bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Useful Individualized Assessment of Immunosuppressive Therapy with Cyclosporine A (CsA) after Allogeneic Stem Cell Transplantation by Simultaneous Analyses of Cytokine Production among CD4+ T Cells and Blood CsA Levels.
Authors: Tsukada Nobuhiro , Furukawa Tatsuo , Ito Hiromi , Izumi Noriko , Momoi Akihito , Okazuka Kiyoshi , Honma Keiichiro , Masuko Masayoshi , Hashimoto Shigeo , Aoki Sadao , Aizawa Yoshifusa 
Published: October 2019

Abstract
Cyclosporin A (CsA) is the most common immunosuppressive agent used for recipients undergoing allogeneic stem cell transplantation (SCT). CsA require therapeutic drug monitoring (TDM) for both its effectiveness and toxicity, but the schedule of administration and optimal blood levels vary among institutions. To establish better assessment of CsA effect on individual immune responsiveness, we analyzed the proportion of IFN-γ+ or IL-2+ cells among CD4+ lymphocytes using 3-color flow cytometric analysis before and after CsA administration. CsA is administered as 3-hour infusion or oral medication twice daily in equally divided doses. 83 peripheral blood samples from 8 allogeneic BMT recipients are analyzed. Cells were cultured in the presence of phorbol 12-myristate 13-acetate, ionomycin, and brefeldin A at 37°C for 4hrs and then stained for surface markers and intracytoplasmic IFN-γ and IL-2. Blood CsA levels were simultaneously measured. We found that the proportion of IFN-γ+CD4+ or IL-2+CD4+ lymphocytes were inversely proportional to blood CsA levels (Figure 1). To achieve profound inhibition of IL-2 production, high concentration of CsA is required (e.g. 600–800 ng/ml for less that 5 % IL-2+CD4+ cells). In vitro experiments were also conducted using lymphocytes from healthy donors with or without activation with CD3 and CD28 to show how the sensitivity to CsA is different in between activated and resting T cells. We found that higher CsA concentration is required for inhibiting IL-2 production from CD4+ lymphocytes activated with CD3 and CD28 than from resting CD4+ lymphocytes (Figure 2). In this regard, our 3 hour intravenous CsA infusion can be superior to continuous intravenous infusion in inhibiting activated T cells. Further analyses are required, but the simultaneous assessment of cytokine production among CD4+ T cells and blood CsA levels may be a useful index to estimate the degree of immunosuppression afforded by CsA and may enable us individualized therapeutic drug monitoring of this agent. Since more and more patients are undergoing cord blood transplantation (CBT) or reduced-intensity stem cell transplantation (RIST), this assessment may also be useful for the establishment of immunosuppressive therapy for those patients.
An Experimental and Clinical Study of CMV Infection after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Wu De Pei , Wu Xiaojin , Li Caixia , Ma Xiao , Sun Aining 
Published: October 2019

Abstract
Objective: To establish quick and reliable diagnostic methods for detecting the cytomegavirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to evaluate their clinical value in early diagnosis of CMV infection
Methods: (1) From March 2001 to December 2003, Seventy-four patients undergoing allo-HSCT were enrolled in this study. After allo-HSCT, all the patients were detected for CMV gB DNA in peripheral blood by haplo-nested PCR methods and 35 of 74 patients for CMV PP65 antigen in peripheral blood by the fluorescent immunohistochemistry (FIHT) assay. The positive rate and correspondence of these two methods were evaluated.
Results: (1) In 35 of 74 patients who were tested for CMV infection by two assays at the same time, the CMV-viremia was first detected at a median of 36 days after transplantation by FIHT assay and 26 days by haplo-nested PCR assay during the follow-up time of 90~720 days. The median time of positive persistence was 19 days by FIHT assay and 28 days by haplo-nested PCR assay. The significant difference of them was observed (P<0.05). The corresponding of the two assays was 88.57%. The difference of the two methods was not significant statistically. The incidence of CMV-agtigenemia and CMV-DNAemia were 65.71% and 71.43% during the follow-up days, respectively. (2) The infection rate in the nonmyeloablative allogeneic peripheral stem cell transplantation (NST) group was 78.95%, in the group of related peripheral blood stem cell transplantation (R-PBSCT) and/or related bone marrow transplantation (R-BMT) 48.57%, and in the group of unrelated bone marrow transplantation (UR-BMT) 61.54%. The infection rate of CMV in the UR-BMT group was higher than that in R-PBSCT and/or R-BMT group, but without significant difference (P>0.05). The infection rate of CMV in the NST group was significantly higher than in R-PBSCT and/or R-BMT group (P<0.05), but only a litter higher than in UR-BMT group (P>0.05). Both CMV-antigen and CMV-DNA were detected in all seven patients undergoing haploidentical hematopoietic stem cell transplantation (Hi-HSCT).
Conclusion: (1) Both FIHT and haplo-nested PCR assays were quick and reliable diagnostic methods for detecting the CMV infection after allo-HSCT and their correspondence was good. However CMV infection could be found earlier by haplo-nested PCR assay than by FIHT assay. (2) The infection rate of CMV is high after allo-HSCT and might be different in different types of allo-HSCT.
Immune Suppressor Factor Confers Enhanced Supporting Activity for Hematopoietic Stem Cells in Bone Marrow Stroma.
Authors: Nakajima Hideaki , Shibata Fumi , Fukuchi Yumi , Goto-Koshino Yuko , Ito Miyuki , Kitamura Toshio 
Published: October 2019

Abstract
Immune suppressor factor (ISF) is a subunit of vacuolar ATPase proton pump that plays a critical role for proton transfer to extracellular space or subcellular organs. Physiological importance of vacuolar ATPase was evident in a variety of cellular functions such as re-absorption of bones by osteoclasts, acidification of lysosomes in macrophages, and acidification of urine in kidney. However, a role for vacuolar ATPase in hematopoiesis is still unknown. We have previously identified a short form of ISF (ShIF) as a stromal cell derived factor that supports factor-independent growth of a mutant subline of Ba/F3, an IL-3 dependent murine hematipoietic cell line. In this study, we addressed whether ISF supports self-renewal and expansion of primary hematopoietic stem cells (HSC). Co-culture of murine bone marrow cells with a stromal cell line overexpressing ISF or ShIF (MS10/ISF or MS10/ShIF) enhanced their colony-forming activity as revealed by the numbers and the size of the colonies. In addition, the numbers of long-term culture initiating cell (LTC-IC) were markedly increased by co-culture on MS10/ISF or MS10/ShIF. Moreover, competitive repopulating activity of c-Kit+Sca-1+Lin- HSC was significantly maintained without any added cytokines when they were co-cultured with MS10/ISF or MS10/ShIF compared with a mock control. In order to check whether these activities were dependent on the proton pump function of ISF, we generated a mutant ISF or ShIF whose proton pump activity was abolished by point mutation. Interestingly, all stem cell supporting activities described above were abolished in the mutant ISF or ShIF, indicating that proton transfer across cellular or endosomal membrane was critical. Analysis of gene expression profile of mock and ISF-transfected cell lines revealed that any cytokines or growth factors previously known to affect hematopoiesis are not modulated at mRNA level. However, downregulation of secreted frizzled related protein (sFRP)-1, an antagonist for Wnt, and up-regulation of matrix metalloproteinase-3 (MMP-3) were clearly noted in ISF/ ShIF-overexpressing cell line, suggesting that relative increase of Wnt activity and the modulation of extracellular matrix are the key molecular events underlying the enhanced supporting activity for HSC. These results propose a novel role for ISF in self-renewal and expansion of HSC in vivo.
Three Hundred and Fifty Cases of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Single Center Study in Korea.
Authors: Park Young-Shil , Jang Pil-Sang , Choi Sangrhim , Chung Nak-Gyun , Cho Bin , Jeong Dae-Chul , Kim Hack-Ki 
Published: October 2019

Abstract
Background: Hematopoietic stem cell transplantation (HST) was first introduced to Korean children in 1983. Since then HST has been a curative method for pediatric malignant or non-malignant hematologic disorders and the number of children receiving HST’s has been increasing steadily.
Method: We analyzed three hundred and fifty cases of pediatric allogeneic hematopoietic stem cell transplantation between Nov. 1983 and Dec. 2003 in the Catholic Hematopoietic Stem Cell Transplantation Center of Korea.
Results: HLA-matched sibling bone marrow transplantations were performed in 206 cases (103 males, 103 females, median age 12 years) with median follow-up of 73 months. The 5-year event-free survival (EFS) of ALL and AML was 70.5 % and 67.22 %, respectively. The 5-year EFS of severe aplastic anemia was 90.9 %. The 5-year EFS of CML/MDS and rare hematologic diseases was 65.5 % and 90.0 %, respectively. Eighty-one children (56 males, 25 females, median age 9 years) underwent unrelated bone marrow transplantation (UBMT), 42 (27 males, 15 females, median age 5 years) cord blood transplantation (CBT) and 21 (14 males, 7 females, median age 8 years) familial haploidentical HST (FHT). Three-year EFS of UBMT, CBT and FHT was 55.6 %, 48.0 % and 38.0 %, respectively.
Conclusion: HLA-matched sibling allogeneic BMT showed better survival in children with hematopoietic stem cell disorders. Recently, transplants using alternative stem cell sources are increasing due to the lack of suitable sibling donors and continued efforts for reducing transplant-related complications are warranted for improved survival.
Nonmyeloablative Allogeneic Stem Cell Transplantation: Hacettepe University Institute of Oncology Experience.
Authors: Koc Yener , Ozdemir Evren , Oyan Basak , Kansu Emin 
Published: October 2019

Abstract
The purpose of this study was to determine the feasibility and efficacy of nonmyeloablative allogeneic stem cell transplantation in patients with hematologic malignancies and metastatic renal cell carcinoma (RCC). Thirty patients with various pathologies (AML/MDS, n=9; CML, n=5; lymphoid malignancy, n=6; Multiple Myeloma, n=7; RCC, n=3) received a fludarabine (F)-based nonmyeloablative regimen (F+Busulphan, n=5; F+TBI, n=18; F+Cyclophosphamide, n=3; others, n=4), followed by unmanipulated peripheral stem cells from HLA-identical sibling donors. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and mycophenolate mofetil. Median age was 43 years (range, 17–62), median time from diagnosis to transplant was 1.6 years (range, 0.4–9.1). Patients underwent a median of 2 prior chemotherapy regimens (range, 0–7). Prior stem cell transplantation failed in seven patients (23%) (autologous, n=6; ablative allogeneic, n=1). Disease phase prior to transplant was complete or partial remission in 16 patients (CR, n=12; PR, n=4) and active disease in 14 patients (Primary refractory, n=1; Relapse, n=10; Untreated, n=3). Recipients were male and donors were female in 15 transplants (50%). The median numbers of mononuclear and CD34+ cells infused were 8.8 x 108/kg (range, 4–26 x 108/kg) and 9.7 x 106/kg (5.2–32.5 x 106/kg) respectively. Neutrophil engraftment achieved after a median of 9 days (range, 6–12) and platelet engraftment occurred after a median of 11 days (range, 9–19). In twelve (40%) patients, absolute netrophil count did not fall below 500/mm3 and 14 patients (47%) required no platelet transfusions. The patients received a median of 2 donor lymphocyte infusions (range, 0–8). Nine patients (30%) had acute GVHD (Grade II-IV, n=5, 17%) and 12 patients (40%) had chronic GVHD (limited, n=4; extensive, n=8, 27%). Three patients (10%) died of nonrelapse treatment-related complications within 100 days post-transplant (Pneumonia, n=2; Bronchoalveolar hemorrhage, n=1). Two patients had graft failure at day 100 post-transplant. Twenty two patients (73.4%) are currently alive with a median follow-up of 6 months. Primary causes of deaths (n=8, 26.6%) are as follows; GVHD (n=3), pneumonia (n=2), bronchoalveolar hemorrhage (n=1), and relapse (n=2). Among 22 evaluable patients, response was obtained in 18 patients (82%) (CR, n=14; PR, n=2; stable disease, n=2) and 4 patients relapsed. Our data suggest that nonmyeloablative allogeneic transplantation is a safe and effective treatment strategy in hematological malignancies.
T Cell-Depleted Related Haploidentical Peripheral Blood Stem Cell Transplantation in a Patient with Fanconi Anemia. Cagliari Experience.
Authors: Sanna Maria Adele , Orofino Maria Grazia , Cossu Fausto , Addari Maria Carmen , Piroddi Antonio , Rizzo Giuseppa Fabiana , Badiali Manuela , Galanello Renzo , Argiolu Francesca 
Published: October 2019

Abstract
Stem cell transplantation is presently the best treatment for Fanconi Anaemia (FA) patients developing bone marrow failure. 70% of success is reported in patients with a HLA identical sibling whereas the outcome for HSCT in those transplanted from unrelated donors is in the range of 29–43%, graft rejection, GVHD and regimen related toxicity beeing the main causes of failure. This results limited the ability to perform marrow transplantation other than HLA identical siblings for this disease. Recently a fludarabine based cytoreductive regimen has been successfully used in T cell depleted haploidentical/mismatched transplant of FA patients. We report a case of a 7 year old boy with bone marrow failure since 1999. Androgens treatment was uneffective, no HLA identical family donor was available and the search for a suitable marrow or cord blood unrelated donor was unsuccessful. After 4 years he underwent T-cell depleted haploidentical PBSCT from his father. Conditioning regimen was: fludarabine 30 mg/mq from day −6 to day −3, cytoxan 300 mg/mq from day −6 to day −3, rabbit ATG (3.75 mg/kg) from day −5 to day −3. GvHD prophylaxis consisted of cyclosporine 1 mg/kg from day −1. The donor received G-CSF 8 ug/kg/dose twice daily for 6 days and underwent leukapheresis on day 5 and 6. Donor stem cells were depleted of T cells by positive selection of CD34+ cells using the Clinimacs device according to the suggested procedures (Milteny Biotec). On day 0, 15.3x106 x kg CD34+ cells were infused with 1.5 x 105 CD3 + cells. The clinical postransplant course was uneventful. Neutrophil engraftment ( >0.5 x 109 ) occurred on day 14, platelet count >100x109 on day 15. He was discharged on day 39 without signs of GVHD. Molecular analysis of DNA-VNTRs at 1, 3, 6, 9, 12 months showed >95% donor chimerism on peripheral blood. At 14 months after transplantation the patient is well, normal blood cell count (WBC 5.4 x 109/l, Hb 13.6 gr /dl, platelets 293x 109 /l). Count of T-cells are reported in the normal reference range ( CD3+ :1865 ug/l, CD8+ :1026ug/l, CD19+ :732ug/l, CD56+: 452). Karnofsky score is 100%.
Conclusion: the case reported shows that the fludarabine based regimen and the infusion of a high number of T-cell depleted CD34+ was successful in absence of peri-transplant complications and can be proposed for the cure of FA patients at high risk of clonal disease and without HLA-matched sibling donor.
Clinical Outcome of Cord Blood Transplantation by Age with Units Shipped from Tokyo Cord Blood Bank.
Authors: Nagamura-Inoue Tokiko , Yan Cui , Kodo Hideki , Mugishima Hideo , Sugo Michiko , Takada Kei , Shioya Mika , Hirai Masako , Takahashi Atsuko , Satomi Aya , Hoshino Mokaku , Tahara Yoshiyuki , Asano Shigetaka , Takahashi Tsuneo 
Published: October 2019

Abstract
Recently, cord blood transplantation (CBT) for adult is rapidly increasing in number, Especially for the patients over 50 years of age. By the end of 2003, 224 units were shipped for the patients Group I: <15 y.o. 39%, Group II: 15~50 y.o.40% and Group III :> 50 y.o.21%. We analyzed 152 patients with hematological malignancies including ALL, AML, CML, MDS, malignant lymphoma, myeloma and neuroblastoma reported from CBT center in the world by the end of 2003.
Patients and Methods:Group I included 58 patients with 13 standard risk and 45 high risk patients and showed mean±SD of age; 5.3 ±4.1y.o.,BW; 20.5±13.4kg, CB volume at collection; 91.6±27.1ml, NC; 5.5±3.3x107/kg, CFC; 8.6±6.4x104/kg, CD34; 1.5±1.1x105/kg, Group II: 64 cases with 25 standard and 39 high risk patients and age; 30.6±10.3y.o., BW; 51.9±9.5kg, CB volume at collection;116.6±27.7ml, NC;2.6±0.7x107/kg, CFC;5.2±2.6x104/kg and CD34;0.8±0.5x105/kg, Group III: 30 cases with 9 standard and 21 high risk patients and age; 54.1±3.3y.o., BW;55.9±11.0kg, CB vol.at collection;118.8±24.7ml NC;2.4±0.4x107/kg, CFC;4.8±1.9x104/kg and CD34;0.8±0.4x105/kg. The patients who underwent CBT for graft failure (GF) of prior transplant were excluded. Conditioning regimen in Group I demonstrated 54 patients with full regimen and 4 with reduced intensity regimen (RIST); in Group II, 62 patients with full regimen and 2 RIST; and in Group III, 14 cases full regimen and 15 cases RIST.
Results: Cumulative myeloid engraftment was seen 67.2% in Group I, 73.4% in Group II and 46.7% in Group III (*Group II vs. Group III: P<0.05). Overall survival /EFS on day 100 showed 73.4%/59.4% in Group I, 74.0%/58.6% in Group II and 43.3%/34.5% in Group III (*Group III vs. others: P<0.05). In Group III, the survival rate indicated 42.8% in full regimen group and 13.3% in RIST group at 1year after CBT. In Group I, four patients died of GF, 13 of relapse, 11 of Transplantation related disease (TRD); in Group II, 5 patients died of GF, 8 of TRD, 10 of relapse. In Group III, four patients died of TRD, 3 of GF and 3 of relapse in full regimen, while in RIST, six patients died of TRD, 1 of relapse and 1 of acute GVHD.
Conclusion: The application of CBT has been expanded to the elderly patients (>50 y.o.), although the conditioning regimen and the special medical care for the complications in the early pahse after UCBT has remained to be discussed.
Results of High Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia.
Authors: Ault Kenneth A. , Case Delvyn C. , Boyd Marjorie A. , Ervin Thomas J. , Aronson Frederick R. , Ebrahim Kurt S. , Hedlund Jaquelyn A. 
Published: October 2019

Abstract
35 patients with acute myeloid leukemia have undergone transplantation at our institution over the past 12 years. Patient selection criteria included age less than 70 years, creatinine less than 2mg/ml, no active infection, cardiac ejection fraction >40%, DLCO > 50% of predicted and no other co-morbid conditions that would jeopardize survival. 31 patients were in first remission, 4 were in second or higher remission. 3 patients had favorable cytogenetics, 25 had intermediate or unfavorable cytogenetics. After achieving remission for at least 30 days, patients were consolidated with Etoposide and AraC, followed by G-CSF. Hematopoietic stem cells were collected when the WBC rebounded to at least 10,000/ml. The target dose of CD34 positive cells was 5x106/kg. The minimum dose given was 2.3 x 106/kg). The average age at transplantation was 41 years (range 22 to 61). Days of neutropenia (AGC<500/ml) ranged from 2 to 10 (average 5.1). The median length of follow up is 2.6 years. Currently 26 patients are alive, and 25 are free from progression. Overall survival is 63%, and progression-free survival is 47% at both 5 and ten years.
Figure Figure
Outcome after Relapse among Children with Standard Risk (SR) ALL Treated on CCG-1952.
Authors: Malempati Suman , Gaynon Paul S. , Sather Harland , La Mei K. , Stork Linda C. 
Published: October 2019

Abstract
The event-free survival (EFS) of children with SR-ALL is now > 80%. Nonetheless, ALL relapse remains a major problem in pediatric cancer, and optimal therapy for these children remains to be defined. We examined post relapse outcomes for children initially treated on the Children’s Cancer Group CCG-1952 study and compared stem cell transplant (SCT) with chemotherapy (CT) as salvage treatment in second remission (CR2). Between 5-96 and 1-00, 2176 eligible patients with SR-ALL (WBC < 50,000/mcl; age ≥ 1, < 10 years) were enrolled on CCG-1952, 321 of whom experienced a relapse after initially achieving M1 remission. Among the relapses, 196 are bone marrow (BM) ± extramedullary (EM) relapses (61%) and 125 are isolated EM (iEM: CNS, testicular, or ocular) (39%) relapses. The mean time (range) from first remission to BM relapse, iCNS relapse, and itesticular relapse is 34 ± 1 (2 to 79) month (mo.), 22 ± 1 (1 to 70) mo., and 37 ± 3 (4 to 74) mo., respectively. The 3-year EFS and overall survival (OS) after relapse for all patients are 41% and 53%. Three-year EFS and OS after BM ± EM relapse are 32% and 40% and after iEM relapse are 55% and 71%. Patients with early BM relapse (CR1 < 36 months) or early iEM relapse (CR1 < 18 months) are 2.3 times (p=0.002) and 2.8 times (p=0.01) more likely to suffer a subsequent adverse event than patients with later relapse by Cox regression analysis after adjustment for age, pre-relapse treatment, day 7/14 BM status, and type of treatment in CR2. The 3-year OS for early and late relapses are 31% vs 59% (p=0.001) for BM relapse and 50% vs 87% (p=0.01) for iEM relapse. We compared 73 SCT and 215 CT patients, excluding 33 patients with adverse events prior to the median time to SCT (130 days, range 56 to 1148 days) using Kaplan-Meier life table analysis and the log rank test. The cohorts are similar with respect to age (p=0.57), duration of CR1 (p=0.96), and initial Day 14 BM status (p=0.69). Thirty-seven percent (n=62) of patients with BM relapse (33 early; 29 late) and 9% (n=11) of patients with iEM relapse (6 early, 5 late) received SCT. Thus far, outcomes are similar between cohorts for patients with any BM relapse (OS, p=0.45; EFS, p=0.70), early BM relapse (OS, p=0.95; EFS, p=0.66), and iEM relapse (OS, p=0.44; EFS, p=0.96). Among patients with later BM relapse, a trend favors CT (OS, p=0.08; EFS, p= 0.14). In summary, duration of CR1 remains the most significant predictor of outcome after either BM or iEM relapse in this SR-ALL cohort. Prognosis after early BM relapse remains poor with either SCT or CT.