bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2X7 Receptor Polymorphisms and Clinical Outcomes in Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Lee Kyung-Hun , Kim Inho , Yoon Sung-Soo , Park Seonyang , Kim Byoung Kook 
Published: April 2020

Abstract
The P2X7 receptor is a key player in processing and release of IL-1 family. We have recently demonstrated that A1513C polymorphism in P2X7 gene is related to the occurrence of infections and survival in HLA-matched sibling allogeneic stem cell transplantation (Lee et al., Haematologica2007;92:651–657). Here we extended our study by examining 3 SNP sites of P2X7 gene (A1513C, H155Y, and H270R) in all transplanted patients with hematological malignancies whose peripheral blood samples clinical data were available. Finally, 220 patients (146 acute leukemia, 30 chronic leukemia, 20 non-Hodgkin’s lymphoma, 19 myelodysplastic syndrome, and 5 multiple myemola) were included in the present study and 3 polymorphism sites of both donors and recipients were analyzed from peripheral blood samples. Donor 1513CC was associated with microbiologically documented bacteremia (56.3% for 1513CC donors vs. 30.9% for 1513AA or AC donors, P=.038). In contrast, recipient H155Y TT genotype was associated with lesser frequency of bacteremia (25.8% for TT recipients vs. 38.6% for CC or CT recipients, P=.055). Overall survival or treatment-related mortality did not differ significantly according to A1513C or H155Y polymorphisms. Recipient H270R GG genotype was significantly associated with shorter progression-free survival after transplantation (median, 567 days for GG recipients vs. 2122 days for AA or AG recipients, P=.042). The differences of overall survival according to H270R polymorphism, however, did not reach statistical significance (median 285 days vs. 314 days, P=.230). We conclude that A1513C, H155Y, and H270R polymorphisms in P2X7 receptor gene are related to the occurrence of infections and recurrences of hematological malignancies after allogeneic stem cell transplantation. Defining the polymorphisms may be helpful in optimal selection of patients and donors.
Progression-Free Survival According to H270R Genotype of Recipients Progression-Free Survival According to H270R Genotype of Recipients
Phenotypic Correction of Adamts13-Deficient Mice by Early Intra-Amniotic Gene Transfer of Lentiviral Vector Encoding ADAMTS13 Genes.
Authors: Niiya Masami , Endo Masayuki , Zoltick Philip W. , Muvarak Nidal E. , Motto David G. , Flake Alan W. , Zheng X. Long 
Published: April 2020

Abstract
ADAMTS13, a member of A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS) family, is mainly synthesized in the hepatic stellate cells, endothelial cells and megakaryocytes or platelets. It controls the sizes of von Willebrand factor (VWF) multimers by cleaving VWF at the Tyr1605-Met1606 bond. Genetic deficiency of plasma ADAMTS13 activity results in hereditary thrombotic thrombocytopenic purpura (TTP), also named Upshaw-Schülman syndrome. To develop a potential gene therapy approach and to determine the domains of ADAMTS13 required for recognition and cleavage of VWF in vivo, a self-inactivating lentiviral vector encoding human wild-type ADAMTS13 or variant truncated after the spacer domain (construct MDTCS) was administrated by intra-amniotic injection on embryonic day 8. Direct stereomicroscopy and immunofluorescent microscopic analysis revealed that the green fluorescent protein (GFP) reporter, ADAMTS13 and MDTCS were predominantly expressed in the heart, kidneys and skin. The synthesized ADAMTS13 and truncated variant were detectable in mouse plasma by immunoprecipitation and Western blot, as well as by proteolytic cleavage of FRETS-VWF73 substrate. The levels of proteolytic activity in plasma of mice expressing ADAMTS13 and MDTCS were 5 ± 7% and 60 ± 70%, respectively using normal human plasma as a standard, and this proteolytic activity persisted for at least 24 weeks in Adamts13−/−mice and 42 weeks in wild-type mice tested (the duration of observation). The mice expressing both recombinant ADAMTS13 and MDTCS showed a significantly decreased ratio of plasma VWF collagen-binding activity to antigen and a reduction in VWF multimer sizes as compared to those in the controls. Moreover, the mice expressing ADAMTS13 and MDTCS showed a significant prolongation of ferric chloride-induced carotid arterial occlusion time (9.0 ± 0.6 and 25.2 ± 3.2 min, respectively) as compared to the Adamts13−/− mice expressing GFP alone (5.6 ± 0.5 min) (p&lt;0.01). The ferric chloride-induced carotid occlusion time in Adamts13−/− mice expressing ADAMTS13 was almost identical to that in wild type mice with same genetic background (C56BL/6) (8.0 ± 0.2 min) (p&gt;0.05). The data demonstrate the correction of the prothrombotic phenotype in Adamts13−/−mice by gene transfer to the fetus by viral vectors encoding human wild type ADAMTS13 and the carboxyl terminal truncated variant (MDTCS), supporting the feasibility of developing a gene therapy based treatment for hereditary TTP. The discrepancy in the proteolytic activity of MDTCS between in vitro (Zhang P et al. Blood, 2007 in press) and in vivo in the present study suggests the potential cofactors in murine circulation that may rescue the defective proteolytic activity of the carboxyl-terminal truncated ADAMTS13 protease seen in vitro.
Elevated Ferritin Is Associated with Poorer Survival Following Nonablative Allogeneic Transplantation.
Authors: Mahindra Anuj , Sobecks Ronald , Rybicki Lisa , Brown Stacey , Pohlman Brad , Kalaycio Matt , Dean Robert , Andresen Steve , Sweetenham John , Bolwell Brian , Copelan Edward 
Published: April 2020

Abstract
Iron overload is a well-established adverse prognostic factor for allogeneic hematopoietic stem-cell transplantation in thalassemia and appears to adversely affect prognosis with myeloablative transplantation for other diseases as well. In thalassemia, modification of the preparative regimen improves prognosis in patients who are at high risk due to iron overload. We analyzed a large group of patients who received a nonablative preparative regimen for allogeneic transplantation to determine whether the adverse impact of iron overload was circumvented by nonablative transplantation. Sixty-four consecutive patients undergoing nonablative allogeneic transplantation between 12/00 and 12/06 had pretransplant ferritin levels within 100 days preceding transplantation. Median age was 57 (range, 24–67) years; 24 patients were female. Median interval from diagnosis to transplant was 14.5 months (range, 2.4 to 151.6). Diseases included AML (n=16), NHL (15), MDS (10), myelofibrosis (6), CLL (6), CML (5), MM (3), Hodgkin (2), and ALL (1). Six had undergone prior transplantation. Median ferritin was 961 ng/mL (range, 302–6251). All but two received Flu/TBI preparation. Thirty-nine were sibling and 25 unrelated donors. Recursive partitioning identified significantly better survival for patients with ferritin ≤ 1615 ng/mL (n=45) compared to those with ferritin &gt;1615 ng/mL (n=19; P=.012) as shown:
Figure Figure
Among age, gender, diagnosis, interval from diagnosis to transplant, extent of therapy prior to transplant, ferritin level, albumin, AST, alkaline phosphatase, bilirubin, LDH, risk group, donor source, degree of HLA match, donor to recipient gender, and CD34+ dose, only ferritin &gt;1615ng/ml (P=.010, HR= 2.74), older age (P=.049, HR= 1.63), and prior transplantation (p=.002, HR=5.78) were adverse prognostic factors for survival in multivariable analysis. The poorer survival was related to both a higher incidence of treatment-related mortality and a higher rate of relapse mortality, neither of which reached statistical significance. The addition of albumin, a negative acute phase reactant, did not change the prognostic impact of ferritin.
Conclusion: Similar to patients who undergo myeloablative transplantation, survival of patients who undergo nonablative allogeneic transplantation is adversely affected by elevated ferritin. It is important to assess the influence of specific factors on comparative results of myeloablative and nonablative transplantation. These results should stimulate study of iron chelation prior to allogeneic transplantations.
Validation of a Pretransplantation Assessment of Mortality (PAM) Score for Predicting Risk of Death in the First Two Years after Allogeneic Hematopoietic Cell Transplantation in a Tertiary Transplant Center.
Authors: Chopra Akhil , D’Abreo Nina , Nagaraj Gayathri , Aljumaily Raid , Styler Michael , Topolsky David , Crilley Pamela , Gracely Edward 
Published: April 2020

Abstract
Mortality rates after allogeneic hematopoietic cell transplantation for hematological malignancies remains high. Recently, a 50-point pretransplantation assessment of mortality (PAM) score was developed by clinical investigators at the Fred Hutchison Cancer Research Center utilizing eight pre-transplant clinical variables including age, donor type, disease risk, conditioning regimen, percentage of predicted FEV1, percentage of predicted DLCO, serum creatinine level and serum ALT level. The PAM score performed well to predict risk of death in the first two years after allogeneic hematopoietic cell transplantation. The objective of our study was to validate the PAM score in a retrospective cohort of patients that underwent allogeneic hematopoietic cell transplantation at Hahnemann University Hospital from 1986 until 2006. 400 patients underwent allogeneic hematopoietic cell transplantation from 1986 to 2006. 170 patients were found to be eligible for retrospective analysis since pre- transplant serum alanine aminotransferase (ALT) levels were not available for the remaining 230 patients. The PAM score was calculated for each patient using the scoring system outlined in the original article. The patients were categorized into four cohorts with scores ranging from 9 to 16 for category 1 (probability of death, 25%), from 17 to 23 for category 2 (probability of death, 25% to 50%), from 24 to 30 for category 3 (probability of death, 50% to 75%), and from 31 to 44 for category 4 (probability of death, 75%). Kaplan- Meier survival curves were generated for each of the four categories. Overall mortality was 62.9% at 2 years. PAM scores ranged from 11 to 36. 41 patients were grouped into category 1, 71 into category 2, 48 patients into category 3 and 10 patients into category 4. Mortality at 2 years was 39% in category 1, 56.3% in category 2, 85.4% in category 3 and 100% in the high-risk category. Compared to the low risk group, group 2 had a hazard ratio of 1.64 (p = 0.092, CI: 0.92 to 2.94); group 3 had a hazard ratio of 3.996 compared to the low risk group (p &lt; 0.001, CI: 2.23 to 7.16) and group 4 had a hazard ratio of 6.73 versus the low-risk group (p &lt; 0.001, 95% CI: 3.01 to 15.04). In conclusion, the PAM score successfully classified patients into distinct survival groups (p &lt; 0.001 for the comparison by log-rank test). Higher PAM scores were associated with progressively increased risk of death.
Figure Figure
Transplant Outcome Is Not Affected by Body Mass Index (BMI) in Patients with Haematological Malignancies.
Authors: Nikolousis Emmanouil , Paneesha Shankaranarayana , Holder Kathy , Bratby Lynn , Pillai Srinivas , Lovell Richard , Milligan Don 
Published: April 2020

Abstract
Bone marrow transplantation is frequently used as a consolidation therapy in patients with haematological malignancies to improve outcome. Obese individuals have larger absolute lean body and fat masses than non-obese individuals of the same age, gender and height, which might lead to altered pharmacokinetics of chemotherapeutic agents. Data on the impact of body mass on transplant outcome is conflicting. This study included 254 patients (M: 151; F: 103) with 283 transplant episodes (Autograft: 178, Allograft: 105). 81 patients had myeloma, 61 non Hodgkin’s lymphoma, 38 Hodgkin’s lymphoma, 34 acute myeloid leukaemia, 28 chronic lymphocytic leukaemia, 15 acute lymphoblastic leukaemia, 9 T cell non Hodgkin’s lymphoma, 6 each myelodysplasia and aplastic leukaemia and 1 each acute promyelocytic leukaemia and myelofibrosis. Statistical analysis was carried out using SPSS 13.0 for Windows. Overall survival (OS) and event free survival (EFS) were estimated by the Kaplan-Meier method. At transplantation 47% patients had normal & 52% high BMI. After a median follow-up of 14 month (range:0–75), mean OS in patients undergoing autograft with normal BMI was 52 months as compared to 54 with high BMI. Mean OS in patients undergoing allograft with normal BMI was 27 months as compared to 39 with high BMI (log rank test p value; autograft: 0.74 & allograft: 0.09). Odds Ratio for survival in autograft patients was 1.305 (95% CI: 0.611–2.786). For normal BMI patients OR for survival was 1.175(95% CI: 0.73–1.891), where as for high BMI patients 0.901 (95% CI: 0.678–1.197). Odds Ratio for survival in allograft patients was 0.512 (95% CI: 0.23–1.136). For normal BMI patients OR for survival was 0.751 (95% CI: 0.534–1.057), where as for high BMI patients 1.468 (95% CI: 0.921–2.341). Mean EFS in patients undergoing autograft with normal BMI was 42 months as compared to 50 with high BMI. Mean EFS in patients undergoing allograft with normal BMI was 26 months as compared to 48 with high BMI (log rank test p value; autograft: 0.4 & allograft: 0.3). This study shows that high BMI does not adversely impact on either OS or EFS in patients undergoing both autologous and allogeneic transplantation for haematological malignancies. On the contrary, the trend for OS appears to better in patients undergoing allograft with high BMI. We recommend patients with high BMI should not be excluded from having autologous transplantation. Studies with greater number of patients are needed to establish the potential beneficial impact of high BMI on survival in patients undergoing allogeneic transplantation.
Figure Figure
Reduced Intensity Conditioning Is Safe and Effective for Transplantation of Patients with Shwachman Diamond Syndrome.
Authors: Bhatla D. , Davies Stella M. , Harris R.E. , Crockett M. , Shoultz L. , Shenoy S. , Bleesing J. , Hansen M. , Jodele S. , Jordan M. , Filipovich A.H. , Mehta Parinda A. 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for the bone marrow dysfunction seen in patients with Shwachman-Diamond Syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced intensity conditioning protocol in 7 patients with SDS and bone marrow aplasia or MDS/AML. Patient demographics are summarized in Table 1 below. The preparative regimen consisted of Campath-1H for 4 successive days (day -22 to day -19), Fludarabine 30 mg/m2/day for 5 days (Day - 8 to day -4) followed by Melphalan 140 mg/m2 for 1 day (day -3). Four patients received matched related marrow, 2 received matched unrelated peripheral blood stem cells (PBSC) and 1 received matched unrelated marrow. All but one were 8/8 allele HLA matched. Graft-versus-host disease (GVHD) prophylaxis consisted of Cyclosporine(CSA) and Methotrexate in all except one patient who received tacrolimus and mycophenolate mofetil as she was CSA intolerant. All patients established 100% donor-derived hematopoiesis. No major regimen related toxicity was seen except hyperglycemia requiring insulin in one patient and Grade II renal insufficiency in 1 patient which resolved with conservative management. Transplant outcomes are described in Table 2. These data indicate that HSCT with reduced intensity conditioning is feasible in patients with SDS and associated with excellent hematopoietic recovery and modest morbidity.
Table 1. Patient Demographics Patients #1 #2 #3 #4 #5 #6 #7 Age(yrs) 8 10 12 6 3 29 1 Gender Male Male Male Male Male Female Female SBDS mutation 183_184 TA to CT 183_184 TA to CT K62X 183_184 TA to CT 183_184 TA to CT IVS2+2 T to C 183_184 TA to CT Clinical status Transfusion dependence, recurrent infections Cytopenias Cytopenias Dysplasia Cytopenias Acute myeloid leukemia Dysplasia, Cytopenias Marrow cytogenetics del20q12 and del7q31 i(7)(q10) del20q12 del20q12 del20q12 Complex karyotype including monosomy 7,del5q Normal Table 2. Transplant outcomes Patients Patients #1 #2 #3 #4 #5 #6 #7 Days to myeloid engraftment 15 12 15 11 14 14 13 Platelet Recovery(days) 27 39 33 18 68 14 not engrafted Donor Chimerism 100% 100% 100% 100% 100% 99.8% 100% Hospital stay(days) 29 32 35 28 29 22 46 Length of follow-up(days) 758 723 679 385 218 65 33 Acute GVHD Gd II skin None None None None Gd I skin None Lansky scale 100% 100% 100% 100% 100% 90% 60%
Myeloablative Intravenous Busulfan/Fludarabine Conditioning Does Not Facilitate Reliable Engraftment of Dual Umbilical Cord Blood Grafts in Adult Recipients.
Authors: Horwitz Mitchell , Chute John , Gasparetto Cristina , Long Gwynn , Rizzieri David , Morris Ashley , McPherson Jackie , Sullivan Keith , Chao Nelson 
Published: April 2020

Abstract
Bone marrow conditioning with the combination of myeloablative doses of intravenous busulfan (IVBu) with fludarabine (Flu) has gained wide acceptance as a viable alternative to the conventional busulfan and cyclophosphamide combination. When followed by transplantation with peripheral blood stem cells from matched related or unrelated donors, IVBu/Flu facilitates reliable engraftment with reduced toxicity (Blood. 2004;104:857). Whether this combination provides sufficient immunosuppression to facilitate engraftment of partially matched umbilical cord blood (UCB) grafts has yet to be reported. Ten patients with median age of 41 years (range 21–54 years) were enrolled in an IRB approved clinical trial with a primary endpoint to assess donor engraftment. Stopping rules were constructed to prevent graft failure from exceeding 20%. Disease characteristics include AML; CR1-1pt, CR2-3pts, MDS-4pts, CML-2pts. Seven of 10 patients had high-risk cytogenetic abnormalities. Conditioning consisted of fludarabine 40mg/m2 daily × 4 days and intravenous busulfan 130mg/m2 once daily × 4 days. Six patients received the drugs sequentially, and 4 concurrently. GvHD prophylaxis was provided by tacrolimus and mycophenolate mofetil. The cord blood grafts were at least 4 of 6 HLA-matched with the recipient and 3 of 6 HLA matched between grafts (low resolution class I, high resolution class II). The median combined cryopreserved total nucleated cell dose was 3.5 × 107/kg recipient body weight (range 2.1 to 4.4 × 107/kg). Engraftment of one or both UCB grafts was detected in only 4 of 10 recipients resulting in premature closure of the study as per graft failure stopping rules. None of the patients with donor engraftment achieved full donor chimerism and all ultimately died of relapsed disease. Of the 6 patients that experienced primary graft failure, 5 underwent second transplants (1 autologous, 4 haploidentical). One haploidentical and one autologous graft recipient remain alive and disease free 18 months and 13 months post transplant, respectively. In summary, 5 of 10 patients died of relapsed disease and 3 patients from treatment-related toxicity. Busulfan pharmacokinetic measurements were performed on the first and fourth dose. Interdose PK variability between day 1 and 4 was less than 15%. The mean and median AUCs were 4181 and 4195 μmol-min, respectively (range, 2634–5279 μmol-min). These levels are comparable to what has been previously reported for once daily IVBu dosing. We conclude that the myeloablative conditioning regimen of once daily IVBu with Flu provides insufficient immunosuppression to allow for engraftment of a partially matched umbilical cord blood graft.
CD34+ Viability Is a Critical Determinant of the Engraftment Potential of Umbilical Cord Blood (UCB) in Double Unit Transplantation.
Authors: Scaradavou Andromachi , Smith Katherine , Hawke Rebecca , Lee Sinda , Schaible Allison , Abboud Michelle , Collins Nancy , Kernan Nancy A. , Van den Brink Marcel , Barker Juliet N. 
Published: April 2020

Abstract
Compared to single unit historical controls double unit UCB transplantation (UCBT) has been associated with improved engraftment and survival in adult recipients, despite sustained donor engraftment of only one of the units. However, the mechanism of this advantage and unit predominance is not understood. Our hypothesis was that superior CD34+ and CD3+ viability (measured by 7-AAD staining) would be associated with unit predominance. Therefore, we evaluated 26 double unit UCBT recipients [median age 36 yrs (9–64); median weight 73 kg (40–111)] with high-risk hematologic malignancies who received myeloablative (n=15) or non-myeloablative (n=11) conditioning according to age and diagnosis. Units were 6/6 (n=2), 5/6 (n=25) and 4/6 (n=25) HLA-A, B antigen, DRB1 allele matched to the patient and ≥3/6 to each other. Flow cytometric evaluation was performed within 2 hours of thaw using CD45-FITC/CD34-PE/7-AAD/CD3-APC (dual-platform, modified ISHAGE protocol). 25/26 patients (96%) demonstrated donor engraftment by STR evaluation of day+21 bone marrow with one unit predominating (the “winner”). The % post-thaw CD34+ and CD3+ viability for the 26 double unit pairs is shown. Patients could be divided into 3 groups: 1) 10 in whom one of the 2 units had CD34+ viability ≥75% (always the winner) and the other &lt;75% (always the loser); 2) 15 in whom both units had CD34+ viability ≥75% (either one was the winner); and 3) 1 in whom both units had CD34+ viability &lt;75% and neither unit engrafted. CD3+ viability strongly correlated with CD34+ viability and was not an independent predictor of unit predominance. In univariate analysis infused viable CD3+ dose/kg was associated with unit predominance, while infused TNC/kg, viable CD34+/kg, CFU-total/kg, CFU-GM/kg, HLA-match and order of infusion were not. In summary, all engrafting units had CD34+ viability ≥75% and none of the units with CD34+ viability &lt;75% engrafted (p: 0.007). Thus, in our analysis of unit predominance we have demonstrated that the % post-thaw CD34+ viability (but not the infused viable CD34+ dose) dictated the “engraftment potential” of a UCB unit, and, using the threshold of ≥75% viability, 12/52 units (23%) were unacceptable. When both CB units had CD34+ viability ≥75%, other factors (possibly related to CD3+ dose) determine unit predominance. Importantly, the finding that CD34+ viability is a marker of unit quality on the day of the transplant, if confirmed, has major implications for the clinical practice of UCBT. It suggests that double unit UCBT is superior because this approach significantly increases the chance that patients will receive at least one unit with engraftment potential.
Figure Figure