bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genoidentical Donor Versus A, B, Cw, DR, DQ, HLA Allelic-Matched Unrelated Donor for Stem Cell Transplantation in Patients with Standard Risk Haematological Malignancy.
Authors: Yakoub-Agha Ibrahim , Boiron Jean-Michel , Michallet Mauricette , Milpied Noel , Bourhis Jean-Henri , Cahn Jean-Yves , Buzyn Agnes , Gratecos Nicole , Esperou Helene , Vernant Jean-Paul , Raffoux Colette , Golmard Jean-Louis , Jouet Jean-Pierre , Kuentz Mathieu 
Published: October 2019

Abstract
To compare outcome of pts with standard risk hematological malignancy undergoing allogeneic stem cell transplantation (allo-SCT) from either allelic A, B, Cw, DR and DQ HLA-matched unrelated (so called 10/10) or HLA-matched sibling donor, we conducted a prospective study including 12 French BMT centres. Between 01/2000 and 12/2002, 236 consecutive pts were enrolled. Fifty five pts received unrelated allo-SCT (pheno-group) and 181 received genoidentical allo-SCT (geno-group). Conditioning regimen associated TBI and Cy in all pts. Pts who received ATG with conditioning were excluded. GVHD prophylaxis consisted on Cs-A plus MTX. Diagnoses of the underlying disease were, AL (n=175) of whom 47 were in CR > 1; CML (n=43) of whom 4 were with accelerated phase and myelodysplastic syndrome (n=18) of whom 11 with untreated disease. The analyses were performed at the reference date of december 31th 2003. The two groups were comparable in terms of patients’ initial characteristics. However, pts of pheno-group were slightly younger and had more often CML whereas those belonging to geno-group had more often acute leukemia in 1st remission . At the date of analysis, the median follow-up was 955d (373–1398). The overall survival was 63% and 52,5% (p=NS) for geno and pheno-group, respectively. Furthermore, the statistical power was insufficient to demonstrate an equivalence of the two survival curves.. Although, the occurrence of acute GVHD of grade ≥2 was statistically higher in pheno-group (67% vs 52%, p=0.0), there was no significant difference en term of TRM between the two groups (27% vs 33% for geno and pheno-group, respectively). Relapse rates were 20% vs 26% and ultimately EFS (56% vs 52%) for geno and pheno-group. In multivariable analysis, only age (>36 years) and positive-CMV serology of recipient were found to adversely influence EFS. Finally, there was no demonstration of an independent prognostic value of the donor origin on outcome. In conclusion, although, the equivalence was not fully demonstrated between the two groups, these preliminary results of allo-SCT from 10/10 HLA-matched unrelated donor compare favourably to those obtained with HLA-matched sibling donor in patients with standard risk haematological malignancies.
Impact of Molecular HLA Matching for Allogeneic Stem Cell Transplantation from Unrelated Donors.
Authors: Chalandon Yves , Halter Joerg , Guengoer Tayfun , Tichelli Andre , de Faveri Grazia Nicoloso , Chapuis Bernard , Seger Reinhard , Schanz Urs , Gratwohl Alois , Roosnek Eddy , Tiercy Jean-Marie , Passweg Jakob R. 
Published: October 2019

Abstract
Two hundred and fourteen unrelated donor transplants (HSCT) using peripheral blood (N=60) or marrow (N=154) as a stem cell source have been performed in Switzerland since 1990. All transplants were coordinated by the Swiss bone marrow donor registry and were performed at 4 different institutions. Median age was 28 (1–61) years, and 132 (62%) patients were male. Twenty-four patients with malignancy underwent transplants with reduced intensity conditioning regimens. T-cell depletion was performed in 45 patients. Patients had CML (62), AML (53), ALL (36), MDS/MPS (31), lymphoid malignancies (14), acquired or congenital aplastic anemia (11), or other inherited disorders (7). Sixty-two patients with AML, ALL or CML were transplanted at an early disease stage, i.e. CR1 or 1st chronic phase, the remainder with more advanced disease. All donor/recipient pairs underwent high resolution HLA typing in the LNRH, the Swiss national reference laboratory for histocompatibility in Geneva. Donor/recipient pairs were HLA-A, -B, -C, -DRB1/B3/B5, -DQB1 matched (130), or were mismatched at the HLA-A or B (10), HLA-C (29) HLA-DR (14), HLA-DQ (16) or at multiple (15) loci. Median follow-up of surviving patients was 34 months. Survival probabilities (± 95% CI) at 2 years were, in decreasing order 62 ± 9% for recipients of HLA 10/10 matched transplants, 46 ± 26% with DQB1 mismatch, 42 ± 20% with HLA-C mismatch, 30 ± 27% with HLA-DRB1 or DRB3 mismatch, 15 ± 26% with HLA-A or B mismatch and 13 ± 18% with multiple mismatches, p<0.0001. In multivariate analysis HLA compatibility, as defined by molecular typing, was the variable most significantly associated with survival and treatment-related mortality.
Multivariate analysis for survival
Factor RR (95% CI) P Age 1.014 (1.001-1.028) 0.04 HLA matching Match 1 0.001 DQ mismatch 1.38 (0.65-2,92) C mismatch 2.12 (1.04-4.32) DR mismatch 2.17 (1.21-3.89) A/B mismatch 3.66 (1.79-7.49) Multiple mismatches 4.35 (2.32-8.14)
Unrelated donor transplantation is increasingly used in Switzerland to treat a variety of disorders. Long term survival in recipients of transplants from HLA-A/B/C/DR/DQ-matched donors (10/10) is comparable to that achieved with genotypically identical sibling donors. Single mismatches at HLA-C or DQB1 loci may be more acceptable than A, B or DR-incompatibilities which are associated with decreased survival. Without a suitable donor, alternative methods to unrelated donor HSCT should be considered.
Comparison between Anti-Thymocyte Globulin and Alemtuzumab and the Possible Impact of KIR-Ligand Mismatch in Melphalan/Fludarabine Dose-Reduced Conditioning Followed by HLA-Matched and Mismatched Unrelated Stem Cell Transplantation in Patients with Multiple Myeloma.
Authors: Kroeger Nicolaus , Shaw Brownen , Iacobelli Simona , Zabelina Tatjana , Peggs Karl , Shimoni Avichai , Nagler Arnon , Binder Thomas , Schwerdtfeger Rainer , Kiehl Michael , Sayer Herbert G. , Ayuk Francis , Eiermann Thomas , Marks David 
Published: October 2019

Abstract
We compared anti-thymocyte globulin (ATG-Fresenius median dose 60 mg/kg: n= 48) with alemtuzumab (Campath-1H 100mg: n=25) in 73 patients with multiple myeloma, who underwent dose-reduced conditioning with melphalan and fludarabine, followed by allogeneic stem cell transplantation from matched (n=63) or mismatched (n=10) unrelated donors. Patients of the ATG group had higher age (median 50 vs 47 years, p=0.05), more prior high-dose chemotherapies (p<0.001), while in the Campath group more bone marrow as stem cell source was used (p<0.001). No primary graft failure occurred in both groups. Patients receiving alemtuzumab had a significant faster engraftment of leukocyte (p=0.03) and of platelets (p=0.02) and a lower incidence of acute GvHD grade II-IV (24 vs 47%, p=0.05). However, after treatment with donor lymphocyte infusion due to persistent disease or mixed hematopoietic chimerism the difference of acute GvHD grade II-IV between alemtuzumab and ATG treated patients did not reach statistical significance (32 vs 47%, p=0.2). No difference in incidence of chronic GvHD was observed (25 vs 33%, p=0.6) More CMV seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs 47%, p=0.001). The cumulative incidence of treatment related mortality at 2 years for ATG and Campath was 29.3% (CI=17–50%) vs 28.5% (CI=15–54%), p=0.7. No significant difference could be observed in the estimated 2 years OS and PFS between ATG and Campath: 53% (CI:38–75) vs 45% (CI:28–73) and 29% (CI:16–54) and 36% (CI: 20–62), respectively. For PFS, in a multivariate analysis relapse to prior high-dose chemotherapy was the strongest negative factor: HR 2.9, p= 0.001. Including only those patients who did not experienced any relapse at time of allogeneic stem cell transplantation the Campath-group had a 2.5 fold higher risk of progression in comparison to the ATG group, but without reaching statistical significance (HR: 2.5, p=0.15). Ten out of 73 patients had KIR-ligand mismatch in GvH direction. While in patients without KIR-ligand mismatch the cumulative incidence of relapse at two years was 50%, none of the KIR-ligand mismatched patients relapsed so far (p=0.02). The immunosuppressive effect from Campath is stronger than ATG resulting in less acute GvHD, but requires more DLI procedures to control diseases and resulted in a trend to a lower PFS in chemosensitive patients. This preliminary data further implicated a major role of KIR-ligand mismatch transplantation in multiple myeloma
Pharmacogenetics of Cyclophosphamide in Patients with Beta Thalassemia Major Undergoing Bone Marrow Transplantation.
Authors: Poonkuzhali Balasubramanian , Salamun Desire , Shaji Ramachandran V. , George Biju , Mathews Vikram , Chandy Mammen , Krishnamoorthy Rajagopal , Srivastava Alok 
Published: October 2019

Abstract
Cyclophosphamide (Cy) is commonly used in conditioning therapy for bone marrow transplantation (BMT). The conversion of Cy to its first active metabolite 4-hydroxy cyclophosphamide (4-HCy) is mediated by several enzymes of the cytochrome P450 (CYP450) family [CYP2B6, 2C9, 2C19 and 3A4]. Since the pharmacokinetics (PK) of 4-HCy is formation rate limited, the AUC ratio of 4-HCy/Cy reflects better the degree of systemic exposure to 4-HCy. The PK of Cy and HCy exhibits up to 20 fold inter-individual variation in patients during conditioning. To understand the mechanisms underlying the variation in Cy metabolism, we analyzed the PK of Cy and 4-HCy in 40 consecutive patients with beta thalassemia major undergoing BMT and correlated them with the common polymorphisms of CYP450 2B6, 2C9 and 2C19 genes and the pre transplant hepatic status (Lucarelli class) of the patient. All patients received Cy at a dose of 50mg/kg as one-hour intravenous infusion for 4 days (day -5 to -2) after 4 days of busulfan (day-9 to -6). Levels of Cy and 4-HCy were measured using high performance liquid chromatography. Genotyping for CYP2B6 G516T, CYP2C9 *2, *3 and CYP2C19*2 and *3 were done using PCR-RFLP methods. There was a 4–20 fold inter-patient variation in the PK of Cy and 4-HCy. Mean AUC of Cy was 2288±1169 mg* h/ml, (range: 674–5126), while that of AUC of 4-HCy was 5.67±2.52 mg* h/ml (range: 0.817–11.17). Patients with wild type CYP2B6 G/G genotype had significantly higher Cy 4-hydroxylation than those with the homozygous mutant genotype (T/T).
CYP4502B6, 2C9, 2C19 genotypes and ratio of AUC 4HCy/AUC Cy
CYP2B6 G/G (n=15) G/T (n=8) T/T (n=16) t-test p value 0.0033±0.0014 0.003±0.0013 0.0023±0.0011 0.03 (G/G vs. T/T) CYP2C9 *1/*1 (n=25) *1/*2 (n=3) *1/*3 (n=9) *2/*3 (n=2) *3/*3 (n=1) 0.003±0.0016 0.0037±0.0009 0.0023±0.0011 0.0014, 0.0015 0.0073 0.076 (*1/*2 vs. *1/*3) CYP2C19 *1/*1 (n=26) *1/*2 (n=10) *2/*2 (n=3) 0.0026±0.001 0.0036±0.0012 0.0029±0.0013 0.016 (1/1 vs. 1/2)
One patient with homozygous mutant genotype CYP 2C9 3/3 showed 2.6 fold higher Cy 4-hydroxylation (0.0073 vs. 0.0026), while two patients with CYP2C9 2/3 genotype had 2 fold lower than the mean of the ratio for all 2C9 genotypes. Patients with CYP2C19 1/2 genotype showed significantly higher ratio than those with CYP2C19 1/1 genotype. No association was found between patients’ pre- transplant liver status (Lucarelli class) and Cy 4-hydroxylation. We conclude that 4-hydroxylation of Cy is significantly influenced by CYP2B6, 2C9 and 2C19 genotypes. This could explain the wide inter individual variation in Cy PK which should be correlated with toxicity and outcome of BMT.
Cytochrome C Related Caspase Activation Determines Treatment Response in Childhood B- Precursor ALL.
Authors: Meyer Lueder H. , Karawajew Leonid , Schrappe Martin , Ludwig Wolf D. , Debatin Klaus M. , Stahnke Karsten 
Published: October 2019

Abstract
Drug resistance and treatment failure in acute leukemia may be attributed to apoptosis resistance in leukemia cells since defects in apoptosis signal transduction are commonly acquired during malignant transformation. Expression analysis of single molecules with regard to clinical outcome could so far not identify common apoptosis defects with prognostic value in primary acute leukemias. We addressed the role of apoptosis signaling for the initial response to induction treatment in pediatric B precursor lymphoblastic leukemia by functional assays. Apoptosis signaling in response to survival factor withdrawal was assessed in 82 primary leukemia samples by measurement of the key apoptotic events, caspase-3 activation and mitochondrial cytochrome c release.
Caspase-3 activation directly correlated to the initial response to treatment assessed by the percentage of leukemia cells in bone marrow on day 15 (p = 0.015). Intact apoptosis signaling was indicated by a significant correlation of caspase activation and cytochrome c release was found especially in the groups of good responding patients (rs 0.375 – 0.502; p = 0.001). Interestingly, this correlation was completely absent in all groups of poor responding patients defined by insufficient leukemia cell reduction on day 8, 15 or 33.
The efficacy of apoptosis signal induction in the individual leukemia is expressed by the parameter CRAC (Cytochrome c Related Activation of Caspase-3), relating the extent of caspase activation to cytochrome c release in a single patient sample. Ten of twelve patients with prednisone poor response (chi square, p= 0.031) and all patients not achieving remission on day 33 (4 of 4) had negative CRAC values, indicating deficient cytochrome c related caspase activation. Furthermore, the CRAC negative group revealed significant higher percentages of leukemia cells in bone marrow on day 15 (n=37, mean 22.8) than the CRAC positive patients (n=30, mean 6.2, p = 0.004). In addition all four relapse patients showed negative CRAC values indicating a prognostic value beyond initial treatment response.
The data show that the intact relation of cytochrome c release and caspase activation indicating an intact apoptosome function is important for efficient remission induction treatment in childhood B precursor ALL. Assessment and quantification of this relation for individual patients by the parameter CRAC may serve as potential factor for treatment stratification.
Defective P38 MAPK Signalling Impairs Chemotactic but Not Proliferative Responses to SDF-1 in Acute Lymphoblastic Leukemia.
Authors: Bendall Linda , Baraz Rana , Juarez Julius , Shen Sylvie , Bradstock Ken 
Published: October 2019

Abstract
The chemokine SDF-1 regulates leukemic cell motility and proliferation but the importance of these functions in the growth and dissemination of leukemia is unclear. We examined SDF-1-mediated responses of cells from 27 cases of acute lymphoblastic leukemia (ALL). Although cells from the majority of cases showed chemotactic and proliferative responses to SDF-1, a subset of cases (18%) did not undergo chemotaxis in response to SDF-1 (unresponsive cases). These unresponsive cases also failed to increase b1 integrin-mediated adhesion to fibronectin or adhesion to bone marrow fibroblast layers. However the unresponsive cases could still elicit a calcium flux in response to SDF-1 and three of the four cases internalised the receptor, CXCR4, following exposure to SDF-1. In contrast, the CXCR4 antagonist, TC14012, inhibited proliferation of both responsive and unresponsive cases in stromal-dependent cultures, demonstrating that the unresponsive cases were still able to undergo proliferative responses to SDF-1. Examination of the signalling pathways activated by SDF-1 in responsive cells revealed increased phosphorylation of AKT, ERK and p38 MAPK 2 to 5 minutes following stimulation. However, cells from the unresponsive cases failed to phosphorylate p38 MAPK kinase when stimulated with SDF-1, while phosphorylation of AKT and ERK were comparable with that observed in responsive ALL cases. Inhibition of p38 MAPK by SB203500 completely inhibited the chemotaxis of responsive ALL cells to SDF-1 gradients suggesting that signalling through p38 MAPK is essential for ALL cell chemotaxis. Therefore it is likely that the absence of p38 MAPK phosphorylation in unresponsive cases underlies their lack of chemotaxis to this chemokine. The ability of the unresponsive cases to undergo SDF-1 driven proliferation in the absence of p38 MAPK phosphorylation suggests that, despite being absolutely required for chemotactic responses, induction of phosphorylation of p38 MAPK is not required for proliferative responses. No correlation was observed between CXCR4 expression and chemotactic function, in vitro migration into bone marrow stromal layers, and engraftment of leukemic cells in NOD/SCID mice. This study suggests that signalling through p38 MAPK is required for ALL cell chemotaxis, but not for proliferation, and that chemotactic responses to SDF-1 are not essential for leukemic cell engraftment.
Efficient Thrombin Generation Requires Molecular Phosphatidylserine, Not a Membrane Surface.
Authors: Majumder Rinku , Weinreb Gabriel E. , Lentz Barry R. 
Published: October 2019

Abstract
Activation of prothrombin to thrombin is catalyzed by “prothrombinase” complex, traditionally viewed as factor Xa (FXa) in complex with factor Va (FVa) on a phosphatidylserine (PS)-containing membrane surface, which is widely regarded as required for efficient activation. Activation involves cleavage of two peptide bonds and proceeds via one of two released intermediates or through “channeling” (activation without release of an intermediate). We ask here whether the PS molecule itself, not the membrane surface, is sufficient to produce fully active human “prothrombinase” complex in solution. Both FXa and FVa bind soluble dicaproyl-phosphatidylserine (C6PS). In the presence of sufficient C6PS to saturate both FXa and FVa2 (light isoform of FVa), these proteins form a tight (Kd = 0.6 ±0.09 nM at 37°C) soluble complex. Complex assembly occurs well below the critical micelle concentration of C6PS, as established in the presence of the proteins by quasi-elastic light scattering and pyrene fluorescence. Ferguson analysis of native gels show that the complex migrates with an apparent molecular mass only slightly larger than that expected for one FXa and one FVa2, further ruling out complex assembly on C6PS micelles. Human prothrombin activation by this complex occurs at nearly the same overall rate (2.2x108 M− 1sec− 1) and via the same reaction pathway (50–60% channeling, rest via meizothrombin intermediate) as activation catalyzed by a complex assembled on PS-containing membranes (4.4x108 M− 1sec− 1). These results question the accepted role of PS-membranes as providing “dimensionality-reduction” and favor a regulatory role for platelet-membrane-exposed PS.
Outcome of Submyeloablative Allogeneic HSCT for Hematologic Malignancies: Development of a Prognostic Model Based on Pre-Transplant Characteristics.
Authors: Mehta Jayesh , Evens A. , Frankfurt O. , Gordon L. , Grinblatt D. , Kaminer L. , Meagher R. , Tallman M. , Williams S. , Winter J. , Singhal S. 
Published: October 2019

Abstract
Our aim was to identify pre-transplant variables affecting the outcome of submyeloablative HSCT in 63 patients (27–66 y, median 52) with NHL/Hodgkin/CLL (n=29), acute leukemia (n=19), and myeloma (n=15). Donors were HLA-matched sibs (n=37), 10/10 allele-matched unrelated (n=19), or 1-locus/allele mismatched (n=7). The conditioning was 100 mg/m2 melphalan with (n=42; no prior auto) or without (n=21; prior auto) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised cyclosporine-mycophenolate (HLA-matched sibs) or tacrolimus-mycophenolate (others). G/GM-CSF were not used. Supportive care was uniform. 16 patients died of transplant-related causes (TRM), and 35 relapsed (8 alive after salvage therapy). Of the variables analyzed in univariate fashion for effect on OS, the following were found to be significant and were entered into a Cox model for TRM, relapse, EFS and OS: age (83% <60 y vs 17% ≥60 y), performance status (33% 0 vs 41% 1 vs 25% ≥2), chemosensitivity (60% refractory vs 40% non-refractory), donor (63% sib vs 37% unrelated), HLA (89% match vs 11% mismatch), donor age (48% ≤45 y vs 52% >45 y), 108/kg CD3+ cells infused (49% <3 vs 51% ≥3), LDH (56% normal vs 44% increased), platelet count (40% <100 vs 60% ≥100), albumin (32% ≤3 vs 68% >3), and hemoglobin (24% <9 vs 76% ≥9). Relapse was higher with refractory disease (RR 3.2; P=0.003) and donor age >45 (RR 2.7; P=0.007), and TRM higher with PS ≥2 (RR 22.7 vs PS 0; P=0.001), donor age >45 (RR 5.3; P=0.013) and increased LDH (RR 8.6; P=0.003). The table shows factors influencing OS and EFS.
Variable OS DFS Adverse Favorable RR (95% CI) P RR (95% CI) P PS ≥2 PS 0 0.17 (0.06–0.47) 0.001 0.28 (0.11–0.78) 0.007 PS ≥2 PS 1 0.48 (0.24–0.98) 0.045 0.50 (0.24–1.03) 0.061 Increased LDH Normal LDH 0.29 (0.14–0.62) 0.001 0.43 (0.22–0.83) 0.012 Refractory disease Non-refractory disease 0.38 (0.15–0.92) 0.033 0.36 (0.17–0.77) 0.008 Donor age >45 Donor age ≤45 0.39 (0.19–0.77) 0.007 0.27 (0.14–0.53) <0.001
Scoring 1 point for each adverse factor (2 for PS ≥2), patients were divided into 4 groups: none (n=9), 1–2 (n=20), 3–4 (n=29), and 5 (n=5). The figures below show adjusted OS and EFS curves derived from the Cox analysis by the number of adverse variables. The figures below show actual OS and EFS Kaplan-Meier curves by the number of adverse variables.
Figure Figure
The figures below show actual OS and EFS Kaplan–Meier curves by the number of adverse variables.
Figure Figure
Interestingly, diagnosis, patient age and type of donor did not affect outcome. These data will allow better prediction of outcome in patients proposed to be treated with this regimen, and suggest that modification of therapy is needed for patients with ≥3 adverse variables to improve survival.
Tyrosine Phosphoproteomics of FLT3 Signaling.
Authors: Gu Tinglei , Nardone Julie , Lee Kim , Gygi Steven , Rush John , Comb Michael , Polakiewicz Roberto 
Published: October 2019

Abstract
Activating mutations of Flt3 are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Recently, FLT3 has been implicated in the pathogenesis of infant and childhood ALL. FLT3 inhibition has been shown to kill ALL cells with high levels of FLT3 expression. Using immunoaffinity purification of phospho-tyrosine peptides followed by tandem mass spectrometry, we not only identified two new AML cell lines with activated FLT3, but also generated phosphotyrosine profiles for five cell lines that express either WT or ITD mutation of FLT3. We identified six novel tyrosine phosphorylation sites in FLT3. To further investigate the FLT3 pathway, we employ stable isotopic amino acids in cell culture (SILAC) to differentially label proteins in FLT3 inhibited versus uninhibited cell lines. Quantitative SILAC experiment identified over 100 proteins, whose tyrosine phosphorylation status are regulated by FLT3. Furthermore, it reveals common and distinct signaling pathways activated by either WT FLT3 in B-ALL or FLT3-ITD in AML. Our study represents a breakthrough in our understanding of FLT3 signaling network. It could have important implications for the design of novel therapeutic approaches and the identification of biomarkers for leukemia with activated FLT3.