bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tacrolimus/Methotrexate (MTX) Versus Cyclosprorine/MTX for Graft-Versus-Host Disease (GVHD) Prophylaxis in Patients with Severe Aplastic Anemia (SAA) Who Received Marrow Transplantation from Unrelated Donors: Results of a Matched Pair Analysis.
Authors: Kojima Seiji , Yabe Hiromasa , Kato Koji , Kigasawa Hisato , Sakamaki Hisashi , Tsuchida Masahiro , Kato Shunichi , Morishima Yasuo , Kodera Yoshihisa 
Published: April 2020

Abstract
Acute and chronic GVHD contribute to much of the morbidity and mortality associated with unrelated bone marrow transplantation (UBMT). Effective prevention of these complications is crucial for the success of UBMT. Cyclosporine(CSA) was introduced for the prophylaxis of GVHD and has been shown to be effective; similar findings have been shown for tacrolimus. However, there are no comparative studies between tacrolimus/MTX and CSA/MTX in patients with SAA who undergo UBMT. We compared tacrolimus/MTX with CSA/MTX in patients with SAA who received UBMT using a matched-pair analysis. Patients with acquired SAA who received UBMT between July 1997 and December 2002 through the Japan Marrow Donor Program were eligible for analysis. Recipients of UBMT were divided into two cohorts for comparison: those who received tacrolimus/MTX and those who received CSA/MTX. Because our previous studies identified that recipient age and conditioning regimen are the most important variables associated with treatment failure, we selected pairs of patients treated with either tacrolimus/MTX or CSA/MTX by matching these variables. We were able to identify 47 pairs that could be matched exactly for the recipient age and conditioning regimens. There was an imbalance of HLA-A, -B, and -DRB1 antigen mismatches, with 18 mismatched pairs in the tacrolimus group and 7 in the CSA group (p=0.005). Other variables were comparable between the two groups. Engraftment took place in 46 patients (98%) in the tacrolimus group and 43 patients (92%) in the CSA group. The median time to neutrophil recovery was the same in the two groups (tacrolimus group: 18.0 days, CSA group: 17.5 days). The cumulative incidence of grade 2 to 4 acute GVHD was 28.9% in the tacrolimus group and 32.6% in the CSA group (p=0.56). The estimate of chronic GVHD occurrence was 13.3% for the tacrolimus group and 36.0% for the CSA group (p=0.10). 8 patients died of transplantation related toxicities in the tacrolimus group and 22 patients in the CSA group (p=0.002). There was a higher frequency of deaths from thrombomicroangiopathy in the CSA group than in the tacrolimus group (6 vs 0: p=0.03). The 4-year survival rate was 82% for patients in the tacrolimus group and 52% for patients in the CSA group (p=0.001). Although a disadvantage existed in terms of HLA disparity in the tacrolimus group, there was no difference in the incidence of acute and chronic GVHD between the two groups. The present study shows the superiority of tacrolimus/MTX over CSA/MTX in overall survival because of lower incidence of regimen-related toxic deaths.
Revised Response Criteria for Malignant Lymphomas From the Members of the International Harmonization Project (IHP) of the Competence Network Malignant Lymphoma, Represented by:.
Authors: Cheson Bruce D. , Pfistner Beate , Juweid Malik E. , Specht Lena , Rosen Steven T. , Gascoyne Randy , Stroobants Sigrid , Diehl Volker 
Published: April 2020

Abstract
Standardized response criteria are essential for interpretation of clinical data, comparisons among clinical trials, development of new therapies, and approval of agents by regulatory agencies. In 1999, an International Working Group (IWG) developed recommendations for response assessment for non-Hodgkin’s lymphomas (NHL) that were adopted internationally by study groups and regulatory agencies and, subsequently, by clinical trials groups for Hodgkin lymphoma (HL) as well (Cheson et al, J Clin Oncol, 17:1244, 1999). Since their publication, several observations compelled a reassessment and, ultimately, revision of those guidelines, e.g., the availability of FDG-PET scans, new insights into lymphoma pathology and biology, the failure of the IWG guidelines to include HL and extranodal NHL, and features of the original guidelines that were found to be unclear as they were implemented into clinical trials. Most notable of these was the interpretation of the response category of Complete Remission unconfirmed (CRu). In the context of the IHP, a group of international lymphoma investigators with expertise in medical hematology/oncology, radiation oncology, nuclear medicine and imaging, pathology, biostatistics, and pediatrics were convened to revise the IWG guidelines. Committees focused on Response Criteria, Pathology/Biology, Endpoints, and Clinical Features, and discussions were initiated to undertake a major revision of the IWG guidelines. The important modifications that will be presented included, but were not limited to, integration of PET according to recent data (Juweid et al, J Clin Oncol, 23:4652, 2005), to facilitate the distinction between persistent tumor and scar/fibrosis, virtually eliminate the designation of CRu, and improve prediction of outcome. Guidelines were provided for the specific indications where this test can be currently recommended. Other proposals involved the role of flow cytometry and assessment of minimal residual disease. Response criteria for extranodal sites were also incorporated. Adoption of these revised guidelines by study groups will further improve the conduct and interpretation of clinical trials leading to more effective therapies for patients with lymphomas.
Acute GVHD May Play a Role in Preventing Relapse Following Reduced Intensity Allografts for Acute Myeloid Leukemia.
Authors: Andritsos Leslie , Augustin Kristan , Vij Ravi , DiPersio John F. , Devine Steven M. 
Published: April 2020

Abstract
The role of reduced intensity allografting in the treatment of patients (pts) with acute myeloid leukemia (AML) and the role that graft versus host disease (GVHD) plays in preventing relapse in this setting is unclear. While more pts may survive the initial period following allografting in comparison to those receiving full intensity transplants, the risk of relapse may be greater, particularly in those not in remission at the time of transplantation. Here we report the results of allogeneic transplants following a reduced intensity conditioning (RIC) regimen given to 158 consecutive pts with AML. All were all conditioned with an identical regimen containing Cyclophosphamide at 120mg/kg iv over 2 days (days −3 and −2) followed by a single dose of total body irradiation at 550cGy on day −1. HLA-identical (HLA-ID) siblings donated cytokine mobilized peripheral blood (PB) to 68 recipients and unrelated donor (UD) bone marrow (BM) was used for 90 patients. GVHD prophylaxis consisted of single agent cyclosporine (CSP) for recipients of HLA-ID allografts and CSP, methotrexate, and methylprednisolone in recipients of UD BM. The median age of recipients was 44 years (range 6–70), with 74 males and 84 females. 43 pts were in CR1, 47 in CR2 or 3, and 68 had relapsed or refractory disease. The majority of UD BM recipients were serologically identical with their donors at 6/6 antigens. There were no graft failures in either group.The median follow-up in survivors was long at 1903 days (range 938–2757). Overall survival (OS) was evaluated in relation to the development of any grade of acute GVHD. There were no significant differences in the incidence of grade 2–4 (30+/− 6%) or grade 3–4 (7+/−3%) acute GVHD in the HLA-ID PB or UD BM groups. Since OS was not significantly different between CR1 and CR2 pts, the results were pooled. The Kaplan-Meier (KM) estimate of 3 year OS in UD BM pts in CR was 45+/−9% in those with no acute GVHD compared to only 25+/−10% with any grade of acute GVHD (p=0.24). In recipients of HLA-ID PB who were in CR, 3 yr OS was 39+/−12% without acute GVHD and interestingly, 54+/−10% with acute GVHD. UD BM recipients not in remission at the time of transplant had dismal outcomes with or without acute GVHD, with less than 5% OS. No recipients of HLA-ID PB with active disease at the time of transplant remained alive if they did not develop acute GVHD versus 19+/−10% if they did (p=0.17).These data obtained in a large group of homogeneously treated pts suggest that acute GVHD may play an important role in preventing relapse after RIC and HLA-ID sibling PB transplantation. Following UD BM, acute GVHD appears to adversely affect OS. RIC should not be proposed in the unrelated donor setting if pts with AML are not in remission. Future efforts aimed at harnessing graft versus leukemia effects in the HLA-ID setting following RIC may lead to improvements in OS and are clearly warranted.
Chronic Graft Versus Host Disease (cGVHD) Following Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT): Higher Response Rate in Recipients of Unrelated Donor (URD) Umbilical Cord Blood (UCB).
Authors: Arora Mukta , Nagaraj Sriharsha , Wagner John E. , Barker Juliet N. , Brunstein Claudio G. , Burns Linda J. , MacMillan Margaret L. , Miller Jeffrey S. , Weisdorf Daniel J. 
Published: April 2020

Abstract
The nature of chronic graft versus host disease (cGVHD) after umbilical cord blood (UCB) transplant has not been well characterized. We analyzed clinical presentation and response to treatment in 170 patients with cGVHD (123 following transplant from an unrelated donor (URD) and 47 following transplant from UCB). URD transplant recipients were significantly younger (median age 25 (0.5–57) versus 39 (0.2–61) years, p = 0.002; and were less likely to receive a transplant from an HLA mismatched donor (33% versus 90%, p&lt;0.0001). Seven% and 43% of patients underwent a transplant using a non myeloablative conditioning in the URD and UCB groups, respectively (p&lt; 0.001). Progressive onset of cGVHD was seen in 27% and 19% of patients in URD and UCB cohorts (p =0.15) and platelet count of &lt; 100,000/μl was seen in 36% and 15% of patients (p =0.014), respectively. The median follow up was 5 (0.14–10.8) and 1.5 (0.02–8.8) years in the 2 groups, respectively. A higher rate of response (CR+PR) to treatment was seen in UCB group across all time periods. Rates of response were 48% versus 74% at 2 months (p =0.005); 49% versus 78% at 6 months (p =0.001) and 51% versus 72% at 1 year (p =0.03) in the URD and UCB groups, respectively. Overall survival at 2 years was 59% (50–67%) versus 71% (53–83%) at 2 years and at 5 years was 54% (44–63%) versus 64% (42–79%) (p=0.17). In multivariate analysis, progressive onset of CGVHD (RR=2.3, 95% CI 1.4–3.8−2.3,p=0.002), platelet count of &lt;100,000/μl (RR=3.5, 95% CI 1.7–7.3,p=0.0009), liver involvement (RR=2.5, 95% CI 1.4–4.6,p=0.002), and no CR or PR at 2 months (RR=3.5, 95% CI 2.1–5.9,p&lt;0.0001) were associated with significantly increased mortality. These data suggests that among patients undergoing transplant from unrelated donor or cord blood, despite similar clinical presentation, higher rates of response to treatment were seen in UCB recipients. Early identification of high risk groups (progressive onset, less than PR at 2 months, platelet count &lt; 100,000/μl and liver involvement should facilitate timely assignment of intensified therapy.
Response to Treatment Response 2 mo 2 mo 6 mo 6 mo 1 year 1year URD UCB URD UCB URD UCB CR+PR 49 (48) 29 (74) 54 (49) 32 (78) 53 (51) 23 (72) SD+Prog 53 (52) 10 (26) 56 (51) 9 (22) 52 (49) 9 (28)
Obesity Independently Predicts Event Free Survival (EFS) in Adults with BCR-ABL-Negative Acute Lymphoblastic Leukemia (ALL). A Retrospective Analysis of Two GIMEMA Studies.
Authors: Butturini Anna , Vignetti Marco , Gubbiotti Stefania , Meloni Giovanna , Recchia Monica , Di Raimondo Francesco , Morra Enrica , Palmieri Salvatore , Fabbiano Francesco , Liso Vincenzo , Pizzolo Giovanni , Marmont Filippo , Cantore Nicola , Cascavilla Nicola , Luppi Mario , Camera Andrea , Ronco F. , Sora F. , Peta Antonio , Tabilio Antonio , Foa Roberto , Mandelli Franco 
Published: April 2020

Abstract
Obesity predicted decreased EFS in pediatric ALL (ASH 2004, Abstract#992). Here we report the effect of obesity, defined as body mass index &gt;30, in 906 adults enrolled in two GIMEMA trials. The first study (1996–2001) included 45 obese (9.5%) and 426 non-obese patients. Obese patients were older, received lower total doses of vincristine (VCR) and daunomicin (DNR) and had more hepatic and pulmonary toxicity during induction than not-obese patients; the incidence of toxic deaths and complete remissions (CR) were similar. By multivariate analysis, obesity, high WBC, age &gt;30y and presence of BCR-ABL at diagnosis independently predicted EFS. Hazard ratios (HR) for any events were respectively 1.506 (1.059–2.142, p=0.0228), 1.002 (1.001–1.003, p=0.0022)), 1.015 (1.006–1.025, p=0.0014) and 1.8 (1.4–2.4, p&lt;0.0001). The effect of obesity on EFS was present across all levels of WBC, but was observed prevalently in BCR-ABL-negative patients. 3y-EFS in obese vs non-obese patients was 22.9% vs 39.5% (p=0.0064) in BCR-ABL negative patients and not significantly different (14% vs 22%, p=0.77 n.s.) in BCR-ABL positive patients. These results were verified in the following study started in 2000, which included 50 obese (11%) and 385 non-obese patients. In this study, obese patients received 28% and 21% less than the planned doses of VCR and DNR respectively; also they were more likely than non-obese patients to be &gt;30 y of age and BCR-ABL-positive. The incidence of toxicity, toxic deaths and CR were similar in obese and non-obese patients. In the BCR-ABL negative patients, obesity tended to predict EFS. 2y-EFS was 26.6% in the obese and 49.4% in the non-obese patients (p=0.067). By multivariate analysis HR for any events of obesity, WBC&gt;50 and age&gt;30 were respectively 1.53 (0.92–2.58, p=0.107), 1.64 (1.12–2.39, p=0.012) and 1.74 (1.19–2.54, p=0.004). In conclusion, obesity seems associated with a poorer EFS in patients with BCR-ABL negative ALL; this might be caused by the lower doses of chemotherapy obese patients receive. Studies aimed to clarify chemotherapy pharmacokinetics, toxicity and efficacy in obese patients are warranted.
Scoring Adherence in Hemophilia Care and Comparing It to Quality of Life (QofL).
Authors: duTreil Sue , Rice Janet , Leissinger Cindy A. 
Published: April 2020

Abstract
Non-adherence to home based treatment even 10% of the time in hemophilia care may portend a poor outcome and long-range quality of life issues, despite a still enormous financial cost. This study was a rigorous effort to quantify adherence and then compare it to QofL. 79 subjects with hemophilia (48 &gt;18-years and 31&lt;18-years) participated in the study and completed the SF-36 or Child Health Questionnaire (validated QofL forms). Subjects were either using on-demand (OD) treatment regimens or on high intensity (HI) treatment strategies i.e. prophylaxis or immune tolerance therapy. Physician’s specific treatment order for dose and frequency of clotting factor concentrate (CFC) were collected. Factor infusion logs kept by patients were reviewed to determine how factor use matched treatment recommendations. Infusion logs were maintained by 47 of 79 subjects (59%). The amount of CFC used was entered into a database along with the date of the infusion and the reason for the infusion. Due to vial size variability doses that were within 80% to 150% of the prescribed dose for children and 80% to 120% for adults were considered adherent. A scoring system was developed for both OD and HI users based on documented usage patterns. A given subject’s adherence score could range from 0 (representing total non-adherence) to 100% (representing perfect adherence). A subject’s adherence percentile was then ranked accordingly: 0% to 33% = Low Adherence, 34% to 66% = Moderate Adherence, 67% to 100% = High Adherence. Chi Square was used to determine the relationship between adherence and treatment regimen and a two-way analysis of variance was used to compare QofL in subjects with treatment logs to adherence and treatment regimen. Subjects on HI had lower adherence patterns than those on OD (p=. 018). Significant findings related to QofL included that body pain in children was higher with OD compared with HI (p=. 036), however this was not demonstrated in adults. Adults with low adherence patterns had higher mean scores in mental health then high (p=. 021) and moderate (p=. 068) adhering adults. Quantifying adherence and attempting to understand the relationship between adherence and QofL is an important component in the management of hemophilia.
Activation of C/EBPα in Hematopoietic Stem Cells Leads to Growth Suppression and Impairment of Megakaryocyte Differentiation.
Authors: Fukuchi Yumi , Shibata Fumi , Ito Miyuki , Goto-Koshino Yuko , Sotomaru Yusuke , Ito Mamoru , Kitamura Toshio , Nakajima Hideaki 
Published: April 2020

Abstract
C/EBPα is a critical regulator of early myeloid differentiation. Resent study showed that the loss of C/EBPα led to an augmentation of competitive repopulating activity of hematopoietic stem cells (HSCs). Our previous study using the transgenic (Tg) mice expressing an inducible form of C/EBPα (C/EBPα-ER) also showed that in vivo activation of C/EBPα by 4-hydroxy tamoxifen (4-HT) led to remarkable decrease of HSC population (Abstract #671, Blood104, 193a, 2004). In order to investigate further the role of C/EBPα in HSC homeostasis, we purified CD34− c-Kithi Sca-1hi lineage− cells (CD34−KSLs) from the C/EBPα-ER Tg mice and examined the effect of C/EBPα activation on their growth, self-renewal, and differentiation potential. Clonal proliferation assay showed that the growth of about 95 % of CD34−KSLs was suppressed in the presence of 4-HT. Single cell colony assay showed that the percentage of CFU-GEMM and CFU-MK remarkably decreased from 80 % to 2.1 % and from 2.1 % to 0 %, respectively by 4-HT treatment. In contrast, percentage of CFU-GEM increased from 0 % to 74 %, indicating that differentiation potential to megakaryocytes (MKs) was selectively lost by C/EBPα activation. To gain more insights into the cell fate determination at clonal level, we performed paired daughter cell colony assay. Sorted CD34−KSLs were clonally deposited into 96-well plates and allowed to divide once to generate daughter cell pairs, which were then separated by micromanipulation, and transplanted into control or 4-HT containing methylcellulose. 26 daughter cell pairs out of assessable 41 colony pairs lost MK differentiation capacity in the presence of 4-HT. In contrast, remaining 15 pairs took the same fate of differentiation in control and 4-HT. Surprisingly, while most of the CD34−KSLs stopped their growth upon C/EBPα activation, approximately 5 % of the cells proliferated even in the presence of 4-HT. These cells grew from a single cell to generate more than 45 cells and sustained multipotentiality to generate GEMM-colonies even after 8-days of culture. To further examine the effect of C/EBPα activation on self-renewal potential of HSCs, clonally sorted CD34−KSLs were allowed to divide once in 4-HT- or control-media, and the fate of each daughter cell was traced in methylcellulose. The result showed that GEMM-colony pairs were generated at similar frequency in control and 4-HT culture, indicating that the self-renewal capacity of CD34−KSLs was not affected by C/EBPα. These results indicated that activation of C/EBPα caused growth suppression and impaired differentiation to MKs in the majority of CD34−KSLs. However, small fraction does not respond to C/EBPα activation, indicating CD34−KSLs could be classified into two subpopulations by their sensitivity to C/EBPα.
Roles of MOZ in Hematopoiesis.
Authors: Katsumoto Takuo , Aikawa Yukiko , Ochiya Takahiro , Kitabayashi Issay 
Published: April 2020

Abstract
The AML1-CBFβ transcription factor complex is the most frequent target of specific chromosome translocations in acute myeloid leukemia (AML). The monocytic leukemia zinc finger (MOZ) gene, which encodes a MYST-type histone acetyltransferase (HAT), is also involved in leukemia-associated translocations such as t(8;16), t(8;22) and inv(8), which are associated with acute myeloid leukemia with M4/5 subtypes. We previously found that MOZ functions as a potent coactivator for AML1. To investigate roles of MOZ in normal hematopoiesis, we generated MOZ-deficient mice using gene-targeting method. MOZ homozygous mutant is embryonic lethal and it died between days 14 and 15 of gestation. In fetal liver of MOZ-deficient E14.5 embryos, the total cell numbers and the colony-forming cells (CFCs) in a methylcellulose medium were remarkably reduced when compared with wild-type littermates. Flow cytometry analysis indicated that hematopoietic stem cells (HSCs) and progenitors of both myeloid and lymphoid lineages were severely reduced in MOZ-deficient embryos. Especially, the levels of c-kit expression were strongly reduced in lineage-negative cells. Differentiation arrest of erythroid progenitors at a terminal stage and increase in the numbers of Mac-1 and Gr-1 positive cells suggest that MOZ also plays roles in cell differentiation of erythroid, monocytic and granulocytic lineages. In E12.5 MOZ deficient fetal liver cells, expression profile analysis revealed decreases in expressions of thrombopoietin receptor c-mpl, Wnt related ligand dkk2 and HoxA9 and increase in HoxA5 expression. To further determine roles of MOZ in HSCs functions and their progenitors differentiation ability, competitive reconstitution assays were performed. Ly5.2+ fetal liver cells from wild-type, heterozygous or homozygous mutant embryos together with Ly5.1+ competitor fetal liver cells were transplanted into γ-irradiated Ly5.1+/Ly5.2+ recipient mouse. Ly5.2+ wild-type cells were observed in recipient mice after transplantation. However, cells derived from MOZ homozygous mutant embryos were not detected in peripheral blood, bone marrow, spleen and thymus. Reduced population of cells derived from heterozygous mutant embryos were observed. These data suggest that MOZ is required for lymphoid and myeloid development and for self-renewal of HSCs.