bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute Graft-Versus-Host Disease: Clinical Presentation and Response to Therapy Following Umbilical Cord Blood Transplant.
Authors: Arora Mukta , Wagner John E. , Barker Juliet N. , Miller Jeffrey S. , Burns Linda J. , MacMillan Margaret L. , Blazar Bruce R. , Defor Todd E. , Weisdorf Daniel J. 
Published: October 2019

Abstract
The nature of aGVHD after umbilical cord blood transplant (UCBT) has not been well characterized. We analyzed acute graft-versus-host disease (aGVHD) incidence and response to therapy in 136 recipients of unrelated UCBT. aGVHD developed in 72 receiving myeloablative (MA) (n=39) and non ablative stem cell transplant conditioning (NST) (n=33) (indicated if age >45 years, prior transplant and major co-morbidity). MA transplant recipients were significantly younger (median age 14 years, range 0.8–50) than NST transplant recipients (median 48 years, range 0.7–59), p < 0.0001 and had fewer advanced malignant disease at transplant (8% versus 24%), p = 0.09. At diagnosis of aGVHD, the clinical grades and organ involvement were similar in the 2 groups. Grade II–IV aGVHD developed in 34% of MA transplant recipients and 45% (p = 0.1) of NST transplant recipients at a median of 35 days (12–137) and 30 days (15–96) post transplant whereas grade III–IV aGVHD developed in 9% and 13% (p=0.6), respectively. 87% of MA vs. 85% of NST recipients (p=0.8) had skin involvement; 39% vs. 49% had GI disease (p=0.4); and 10% vs.9% (p=0.9) had liver GVHD, respectively. Response to therapy was assessed at 28 and 56 days after diagnosis of aGVHD. A high frequency of complete response (CR) was seen across all grades at day 28 (47%, 48% and 43% CR in grades I, II and III–IV, respectively). At day 56, CR was more frequent in grade I aGVHD (68% vs 64% and 50% in patients with grade II and III–IV disease, respectively, p 0.08). Response rates were similar in MA and NST transplant recipients (CR in 49% vs 46% by day 28, p=0.1, and 64% vs 61% by day 56, p=0.5. Age < 20 years (CR or PR 82% vs 64%, p = 0.09) and single organ GVHD (81% vs 52%, p=0.01) were associated with a higher response. A higher response rate was seen in patients with skin GVHD (85%) vs GI disease (63%) vs skin + GI (56%) vs liver involvement with skin/GI (43%), p=0.04. After a median follow up of 1.0 year (0.8–7 years) in both groups, 67% (95% CI 52%–81%) of MA versus 45% (95% CI 28%–62%) of NST patients survive (p=0.05). Higher 1 year survival of 70% (95% CI 58%–83%) was seen in patients with day 28 CR or PR to treatment versus non responders (24%, 95% CI 6%–42%), p<0.0001.
This data suggests that among unrelated UCBT recipients using either MA or NST preparative regimens, similar incidence, clinical presentation and response to therapy of aGVHD was seen. Early identification of high risk group (age >20, multiorgan disease, GI or liver GVHD) should facilitate timely assignment of intensified therapy.
Favorable Outcome for Infant ALL Following Hematopoietic Stem Cell Transplantation (HSCT).
Authors: Jacobsohn David A. , Hewlett Brad , Morgan Elaine , Duerst Reggie E. , Kletzel Morris 
Published: October 2019

Abstract
There exists controversy regarding the benefit of HSCT in infant ALL. At our institution, the standard treatment for high-risk infant ALL has been intensive chemotherapy per POG 9407 followed by HSCT in CR1. We retrospectively reviewed the outcome of the 15 patients (9 males, 6 females) with infant ALL that underwent allogeneic HSCT since 1992. We defined “very high-risk” as an infant with one or more of the following criteria: age 6 months or less at diagnosis, MLL+ or t(4:11), or WBC>100,000 at diagnosis. Fourteen of fifteen patients are considered “very high-risk.” All except one were under 12 months at diagnosis (range 2–14 months, median 7). The fourteen month old was included as she displayed infant ALL biology, with MLL+ and WBC>500,000. Seven were 6 months or under at diagnosis. Cytogenetics at diagnosis showed MLL+ or t(4:11) in 9, normal in 4, and indeterminate in 2 patients. WBC count at diagnosis was 4,300–1,000,000 (median 360,000). Twelve of the patients were CALLA-negative and four had CNS involvement at diagnosis. Time from diagnosis to transplant was 2.3–13.6 months (median 4.2). All patients were in morphologic CR1 at time of HSCT but one patient had persistent t(4:11).
Cytoreduction: Patients received TBI 150cGy x 8 (d-10 to-7); VP-16 1g/m2 CI (d-5 to-4); cyclophosphamide 60 mg/kg/day x 3(d-4 to-2). GVHD prophylaxis: CSA, short-course MTX, and ATG d +1, +3, +5, +7 (for unrelated cord blood (UCB)). Grafts were not T-cell depleted.
Stem cell sources: 8 UCB, 6 HLA-identical sibling bone marrow, 1 HLA-identical sibling PBSC. Days to neutrophil engraftment was 11–25 days (median 16) and to platelet engraftment was 17–82 days (median 37). CNS prophylaxis consisted of intrathecal methotrexate and Ara-C monthly x 6 post-HSCT. Acute GVHD: 2 grade II and 1 grade III. Chronic GVHD: 3 limited, 1 extensive.
Mortality: 4 patients have died. 2 (13%) of transplant-related mortality (TRM) within 100 days of HSCT and 2 of relapse (15% of evaluable patients), which included the patient with t(4:11) at time of HSCT. Range of follow-up is 0.1–11.8 years with a 73% event-free survival (EFS) and overall-survival at a median follow-up of 3.5 years. We conclude that patients with infant ALL who attain a CR1 (morphologic and cytogenetic) have good EFS with acceptable TRM following HSCT using either UCB or HSC from a matched-sibling. Long-term follow-up, including developmental assessments, are being pursued to document the impact of this intensive therapy in young children.
Figure Figure
Outcomes of Transplantation with Matched-Related Donor (MRD) and Alternative Donor (AD) Stem Cells in Children with Severe Thalassemia.
Authors: Hongeng Suradej , Pakakasama Samart , Chuansumrit Ampaiwan , Sirachainan Nongnuch , Chaisiripoomkere Watana , Ungkanont Artit , Jootar Saengsuree 
Published: October 2019

Abstract
Allogeneic stem cell transplant (SCT) from an HLA identical family donor is an accepted option for severe thalassemia. However, the availability of MRD is only 30%. Therefore, AD is another option. The aim of this study is to explore the outcomes of allogeneic SCT with MRD and AD in our institution. We studied 46 consecutive patients (pts) who received MRD (n = 24) or AD; matched unrelated and haploidentical donors (n = 22) stem cells (SCs) for severe thalassemia between September 1992 and July 2004. In MRD group, 3 pts received 1 Ag HLA-mismatched SCs and in AD group, 2 pts received haploidentical SCs. The characteristics of both groups were followed.
The conditioning regimen consisted with busulfan 16 mg/kg, cyclophosphamide 200 mg/kg for MRD and additional ALG (Fresineus) 40 mg/kg for matched unrelated donor (MUD) and CBT and busulfan 8–12 mg/kg, fludarabine 175 mg/m2, ALG, + thiotepa, and + total lymphoid irradiation for NST. GVHD prophylaxis was cyclosporin and MTX for MRD, FK 506 and MTX or MMF for MUD, cyclosporin, and prednisolone for CBT, and FK 506 and MMF for NST. The 2 yr thalassemia free survival rate for MRD is 83% and AD 81% (p = 0.6). The 2 yr overall survival rate for MRD is 95% and AD 90 % (p = 0.5). Two (8%) pts of MRD and 2 (9%) of AD had severe acute GVHD grade 3–4. Three pts of MRD had chronic GVHD (2;limited, 1;extensive). Three pts of AD had limited chronic GVHD. Rejection rate of MRD group is 12.5% (n=3). Two of 3 MRD pts who had graft failure after first transplant were successful for second transplant. Rejection rate of AD group is 9% (n=2). In conclusion, the outcomes of transplantation with MRD and AD stem cells in children with severe thalassemia are both equally favorable. Further study should be investigated in a larger group of patients to confirm our findings.
MRD (n = 24) AD (n = 22) Age (yr) (median) 2-19 (4) 1-17 (7) β thalassemia major 8 9 β thalassemia / HbE 16 13 Lucarelli class I 12 16 Lucarelli class II and III 12 6 Bone Marrow Transplant (BMT) 11 19 Peripheral Blood Stem Cell Transplant (PBSCT) 8 – Cord Blood Transplant (CBT) 3 1 Nonmyeloablative Stem Cell Transplant (NST) 2 2
Flt3 Receptor Expression Rescues Dendritic Cell Developmental Potential in Megakaryocyte/Erythrocyte Progenitor Cells.
Authors: Onai Nobuyuki , Onai Aya , Tussiwand Roxane , Lanzavecchia Antonio , Manz Markus G. 
Published: October 2019

Abstract
Flt3/Flt3-ligand has a non-redundant role in dendritic cell (DC) and interferon producing cell (IPC) development from hematopoietic progenitor cells. Flt3-ligand−/− mice display a severe reduction of DCs and IPCs, and both, Flt3-ligand injection and conditional over- expression of Flt3-ligand in mice leads to an increased pool size of both cellular subsets. Furthermore, DC and IPC developmental precursor activity segregates with Flt3+ progenitor populations in mouse bone marrow. We have reported that common myeloid progenitors (CMPs) and their progeny granulocyte/macrophage progenitors (GMPs) as well as common lymphoid progenitors (CLPs) and pro-T cells can give rise to DCs in vitro and in vivo. DC developmental potential was lost, however, once definitive megakaryocyte/erythrocyte or B cell commitment occurs, both steps that are accompanied by loss flt3 receptor expression. To test if DC/IPC developmental potential can be regained, we evaluated the effect of ecotropic expression of human Flt3 in lin−c-kit+Flt3−Thy1.1−IL-7Ra− cells (flt3− progenitors) and in megakaryocyte/erythrocyte progenitors (MEPs).
hFlt3 was transduced into purified flt3− progenitors, MEPs, and GMPs using a retrovirus vector carrying both hFlt3 and GFP. The transduction efficiencies were 20~25%. hFlt3-transduced flt3− progenitors gave rise to functional DCs and IPCs, but not control-GFP-transduced flt3− progenitors in vitro. Similarly, hFlt3-transduced MEPs differentiated into functional DCs in Flt3L, SCF, GM-CSF, IL-4, and TNF-a supplemented cultures but not into TER119+ erythroid cells. DC developmental potential of hFlt3-transduced MEPs was comparable to GFP-transduced GMPs. Over expression of hFlt3 in GMPs resulted in augmentation of its DC developmental potential. Interestingly, both hFlt3-tarnsduced MEPs and GMPs preferentially differentiated into IPCs in Flt3L supplemented medium. RT-PCR analysis revealed that enforced Flt3 signaling in MEPs lead to up-regulation of GM- and/or DC-development affiliated genes such as G-CSF receptor, M-CSF receptor, and GM-CSF receptor, PU.1, C/EBPa and STAT3. Furthermore, hFlt3-transduced MEPs gave rise to myeloid colonies (CFU-GM/G/M) but not CFU-Mix colonies in GM-CSF, IL-3, SCF, Flt3L, Tpo, and Epo supplemented methylcellulose medium. These results show that artificial Flt3 signaling in otherwise Flt3− progenitors is sufficient to reestablish DC/IPC differentiation and GM-differentiation programs.
Involvement of Anti-Apoptotic Signaling in Flt3-Dependent B Lymphopoiesis.
Authors: Jensen Christina T. , Sasaki Yutaka , Sitnicka Ewa , Jacobsen Sten Eirik W. 
Published: October 2019

Abstract
Cytokine signaling through the tyrosine kinase receptor flt3 and the hematopoietin Interleukin-7-receptor a chain (IL7Ra) is critically involved in regulation of B lymphopoiesis. Specifically, we have recently demonstrated that mice double deficient in flt3 and IL7Ra signaling fail to support B cell commitment and development during embryogenesis as well as in adult hematopietic tissues (Sitnicka et al, J. Exp. Med; 198:1495, 2003). Previous studies have through generation of IL7Ra knockout mouse on a Bcl-2 transgenic background suggested that IL-7 induced triggering of anti-apoptotic pathways is critically involved in T cell but not B cell development (Akashi et al, Cell; 89:1033, 1997, Kondo et al, Immunity; 7:155, 1997). Thus, we here investigated whether anti-apoptotic signaling might rather be involved in flt3-dependent B cell development, through generation of a H2k driven human Bcl-2 transgenic/Flt3 ligand (FL)−/− (Bcl-2/FL−/−) mice. Strikingly, numbers of Common Lymphoid Progenitors (CLP; lin−c-kitloSca-1loIL7Ra+), pro-B (B220+CD19+AA4.1+CD43+), pre-B (B220+CD43−IgM−) and mature B cells (B220+CD43−IgM+) in the BM of 7–8 weeks old Bcl-2/FL−/− mice were all comparable to those observed in wild type mice. More importantly, the pronounced reductions in CLP, pro-B and pre-B progenitors seen in FL−/− mice on a wild type background were compensated by approximately 50% when FL-deficiency was rather induced on a bcl-2 transgenic background (Bcl-2/FL−/−). Thus, in contrast to IL7Ra, the critical role of flt3 in B cell commitment and development might involve triggering of anti-apoptotic pathways.
Development of a Disease-Specific Utility Instrument for Hemophilia.
Authors: Wasserman Joan E. , Hoots William K. 
Published: October 2019

Abstract
Research has shown that disease-specific health-related quality of life (HRQoL) instruments are more responsive than generic instruments to particular disease conditions. However, only a few studies have used disease-specific instruments to measure HRQoL in hemophilia. The goal of this project was to develop a disease-specific utility instrument that measures patient preferences for various hemophilia health states. The visual analog scale (VAS), a ranking method, and the standard gamble (SG), a choice-based method incorporating risk, were used to measure patient preferences. Study participants (n=128) were recruited from the UT/Gulf States Hemophilia and Thrombophilia Center and stratified by age: 0 – 18 years and 19 +. Test retest reliability was demonstrated for both VAS and SG instruments, overall within-subject correlation coefficients were 0.91 and 0.79, respectively. Results showed statistically significant differences in responses between pediatric and adult participants when using the SG (p=.045). However, no significant differences were shown between these groups when using the VAS (p=.636). When responses to VAS and SG instruments were compared, statistically significant differences in both pediatric (p<.0001) and adult (p<.0001) groups were observed. Stratification of the study sample into mild, moderate and severe disease categories yielded no statistically significant differences in patient preference values among the three groups for both instruments (VAS (p =0.578 for mild vs. moderate, p =0.590 for mild vs. severe and p= 0.920 for moderate vs. severe and SG (p= 0.578 for mild vs. moderate, p = 0.590 for mild vs. severe and p=0.920 for moderate vs. severe). The utility measures obtained from this study can be applied in economic evaluations and decision models that analyze the cost/utility of alternative hemophilia treatments. Results derived from the SG indicate that age can influence patients’ preferences regarding their state of health. This may have implications for considering treatment options based on the mean age of the population under consideration. Data from this study also demonstrated that persons with varying severity of disease were able to objectively evaluate a wide range of health states for hemophilia. When assessing HRQoL for a rare disease such as hemophilia, it is important to establish that HRQoL measurements can be applied broadly across the population. Although the VAS and SG independently demonstrated reliability and validity, results indicate that the two measures may not be interchangeable.
Highly-Purified Aspergillus Fumigatus Specific T-Cells as a Potential Treatment Option of Invasive Aspergillosis.
Authors: Beck Olaf R. , Topp Max S. , Koehl Ulrike , Hanisch Mitra , Hebart Holger F. , Latge Jean-Paul , Einsele Hermann , Klingebiel Thomas , Lehrnbecher Thomas 
Published: October 2019

Abstract
Invasive aspergillosis is still a life-threatening complication, in particular in patients after allogeneic hematopoietic stem cell transplantation (HSCT). Whereas prolonged neutropenia is a well established risk factor for invasive fungal disease, there is a growing body of evidence that T-cells also play an important role in the immunological response to Aspergillus species. Since invasive aspergillosis often occurs during the phase of postengraftment, which is characterized by impaired cell-mediated immunity, Aspergillus-specific T-cells could be a potential therapeutic target in these patients. We therefore analyzed in a first step the response of T-cells to several potential antigens of Aspergillus fumigatus by means of 3H-thymidine incorporation assay. In order to generate Aspergillus-specific T-cells, the antigens with the highest proliferation indices (EC-SAB and 90 kDa catalase) were used to stimulate 1.0 x 108 mononuclear cells from healthy donors. The activated T-cells were isolated on the following day using the IFN-γ secretion assay (Miltenyi Biotec, Germany) and then expanded for 14 days. Intracellular cytokine analysis of EC-SAB generated cell lines (n=7) revealed a significant IFN-γ secretion by 13.6%±2.3 of CD4+ cells (seven out of seven tested cell lines) and an Aspergillus-specific IL-2 secretion by 6.5%±1.9 of CD4+ cells (three out of three tested cell lines), which supports the TH1 response of the generated cells to Aspergillus antigen. In contrast to EC-SAB generated T-cell populations, all three cell lines which were generated with 90 kDa catalase were not informative. Further analysis showed that restimulation with EC-SAB induced a strong proliferation of EC-SAB generated T-cell populations (all three populations tested), whereas alloreactivity was unaffected. The number of these cells could be expanded within 14 days up to 20fold using OKT-3, IL-2 and feeder cells. Currently, we investigate the impact of these Aspergillus-specific cell populations in the defense to different species of Aspergillus. Our preliminary results suggest that Aspergillus-specific T-cells could be an interesting option in prophylaxis and therapy of invasive aspergillosis in patients undergoing HSCT.
Pamidronate Therapy for One Year after Allogeneic Bone Marrow Transplantation (AlloBMT) Reduces Bone Loss from the Lumbar Spine, Femoral Neck and Total Hip.
Authors: Grigg Andrew C. , Shuttleworth Peter , Reynolds John , Szer Jeff , Schwarer Anthony P. , Roberts Andrew W. , Bradstock Ken F. , Hui Chi-Hung , Herrmann Richard , Ebeling Peter 
Published: October 2019

Abstract
We and others have demonstrated that substantial loss of bone mineral density (BMD) is very common following alloBMT, in part due to prolonged use of glucocorticoids. Intravenous (IV) pamidronate is a potent bisphosphonate with efficacy in preventing glucocorticoid-induced bone loss in the non-BMT setting. 116 alloBMT recipients were randomised at 5 institutions to receive pamidronate 90mg IV monthly from day-7 to one year post-transplant (n=63) or no pamidronate (n=53) in an open label, prospective, controlled trial. All patients received oral vitamin D and calcium supplements and all women also received hormone therapy with an oestrogen and progestin. The primary end-point was the reduction in bone loss from the lumbar spine, femoral neck and total hip at 12 months post BMT. Age, sex and conditioning regimen (total body irradiation versus chemotherapy only) were not significantly different between the groups. 37 patients were not evaluable, predominantly due to early death (n=29) or protocol violations (n=4). Significant reductions in BMD loss at 12 months were seen in all 3 evaluated sites in patients treated with pamidronate.
Site No pamidronate Pamidronate p value n % change* n % change* *percentage change in BMD at 12 months Lumbar Spine 28 −3.77 46 2.53 <.0001 Femoral neck 27 −9.33 45 2.82 <.0001 Total Hip 23 −8.35 38 −3.32 .0072
There were no significant differences in the 12-month changes associated with age class (<30, 30–40, 40–50, >50 years) or sex. In preliminary analyses of steroid dose subgroups, statistically significant improvements in BMD loss were found in patients whose average daily equivalent prednisolone dosage in the first six months post transplant was i) >25mg for all sites and ii) 10–25mg daily for the lumbar spine. We conclude that prophylactic pamidronate significantly reduces bone loss from the spine and hip after alloBMT. The impact on clinically relevant endpoints such as the subsequent incidence of fractures and avascular necrosis in these patients will determine the utility of this intervention.
The Grey Zone between Burkitt and Diffuse Large B Cell Lymphomas: Impact of Chromosomal Breakponts at Myc and Other Loci.
Authors: Haralambieva Eugenia , Boerma Evert-jan , van Imhoff Gustaaf , Rosati Stefano , Schuuring Ed , Mueller-Hermelink Hans-Konrad , Kluin Philip M. , Ott German 
Published: October 2019

Abstract
A prompt distinction of Burkitt lymphoma (BL) versus diffuse large B cell lymphoma (DLBCL) has important clinical implications. We analyzed 74 adult grey zone lymphomas (BL/DLBCL) and 10 reference pediatric BL using immunohistochemistry for Ki-67, CD10, bcl2 and bcl6, and Fluorescence In Situ Hybridization (FISH) for MYC, BCL2 and BCL6 breakpoints. Four hematopathologists reached a final (consensus) diagnosis independently in 80% of the reference BL, 24% of the test BL and 69% of the DLBCL. A MYC breakpoint was detected in all reference BL, 95% of the test BL and 35% of the DLBCL. BCL2 and BCL6 breakpoints were infrequent in BL (5 and 6%) and DLBCL (13% and 16%). Three BL and 5 DLBCL contained double breakpoints. A phenotypic shift to BL in the DLBCL group was indicated by the expression of CD10 and bcl6 in 67% and 91% of the cases, respectively. One third of all lymphomas showed a classical genotype and expression pattern of BL (MYC breakpoint+, Ki-67>90%, CD10+, bcl6+, bcl2-) but only 63% of these cases were classified as BL. Our data indicate that a subgroup of DLBCL shares markers with BL, which is probably due to an overlapping histogenesis of both tumors.
Value of immunohistochemistry and additional FISH for BCL2 and BCL6 breakpoints to reach the consensus diagnosis in 38 MYC breakpoint carrying cases of adult grey zone BL / DLBCL lymphomas
BCL2 and BCL6 breakpoint no restriction not present no restriction not present 38 / 74 cases carried a MYC/8q24 breakpoint phenotype no restriction no restriction Ki67>90%, CD10+, bcl6+, bcl2- Ki67>90%, CD10+, bcl6+, bcl2- N 38 30 24 22 Burkitt (%) 20 (53) 17 (57) 15 (63) 15 (68) DLBCL (%) 18 (47) 13 (43) 9 (37) 7 (32)