bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Risk of Epstein-Barr Virus Associated Post-Transplant Lymphoproliferative Disorder (EBV-PTLD) after Anti-Thymocyte Globulin (ATG) Non-Myeloablative (NMA) Conditioning for Umbilical Cord Blood Transplantation (UCBT).
Authors: Brunstein Claudio G. , Weisdorf Daniel J. , DeFor Todd , Tolar Jakub , Wagner John E. 
Published: April 2020

Abstract
EBV-PTLD is a known complication of alternative donor hematopoietic stem cell transplantation (HSCT) particularly when used in combination with HSC T-cell depletion and ATG. Initial reports in the setting of UCBT suggested a low incidence of EBV-PTLD (2–5%). We reviewed 335 consecutive patients (pts) who underwent UCBT at our institution between 7/19/94 and 3/29/05. Median age, weight, and follow-up were 16 years (0.2–69), 53.7kg (3.8–134.0) and 1.2 years (77 days9.2 years), respectively. Equine ATG (ATGAM) was used as part of a myeloablative (MA, Cy 120 mg/kg and TBI 1320–1375 cGy ± Flu 75 mg/m2) and non-myeloablative (NMA, Cy 50 mg/kg, Flu 200 mg/m2 and TBI 200 cGy) preparative regimen in 175/240 and 30/95 patients, respectively. As previously reported the overall incidence of EBV viremia and EBV-PTLD remained low. Overall, use of ATG lead to an increase in the incidence of EBV viremia (defined as &gt; 1,000 copies of EBV DNA per mL of whole blood) and EBV-PTLD (14/205 [7%] with vs. 1/130 [0.7%] without ATG [p=0.16]), but this was not statistically significant. In recipients of a MA preparative regimen, EBV viremia or EBV-PTLD was observed in 8/175 (5%) who received ATG and in 0/65 who did not (p=0.81). However, a higher risk of EBV viremia and PTLD was observed in recipients of ATG and a NMA preparative regimen. EBV viremia or EBV-PTLD after NMA preparative regimen was observed in 6/30 (20%) pts who received ATG and 1/65 (2%) who did not (p&lt;0.01) For the whole group, median time to development of EBV-PTLD was 133 days (54–407) with no difference between the MA and NMA groups [132 days (92–407) vs. 133 days (54–247)]. Among 9 pts who developed EBV-PTLD, 5 are alive (2 MA and 3 NMA) 113-1668 days after UCBT. Therefore, we conclude that patients undergoing a NMA UCBT with ATG are at uniquely higher risk for the development of EBV reactivation or EBV primary infection and EBV-PTLD. Routine monitoring of EBV viral load and pre-emptive treatment of patients who develop a positive viral load must be considered for this group of patients.
Donor KIR Genotype Does Not Affect VZV Reactivation after Allogeneic Haematopoietic Stem Cell Transplantation.
Authors: Narayanan Sujaatha , Nagra Sandeep , Mahendra Premini , Clark Fiona J. , Craddock Charles F. , Osman Husam , Briggs David C. , Moss Paul A. , Cook Mark A. 
Published: April 2020

Abstract
Background. Varicella zoster virus (VZV) reactivation is a common occurrence after allogeneic haematopoietic stem cell transplant (HSCT) and a cause of significant morbidity. We have recently demonstrated the protective effect of donor KIR genotpye against cytomegalovirus (CMV) reactivation- specifically the protective effect of the broad ’B’ haplotype containing multiple activating KIR genes1. This retrospective study was designed to investigate whether donor KIR genotype confers an equivalent protective effect against VZV reactivation.
Method. 152 patients who underwent allogeneic HSCT at a single centre were identified. Those with pre-transplant serology consistent with previous exposure to VZV were defined as at risk of VZV reactivation. All patients received aciclovir 800mg daily as routine prophylaxis. The diagnosis of VZV reactivation was made clinically. Cases of VZV reactivation were identified by examination of the case records. KIR genotyping was performed on donor DNA using PCR-SSP. The individual KIR genes KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5 and 3DS1, as well as the broad KIR haplotypes ’A’ and ’B’, were assessed by univariate and multivariate analysis for an effect on VZV reactivation. Also assessed was the impact of recipient HLA-C type, recipient HLA-Bw4/Bw6, donor type (sex-matched sibling, sex-mismatched sibling, volunteer unrelated), reduced intensity conditioning (RIC) regimen, the use of alemtuzemab as in vivo T cell depletion, CMV reactivation, and grade 2 or greater GVHD requiring steroid therapy.
Results. 128 (84.2%) patients had evidence of past infection and thus were deemed at risk of VZV reactivation. Of these, 47 (36.7%) had clinical evidence of reactivation. 60% of transplants were from a donor possessing the broad ’B’ haplotype. The rate of reactivation in the presence of donor ’B’ haplotype was 40% compared to 32% when no donor ’B’ haplotype was present (p=0.237). None of the individual donor KIRs were shown to significantly reduce the rate of VZV reactivation. Neither the use of a RIC regimen nor the presence of alemtuzemab in the conditioning regimen were shown to have an impact. None of the other factors analysed were associated with an increased rate of zoster reactivation.
Conclusion. Donor KIR genotype does not influence VZV reactivation after allogeneic HSCT. This contrasts with the findings for CMV reactivation. No influence of donor type, conditioning or GVHD could be demonstrated. This suggests 1) that there are differing mechanisms that control the reactivation of different Herpes viruses after transplantation and 2) that KIRs may have specificity for CMV.
The Peptide hLF1-11 as Broad Spectrum Antmicrobial Prophylaxis in HSCT Patients.
Authors: Wulferink Marty , Brouwer Carlo P. , Sluiter-van Dijk Astrid M.C. , Blijlevens Nicole N.A. , Donnelly J. Peter , Velders Markwin P. 
Published: April 2020

Abstract
hLF1-11, comprising the N-terminal 11 AA of the human lactoferrin protein, has previously been shown to have a broad antimicrobial spectrum. The efficacy towards several strains of bacteria and fungi was demonstrated in in vitro and in vivo models. At this moment, hLF1-11 is in clinical development for use as broad spectrum anti-fungal and anti-bacterial prophylaxis in hematopoetic stem cell transplantation (HSCT) patients. There is data to support that the hLF1-11 mechanism of action is not restricted to direct killing of the pathogen, but that the indirect, immune modulatory and immune activating properties are important for hLF1-11 efficacy in vivo at low doses. In earlier studies, efficacy of hLF1-11 was shown in neutropenic animals systemically infected with Candida albicans. In the present studies antimicrobial efficacy and safety of hLF1-11 was tested in animal models that resemble the immune compromised state of HSCT patients shortly after transplantation. In cyclophosphamid and cyclosporin treated animals, hLF1-11 significantly reduced intra muscular infection with methicillin resistant Staphylococcus aureus (MRSA) when injected 24 hours after infection. In the same model hLF1-11 showed prophylactic properties in that it was effective even when administered as a single injection 24 hours before local infection with MRSA. In order to assess drug-drug interactions of hLF1-11 with common antibiotics, hLF1-11 was co administered with either vancomycin or ciprofloxacin in the local MRSA infection. Data from these models show that hLF1-11 is effective in combination with standard antibiotic and immunosuppressive care in a HSCT setting. Moreover, the hLF1-11 peptide does not inhibit antibiotic activity of currently used antibiotics. Besides these preclinical safety data, clinical safety was evaluated in a single and multiple ascending dose study in human volunteers. During these studies pharmacokinetic and pharmacodynamic parameters were measured and no drug related adverse effects were observed. Now, preparations are made to evaluate safety and efficacy of hLF1-11 in autologous and allogenic HSCT patients as anti-fungal and anti-bacterial prophylaxis. In conclusion, hLF1-11 is a promising peptide to prevent and treat opportunistic infections in HSCT patients and other immune suppressed patient populations.
An Integrated Epigenomic Analysis Approach To Determine the Molecular Basis of Acute Leukemias.
Authors: Figueroa Maria E. , Ye Kenny M. , Paietta Elisabeth , Greally John M. , Melnick Ari M. 
Published: April 2020

Abstract
Acute leukemias are classified based on their immunologic, cytogenetic and morphologic characteristics. However, in most instances, response to treatment and survival probability cannot be accurately predicted, suggesting that the disease is even more complex and heterogeneous than can be shown with current techniques. Although prognostic value has been shown for certain gene expression profiles, expression profile studies are limited by the fact that only a snapshot of mRNA content is obtained in a basal state, failing to represent how genes will respond to different stresses, also failing to detect the roles of genes expressed at lower levels for which major changes in expression levels are often lost in the “noise” of expression arrays. In order to overcome these issues and to provide a more accurate molecular phenotype of acute leukemias, we established an integrated epigenomic and genomic high-throughput platform using novel techniques and custom high-density oligonucleotide arrays. We combine studies of i) genome-wide cytosine methylation using a novel technique we developed that provides accurate quantitative determination of DNA methylation levels, using genome-wide custom oligo arrays, ii) chromatin structure by ChIP on chip for histone code settings associated with active or repressed genes using 24 K promoter tiling arrays, iii) gene copy number by array-based comparative genomic hybridization (array CGH) at 6 kb resolution genome-wide and iv) 36 K gene expression arrays. Results are validated by single locus quantitative PCR techniques. Cross platform integration is facilitated by use of NimbleGen oligo arrays for all studies and analysis using novel bioinformatics and statistical models. We used this integrative analysis platform to perform an in-depth analysis of the epigenomic basis of AML and ALL using primary patient samples and cell lines. The data allowed us to generate a “gene activity index” which identified the ability of genes to be expressed to be characterized genome-wide in AML and ALL cells. This data also allowed a much more comprehensive analysis of pathways active in these cells to be identified in comparison to expression arrays alone. Our current studies apply integrative platform and gene activity indexing to large series of patients enrolled in multicenter clinical trials in order to provide high-resolution analysis of the molecular basis of acute leukemia.
CALM-AF10 and HOX11L2 Abnormalities Define Poor Prognostic Subgroups in Pediatric T-Cell Acute Lymphoblastic Leukemia.
Authors: van Grotel Martine , Meijerink Jules P.P. , van Noesel Max M. , Beverloo H. Berna , Langerak Anton W. , Poulsen Tim S. , van Wering Elisabeth R. , Janka-Schaub E. Gritta , Pieters Rob 
Published: April 2020

Abstract
Recognition of specific T-ALL subgroups based upon cytogenetic aberrations may have prognostic relevance. The prognostic relevance of recurrent molecular-cytogenetic abnormalities using RQ-PCR and FISH was established for T-ALL patients enrolled on the DCOG protocols, and assigned to SIL-TAL, HOX11, HOX11L2, or CALM-AF10 subgroups or a rest group lacking any of these abnormalities. RQ-PCR data almost completely matched with FISH data. CALM-AF10 was associated with a poor outcome (p=0.005), whereas HOX11L2 and TAL1 subgroups demonstrated a strong trend towards poor and good outcome, respectively. A significant association between HOX11L2 and poor outcome was validated in a second T-ALL cohort comprising 53 pediatric patients that were enrolled on the COALL97 protocol (p=0.01). The TAL1 subgroup was committed to αβ-lineage T-cell developmental stage. HOX11 T-ALLs were all CD1 positive without expression of Cytβ and/or TCR expression reflecting an early cortical developmental stage. The immunophenotype of the HOX11L2 subgroup was rather heterogeneous consisting of samples with TCRγδ expression as well as phenotypic immature cases. Only 41% of HOX11L2 positive cases expressed CD1, indicating that HOX11L2 and HOX11 represent different T-cell developmental stages. CALM-AF10 was associated with a very immature immunophenotype, frequently expressing CD34 and myeloid markers. The TAL1 subgroup was characterized by high expression levels of TAL1, but about half of the samples with no or other aberrations also highly expressed TAL1. LYL1 was highly expressed in the other subgroups, with the highest expression levels in the most immature subgroups. LMO2 gene expression levels closely matched with LYL1 levels. In conclusion, the presence of CALM-AF10 and HOX11L2 abnormalities define poor prognostic subgroups in pediatric T-ALL.
P-Loop an T315I BCR-ABL Mutations in Chronic Myelogenous Leukemia (CML) Patients Are of Poor Prognosis, but the Y253H + E255K P-Loop Mutations Are of Even More Severe Prognosis in Chronic Phase. On the Behalf of the French Intergroup of CML (Fi-LMC Group).
Authors: Nicolini Franck E. , Corm Sélim , Lê Quoc-Hung , Hayette Sandrine , Sorel Nathalie , Bories Dominique , Giraudier Stéphane , Tulliez Michel , Rousselot Philippe , Cayuela Jean-Michel , Mahon François-Xavier , Cony-Makhoul Pascale , Kiladjian Jean-Jacques , Tournilhac Olivier , Guilhot François , Roche-Lestienne Catherine , Preudhomme Claude , Michallet Mauricette 
Published: April 2020

Abstract
In CML, the most frequent mechanism responsible for IM resistance is the onset of BCR-ABL mutations. Mutations interfering with IM binding to the ABL-kinase domain that restore the tyrosine kinase activity of BCR-ABL (T315I and P-loop mutations) are of poor prognosis. In a retrospective analysis, we analysed the features and clinical outcomes of 50 CML patients and presenting IM resistance, and harbouring 33 P-loop (1 patient had mutations) [Group 1 (G1)] and 18 T315I mutations [Group 2 (G2)] detected by direct sequencing. Twenty-eight patients were in chronic phase (CP), 12 in accelerated phase and 9 in blastic phase when IM was started, with no difference between P-loop and T315I groups. There were 23 M and 9 F, with a median age of 53 (13–74) for G1; and 14 M and 4 F, with a median age of 52 (28–70) for G2. The median duration of IM was 25 Mo (2.4–50) for G1 and 20 (0.5–145) for G2 (p=ns). The duration of IFN prior to IM was equivalent for both groups (12 Mo (0–86) for G1 vs 10 Mo (4–131) for G2, p=ns). The median interval between diagnosis and day 1 of IM was 50 Mo(0.4–128) for G1 and 20 Mo (0.5–145) (p=ns) for G2. Multivariate analysis for gender, age, prior IFN, interval diagnosis-IM start, and major cytogenetic remission achievement with IM, did not show any significant impact of these variables. Overall and Progression free survival (PFS) Kaplan Meier curves for all phases did not show any difference, however, PFS curves for CP only showed a somewhat worse survival for Y253H+E255K P-loop mutations than for other P-loop mutations or T315I (p=0.05).
Figure Figure
Median survival for CP was 7 Mo for Y253H+E255K P-loop mutations, vs 24 for T315I vs 36 for other P-loop mutations. In conclusion, P-loop and T315I mutations are of equivalent poor prognosis, but for CP patients, the Y253H+E255K P-loop mutations are particularly severe within the P-loop group, as suggested by in vitro data.
Philadelphia Chromosome Positive Acute Myeloid Leukemia: An Aggressive Acute Leukemia with Clinicopathologic Features Distinct from Chronic Myeloid Leukemia in Blast Crisis.
Authors: Soupir Chad P. , Vergilio Jo-Anne , Dal Cin Paola , Muzikansky Alona , Kantarjian Hagop M. , Jones Dan , Hasserjian Robert P. 
Published: April 2020

Abstract
Philadelphia chromosome positive acute myeloid leukemia (Ph+ AML) is a rare entity reported to comprise 1% of tumors bearing the Philadelphia chromosome. Controversy exists over whether this represents a distinct entity or is merely presentation of patients in the blastic phase of chronic myeloid leukemia (CML). Our study sought to determine the clinicopathologic characteristics of Ph+ AML in comparison to CML in blast crisis. We searched the archival files of Massachusetts General Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, and MD Anderson Cancer Center from 1995 to 2005 for cases of apparent de novo Ph+ AML. After excluding biphenotypic leukemias and cases with any evidence of prior CML or other myeloid neoplasia, we retrieved 18 Ph+ AML cases. 20 cases of documented CML in myeloid blast crisis (CML-MBC) who had not received prior imatinib mesylate therapy or bone marrow transplant were used as a control group. The clinical and laboratory features, bone marrow morphology, immunophenotype, cytogenetics, and type of BCR/ABL transcript were analyzed. The Ph+ AML patients included 13 males and 5 females with a median age of 55 years, which was not significantly different from CML-MBC patients. The median WBC at presentation was 15.7 x 109/L. Compared to CML-MBC patients, the Ph+ AML patients were less likely to have splenomegaly (22% vs. 68%, p=0.008) or peripheral basophilia (median absolute basophil count 0.16 vs. 1.24 x 109/L, p=0.003). The bone marrow in Ph+ AML patients was less cellular (median cellularity 80% vs. 98%, p=0.002) with a lower myeloid:erythroid ratio (1.3 vs. 4.8, p=0.01), but more prominent erythroid and myeloid lineage dysplasia (p=0.04) than that of CML-MBC patients. While cytogenetic abnormalities in addition to t(9;22) occurred in 67% of Ph+ AML cases, the typical additional cytogenetic changes of CML-MBC (+8, +19, iso17q, and +Ph+) were uncommon (22% vs. 87% for CML-MBC, p=0.0004). In 5/6 Ph+ AML cases with multiple clones, the Ph+ was present in all clones, suggesting that this represents an early event in the evolution of these leukemias. RT-PCR revealed a predicted BCR/ABL product of p210 (10/13 cases), p190 (2/13 cases) or p230 (1/13 cases). 6/7 Ph+ AML patients treated with imatinib showed at least a partial hematologic response, but this was of a short duration (median 2.5 months, range 1–6 months) in comparison to the reported median response duration of 10 months in imatinib-responsive CML-MBC. The median survival of the Ph+ AML patients was 10.5 months, similar to that of CML-MBC and AML with adverse cytogenetics. In summary, Ph+ AML is a rare entity distinct from CML-MBC, with an aggressive clinical course and only transient response to imatinib.
Standardization of WT1 mRNA Quantification for Minimal Residual Disease (MRD) Monitoring in Acute Leukemia Patients: A European LeukemiaNet Concerted Action.
Authors: Gottardi Enrico , Cilloni Daniela , Daly Sarah , Green S. , Pallisgaard Niels , Hokland P. , Ostergaard M. , Nyvold C. , Nomdedeu J. , Pane Fabrizio , Schnittger Susanne , Van der Velden Vincent , Tobal Kalid , Jal Y. Yin , Hermitte Fabienne , De Witte Teo , Hehlmann R. , Saglio Giuseppe , Grimwade David 
Published: April 2020

Abstract
Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemia. In acute myeloid leukemia (AML), the reliability of real-time quantitative PCR (RQ-PCR) and its potential clinical value for MRD studies using fusion gene (FG) transcripts as PCR targets such as PML-RARa, AML1-ETO and CBFb- MYH11 has been demonstrated, but these markers are present only in a minority of cases. In order to overcome this problem several groups looked for alternative markers and growing evidence has suggested that the high expression of WT1 in a significant proportion of acute leukemia cases provides a suitable target for therapy as well as for monitoring of MRD. However, heterogeneity of molecular approaches resulted in a lack of comparability between different MRD studies. This has been solved using RQ-PCR in a network of 9 laboratories within the European LeukemiaNet. Overall 8 primer/probe sets were evaluated including published and “in-house” sets. The assays analyzed differed significantly in terms of efficiency and sensitivity. Three assays with superior performance were identified, achieving sensitivities of at least 1 in 10,000 in serial dilutions of HL60 cells (WT1 positive). Subsequent analysis of two of the primer/probe sets, which amplify ex. 6/7 and 7/8 of WT1 respectively, revealed the potential for false negative results, following documentation of deletions of the WT1 gene in this region in primary AML samples. In two of these cases, different deletions of sequences corresponding to part of WT1 ex.8 were documented by WT1 RNA sequencing. Therefore, a primer/probe set amplifying ex. 1/2 of WT1 has been subject to further analysis in a QC round involving 9 labs. The analysis of 33 normal BM, 32 normal PB and 12 CD34 enriched PBMNCs gave the following results: BM, mean 70,32 WT1 copies/104 ABL copies (range 8,99–209,82); PB, mean 3,30 WT1 copies/104 ABL copies (range 0–13,55); CD34 enriched PBMNCs, mean 8,16 WT1 copies/104 ABL copies (range 1,55–26,16). Overall, these analyses underline the importance of standardization in the development of RQ-PCR assays for MRD detection in leukemia. There is increasing interest in identification of genes that are over-expressed in leukemia as potential MRD targets. However, it is clear that incorporation of such MRD targets into risk-directed treatment protocols is critically dependent upon establishing thresholds of expression in normal blood and marrow on regeneration following myeloablative therapy.
Rac1 and Rac2 GTPases Play Redundant but Critical Role in T-Cell Development and Survival.
Authors: Guo Fukun , Hildeman David , Williams David A. , Zheng Yi 
Published: April 2020

Abstract
The Rac subfamily GTPases of the Rho family have been implicated in the control of actin dynamics, cell proliferation, apoptosis, adhesion and migration of many blood cell types including hematopoietic stem/progenitors, neutrophils and macrophages, but their role in T cell development remains poorly understood. T cells from the Rac2 deficient mice appear to mostly undergo normal development, whereas previous constitutively active mutant Rac2 or Rac1 overexpression studies suggest Rac GTPases are required for CD4+ and CD8+ T cell maturation. Using conditional gene targeting, we have achieved specific deletion of Rac1 or Rac1 together with Rac2 in the T cell lineage by cross-breeding the Lck-Cre transgenic mice with the Rac1flox/flox mice that contain a pair of loxP sites sandwiching the exon 1 sequences of Rac1 or the Rac1flox/flox;Rac2−/− mice. We show that similar to Rac2 deficiency, inactivation of Rac1 alone had little effect on various developmental stages of T cells in the animal. However, deletion of both Rac1 and Rac2 significantly affected both the immature CD4−CD8− (2.3 fold increase) and CD4+CD8+ (13% decrease) populations in the mouse thymus and the mature CD4+ and CD8+ populations in the thymus and spleen (Table). These developmental defects are associated with proliferation defects of thymocytes and splenocytes in response to ConA or PMA/ionomycin stimulation and deficient survival of various T cell populations at different developmental stages (Table). Together, these data show that Rac1 and Rac2 play overlapping and obligatory roles in T-cell development and serve as important cell survival regulators at various stages.
Table. Frequency and apoptosis rate of different T-cell subsets in thymocytes and splenocytes T cell subsets WT (n=10) Rac1−/− (n=6) Rac1−/−Rac2−/−(n=6) Total thymocyte number (×106) 101.3±30.0 98.0±25.0 44.7±25.5 CD4−CD8− thymocyte frequency (%) 5.5±1.9 4.5±0.7 12.7±4.3 apoptosis rate (%) 20.1±2.2 15.0±1.3 CD4+CD8+ thymocyte frequency (%) 76.2±3.2 77.3±4.1 66.2±5.4 apoptosis rate (%) 18.8±4.3 27.9±2.8 CD4+ thymocyte frequency (%) 14.5±3.4 14.4±2.4 7.9±2.3 apoptosis rate (%) 13.3±2.3 21.5±4.5 CD8+ thymocyte frequency (%) 3.9±1.2 3.8±1.0 13.2±2.2 apoptosis rate (%) 12.5±2.2 8.8±1.1 Total splenocyte number (×106) 60.4±21.8 62.0±13.0 51.1±28.9 CD4+TCRβ+ splenocyte frequency (%) 9.7±2.2 8.0±2.3 3.2±1.1 apoptosis rate (%) 15.1±3.1 27.5±6.9 CD8+TCRβ+ splenocyte frequency (%) 3.2±0.8 2.4±0.9 0.6±0.4 apoptosis rate (%) 13.1±3.0 24.5±6.4