bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzymatic Replacement Therapy (ERT) with Low Doses in Gaucher Disease in the State of Sao Paulo (Brazil).
Authors: Sobreira Elisa A.P. , Bortolheiro Tereza C. , Martins Ana M. , Porta Gilda 
Published: October 2019

Abstract
INTRODUCTION: The authors, who are members of the Gaucher Disease (GD) Specialists Committee of Sao Paulo State, Brazil, provide demographic data and report the evolution of patients from this Brazilian State, who were treated according to the Clinical Protocol and Therapeutic Instructions for GD treatment created by the Health Department www.saude.gov.br, Notice SAS/MS 449 of 08/07/2002.
METHODS: In May 2004, 130 patients were analysed. One hundred and thirteen of the the130 received Enzymatic Replacement Therapy (ERT) with imiglucerase and 75% of them (85 /113) were > 12 years old. The GD symptoms were investigated in patients above this age who received 15–30 U/kg/2 weeks, according to the Health Department Protocol between August 2002 and November 2003.
OBJECTIVES: Present the evolution of patients > 12 years old having a dose reduction in ERT following said Protocol.
RESULTS: For the 85 patients > 12 years, the mean dose of ERT was 37,6 U/kg/2 weeks (13 to 62 U/kg/2weeks), 4 cases improved without sign of pain and maintained a low dose. Fourteen cases again suffered from bone pain. One of them developed bone infarct and 1 experienced a painless bone lytic lesion. The patients who were in a worse condition received a dose increase (up to 60 U/kg/2 weeks). Of the patients taking doses between 20 and 30 U/kg/2 weeks, 6 had bone pain again and 1 case experienced Parkinsons’ disease. The latter received a dose increase up to 60 U/kg/2 weeks
CONCLUSION: The authors concluded that the dose in ERT must be individualised and that in many times, low doses (15 U/kg/2 weeks) are not enough to avoid GD complications.
Maintenance Treatment with Thalidomide after Autologous Transplantation for Myeloma : First Analysis of a Prospective Randomized Study of the Intergroupe Francophone du Myelome (IFM 99 02).
Authors: Attal Michel , Harousseau Jean-Luc , Leyvraz Serge , Doyen Chantal , Hulin Cyrille , Benboubker Lofti , Facon Thierry , Bourhis Jean-Henri , Garderet Laurent , Sotto Jean-Jacques , Michallet Mauricette , Renaud Marc , Voillat Laurent , Berthou Christian , Marrit Gerald , Monconduit Mathieu , Coiffier Bertrand , Caillot Denis 
Published: October 2019

Abstract
High dose therapy (HDT) supported with autologous stem cell transplantation has been introduced in the management of aggressive myeloma. However, after single or tandem transplantation, almost all patients ultimately relapse. New strategies are required to control any residual disease after HDT. The Intergroupe Francophone du Myelome (IFM) initiated a trial designed to evaluate the impact of maintenance treatment with Thalidomide on the duration of response after HDT.
From April 2000 to October 2003, 1004 myeloma patients at diagnosis under the age of 65 years were enrolled in the IFM 99 protocol. 780 of them, without or with only one adverse prognostic factor (beta-2 microglobuline >3 mg/l or deletion of chromosome 13), were enrolled in the IFM 99 02 protocol. They were to receive the following treatment: 1) 3–4 cycles of the VAD regimen; 2) a first autologous transplant prepared with Melphalan 140 mg/m2; 3) a second autologous transplant prepared with Melphalan 200 mg/m2. Patients without progressive disease 2 months after the second transplant were randomized to receive: no maintenance treatment (arm A), maintenance treatment with Pamidronate (arm B) or maintenance treatment with Thalidomide and Pamidronate (arm C).
As of May 2004, 580 patients (74%) have been randomized: 195 in arm A, 190 in arm B and 195 in arm C. Clinical characteristics of each group were similar. The median follow-up from diagnosis was 26 months (range: 6–50)
Thalidomide was found to improve the Progression-free survival (PFS; p<0.007) and the Event-free-survival (EFS; p<0.01).
Indeed, the 40-months post-diagnosis probability of PFS was 70% (95% CI= 42–80) in the Thalidomide arm versus 53% (95% CI= 37–65) in arm A, and 52% (95% CI= 36–68) in arm B.
Most patients (60%) enrolled in arm A and B received Thalidomide at time of relapse. The overall survival was similar in the 3 treatment groups.
Among the 580 randomized patients, 2 factors were found to be associated with a longer EFS : low beta-2-microglobulin at diagnosis (p<0.01) and treatment arm (p<0.01). Deletion of chromosome 13 (FISH analysis) was not related to EFS.
In conclusion, the first analysis of the IFM9902 trial strongly suggests that Thalidomide is an effective maintenance treatment after high dose therapy for myeloma. The next analysis (November 2004) will be presented during the meeting.
Induction and Patterning of Pre-Hemato-Vascular Mesoderm by the Mouse Mix Homeodomain Protein.
Authors: Baron Margaret H. , Willey Stephen , Sahr Kenneth , Zhang Hailan , Balbi Kevin , Dyer Michael A. , Adlam Matthew 
Published: October 2019

Abstract
Members of the Xenopus and zebrafish Mix/Bix family of paired class homeodomain proteins play determining roles in both mesoderm and endoderm development and are induced by members of the TGFbeta/BMP family of signaling molecules. A single Mix gene has been identified in mouse, humans and chick. Prior to gastrulation, the mouse Mix (mMix) gene is expressed in the visceral endoderm and later in the primitive streak and nascent mesoderm, where it overlaps, in part, with T. Mix expression in ES-derived embryoid bodies is early and transient, overlapping partially with Flk1 activation around the time of formation of hemangioblasts. Both mMix mRNA and protein are found in a FACS-sorted population of T+Flk1+ cells from ES cell-derived embryoid bodies (EBs) which contains hemangioblasts. A complex embryonic lethal phenotype has been reported for Mix deficient embryos, including defects in allantoic (vascular) and cardiogenesis. Mesoderm forms in these embryos but is not patterned properly. Embryonic lethality occurs around E10.5–11, presumably as a result of the cardiovascular defects. We have generated inducible ES cell lines in which expression of Mix protein is responsive to doxycycline. Ectopic expression of Mix in EBs results in premature, enhanced expression of hemangioblast, angioblast and hematopoietic stem cell markers (mRNA and FACS analyses) and increased formation of stem/progenitor cells in clonogenic assays in methylcellulose. Together, the expression analyses, knockout phenotype, and gain-of-function studies in ES cells suggest that mMix functions early in induction and patterning of mesoderm, including formation of hematopoietic and endothelial lineages. Potential mMix target genes are being identified by microarray analyses of the inducible Mix ES lines. To examine mMix activities in vivo, we have generated null and conditional mMix knockout mice from several independently targeted ES cell lines. Analysis of these animals is in progress. Like Xenopus Mix.1, mouse Mix may represent an important connection between the TGFbeta/BMP pathway and hematopoietic/vascular development in the embryo.
New Treatment Options Have Changed the Natural History of Follicular Lymphoma.
Authors: Fisher Richard I. , LeBlanc Michael , Press Oliver W. , Maloney David G. , Miller Thomas P. 
Published: October 2019

Abstract
The natural history of follicular lymphoma has not changed over the last 30 years (Horning, S.J., Seminars in Oncology20: 1993, 75–88). Median survivals have ranged from 7 – 10 years and the disease is generally considered incurable as there has been no plateau in the survival curve. However, multiple new treatment options, including biologic agents, have been developed in the last decade and their impact on the natural history of follicular lymphoma remains unknown. In order to determine the cumulative effects of all these new treatment options, we identified all previously untreated, advanced stage, follicular lymphoma patients treated with three sequential treatment approaches: CHOP chemotherapy +/− nonspecific immunostimulants (SWOG 7426 and 7713: 1974 – 1978), ProMACE-MOPP +/− interferon (SWOG 8809: 1988 – 1994), and CHOP followed by monoclonal antibody therapy (SWOG 9800 and 9911: 1998 – 2000) and determined their Progression-Free Survival (PFS) and Overall Survival (OS). More specificially, the monoclonal antibody trials included CHOP followed by rituximab (SWOG 9800) and CHOP followed by 131I-Tositumomab (SWOG 9911). The PFS are shown below:
Progression-Free Survival by Treatment Strategy
TREATMENT N DEATH/PROGRESSION 4-YR PFS CHOP + MoAb 179 75 61% ProMACE 425 290 48% CHOP 356 257 46%
The results demonstrate that the PFS remained unchanged until the recent studies that utilized CHOP followed by a monoclonal antibody for initial treatment. The results of OS from these three groups are shown below.
Overall Survival by Treatment Strategy
TREATMENT N DEATH 4-YR OS CHOP + MoAb 179 18 91% ProMACE 425 189 79% CHOP 356 226 69%
In contrast to the PFS, OS has increased with each subsequent study.
These data are consistent with the hypotheses that initial therapy with chemotherapy followed by a monoclonal antibody has a significant impact on PFS (p= .005) and OS (p < .0001) and that, even in earlier studies where we could not demonstrate improved initial treatment, sequential new treatment options have also changed the OS (p < .0001) and thus the natural history of follicular lymphoma.
Evidence for Fcγ Receptor IIIA-Independent Rituximab Effector Mechanisms in Patients with Follicular Lymphoma Treated with Combined Immuno-Chemotherapy.
Authors: Boettcher Sebastian , Pott Christiane , Ritgen Matthias , Hiddemann Wolfgang , Unterhalt Michael , Kneba Michael 
Published: October 2019

Abstract
The response to the anti-CD20 antibody Rituximab used as a single agent in follicular lymphoma (FL) patients can be predicted by the valine/phenylalanine (V/F) dimorphism of amino acid 158 of Fcγ Receptor IIIA (Fcγ RIIIA) (Cartron et al., Blood99: 754, 2002; Weng and Levy, JCO21: 3940, 2003). This suggested important contributions for Fcγ RIIIA mediated mechanisms like antibody dependent cellular cytotoxicity to the efficacy of the antibody. Recently, the German Low Grade Lymphoma Study Group (GLSG) demonstrated a significant shorter time to treatment failure (TTF) in patients who received standard CHOP (cyclophosphamide d1, doxorubicin d1, vincristin d1, prednisone d1-5) chemotherapy only compared to patients who received Rituximab (d1) plus CHOP (R-CHOP). Estimated median TTF was 2.6 years in FL patients treated with CHOP and was not reached after 3 years observation time in R-CHOP treated FL patients (p<0.0007) (Blood 102, Abstract # 352, 2003). We examined the Fcγ RIIIA dimorphism in 75 FL patients from this GLSG trial who were treated with 6 to 8 cycles R-CHOP followed by interferon maintenance or high dose chemo-radiotherapy and autologous stem cell transplantation. Using a TaqMan assay with allele specific fluorochrome labelled probes we detected a V/V genotype in 8 patients (10.7%), a V/F genotype in 38 patients (50.6%), and an F/F genotype in 29 patients (38.7%). Patients with different Fcγ RIIIA status responded similarly to R-CHOP (CR rate: V/V 37.5%, V/F 36.8%, F/F 24.1%; overall response rate: V/V 100.0 %, V/F 97.4%, F/F 96.6%; ns). Moreover, TTF was not significantly different between the groups with V/V, V/F, and F/F Fcγ RIIIA(log rank p = 0.48) after a median observation time of 24 months. A correlation between the Fcγ RIIIA status and the efficacy of R-CHOP could not be demonstrated in this large patient cohort. On the other hand it is evident that R-CHOP treated patients significantly benefited from the addition of Rituximab to CHOP chemotherapy in comparison to the standard arm of this randomized trial. This observation supports the hypothesis that the anti-lymphoma effects of Rituximab when used in combination with chemotherapy might be mediated by Fcγ RIIIA-independent mechanisms such as complement dependent cytotoxicity or direct apoptosis induction.
Absence of Inducible Costimulator (ICOS) on Alloreactive T Cells Reduces Graft-versus-Host-Disease While Leaving Graft-Versus-Tumor Activity Intact.
Authors: Hubbard Vanessa M. , Eng Jeffrey M. , Tjoe Kartono H. , Ramirez-Montagut Teresa , Muriglan Stephanie J. , Kochman Adam A. , Terwey Theis H. , Schiro Raffaella , Alpdogan Onder , van den Brink Marcel R.M. 
Published: October 2019

Abstract
Inducible costimulator (ICOS) is a member of the B7 family that is expressed on activated and memory T cells and is involved in the regulation of TH1 and TH2 effector cytokine production after CD3/TCR stimulation. Studies with ICOS inhibition or ICOS−/− recipients have demonstrated prolonged allograft survival after heart or liver transplantation in animal models. To study the role of ICOS expression on alloreactive T cells in graft-versus-host disease (GVHD), we used allogeneic MHC class I and II disparate hematopoietic stem cell transplantation (allo-HSCT) models. We first analyzed the expression of ICOS by transferring CFSE-labeled donor T cells into irradiated allogeneic recipients and observed an increased expression of ICOS on alloreactive T cells compared to non-alloreactive T cells. We then studied B6-ICOS−/− alloreactive T cells and found intact proliferation in vivo (as determined by adoptive transfer of CFSE labeled T cells and donor T cell numbers in the spleen of allo-HSCT recipients), intact cytotoxicity, intact up regulation of activation markers, but decreased IFN-γ production in vitro. We then performed GVHD experiments in two models with full MHC class I and II disparity and observed significantly less GVHD morbidity and mortality in recipients of ICOS−/− donor T cells. Furthermore, histopathological analysis demonstrated less GVHD in all target organs (skin, liver, small bowel and large bowel) of recipients of ICOS−/− splenic T cells compared to recipients of wild type T cells. We harvested target organs (spleen, thymus, liver and gut) on days 7, 14, and 21 to examine donor T cell content (naïve and activated T cells) and found no significant difference in the total T cell numbers and subpopulations. Interestingly, in GVHD/graft-versus-tumor (GVT) experiments, ICOS−/− donor T cells displayed intact GVT activity, while their GVH activity was diminished. We then tested the levels of IFN-γ in the sera of mice undergoing GVHD and observed decreased serum levels in recipients of B6-ICOS−/− T cells. In conclusion, alloreactive ICOS−/− donor T cells display less GVHD morbidity and mortality due to decreased IFN-γ production, while proliferation, infiltration and GVT activity remain intact. These data suggests that strategies to inhibit ICOS could be useful for the prevention and/or treatment of GVHD in recipients of an allo-HSCT.
Molecular Mechanism of Nef-Mediated Inhibition of T Cell Migration in Response to SDF-1α.
Authors: Park In-Woo , Mitsuya Yumi , Groopman Jerome E. 
Published: October 2019

Abstract
Lymphocyte trafficking comprises an intricate multistep process, in which lymphocyte surface integrins, endothelial adhesion molecules, and chemokines produced in the local microenvironment play key roles. We previously reported that HIV-1 nef inhibits T cell chemotaxis in response to the physiological ligand SDF-1αwithout altering CXCR4 expression. Here, we explore the mechanism of this effect. HIV-1 nef significantly reduced the expression of LFA-1, inhibited the adhesion of nef-expressing Jurkat T cells to the HUVEC endothelium, and reduced their transendothelial migration. To gain further insight into how nef mediated these effects, substitution or deletion mutations were introduced into the nef gene, and transwell and transendothelial migration assays were performed. Deletion of the N-terminus proximal basic-rich domain did not change the nef-mediated inhibitory effects on T cell migration, whereas removal of the myristoylation site or the proline-rich amino acid sequence motif of Nef abolished these effects. Similarly, HIV-1 nef blocked the transendothelial migration of Jurkat T cells across the HUVEC monolayer. However, the observed inhibition of transendothelial migration conferred by the wild type nef expression was significantly but not completely reduced by introduction of mutations in the myristoylation site and proline-rich motif, indicating the involvement of other regions in the nef gene. Taken together, these results demonstrate that HIV-1 nef can impair the transendothelial migration of T cells in response to SDF-1αby disturbing different steps in the process, and that the myristoylation site and/or proline-rich motif are key to this effect. These data help to establish the molecular mechanisms of nef-mediated impairment of the T cell migratory response, an essential component of host defense, and provide the basis for targeted therapeutic interventions in patients with AIDS.
Treatment of Adult Patients with High Risk Acute Myeloblastic Leukemia up to 60 Years: Role of Consolidation Therapy within a Prospective Multicenter Trial.
Authors: Krauter Jürgen , Heil Gerhard , Hoelzer Dieter , Ottmann Oliver , Martin Hans , Lübbert Michael , Finke Jürgen , Heit Wolf , Fiedler Walter , Hossfeld Dieter , Kanz Lothar , Schlimok Günter , Kirchner Hartmut , Raghavachar Aruna , Brugger Wolfram , Ganser Arnold 
Published: October 2019

Abstract
In our prospective multicenter AML 01/99 trial for risk-adapted therapy of patients aged up to 60 years with acute myeloblastic leukemia, patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (up to 5% blasts in day 15 BM) were considered standard risk (SR), all other patients as high risk (HR). Patients with acute promyelocytic leukemia were excluded. Between January 1999 and May 2004, 421 patients (328 with with de novo and 93 with secondary AML) were treated. Induction course I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21 as double induction. In patients with bad response (>5% bone marrow blasts on day 15), the second cycle consisted of either IVA-II or FlAG/Ida. Double induction was followed by an early consolidation with intermediate dose araC. As late consolidation, HR patients were allo- [HLA-matched sibling or matched unrelated donor (MUD)] or autotransplanted. Matched sibling allotransplantation was done in all participating centers whereas MUD transplantation was favoured by only two centers. The remaining centers performed autologous PBSCT if there was no sibling donor available. 199 patients were classified as HR, of whom 118 (59%) achieved CR, and 25 (13%) of the HR patients died during induction. After 55 months, overall survival was significantly worse for HR patients (25%) than for SR patients (49%). This was also true for the relapse-free survival (32% vs. 42%; p = 0.049). In the HR group, there was no difference in overall and relapse-free survival between those patients classified as HR because of bad response to IVA-1 (n = 65), unfavourable karyotype (n = 71) or both characteristics (n = 63). Regarding the different regimens for late consolidation, the “as treated” analysis of the HR patients revealed that overall (59% vs. 20%) and relapse-free survival (59% vs. 20%) was significantly better after an allogeneic HLA-matched sibling transplantation (n = 26) than after autoPBSCT (n=24). Overall and relapse-free survival for the 23 patients who underwent MUD transplantation were 59% and 45% respectively.
In conclusion, in HR patients with an HLA-identical sibling donor an allotransplantation should be performed. The results obtained with MUD transplantation in this particular patient group are encouraging. Therefore, in HR patients without an HLA-identical sibling allografting from unrelated donors should be considered in first CR. On the other hand, HR patients as defined by our risk stratification do not seem to benefit from autografting even after intensive induction and consolidation therapy.
Survival Difference of AML Patients Receiving HLA Matched Sibling Allogeneic Bone Marrow Transplants (ABMT) Correlates with HLA-Cw Ligand Groups for Killer Immunoglobulin-Like Receptors (KIRs).
Authors: Sobecks Ronald , Ball Edward , Rybicki Lisa , Brown Stacey , Kalaycio Matt , Pohlman Brad , Maciejewski Jaroslaw , Bolwell Brian 
Published: October 2019

Abstract
The reactivity of NK cells and some T cell populations is regulated by the interaction of KIRs with target cell HLA class I molecules. KIR interactions have been suggested to influence outcomes of haploidentical and HLA-identical allogeneic hematopoietic stem cell transplants, particularly for AML patients. We analyzed the KIR ligand phenotypes of 60 AML patients who received HLA-identical sibling myeloablative ABMT from 4/9/97-11/5/03. The median age was 45 yrs (range 8–62). At the time of transplant 24 patients (40%) were in CR. All patients received a busulfan/cyclophosphamide-based preparative regimen and all received bone marrow (T-cell replete) as their stem cell source. Patient HLA KIR ligands were categorized as: 1) HLA-Cw groups C1/C1, C2/C2, C1/C2; 2) HLA-Bw4 (+ or −); 3) HLA-A3 or A11 (+ or −) (as reviewed in Farag et al Blood100:1935,2002). Recursive partitioning analysis for post-transplant time-related outcomes (acute GVHD, grade 3/4 acute GVHD, chronic GVHD, extensive chronic GVHD, freedom from relapse and survival) was performed for each KIR ligand group. Patients with C1/C1 or C2/C2 (n=26) had improved survival compared to the C1/C2 group (n=34) (median survival 43.5 months vs. 5.8 months, respectively, p=0.018), as shown below:
Figure Figure
This survival difference was associated with more relapse in the C1/C2 group (p=0.048), but not with incidence or severity of acute or chronic GVHD, age, infection or pretransplant disease status. There were 26/34 (76%) deaths in the C1/C2 group with 15 (58%) due to relapse as compared to 13/26 (50%) deaths in the C1/C1 + C2/C2 group where 4/13 (31%) were due to relapse. The median follow up of survivors was 36.3 mos (range 7.8–72.4 mos). No significant differences in outcomes were observed when patients were analyzed for the presence or absence of HLA-Bw4 or A3/11. The majority of patients had KIR genotyping performed for those KIRs with established HLA ligands. Among those tested there were no cases in which the donor did not have at least one inhibitory KIR gene specific for a Cw ligand present in the patient or donor. This may suggest that KIR expression at the cellular level rather than KIR genotype alone should be investigated. In conclusion, AML patients undergoing matched sibling donor ABMT who were heterozygous for HLA-Cw KIR ligand groups (C1/C2) had reduced survival compared to patients homozygous for these groups. The higher relapse rate observed in the heterozygous ligand group may suggest a less effective graft-versus-leukemia (GVL) response. Since C1/C2 heterozygotes have a greater opportunity to engage inhibitory KIRs than do C1 or C2 homozygotes, they may more effectively inhibit KIR-positive NK and T cell populations involved in GVL responses.