of MBL deficiency differs between diagnostic groups and may be most important in those patients who are at higher risk of severe FN by virtue of their underlying diagnosis and treatment regime.
The Wilms’ Tumor Gene WT1 Is Over-Expressed in Immature Leukemia Cells but Not Necessary for Leukemia Development in Mouse Leukemia Models.
Authors: Hosen Naoki , Sugiyama Haruo , Weissman Irving L. 
Published: October 2019

Abstract
The Wilms tumor gene WT1, which is over-expressed in almost all leukemia, is one of the most promising targets for immunotherapy. To clarify which cells express WT1, we generated a knock-in reporter GFP mice (WT1GFP/+) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term hematopoietic stem cells (HSCs) and very few (<1%) of multipotent progenitor cells. WT1 was expressed in 17.4% of megakaryocyte-erythrocyte progenitor cells and 4.1% of common myeloid progenitor cells, while the frequencies of WT1 expressing cells in mature granulocyte or lymphocyte were very low (~1%). In contrast, in murine leukemias induced by TEL/PDGFβR + AML1/ETO or BCR/ABL, WT1 was expressed in 40.5% or 38.9% of c-kit+lin-Sca-1+ (KLS) leukemia cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSC). Furthermore, WT1 was not expressed fetal liver HSC population, mobilized HSCs by cyclophosphamide and granulocyte-colony stimulating factor, or HSCs stimulated with SCF, Flt3L, and IL3 in-vitro. These results suggest that WT1 expression in is not a surrogate marker of cell proliferation. To examine the function of WT1 in leukemogenesis, we used recombinant lentivirus to overexpress WT1. HSCs transduced with either empty or WT1-expressing lentivirus were transplanted into lethally irradiated recipients. The FACS analysis of BM cells at 4 months post transplant showed very low chimerism of WT1-expressing cells compared to control GFP-expressing cells. Moreover, differentiation block of WT1-expressing cells was not observed. These results indicate that WT1 does not induce proliferation or block differentiation in-vivo. Next, we tested whether leukemias could be induced from the WT1-deficient fetal liver hematopoietic cells. All of three mice transplanted with E13.5 WT1-defeicient fetal liver cells transduced with TEL/PDGFβR+AML1/ETO developed leukemia. Similarly, 3 out of 4 mice transplanted with p210BCR/ABL-transduced WT1-deficient fetal liver cells developed leukemia. These results indicate that WT1 is not necessary for leukemia development in two leukemia models examined. Collectively, WT1 is expressed on immature leukemic cells but not normal HSCs, highlighting its potential as a specific target for therapy. However, the exact function of WT1 in leukemogenesis remains unclear from these studies.