bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Outcome of Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hemophagocytic Lymphohistiocytosis in Korea.
Authors: Lee Jae Hee , Yoon Hoi Soo , Song Joon Sup , Im Ho Jun , Moon Hyung Nam , Ghim Thad T. , Kang Hyeong Jin , Shin Hee Young , Ahn Hyo Seop , Yoo Keon Hee , Sung Ki Woong , Koo Hong Hoe , Cho Bin , Kim Hack Ki , Jeong Dae Chul , Lee Mee Jung , Kook Hoon , Hwang Tai Ju , Seo Jong Jin 
Published: October 2019

Abstract
Objective: Chemoimmunotherapy based treatments improved the survival of patients with hemophagocytic lymphohistiocytosis (HLH), but the outcome is still unsatisfactory. We analyzed the outcome of pediatric patients with HLH after hematopoietic stem cell transplantation (HSCT) in a nation-wide HLH registry.
Methods: Retrospective nation-wide data recruitment for HLH pediatric patients diagnosed between 1996 and 2005 was carried out by Histiocytosis Working Party of the KSH and KSPHO. Sixteen patients who received HSCT among enrolled 129 pediatric patients with HLH were analyzed for transplant related variables and events.
Results: The probability of 3-year survival after HSCT was 81.2% with median follow-up of 27.5 months compared to the 35.2% for patients who were treated with chemoimmunotherapy only (P=0.03). The reasons for HSCT were active disease at 2 months after treatment (n=8), relapsed disease (n=5), and familial HLH (n=3). Eight patients received transplants from matched unrelated donors, 5 from matched siblings and 3 using unrelated cord blood units. Stem cell sources were bone marrow for all the 13 allogeneic transplants other than 3 cord blood transplants. Conditioning regimens were busulphan, cytoxan, and VP-16 with (5) or without (7) antithymocyte globulin (ATG) in 12 patients, fludarabin and melphalan in 3, and other regimen in 1. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CSA) + MTX in 11 patients, CSA +MMF in 2, and others in 2. Twelve patients are alive in complete remission state, 3 patients died of infection and graft failure at early post-transplant period, and 1 patient relapsed at post-transplant 30 days. The relapsed patient developed tuberculous encephalitis after retreatment with chemoimmunotherapy, and alive with supportive care. After HSCT, acute GVHD developed in 5 patients, infection in 5, veno-occlusive disease (VOD) in 2, graft failure in 2, and post-transplant lymphoproliferative disease (PTLD) in 1. Acute lymphoblastic leukemia developed in 1 patient about 2 years after HSCT. Variables such as age at diagnosis, etiology of HLH (familial or secondary), central nervous system (CNS) involvement, disease state after 8 weeks of initial treatment, conditioning regimens, and stem cell sources were not associated with significant difference with regard to 3-year overall survival after HSCT.
Conclusion: HSCT revealed excellent outcome for patients with familial, relapsed, or severe and persistent secondary HLH in Korean nation-wide HLH registry.
Haplo-Identical Allogeneic Stem Cell Transplantation Using GCSF-Mobilized Marrow Plus Blood Stem Cells from Parent Donors for Children with High-Risk Leukemia.
Authors: Lu Quanyi , Niu Xiaoqing , Zhang Peng , Liu Delong 
Published: October 2019

Abstract
Increasing number of patients in China have difficulty of finding sibling donors due to limited number of siblings. We therefore explored the feasibility using haploidentical parent donors for allogeneic hematopoietic stem cell transplantation. Eight leukemia patients were studied in our hospital. These included 2 CML-BC, 2 MDS-RAEB, 3 relapsed ALL and 1 relapsed AML. The median age was 12 (7–17). GCSF- mobilized bone marrow and peripheral blood stem cells were collected from parents (1 to 3 locus mismatched). The conditioning regimen consisted of fludarabine (30mg/m2/d x5), bulsulfan (4mg/kg/d x3) and cyclophosphamide (50mg/kg/d x2). Cyclosporin A, mycophenolate mofetil, methotrexate, and ATG were used for GVHD prophylaxis. The total number of CD34+ cell in the grafts ranged between 5–10 x 106/kg. The median follow- up was 13 months (6–24). One patient failed to engraft, the other 7 patients achieved full donor chimerism at day 28. The incidence of acute GVHD (grade II-IV) was 57.1% (4 of 7). The incidence of chronic GVHD of limited stage occurred in the same 4 patients. One patient died of lung complication at 17th month, another patient with CML-BC relapsed 10 months after transplantation. The rest 6 patients are alive without disease. These results suggested that parents could be considered as stem cell donors in the absence of alternative donors for young patients with high-risk diseases. GCSF-primed bone marrow plus peripheral blood stem cells might be beneficial to reduce the risk of GVHD for leukemia children in China. More patients are needed to further study this approach.
Low Transplant Related Mortality Following Matched Unrelated Donor Allogeneic Transplantation in High Risk Patients Utilizing Low Dose Subcutaneous Campath.
Authors: Solomon Scott R. , Manion Karen , Bashey Asad , Morris Lawrence E. , Holland H. Kent 
Published: October 2019

Abstract
The administration of alemtuzumab (Campath 1H) as part of the conditioning regimen prior to allogeneic stem cell transplantation (ASCT) results in a low incidence of acute and chronic GVHD. However, intravenous Campath administration is also associated with significant infusional toxicities and a higher risk of infectious complications post-transplant. We evaluated the role of low-dose subcutaneous Campath prior to unrelated donor ASCT in 13 patients deemed to be at high risk for mortality (age>40years, significant comorbidity, or prior autologous transplant). Median age of transplant recipients was 54 (37–61) years and three patients had a prior autograft. Diseases included secondary/poor risk AML-5, CML-1, MPS-2, relapsed HD-1, NHL-3, and CLL-1. The preparative regimen consisted of fludarabine and targeted oral busulfan (myeloid malignancies) or cytoxan±rituximab (lymphoid malignancies). Campath was administered subcutaneously from d-5 to d-3 at a total dose of 43mg. Low dose Campath was well tolerated with no untoward toxicity. Early mixed T cell chimerism generally occurred (median day +100 donor CD3 60% (8–100) and CD33 100% (67–100)), requiring door lymphocyte infusion (DLI) in 10 of 13 patients. Ten of 11 evaluable patients achieved complete donor chimerism at a median of 112 days (32–260), and no graft failures have occurred. Acute graft-versus-host disease (GVHD) occurred in 5/13 patients (38%) at median day +58 (23–152) (grade I[1] and II[4]). Chronic GVHD occurred in 6/12 evaluable patients (3 limited, 3 extensive) and no GVHD mortality has occurred. CMV reactivation occurred in 5 of 9 at-risk patients (55%) with a median day to reactivation of day +25 (9–38), median number of reactivations of 2 (1–4), but no CMV disease or mortality. After a median follow-up of 340 (84–631) days, eleven of thirteen patients survive for a one year actuarial survival of 83%. No patient has died from treatment-related mortality. Relapse occurred in 5/13 patients resulting in the death of two patients. Low dose subcutaneous campath administered during conditioning results in low TRM and promising survival in older high risk patients undergoing unrelated donor ASCT.
Figure Figure
Total Body Irradiation (TBI) Based Versus Chemotherapy-Based Preparative Regimens Before Autologous Stem Cell Transplant for Non-Hodgkin’s Lymphoma.
Authors: Liu Hongwei , Seftel Matthew , Demers Allain , Nugent Zoann , Schroeder Garry , Butler Jim , Rubinger Morel 
Published: October 2019

Abstract
OBJECTIVES: The optimum high dose preparative regimen for non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT) is unknown. We compared the radiation-based regimen of cyclophosphamide, etoposide and 12 Gy total body irradiation (CY/E/TBI) to carmustine, etoposide, cytarabine and melphalan (BEAM) in NHL patients who received ASCT. We investigated acute and long-term toxicities, disease free survival (DFS), overall survival (OS) of these two regimens.
METHODS: A historical cohort study was performed at a provincial cancer centre. Cause specific survival was determined with the Kaplan-Meier method. Survival between groups was compared using the log-rank test.
RESULTS: From Mar-1991 to Sep-2005, 79 patients received CY/E/TBI (n=32) or BEAM (n=47). Histology was indolent in 30 and aggressive in 49 patients. Cell source was bone marrow in six and 73 received peripheral blood progenitor cells. Prior to ASCT, ten patients were in complete remission, 47 had chemo-sensitive disease and 22 had chemo-resistant disease. There were only two cases of interstitial pneumonitis, with one in each preparative regimen group. There were six transplant related deaths; two in the BEAM group and four were in TBI group. The TBI based group has a higher mean mucosits score (p=0.03). Five year DFS was 47% and 51% in the TBI and BEAM groups, respectively (p=0.41). Five year OS was 50% and 64% for the TBI and BEAM based groups (p=0.07). Multivariate analyzes revealed that patients with more advanced disease and raised LDH at ASCT independently predicted inferior DFS. There was one case of acute myeloid leukemia and two of prostate cancer, all of whom were in the TBI group.
CONCLUSIONS: In this study, a 12 Gy TBI-based regimen resulted in a similar DFS but a trend toward poorer OS and higher second malignancies than a BEAM-based regimen. However, there did not appear to be excess pulmonary acute toxicities in the TBI based group.
Late Relapses Characterize Autologous Transplantation (ASCT) in First Complete Remission (CR) for Peripheral T-Cell Lymphoma (PTCL).
Authors: Kewalramani Tarun , Horwitz Steve , Zelenetz Andrew D. , Nimer Stephen D. , Moskowitz Craig H. 
Published: October 2019

With the exception of ALK-positive anaplastic large cell lymphoma (ALCL), standard-dose chemotherapy is curative in a minority of patients (pts) with PTCL, and most pts have progressive disease less than 2 years from completing treatment. Several studies suggest that ASCT in 1st CR significantly improves the short-term outcome of pts with PTCL, but its long-term efficacy is not known. To address this, we assessed the outcome of sequential patients who underwent ASCT in 1st CR (n=15). Histologic subtypes were PTCL, unspecified, in 6 pts, angioimmunoblastic T-cell lymphoma in 5 pts, ALK-negative ALCL in 3 pts and hepatosplenic gamma delta T-cell lymphoma in 1 pt. Induction chemotherapy was CHOP (n=2) or CHOP-ICE hybrid (n=12) in 93% of pts. The age-adjusted IPI (AAIPI) was 2–3 in 9 of 14 assessable patients (64%), and 11 pts (73%) had stage III–IV disease. The conditioning regimen consisted of BEAM or CBV in 10 pts and TBI/Cy/VP-16 in 5 pts. All patients received peripheral blood progenitor cells for hematopoietic support. The median follow-up of all patients is 24 months (range 4.5–70). Five pts (33%) have progressed, with a median time to progression of 50 months (range 10–70). Four of the 5 pts who progressed did so more than 2 years from ASCT; they comprise 57% of patients with more than 2-years of follow-up. Four of 5 patients with progressive disease have died, with a median time from progression to death of 1 month (0.6–14.6). In this small series the AAIPI was not predictive of PFS or OS. While our results confirm the that ASCT in 1st CR significantly delays the time to progression, they suggest that it may not be curative in the majority of patients. If confirmed in ongoing larger prospective studies, this observation warrants trials of post-ASCT maintenance treatment and, for younger patients, trials of allogeneic transplantation in 1st CR or sequential ASCT followed by allogeneic transplantation.
Figure Figure
Single and Tandem Autologous Peripheral Blood Stem Cell Transplantation for Patients with Multiple Myeloma: A Korean Multicenter Retrospective Study.
Authors: Sym Sun Jin , Kwak Jae Yong , Min Chang Ki , Won Jong Ho , Lee Seung-Tae , Kim Kihyun , Suh Cheolwon 
Published: October 2019

Abstract
High-dose therapy with autologous stem cell transplantation (ASCT) is now considered the standard of care in patients with multiple myeloma (MM). This retrospective case analysis evaluated the prognostic influence of pre-transplant characteristics, transplant modalities, and disease status at post ASCT on survival to define patients with better prognosis. A total of 269 MM patients (median age: 53 years) who were transplanted between 1997 and 2007 from 6 centers in Korea were analyzed. All patients received peripheral blood stem cell support after conditioning with melphalan 140 mg/m2 or 200 mg/m2. In all, 190 patients received single ASCT and 79 patients received tandem ASCT. After a median follow-up of 28.5 months for surviving patients form single transplant, median progression-free survival (EFS) and overall survival (OS) were 19.2 months (95% CI, 15.9–22.6 months) and 71.3 months (95%CI, 56.9–85.7 months) with 18% and 55% probabilities of being progression-free and survival after 5 years, respectively. Treatment-related mortality within 90 days after ASCT was occurred in 12 patients (4.4%). Univariate analysis revealed that significant prognostic factor of PFS included age ≤ 50 at ASCT (p=0.024) and tandem ASCT (p<0.001). Significant prognostic factor for OS was tandem ASCT (p=0.029). The absence of unfavorable cytogenetic abnormalities was marginally significant for OS (p=0.074). In Cox analysis, it was seen that significantly longer PFS occurred for patients who received tandem ASCT (p=0.002). Age ≤ 50 at the time of ASCT was marginally significant prolonged PFS (p=0.054). Tandem ASCT independently correlated with better OS (p=0.044). We conclude that tandem ASCT independently correlated with better PFS and OS.
Development of Megakaryocyte-Specific Lentiviral Vectors for Gene Therapy of Platelet Disorders.
Authors: De Waele Liesbeth , Freson Kathleen , Thys Chantal , Van Geet Christel , Collen Désiré , VandenDriessche Thierry , Chuah Marinee 
Published: October 2019

Abstract
The prevalence of congenital platelet disorders has not been established but for some life-threatening bleeding disorders the current therapies are not adequate, justifying the development of alternative strategies as gene therapy. In the case of platelet dysfunction and thrombocytopenia as described for GATA1 deficiency, potentially lethal internal bleedings can occur. The objective of the study is to develop improved lentiviral vectors for megakaryocyte(MK)-specific long term gene expression by ex vivo transduction of hematopoietic stem cells (HSC) to ultimately use for congenital thrombopathies as GATA1 deficiency. Self-inactivating lentiviral vectors were constructed expressing GFP driven by the murine (m) or human (h) GPIIb promoter. These promoters contain multiple Ets and GATA binding sites directing MK-specificity. To evaluate the cell lineage-specificity and transgene expression potential of the vectors, murine Sca1+ and human CD34+ HSC were transduced in vitro with Lenti-hGPIIb-GFP and Lenti-mGPIIb-GFP vectors. After transduction the HSC were induced to differentiate in vitro along the MK and non-MK lineages. The mGPIIb and hGPIIb promoters drove GFP expression at overall higher levels (20% in murine cells and 25% in human cells) than the ubiquitous CMV (cytomegalovirus) or PGK (phosphoglycerate kinase) promoters, and this exclusively in the MK lineage. Interestingly, in both human and murine HSC the hGPIIb promoter with an extra RUNX and GATA binding site, was more potent in the MK lineage compared to the mGPIIb promoter. Since FLI1 and GATA1 are the main transcription factors regulating GPIIb expression, we tested the Lenti-hGPIIb-GFP construct in GATA1 deficient HSC and obtained comparable transduction efficiencies as for wild-type HSC. To assess the MK-specificity of the lentiviral vectors in vivo, we transplanted irradiated wild-type C57Bl/6 mice with Sca1+ HSC transduced with the Lenti-hGPIIb-GFP constructs. Six months after transplantation we could detect 6% GFP positive platelets without a GFP signal in other cell lineages.
Conclusion: In vitro and in vivo MK-specific transgene expression driven by the hGPIIb and mGPIIb promoters could be obtained after ex vivo genetic engineering of HSC by improved lentiviral vectors. Studies are ongoing to study whether this approach can induce phenotypic correction of GATA1 deficient mice by transplantation of ex vivo Lenti-hGPIIb-GATA1 transduced HSC.
LFA1 Mediated Attachment of Primary Human Monocytes to Activated Brain Microvascular Endothelial Cells Is Regulated by SDF-1α through the SRC Family Kinase Lyn; Potential Involvement of This Signaling Pathway in HIV-Associated Dementia.
Authors: Malik Mobeen , Chen Ying-Yu , Kienzle Martha F. , Collman Ronald G. , Ptasznik Andrzej 
Published: October 2019

Abstract
Infiltration of activated monocytes into the brain of HIV-infected patients is a prerequisite for the development of HIV-associated dementia (HAD). The chemokine stromal derived factor-1α (SDF-1α) is expressed at increased levels in the central nervous system (CNS) of HAD patients and elicits chemotaxis and other cellular effects through its receptor CXCR4. In this project, we investigated the intracellular signaling pathway by which SDF-1α mediates the movement and attachment of monocytes to brain microvascular endothelia, and which may contribute to their infiltration into the CNS in HAD. We demonstrated that SDF-1α stimulates migration of primary human monocytes through its receptor CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1. SDF-1α also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) activated with the pro-inflammatory cytokines TNF-α or IL-1β, or with recombinant HIV-1 envelope glycoprotein (gp120), which increase endothelial cells expression of ICAM-1. The decreased monocyte adherence was linked to down regulation of the activation-dependent epitope of the β2 integrin LFA-1 which is a ligand for ICAM-1. We then demonstrated that the Src family kinase Lyn is a central modulator of migration and LFA-1-mediated adhesion of SDF-1α-stimulated primary monocytes. Using siRNA knockdown we achieved 80% down regulation of Lyn kinase in human monocytes. Lyn down regulation decreased SDF-1α-mediated migration and prevented its inhibition of monocyte attachment to ICAM-1 coated surfaces and activated BMVEC. These data indicate that in SDF-1α-stimulated primary human monocytes Lyn is a positive regulator of cell migration, and a negative regulator of cell adhesion to BMVEC by inhibiting the ICAM-1 binding activity of the LFA-1 integrin. Thus, CXCR4-triggered inside-out integrin signaling, through Lyn, inhibits adherence and stimulates movement of monocytes towards SDF-1α gradient on BMVEC monolayers. These results provide new insight into the intracellular signaling cascade that controls primary human monocytes movement and attachment at the blood brain barrier.
The Economic Impact of Anamnestic Response in the Management of Hemophilia Patients with Inhibitors Undergoing Immune Tolerance Induction in Germany.
Authors: Odeyemi Isaac , Møller Anne D. 
Published: October 2019

Abstract
The aim of this analysis was to estimate the economic impact of bleed control treatments prior to immune tolerance induction (ITI) in patients with hemophilia with inhibitors in Germany. “Poor risk” hemophilia patients presenting at ITI are more costly to manage as they require higher-dose factor VIII treatment over a longer period, compared to “good risk” patients. Thus, factors that improve patient risk status for ITI, and permit the lowering of factor usage during ITI while maintaining clinical efficacy, are expected to result in cost-effective outcomes. The phenomenon of anamnestic response (AR) which occurs following treatment of hemophilia bleeds with immunogenic products results in significant elevation of titer levels, conferring a “poor risk” status on these patients at ITI. We therefore hypothesize that the prevention of AR pre-ITI, by avoiding immunogenic agents, would result in fewer “poor risk” patients requiring high-dose regimen during ITI, resulting in a cost-effective outcome. A cost-minimization model compared two strategies for the management of patients with severe hemophilia A with inhibitors. One strategy involved management of bleeds with a bypassing agent (activated prothrombin complex concentrates; aPCC) prior to ITI, while the other involved management of bleeds by use of a product which does not provoke AR (recombinant activated factor VII; rFVIIa) prior to ITI. Data on resource use and probabilities of clinical outcomes were derived from published literature, and the model validated by clinical experts with experience in managing inhibitor patients. The mean cost of ITI in inhibitor patients previously treated with rFVIIa is €1,073,327 compared to €1,420,825 for patients previously treated with aPCC. The model also estimated the incremental cost attributable to anamnesis in the management of a hemophilia patient who has undergone ITI to be €186,665. Sensitivity analyses suggest that the model is robust to the price of aPCC, but sensitive to the proportion of patients with AR post-aPCC treatment and the cost and dosage of FVIII at ITI. Anamnestic response is an unpredictable but avoidable consequence of managing bleeding episodes in inhibitor patients and confers significant additional costs to the management of high-responding inhibitor patients undergoing ITI. Avoiding AR prior to ITI by managing spontaneous bleeding episodes with bypassing agents which do not provoke AR has the potential for significant cost savings.