bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-Murine Thymocyte Globulin Prevents Acute Graft-Versus-Host Disease and Induces Foxp3+ T Cells in Target Organs.
Authors: Ruzek Melanie C. , Waire James S. , Weber William , Williams John M. , Richards Susan M. , Garman Richard D. 
Published: October 2019

Abstract
Rabbit anti-human thymocyte globulins (ATG) (Thymoglobulin®) are widely used for treatment and prevention of solid organ transplant rejection. However, more recently these therapies have been shown to also reduce the severity of graft-versus-host disease (GVHD) following allogeneic stem cell transplantation. However, dose and schedule of ATG administration in the clinic has not been well defined, and thus, the studies reported here were undertaken to explore optimal dosing and timing regimens as well as possible mechanisms of action of anti-thymocyte globulin in an in vivo murine model of GVHD. We demonstrate that a murine version of ATG, rabbit anti-murine thymocyte globulin (mATG), completely inhibits the development of acute GVHD in a model of allosplenocyte transfer into immunodeficient recipient mice (C57BL/6→BALB/c RAG-2−/ −). This protection is observed even when mATG administration is delayed for up to three days following allosplenocyte transfer. Administration of mATG six or more days following induction of GVHD still ameliorates disease in up to 50% of the animals, depending on the timing of mATG treatment. Murine ATG also remains completely protective down to doses of 1mg/kg if administered at the time of allosplenocyte transfer. Although T cell depletion is still observed at this low, but efficacious dose of mATG, we also find significant increases in Foxp3+ CD4+ regulatory T cells in the spleen (30 fold over control) as well as increased Foxp3+ expression in liver and intestines (3 fold over control). These results demonstrate a potent protective effect of murine ATG in this model of acute GVHD and suggest that the induction of regulatory T cells may participate in the protective effects observed.
Chimerism May Prolong Islet Allograft Acceptance through the Preservation of CD4+CD25+FoxP3+ Treg in Diabetic NOD Mice.
Authors: Bozulic Larry D. , Huang Yiming , Xu Hong , Atay Safinur , Ildstad Suzanne T. 
Published: October 2019

Abstract
In the past several years, novel insights into the role of costimulatory molecules in generating adaptive immune responses have led to the development of new approaches for tolerance induction. We previously demonstrated that preconditioning of diabetes-prone NOD mice with anti-CD8 and combined with blockade of CD40L (anti-CD154) allowed chimerism to be established with 550 cGy TBI. Here, we investigated whether combined costimulatory blockade of CD40L, inducible co-stimulator (ICOS) and OX40L (CD134L) would enhance bone marrow chimerism and promote islet allograft survival in diabetic NOD mice. We also determined whether CD4+/CD25+/FoxP3+ regulatory T-cells (Treg) play an important role in maintenance of tolerance. Spontaneously diabetic NOD mice (blood glucose levels >350 mg/dL) were treated with anti-CD8 antibody (day -3). After 500 cGy TBI (day 0), NOD mice were transplanted with 30 × 106 B10.BR bone marrow cells (day 0) followed by transplantation of 300–400 B10.BR islets under the renal capsule and administered anti-CD154, anti-OX40L, and anti-ICOS mAbs IP (day 0, 1, 2, 3). Chimerism and peripheral blood CD4+/CD25+/FoxP3+ Treg cell expression were quantitated by flow cytometry. Urine and blood glucose levels were monitored. Nonmyeloablatively conditioned mice transplanted with islet allografts and infused with bone marrow (BM) demonstrated acceptance and continued function of islet allografts, with hyperglycemic reversal ≥ 45 (A) and 95 (B) days (Figure 1). Recipients of islet allografts and BM (∼5–12 days), islet allografts and antibody treatment (∼20 days) or islet allografts alone (∼5 days) rejected their grafts. Blood glucose returned to pretreatment hyperglycemic levels in the rejected islet allograft recipient (C) treated in the same manner as the acceptors (A and B) as well as in the control recipients. Donor chimerism at one month post-BMT was 58.5% (A), 89.7% (B) and 0% (C), respectively. Although CD4+/CD25+/FoxP3+ Treg expression was similar between the islet allograft acceptor and rejector recipients, the ratio of CD4+/CD25+/FoxP3+ Treg to CD4+/CD25+/FoxP3− T-effector cells was 2-fold greater in the islet acceptors (3.6 vs. 1.8) (Figure 2). Taken together, our data suggest that prolongation of donor-specific chimerism is associated with tolerance to islet allografts and that CD4+/CD25+/FoxP3+ Treg may be important in maintaining peripheral tolerance. Studies are underway to determine if CD4+/CD25+/FoxP3+ Treg may prevent intra-islet infiltration by autoimmune effector cells, thereby maintaining tolerance to islet allografts.
Figure 1 Figure 1. Figure 2 Figure 2.
Differential Impact of Host Derived Interleukin-18 on Regulatory and Conventional T Cell Expansion Following Murine Allogeneic Hematopoietic Cell Transplantation.
Authors: Zeiser Robert , Zambricki Elizabeth A. , Leveson-Gower Dennis B. , Beilhack Andreas , Kambham Neeraja , Negrin Robert S. 
Published: October 2019

Abstract
Allografting as a curative approach for many hematological malignancies is hampered by the occurrence of acute graft-versus-host disease (aGvHD). Interleukin (IL)-18 stimulates T helper 1 (Th1) and Th2-mediated immune responses and has been shown to modulate aGvHD. It is still unknown whether increased IL-18 levels during aGvHD are of host or donor origin and how the absence of IL-18 impacts migration and expansion of conventional CD4+CD25− (Tconv) and CD4+CD25+ regulatory (Treg) T cells in vivo. By utilizing IL-18 gene deficient donor versus recipient animals we found that the major cytokine production during the early phase of aGVHD induction was recipient derived, while donor hematopoietic cells contributed significantly less. By generating IL-18−/ − luciferase transgenic mice we were able to investigate the impact of IL-18 on Tconv and Treg expansion and trafficking with in vivo bioluminescence imaging. While migration to secondary lymphoid organs was not significantly impacted by the absence of host IL-18, Tconv but not Treg expansion increased significantly. Absence of host IL-18 production translated into lower IFN-γ levels in the early phase after transplantation. We conclude that host derived IL-18 is a major factor for IFN-γ production that may have a protective effect on CD4+ mediated aGvHD, but is non-essential for Treg expansion in an allogeneic environment.
Soluble CD44 Is Increased in Haematopoietic Stem Cell Grafts of Patients with Acute Myeloid Leukemia, Multiple Myeloma and Non-Hodgkin’s Lymphoma.
Authors: Krause Daniela S. , Stowell Christopher P. 
Published: October 2019

Abstract
Autologous haematopoietic stem cell transplantation (autoHSCT) after high dose chemotherapy is a widely used form of therapy for patients with leukemia, lymphoma and multiple myeloma. Malignant cells remaining in the graft, however, may reengraft leading to relapse of the original disease. CD44, a transmembrane glycoprotein, which is overexpressed in many malignancies, including most haematological malignancies, and which plays a role in the engraftment of leukemia-initiating cells, is shed from the surface of malignant cells. In order to establish whether there is a correlation between the amount of CD44 shed from the surface of the malignant cells with the number of contaminating cells remaining in the graft, the engraftment potential of the malignant cell population, or clinical outcome after autoHSCT, we measured soluble CD44 (sCD44) in 86 haematopoietic stem cell grafts from patients with haematological malignancies by enzyme-linked immunosorbent assay (ELISA) and compared the results to sCD44 levels in the HSC grafts from 33 healthy donours. The levels of sCD44 were almost 2fold higher in the grafts of patients with acute myeloid leukemia (AML) (mean: 30,015 ng/ml ± 8524), multiple myeloma (mean: 27,564 ng/ml ± 7,801) and diffuse large B-cell Non-Hodgkin-Lymphomas (mean: 22,539 ng/ml ± 8,382) than in healthy HSC donour grafts (mean: 13,035 ng/ml ± 10,075). As expected, levels of sCD44 were highest in auto HSCT grafts of patients with AML. The majority of patients who achieved a complete remission after autoHSCT had relatively low sCD44 values (mean: 22,610 ng/l ± 7439). Levels of sCD44 were greatest in patients who experienced progressive disease (mean: 28,918 ng/ml ± 10,431), and somewhat less elevated in patients with relapsed disease after auto HSCT (mean: 26,171 ng/ml ± 7616). In addition, patients who had levels of sCD44 <25,500 ng/ml had increased survival (33% at 120 months after autoHSCT versus 18% in patients with sCD44 levels of >25,500 ng/ml). These results argue that the levels of soluble CD44 in an HSC graft could serve as a biomarker for the engraftment potential of contaminating malignant cells in the graft, and may correlate with clinical outcome after autoHSCT. Further, these results raise the possibility that CD44 blocking strategies may be beneficial in autoHSCT.
In Vivo Growth Advantage of Cells Expressing Acquired CSF3R Mutations in Patients with Severe Congenital Neutropenia.
Authors: Germeshausen Manuela , Ballmaier Matthias , Welte Karl 
Published: October 2019

Abstract
Congenital neutropenia (CN) is a heterogeneous group of disorders, characterized by an absolute neutrophil count (ANC) of less than 500 cells per mm3 from birth on and a predisposition of the patients to recurrent and partial life threatening bacterial and fungal infections as a consequence thereof. CN is associated with an exclusive deficiency in neutrophil development. It usually presents early in infancy during the first year of life, and its infectious complications include cellulitis, perirectal abscesses, pneumonitis, peritonitis, stomatitis, and meningitis due to the extremely low ANC (< 200 cells mm 3). The numbers of circulating monocytes and eosinophils are often increased. However, there is a cumulative incidence of 21% for a malignant transformation in CN after 10 years on G-CSF. Point mutations in the gene for the G-CSF receptor CSF3R have been implicated in the progression of CN to leukemia: In 42% out of 219 CN patients tested so far we could demonstrate acquired nonsense mutations in the CSF3R gene. However, in the subpopulation of patients who have developed leukemia 78% are revealing CSF3R mutations. To clarify the involvement of CSF3R mutations in the process of malignant transformation it is important to know at which stage of hematopoietic development these mutations emerge. Therefore we analyzed single cells of flow cytometrically sorted subpopulations of hematopoietic progenitors and mature hematopoietic cells from bone marrow and peripheral blood of 4 CN patients for the existence of CSF3R mutations. The different cell populations reflect the different lineages of hematopoietic development (CD33+, CD34+, CD14+, CD3+, CD19+, CD16+). Two patients characterized by the occurrence of multiple mutations were screened before any signs of malignant transformation and two patients were analyzed at time of secondary AML. Mutated cells were found in all analyzed populations including lymphocytes. However, in the CD34+ cells, eosinphil granulocytes and in the lymphocytic cells the frequency was much lower than in the G-CSFR expressing monocytes and neutrophil granulocytes. These results suggest an in vivo growth advantage of cells expressing a truncated G-CSFR confirming in vitro results with transfected cell lines and underlines the significance of CSF3R mutations in leukemogenesis in CN patients.
Serum Amyloid A Induces G-CSF Expression and Granulocytosis Via Toll-Like Receptor 2.
Authors: He Rong L. , Zhou Jian , Hanson Crystal L. , Chen Jia , Ye Richard D. 
Published: October 2019

Abstract
As a major acute-phase protein, serum amyloid A (SAA) is commonly used as a marker for inflammatory diseases; however, its precise role in inflammation and infection, which often result in granulocytosis or neutrophilia, remains ambiguous. In this study, we demonstrate that SAA is a potent endogenous stimulator of granulocyte colony-stimulated factor (G-CSF), a principle cytokine regulating granulocytosis, and this effect of SAA is mediated by Toll-like receptor 2 (TLR2). Our data showed that in mouse macrophages, the elevation of the G-CSF mRNA level was observed within the first two hours of SAA stimulation while the secretion of the G-CSF protein was significantly increased after eight hours and sustained for 24 hours. The induction of G-CSF by SAA was blocked by the specific anti-TLR2 antibody and significantly decreased in TLR2 knockout mouse macrophages. We also showed that SAA-stimulated G-CSF expression correlates with the activation of nuclear factor κB (NF-κB), the p65 subunit of which was bound to the CK-1 element of the G-CSF promoter region within 30 minutes of the stimulation. In addition, the SAA increased production of G-CSF was tested to be sensitive to heat, yet insensitive to polymyxin B treatment, indicating that the induction is a direct effect of SAA. Furthermore, our in vivo studies confirmed that SAA significantly increases the plasma concentration of G-CSF and the number of neutrophils in the blood circulation while such phenomenon vanishes in G-CSF or TLR2 knockout mice.
Cyclic Neutropenia Is Not Associated with Transformation to MDS and AML.
Authors: Dale David C. , Bolyard Audrey Anna , Newburger Peter E. , Bonilla Mary Ann , Kannourakis George , Dror Yigal , Link Daniel C. , Alter Blanche P. , Rosenberg Philip S. , Boxer Laurence A. 
Published: October 2019

Abstract
Cyclic neutropenia is a rare hematological disorder characterized by recurrent severe neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe neutropenia (neutrophils <500/μL, usually <200/μL) lasting for 2–4 days at approximately 21-day intervals, documented by serial blood counts (a minimum of 2–3 complete blood counts per week for at least six weeks). Severe congenital neutropenia is a similar, but usually more severe disease. Mutations of the ELA2 gene are regarded as the cause of most cases of both cyclic neutropenia and severe congenital neutropenia. However, only patients with severe congenital neutropenia, not cyclic neutropenia, are thought to be at risk of evolution to MDS/AML. Since its founding in 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has utilized data from previous studies and enrolled patients with cyclic neutropenia based on the clinical information from their treating physicians. We reviewed 190 cases of cyclic neutropenia (including 30 families) enrolled for 0.5 to 19.9 years, (median 11 years) with a total of 2,035 patient years of observation. 173 of 190 patients were treated with G-CSF (median dose 2.82 mcg/kg/day). We identified three patients who were reported to have developed MDS/AML. Further analysis by three experts from the SCNIR revealed that all three patients lacked sufficient serial blood count data to show well-defined neutrophil cycles prior to G-CSF. Two of the three patients lacked a clinical history of mouth ulcers and fevers consistent with the diagnosis, and the bone marrow evaluation was not consistent with cyclic neutropenia in all three cases. One of two patients tested did not have an ELA2 mutation. Thus, using standard criteria for the diagnosis of cyclic neutropenia, none of the three patients fully satisfied the criteria for this diagnosis. In addition, previous family studies, reviews of the published literature, and personal experience of the authors have revealed only one case of leukemia. This case of CML emerged in a 35 year-old patient, who was never treated with G-CSF, 31 years after the diagnosis of cyclic neutropenia. Based upon the review of these cases, we believe it is extremely important to make the diagnosis of cyclic neutropenia by careful analysis of serial blood counts. When the diagnosis is made confidently, it is also important to assure patients that with or without G-CSF treatment, the possibility of evolution to leukemia is unlikely.
Ongoing Strong Improvement in Survival after Diagnosis with Childhood Hematologic Malignancies.
Authors: Pulte Dianne , Gondos Adam , Brenner Hermann 
Published: October 2019

Abstract
PURPOSE: Advances in the treatment of childhood hematologic malignancies have led to improvements in survival in several of these conditions during the past few decades. Here we use the novel method of modeled period analysis to disclose most recent trends in survival among patients diagnosed with hematologic malignancies at less than 15 years of age1.
METHODS: We estimated trends in 5-, 10-, and 25-year survival in children with common hematologic malignancies in the US over three 5-year intervals: 1990–94, 1995–99, and 2000–04, using data from the Surveillance, Epidemiology, and End Results program. Expected survival for 2005–09 was estimated by modeling from trends in the preceding intervals2.
RESULTS: Major improvements in 5- and 10-year relative survival between 1990–94 and 2000–04 were seen in acute lymphoblastic leukemia (ALL) (+7.3 and +10.4% points, respectively), acute non-lymphoblastic leukemia (ANLL) (+18.0 and +20.4% points) and non-Hodgkin lymphoma (NHL) (+11.1 and +13.9% points). Improvements in survival for patients with ALL were particularly strong in older patients, so that the significance of age as a prognostic factor decreased for children diagnosed with ALL in the early 21st century. For Hodgkin’s disease (HD), 5 and 10-year survival were as high as 96.1% and 94.1% in 1990–94 and did not show recent changes. However, it is notable that the 5- and 10-year survivals for HD in 2000–04 were identical, that is, no further deaths occurred between 5 and 10 years. Twenty-five year survival was lower for all of the malignancies examined, with 25-year survivals of about 80% for ALL, HD, and NHL and about 50% for ANLL. Projected 10-year survivals for children diagnosed in 2005–09 are 88.0%, 63.9%, 90.6%, and 94.3% for ALL, ANLL, NHL, and HD, respectively.
CONCLUSION: Application of period analysis to a population-based study of hematologic malignancies reveals ongoing strong improvement in 3 of the 4 common childhood hematologic malignancies. Projections for 2005–09 suggest chances of 10-year survival to be close to 90% or higher for children with ALL, HD, or NHL and to approach 65% for children with ANLL. Long term outcomes remain problematic, with some excess loss of life occurring as late as 25 years after diagnosis.
Period estimates of 10-year survival for childhood hematologic malignancies Malignancy 1990–94 (SE) 1995–99 (SE) 2000–04 (SE) Difference P-val Projected for 2005–09 (SE) ALL-total 73.4 (1.5) 81.0 (1.3) 83.8 (1.2) +10.4 <0.0001 88.0 (1.4) ALL-0-2 yr 72.3 (3.3) 80.9 (2.9) 83.4 (2.8) +11.1 0.01 87.9 (3.0) ALL-3–4 yr 80.9 (2.4) 84.9 (2.1) 88.9 (1.8) +8.0 0.006 91.6 (2.0) ALL-5–9 yr 71.4 (2.7) 80.4 (2.4) 81.4 (2.2) +10.0 0.004 86.1 (2.6) ALL-10–14 yr 61.3 (2.1) 72.3 (4.1) 78.2 (3.6) +16.9 0.007 83.9 (4.0) ANLL 38.7 (4.0) 42.7 (3.8) 59.1 (3.7) +20.4 0.0005 63.9 (4.8) HD 94.4 (2.1) 90.8 (2.6) 95.4 (1.8) +1.0 0.79 94.3 (3.0) NHL 73.0 (4.0) 81.7 (3.4) 86.9 (2.6) +13.9 0.005 90.6 (2.8)
Utilization of Resources and Overall Outcome in Patients Undergoing Hematopoietic Stem Cell Transplantation Related to Psychosocial Factors as Measured by the Transplant Evaluation Rating Scale (TERS).
Authors: Speckhart Dawn S. , Holland H.K. , Solomon Scott R. , Morris Lawrence E. , Bashey Asad 
Published: October 2019

Abstract
Several studies have begun to examine the relationship between psychosocial variables and outcome in hematopoietic stem cell transplantation (HSCT). Data presented at the 2006 ASH Convention, demonstrated a significant relationship between psychosocial variables, such as those assessed on the Transplant Evaluation Rating Scale (TERS), and objective outcomes, such as length of hospitalization and survival. The 2006 data included 200 consecutive patients (136 autologous, 65 allogeneic) undergoing HSCT. Based on the patient’s TERS score, each patient was stratified into one of two groups (low/moderate risk (n=173) vs. high risk (n=28)) based on their predicted psychosocial risk for problems during transplant. With the addition of 166 patients (Current N=366: 239 autologous, 127 allogeneic) the difference in length of hospitalization between low/moderate risk (10 days) versus high risk (19 days) patients remains significant (p<.02). For allogeneic patients (N=127), there continues to be an improved overall survival in low/moderate risk patients in the first 12 to 18 months following HSCT compared to high risk patients (p = .246). To determine whether similar factors impact utilization of resources in patients undergoing HSCT, we prospectively conducted psychosocial assessments on 112 consecutive allogeneic HSCT patients. An analysis of cost was completed for all patients in both the low/moderate risk group and high risk group. The mean cost differential for high risk patients is noted to be 27% higher than those patients in the low/moderate risk group (p = .122). This trend reinforces earlier data presented and suggests a correlation between pre-transplant psychosocial risk factors and resource utilization in HSCT.
Overall Survival Overall Survival
Economic Evaluation of Posaconazole Versus Standard Azole Prophylaxis in High Risk Neutropenic Patients in The Netherlands.
Authors: Stam Wiro B. , O’Sullivan Amy K. , Rijnders Bart , Lugtenburg Elly , Span Lambert F. , Janssen Jeroen J. , Jansen Jeroen P. 
Published: October 2019

Abstract
Background: Acute leukemia and high risk myelodysplastic syndrome patients experience prolonged neutropenia after treatment with intensive chemotherapy, leading to a high risk of acquiring potentially fatal invasive fungal infections (IFI). Pharmacoeconomic analysis is considered a valuable tool to justify the significant costs involved in managing these fungal infections. The present study evaluates the cost-effectiveness of posaconazole versus standard azoles for the prevention of IFIs in neutropenic patients in the Netherlands.
Methods: A decision-tree model was developed that starts with the choice of antifungal prophylaxis: posaconazole or standard azole treatment (fluconazole or itraconazole). The decision tree was estimated using data from a recently published prospective, randomized, double blind, multi-center trial that compared both treatments in neutropenic patients receiving remission-induction chemotherapy for AML/MDS (Cornely et al., 2007). Following initiation of prophylaxis, clinical events are modeled with chance nodes reflecting probabilities of IFIs, IFI related death, and death from other causes. It is assumed that patients surviving the prophylactic period will have a life expectancy that reflects that of the underlying condition. This allows translation of the trial outcomes to a lifetime horizon. Data on life expectancy, quality of life, medical resource consumption and costs were obtained from the literature. Model outcomes include incremental cost per IFI avoided, incremental cost per life years saved and incremental cost per QALYs gained.
Results: The total cost (treatment of breakthrough IFI + prophylaxis) for posaconazole amounted to €4,566 (95% uncertainty interval €3,574 –€5,769), which is €63 (−€1,552 - €1,903) less than costs with standard azoles. Posaconazole prophylaxis resulted in 0.1 (0.03 – 0.15) QALYs gained in comparison to prophylaxis with standard azoles. Results from a probabilistic sensitivity analysis indicate that there is a 87% probability that the cost per QALY gained with posaconazole is below €20,000, a commonly accepted threshold for cost-effectiveness. Additional scenario analyses with different assumptions confirmed these findings.
Conclusion: Given the underlying data and assumptions, our economic evaluation demonstrated that posaconazole prophylaxis is cost and QALY saving compared to fluconazole / itraconazole in neutropenic AML/MDS patients after intensive chemotherapy.