bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy Comparison of Oral Versus Intravenous Busulfan in a BuCy Conditioning Regimen for Allogeneic BMT.
Authors: Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Seol Miee , Lee Young-Shin , Ryu Seong-Gil , Kang Young-Ah , Lee Kyoo-Hyung 
Published: October 2019

Abstract
Intravenous administration of busulfan (I-Bu) or targeted busulfan dosing has replaced oral administration of busulfan (O-Bu) in a conditioning therapy for BMT mainly due to erratic gastrointestinal absorption of oral busulfan. Several retrospective study results have demonstrated that use of I-Bu resulted in lower transplant-related morbidity and mortality compared to O-Bu, but the efficacy of I-Bu and O-Bu has not been compared. In this retrospective study, we compared the efficacy of I-Bu vs. O-Bu in a BuCy conditioning regimen for allogeneic BMT in a single institute. To avoid the bias of retrospective comparison, we restricted the patient eligibility to the followings:
patients with AML having intermediate or poor cytogenetic risk groups at the time of diagnosis, those in the first complete remission at the time of BMT, those who were treated with BuCy conditioning regimen, and those who received bone marrow as a stem cell source.
A total of 80 patients were eligible in this study among the patients who were transplanted at the Asan Medical Center between December 1993 and July 2007: 42 patients received O-Bu (4 mg/kg/d x 4d) and 38 patients received I-Bu (Busulfex, 3.2 mg/kg/d x 4d). The same dose of cyclophosphamide (60 mg/kg/d x 2d) was given to all the patients. We collected clinical and laboratory data from the BMT database of the Asan Medical Center. The efficacy was compared in terms of cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS). Propensity score analysis was used to adjust the confounding factors between O-Bu and I-Bu groups. Several baseline clinico-laboratory factors at the time of BMT such as age, number of consolidation therapy prior to BMT, time from diagnosis to BMT, use of methotrexate for GVHD prophylaxis, and transfusion requirement before BMT were significantly different between 2 groups. Times to engraftment, transfusion requirements, infectious complications, hepatic VOD, and acute and chronic GVHD were similar between 2 groups. The cumulative incidence of non-relapse mortality was 14.3% in O-Bu group and 10.3% in I-Bu group (adjusted P-value, 0.990). The CIR at 4-year was 28.6% in O-Bu group and 16.9% in I-Bu group (adjusted P-value, 0.430). The 4-year probabilities of EFS and OS were 57.1% and 64.3% in O-Bu group and 72.6% and 69.3% in I-Bu group (adjusted P-values, 0.496 and 0.634, respectively). In summary, EFS and CIR were superior in I-Bu group compared to O-Bu group without statistical significance. Our results suggest that intravenous busulfan is as effective as oral busulfan in a conditioning therapy for BMT.
Outcome of Sibling Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantations in Low-Grade B Cell Lymphoproliferative Disorders. A Single Centre Experience.
Authors: Desmond Ronan , David Marianna , Conneally Eibhlin , Browne Paul , Conghaile Mairead Ni , McCann Shaun , Vandenberghe Elizabeth 
Published: October 2019

Abstract
Reduced intensity conditioning allogeneic stem cell transplantations (allo-SCT) have been developed to exploit graft-versus-malignancy effect while reducing the toxicity of allo-SCT. We report the outcome of 21 patients with low-grade B cell lymphoproliferative disorders transplanted in a single center. The mean age of the patients was 54 years (range 32–66) with 11 males, 10 females. Follicular lymphoma was the diagnosis in 10 patients, CLL in 5, mantle cell lymphoma in 4, MALT lymphoma in 1 and lymphoplasmocytoid lymphoma in 1 patient. The median number of prior treatment lines was 2. All patients received peripheral blood stem cell transplants from sibling donors and no patients had undergone a prior autologous SCT. 12/21 patients (57%) received a ATG based conditioning regimen while the remainder, 9/21 (42%) received a Campath containing conditioning regimen. Full donor chimerism was confirmed in 17/19 (89%) patients. Acute graft versus host disease (GVHD) developed in 5/21 (23%) of the patients. Chronic GVHD occurred in 7/21 (33%) with 5/21 occuring post donor lymphocyte infusion (DLI). DLI has been administered in 11/21 patients (52%), 2 for progressive disease and 9 for re-emerging mixed chimerism. Non-relapse mortality (NRM) at 100 days and 1 year were 5% and 12.5% respectively. With a median follow up of 21 months (range 3–54) the overall survival rates (OS) at 1 year and 2 years were 72% and 58% respectively. Progression free survival (PFS) at 1 year and 2 years were 66% and 50%. We have shown that reduced intensity conditioning allogeneic stem cell transplantation is associated with a low TRM comparible to that of autologous transplantation and allows long term control of low grade B-cell lymphoproliferative disorders.
Nonsense-Mediated mRNA Decay Is Essential for the Hematopietic Compartement.
Authors: Weischenfeldt Joachim , Damgaard Inge , Bryder David , Nerlov Claus , Porse Bo 
Published: October 2019

Abstract
Nonsense-mediated mRNA decay (NMD) is a conserved cellular surveillance system that degrades mRNAs with premature termination codons (PTCs). PTC-containing transcripts can arise from faulty events such as erroneous mRNA processing events as well as mutations, and their translation may lead to the synthesis of deleterious proteins. In addition to serving as a genomic protection system, experiments in tissue culture cells have demonstrated that NMD regulates 5% of the normal mRNA pool suggesting that the NMD pathway may have a broader role in gene regulation. Finally, NMD has also been proposed to be important during lymphocyte development as a tool of riding the cells of transcripts resulting from unproductive re-arrangements events of T cell receptor and immunoglobulin genes. Although NMD has been studied extensively at the biochemical level, the actual role and importance of NMD in the mammalian organism has not been investigated. We therefore generated a conditional Upf2 knock-out mouse line (UPF2 being an essential NMD factor) which we crossed to different hematopoietic relevant Cre expressing lines. Full ablation of UPF2 (using the inducible Mx1-Cre deleter) led to complete loss of all nucleated cells in the bone marrow and death of the animals within 10 days. A similar phenotype was observed when Upf2fl/fl; Mx1Cre BM cells were transplanted into lethally irradiated WT recipients and induced with poly-IC, demonstrating the cell autonomous nature of the phenotype. Deletion of UPF2 in the myeloid lineage using the LysM-Cre deleter resulted in efficient ablation of UPF2 and the absence of NMD in reporter transfected bone marrow derived macrophages (BMDMs). However, the steady state levels of myeloid cells appeared unaltered. Finally, deletion of UPF2 in T cells using a Lck-Cre deleter led to a marked reduction of both CD4/CD8 double-positive and single-positive T cells and accumulation of PTC containing transcripts. Gene expression profiling experiments of BMDM and thymocytes from WT and UPF2-ablated animals identified a common core set of 27 up-regulated genes consistent with the role of NMD as a mRNA degrading system. The gene expression profiling data suggest that ablation of NMD leads to accumulation of unfolded proteins. In summary, these studies demonstrate the vital and cell-autonomous role of NMD in the hematopoietic system.
Cotransplantation of HLA-Identical Mesenchymal Stem Cells and Hematopoietic Stem Cells in Chinese Patients with Hematologic Diseases.
Authors: Zhang Xiaoyan , Li Jianyong , Cao Kejiang , Wu Hanxin , Lu Hua , Liu Peng , Qian Sixuan , Xu Wei , Shen Wenyi , Zhu Yu 
Published: October 2019

Abstract
Background: Mesenchymal stem cells(MSCs) can be isolated from bone-marrow and expanded ex-vivo, may support hematopoietic reconstruction and mitigate graft-versus-host disease (GVHD) in hematopoietic stem cells transplantation (HSCT). We hope to explore the feasibility and safety of cotransplantation culture-expanded MSCs and hematopoietic stem cells (HSCs) from the same human leucocyte antigen (HLA)-identical sibling donor in patients with hematologic diseases.
Methods: Bone marrow mononuclear cells from healthy donors were cultured and expanded ex-vivo. Immunophenotype, karyotye, immunosuppressive property of the harvested MSCs were characterized. Patients were cotransplanted with HSCs and MSCs from the same donor. Hematopoietic reconstruction, complications and clinical outcomes after transplantation in these patients were observed.
Results: (1.77±0.40)×106/kg (donor’s weight) MSCs were successfully expanded from 23.6±5.96ml bone marrow samples. They had normal karyotype and were CD73, CD90, CD105 positive and CD34, CD45, HLA-DR negative. They can inhibit mixed lymphocyte reactions (MLRs). Twelve patients were undergoing cotransplantation. No adverse response was observed during and after the infusion of allogenic MSCs. Hematopoietic reconstruction were rapid. Two patients developed grade II∼IV acute GVHD. Two patients developed systermatic chronic GVHD. Four patients suffered from cytomegalovirus (CMV) infection but were cured at last. Till now, seven patients have been alive for 29∼57 months and five patients died.
Conclusion: MSCs identified by immunophenotype analysis can be isolated from human bone marrow, expanded effectively by culture. Their quality and quantity are suitable for clinical use. It is safe and feasible to cotransplant patients with allogenic culture-expanded MSCs and HSCs.
Successful Engraftment of Cord Blood Transplantation Following Reduced-Intensity Conditioning Regimen Using Fludarabine and Busulfan for Advanced Hematologic Malignancies.
Authors: Satou Yuji , Nagasawa Toshiro , Azuma Takayuki , Miura Yuji , Komatsu Tsunehiko 
Published: October 2019

Abstract
Background: The potential role of reduced-intensity cord blood transplantation (RI-CBT) without total body irradiation (TBI) in adults remains unclear. We investigated the feasibility of RI-CBT using non- TBI regimen for the treatment of patients with advanced hematologic malignancies.
Methods: Twenty-three patients (median age, 61, range, 38–74) with advanced hematologic malignancies were enrolled in this study (18 patients in refractory or relapsed phase,5 patients in remission or chronic phase). Conditioning regimen comprised of fludarabine 30 mg/m2 on days −8 to −3, busulfan 4 mg/kg p.o. or 3.2 mg/kg i.v. on days −6 to −5. In one cases. we administered busulfan 3.2mg/kg i.v. on days −6 to −3, because of blastic crisis. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus alone. Engraftment was defined as an absolute neutrophil count > 0.5 x 10E9/l. Primary graft failure was defined as the complete loss of donor-type hematopoiesis without engraftment. Secondary graft failure was defined as the loss of donor-type hematopoiesis after primary engraftment. Median follow-up of surviving patients was 1096 days (range, 53–1207). Primary endpoint was engraftment. All patients provided informed consent in accordance with the requirements of Institutional Review Board.
Results: All the patients tolerated the conditioning regimen. Median dose of infused nuclear cells was 2.7x10E7 /kg (range, 1.9–4.6). Twelve patients achieved engraftment at a median of day 20.5 (range, 10–36), but two of them developed secondary graft failure. Complete donor-type chimerism was documented within 30 days of transplant in six patients. Primary graft failure was diagnosed in remaining eleven patients. Six of them, underlying disease progressed despite conditioning regimens. As of August 2007, five patients survived (3 patients in complete remission, one patients relapsed after transplantation, the other one not reached remission). Estimated 1-year overall survival rate was 20.7% (95% confidence interval, 3.0–38.4%).
Conclusions: Though the pre-transplant condition of patients were not good, engraftment was obtained with approximately the half patients. This study demonstrated the feasibility of RI-CBT using non-TBI regimen for adult patients with advanced hematological diseases; however, high incidences of disease progression before engraftment was significant problem. RI-CBT may become the choice of treatment for patients with advanced hematologic malignancies that are incurable with conventional treatments.
Long-Term Survival after HLA-Haploidentical Stem Cell Transplantation from Non-Inherited Maternal Antigen-Mismatched Family Donors: Impact of Chronic Graft-Versus-Host Disease.
Authors: Ichinohe Tatsuo , Shimazaki Chihiro , Hamaguchi Motohiro , Watanabe Arata , Ishida Hiroyuki , Yoshihara Takao , Morimoto Akira , Uoshima Nobuhiko , Adachi Souichi , Inukai Takeshi , Sawada Akihisa , Oka Koji , Itoh Mitsuru , Hino Masayuki , Kanda Junya , Uchiyama Takashi , Kodera Yoshihisa 
Published: October 2019

Abstract
Background: We previously reported that T-cell-replete HLA-haploidentical hematopoietic stem cell transplantation (SCT) from a microchimeric noninherited maternal HLA antigen (NIMA)-mismatched related donor offers a feasible treatment option in patients with poor-risk hematologic malignancies who lack an immediately available stem cell source (Ichinohe T, et al. Blood2004;104:3821). However, long-term outcomes and late effects among patients undergoing such transplantation are largely unknown.
Methods: We studied 16 patients who had survived more than 3 years after T-cell-replete HLA-haploidentical NIMA-mismatched SCT to evaluate the impact of late complications on morbidity and mortality. The patients received bone marrow (n=5) or peripheral blood stem cell (n=11) between 01/2001 and 07/2004 at 11 centers with a median age of 19 years (range, 2 to 56) as treatment for acute myeloid leukemia (n=6), acute lymphoblastic leukemia (n=3), chronic myeloid leukemia (n=4), and other B-cell neoplasms (n=3). At the time of SCT, 6 patients had a chemosensitive disease and 10 had a chemorefractory disease. Type of donor was NIMA-mismatched sibling in 9, mother in 6, and daughter in 1; all patient-donor pairs had two or three serologic mismatches at HLA-A, −B, and −DR in the graft-versus-host direction. Organ-specific symptoms related to chronic graft-versus-host disease (cGVHD) and their severity were evaluated by clinical scoring system proposed by the National Institutes of Health consensus development project.
Results: At a median follow-up of 56 months (range, 38 to 74), 13 (81%) of 16 patients were alive and free of their primary disease. One patient was alive with relapsed disease; 2 died from bronchiolitis obliterans at 51 and 52 months in continuous remission. Karnofsky or Lansky performance score among 14 survivors was 100% in 6 (43%), 80–90% in 5 (36%), 70% in 2 (14%), and less than 70% in 1 (7%). Thirteen (81%) patients developed extensive cGVHD and eleven of them experienced organ symptoms corresponding to the consensus score greater than 1. The commonly involved organs (score>1) were lungs (n=5), skin (n=4), eyes (n=3), and liver (n=3). Seven patients were successfully withdrawn from immunosuppressive agents between 3 and 46 months (median, 19) after transplantation.
Conclusions: T-cell-replete HLA-haploidentical SCT from a microchimeric NIMA-mismatched donor confers long-term survival in selected patients without compromising their performance status, although a high incidence of moderate to severe cGVHD may limit its usefulness as compared with conventional SCT.
Inclusion of High-Dose Treosulfan Followed by Autologous Transplantation in the Tandem Transplantation for Patients with Multiple Myeloma <60 Years.
Authors: Reichle Albrecht , Burgmayer Nina , Holler Ernst , Berand Anna , Andreesen Reinhard 
Published: October 2019

Abstract
High-dose treosulfan followed by autologous transplantation is a tolerable and efficacious regimen in quite different tumor types. Aim of the present study was to proof safety and efficacy of high-dose treosulfan in an intraindividual comparison with melphalan. Between August 2003 and July 2006, 20 patients with multiple myeloma, age< 60 years were enrolled onto an unicentric phase II trial. The median age was 55 years. All patients received pretreatment with 3 to 4 cycles idarubicin and dexamethasone (90%) or CAD (10%). After induction the peripheral blood stem cells were mobilized with a combination of ifosfamide, epirubicin, etoposide (IEV) followed by G-CSF. Stem cell harvest was successful in all patients. Thereafter, the patients received tandem transplantation in an interval of 2 months, first after conditioning with high-dose treosulfan on day −4 to −2, 14g/m2 daily, then after high-dose melphalan 140 mg/m2. Maintenance therapy with interferon-alpha was administered in 30% of the cases. For all patients the completion rate of the first transplantation was 100%, for the second 85%. Three patients did not proceed to the second autologous transplantation due to a severe ischemic colitis (n= 1) or a high-risk profile (allogeneic transplantation in 2 cases). Two patients received an allogeneic transplantation during the further course of the disease. Overall the conditioning regimens were well tolerable. Hematotoxicity grade 4 was observed after each high-dose cycle. Grade 3/4 infections and stomatitis were present in 5%/5% after treosulfan and in 18%/6% after melphalan. An acute coronary heart syndrome occurred after Mel140. The duration of severe leukopenia (< 1.0 leukocytes) was significantly shorter after treosulfan (6.4 days vs. 7.9 days, p= 0.009), whereas time to leukocyte recovery did not significantly differ between the regimens. No treatment related deaths occurred. Best response after transplantation was CR 30%, PR 60%, NC 5%, and PD 5%. In comparison to the preceding chemotherapy a further >50% decline of the paraprotein was achieved by treosulfan in 3 cases, by melphalan in 2 cases. In the intraindividual comparison treosulfan and melphalan, respectively, have shown two times superior response. The median event-free survival was 28 months, and the overall survival at 4 years was 81%. In conclusion, high-dose treosulfan may be more favorable for patients at risk for infections than melphalan, and seems to be as efficacious as melphalan for the treatment of multiple myeloma. Treosulfan should be further investigated in multiple myeloma patients.
Darbepoietin in Autologous Peripheral Blood Stem Cell Transplantation (ASCT): A Pilot Study.
Authors: Chierichini Anna , Anaclerico Barbara , Borza Paola Anticoli , Fenu Susanna , Nobile Carolina , Cedrone Michele , Bongarzoni Velia , Bartolini Maurizio , Ronci Benedetto , Annino Luciana 
Published: October 2019

Abstract
In patients undergoing ASCT, RBC transfusions are depending on donor availability and correlated with early and late side effects such as immune reactions and infections. Three weeks long acting Darbepoietin is currently available, but its role in ASCT in terms of efficacy, safety and cost has not yet been established.
Aim: This pilot study was activated in ASCT patients to test
the impact of Darbepoietin on the haemoglobin level; RBC transfusion requirement; the total cost of Darbepoietin therapy during the first 30 days after ASCT.
Material and methods. From September 2006 to June 2007, 10 patients - 5 males, median age 57 years (range 20–71) - with Multiple Myeloma (MM n=7) in 1st response, Non-Hodgkin (NHL n=2) and Hodgkin (HL n=1) Lymphoma in 2nd complete remission entered the study. As conditioning regimens, the patients received Mel 200 (n=8) or BEAM (n=2). Baseline Hb and Epo median values were: 12,1g/L (range 10.3 – 16.2 g/L), and 28.7mU/mL (range, 4.1–220 mU/L), respectively. The median value of CD34+ cells infused was 4.99 x109/L (range 3.04 – 5.07) and the median time to engraftment was 10 days (range 8–11). To prevent anaemia, patients were given i.c. single dose 500 U Darbepoietin on day +1, associated with iron therapy and B12 vitamin /weekly, plus folinic acid and B6 vitamin/daily. RBC transfusion was mandatory for Hb level ≤ 8g/L.
Results: At day +30, in 9/10 patients (7 MM, 1 NHL and 1HL) the median Hb value was 13.2 g/L (range 10.2 – 15.1g/L), and none of them were transfused. Only 1 NHL received 1 RBC unit on day +7 because of Hb was 8g/L; in this case, the baseline dosage of Epo was high (220 mU/L). On the follow-up (median time 4 months, range 1–11), no thromboembolic events or other side effects occurred. Finally, in our Country the price of 1 vial Darbepoietin and 1 RBC transfusion (packed, filtered and irradiated) is 744.60 and 340 euro, respectively. Therefore,, the cost of the entire supportive therapy in our 10 patients has been 7.786 euro. Comments Despite the small number of patients, from this pilot study we can drawn the conclusion that Darbepoietin seems an effective and safe therapy and could represent an appropriate support in ASCT patients with baseline low/normal Epo level. Only a prospective, randomized study on a large number of patients will be able to answer the question on the Darbepoietin cost-efficacy in ASCT.
Human Herpesvirus 8 K1 Derived Peptides Reduced the Levels of Apoptosis Inhibitory Fas-K1 Complex: A Strategy for Stimulating Death Receptor Mediated Apoptosis.
Authors: Wang Shu , Berkova Zuzana , Wang Suizhao , Pharm Jaehoon Jung D. , Maeng Hoyoung , Samaniego Felipe 
Published: October 2019

Abstract
Background: Human herpesvirus 8 (HHV-8) infection is associated with the development of primary effusion lymphoma, Kaposi’s sarcoma and multicentric Castleman’s disease. The K1 gene of HHV-8 is expressed in some of these tumor cells as a transmembrane protein with an immunoglobulin like domain in its ectodomain and an immunoreceptor tyrosine-based activation motif (ITAM). We demonstrated that K1 protein activates nuclear factor of kappa B (NF-κB), and K1 expression in transgenic mice stimulated accumulation of lymphatic cells and development of lymphoma. How K1 blocks apoptosis, induces hyperplasia and lymphomas is not known. We hypothesized that K1 contributes to lymphoma development partly by suppressing apoptosis and this suppression combined with its NF-κB activation produces lymphoma.
Results: We mapped the region K1 uses to bind to Fas as an immunoglobulin (Ig) chain-like domain by expressing deletion mutants of K1. Overexpression of an Ig domain-contain protein CD79b competed with K1-Fas binding that was dose-dependent. Two 20 amino acid peptides (N251, N253) representing the Ig domain of K1 competed with K1-Fas binding in immunoprecipitation/immunoblotting analysis. The N251 and N253 peptides (100 μM) enhanced anti-Fas-(Ch-11, 50 ng/ml) induced apoptosis of BJAB lymphoma cells that expressed K1 but not of vector transfected BJAB cells. Ig deleted K1 (K1dIg) transfected mice were not protected (0/6) and K1 transfected mice were protected (7/10), P<0.01) against the lethal effects of agonistic anti-Fas (Jo2) antibody. K1dIg expressed in mice did not form complexes with Fas suggesting that the Ig is essential for K1-Fas binding and suppression of apoptosis.
Conclusion: Collectively, these results indicate that K1 potently blocks apoptosis and this effect is mediated through the Ig-like domain of K1. Because viral proteins mimic cellular proteins these results predict the presence of functional cellular homologues of K1 that have key roles in death receptor regulation.