bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tie-2 Activation Is Required for Regeneration of Marrow Vasculature, Supporting Hematopoietic Reconstitution.
Authors: Kopp Hans-Georg , Avecilla Scott T. , Tejada Rafael , Crystal Ronald G. , Hackett Neil R. , Rafii Shahin 
Published: April 2020

Abstract
Accumulating evidence from our lab (Nature Med.2004; 10(1): 64–71) and others have shown that myelosuppression not only results in apoptosis of the hematopoietic cells but also in regression of bone marrow (BM) sinusoidal vessels. Remarkably, we have shown that restoration of hematopoiesis is dependent on the regeneration of BM sinusoidal neo-vessels. However, the mechanism whereby vascular reconstitution is regulated is unknown. Because Tie2/Angiopoietins are critical in the remodeling of neo-vessels, we hypothesized that activation of Tie2 plays a role in regeneration of sinusoidal neo-vessels and restoration of hematopoiesis. To this end, we took advantage of transgenic mice where the Tie2 promoter drives the expression of beta-galactosidase (LacZ) in order to follow the expression of Tie2 in hematopoietic progenitor cells after myelosuppression. Under steady-state conditions, only few LacZ/Tie-2+ cells were localized in the endosteal/osteoblastic region, without any expression within the BM sinusoidal neo-vessels. However, after a myelosuppressive dose of 5-Fluorouracil (5-FU) there was a robust expression of Tie2 expression in the regenerating BM sinusoidal neo-vessels. The expression of Tie2 on the regenerating neo-vasculature reached a maximum at day 10 and reverted back to steady-state by day 20 post 5-FU, the time in which the majority of the neo-vessels were functionally assembled.
Blocking angiopoietin/Tie2 signaling with the soluble decoy-receptor, Tie2Fc, after 5-FU inhibited platelet recovery as well as vascular reconstitution. There was a paradoxical accumulation of megakaryocytes in the bone-marrow during the prolonged thrombocytopenic phase, which we have previously shown to be due to vascular niche disruption and inability of megakaryocytes to release platelets.
To examine the possibility that Tie2+ progenitors can reconstitute BM sinusoids in the recipient mice, lethally irradiated wildtype mice were transplanted with the BM of Tie2-lacZ knock-in mice. After full recovery, the chimeric mice were challenged with a myelosuppressive dose of 5-FU and Tie2+ neo-vessels were detected histologically on day 5, 10, and 14 by LacZ staining. Remarkably, the reconstituted bone marrow showed the presence of Tie2+ vessels, which unambiguously demonstrates the contribution of donor-derived endothelial progenitors to the reconstitution of the regressed vasculature.
Together, our data support the hypothesis that Tie2/angiopoietin signaling is essential for functional regeneration of BM sinusoidal neo-vessels and contributes to the reconstitution of hematopoiesis, specifically to thrombopoiesis. In addition, the use of Tie2-LacZ mice provides an invaluable model to quantify the number of regenerating BM neo-vessels. Angiopoietins may be used in clinical setting in conjunction with other lineage specific cytokines to enhance hematopoiesis after myelosuppression.
Elderly Patients with Early-Unfavorable Stage Hodgkin’s Disease (HD) Have a Poorer Outcome When Treated with Combined Modality Treatment and Extended Field Radiotherapy (EF): A Retrospective Analysis of the German Hodgkin Study Group.
Authors: Engert Andreas , Haverkamp Heinz , Eich Hans T. , Josting Andreas , Pfistner Beate , Diehl Volker 
Published: April 2020

Abstract
Purpose: The HD8 study of the German Hodgkin Study Group (GHSG) demonstrated that involved field (IF) radiotherapy is equally effective when compared with EF radiotherapy after four cycles of chemotherapy (2 x COPP/ABVD). Since there are indications that elderly patients with HD might fare worse depending on the type of treatment applied, we revisited the HD8 data for possible differences between younger and older patients.
Methods and results: A total of 1204 patients were randomised to receive two double cycles of COPP/ABVD and either 30 Gy EF + 10 Gy bulk or 30 Gy IF + 10 Gy bulk. Of these, 98 evaluable patients were older than 60 years and 1038 patients were younger than 60 years. In general, there were more risk factors such as B-symptoms, elevated ESR, and poorer Karnofski index in the elderly group. On the other hand, there were fewer bulky tumours, large mediastinal tumours and a lower number of lymph node areas involved in elderly patients. The toxicity of treatment was more pronounced in elderly patients with 76 of 96 patients experiencing chemotoxicity Grade III or IV (79%) compared with 699 of 1018 (69%) in those younger than 60 years. After a median follow up of 52 months, the 5-year-FFTF was 85% in younger patients and 63% in patients older than 60 years (p &lt;0.001). The 5-year-overall survival was 94% for patients younger than 60 years and 66% for patients older than 60 years (p &lt; 0.001). In addition, patients older than 60 years treated with EF had a trend for worse FFTF and overall survival compared to those receiving IF radiotherapy.
Conclusion: Event-free and overall survival of patients older than 60 years old are worse compared with younger patients. In particular, patients older than 60 years receiving EF radiotherapy had a poorer prognosis.
Comparison of Patients (Pts) Characteristic and Treatment Outcomes in Lymphocyte-Predominant (LPHD) and Classical Hodgkin’s Disease (cHD): A Report from the German Hodgkin Lymphoma Study Group (GHSG).
Authors: Nogova Lucia , Reineke Thorsten , Josting Andreas , Behringer Karolin , Pfistner Beate , Diehl Volker , Engert Andreas 
Published: April 2020

Abstract
Introduction: LPHD differs in histological and clinical presentation from cHD. Treatment of LPHD patients (pts) using standard Hodgkin disease (HD) protocols leads to complete remission (CR) in more than 95% of pts. However, differences in terms of relapse rates, survival and freedom from treatment failure (FFTF) between clinical stages of LPHD and cHD pts were suggested by a recent intergroup analysis. To obtain a more comprehensive picture, we reviewed all LPHD-cases registered in the GHSG database and compared patient characteristics and treatment outcome with cHD pts.
Patients and methods: We retrospectively analysed 8298 HD pts treated within the GHSG trials (HD4 to HD12): 394 LPHD pts and 7904 cHD pts. From 394 LPHD pts 63% were in early stage, 16% in intermediate and 21% in advanced stage of disease. Of the 7904 cHD pts analysed, 22% were in early, 39% in intermediate and 39% in advanced stages. 9% of LPHD pts had B symptoms compared to 40% in cHD pts.
Results: 87.5% LPHD pts reached CR/CRu compared to 81.1% cHD pts. 0.3% LPHD pts developed progressive disease (PD) compared to 3.7% cHD. The relapse rate of LPHD pts was very similar to cHD (6.9%). 0.8% LPHD pts and 3.1% cHD had early relapse, 6.9% LPHD pts and 4.2% cHD pts suffered from late relapse. LPHD pts with late relapse were in intermediate stages (12.5%). In contrast, only 3.9% of cHD pts in intermediate stages had late relapses. There were 2.5% secondary malignancies in LPHD and 3.7% in cHD pts. 4.3% LPHD pts and 8.8% cHD pts died. The FFTF rates for LPHD or cHD pts at a median observation of 41 or 48 months, respectively were as follows: early stages 93% vs. 87%, in intermediate stages 87% vs. 85% and in advanced stages 77% vs. 75%. The OS rates for LPHD or cHD pts were 98% vs. 96% for early stages, 94% vs. 93% for intermediate stages and 91% vs. 87% for advanced stages. The multivariate analysis of prognostic and risk factors will be presented.
Conclusion: cHD pts present more frequently with advanced stages and B symptoms compared to LPHD pts. Comparing LPHD and cHD pts we found differences in treatment outcome in respect of CR/CRu, progressive disease and mortality. Surprisingly, there were no differences in terms of relapses. The majority of late relapses in LPHD pts were in intermediate stages. In contrast to previous reports, our data suggest that relapses in LPHD and cHD pts seem to be comparable and not more frequent. Thus new treatment strategy for LPHD pts in intermediate stages should be considered.
Impact of Course of Therapy on Response Rate and Duration with the Bexxar® Therapeutic Regimen (Tositumomab and Iodine I 131 Tositumomab) and with Chemotherapy.
Authors: Leonard John P. , Zelentz Andrew D. , Vose Julie M. , Kaminski Mark S. 
Published: April 2020

Abstract
Low grade NHL with or without transformation is characterized by recurrence. Initial response rates with chemotx are high, but all patients ultimately relapse, and the response rates and durations of response typically decline with each subsequent course of chemotx. In the pivotal trial of Bexxar (JCO 19:3918 2001) there were significantly more patients with longer durations of response than after their last qualifying chemotx. The aim of the current retrospective study was to evaluate the efficacy of Bexxar and prior chemotx by course of treatment in a larger group of patients. Response rates (RR) and duration of response data were available from the treatment histories of the 230 patients from five clinical studies. Demographics: median age, 56 years; age &gt; 60, 34%; median number of prior regimens, 3 (range 1–13); bone marrow involvement, 48%; bulky disease, 32%; transformed histology 28%; IPI score ≥ 2, 81%; and refractory to their preceding regimen, 80%. The patient-specific dosing regimen for Bexxar was previously described (JCO 19:3918). RR and durations for chemotx used as the 2nd, 3rd, 4th, 5th, 6th and &gt;6th treatment were compared to Bexxar for the same numerical treatment. At each successive treatment course, there was a consistently higher RR and duration of response after Bexxar than after chemotx (Table). The actual differences in RR may be greater, as the data for Bexxar are based on responses observed on at least 2 evaluations &gt;4 weeks apart, as assessed by an independent, blinded Masked Independent Randomized Radiology and Oncology (MIRROR) panel. The reported RR for chemotx are based on Investigator-assessed unconfirmed responses. Of note, the % responding pts in continuous response at ≥ five year after receiving Bexxar for the 2nd, 3rd, 4th, 5th, 6th and &gt;6th relapse were 41%, 21%, 25%, 35%, 36 and 9%, respectively. While RR decreased with number of prior therapies, the durations of response and percent in continuous response after Bexxar were substantial and consistent across the range of the number of prior therapies.
Treatment/Regimen Number Chemotx Bexxar n Response Rate (Unconfirmed) Median Duration of Response (months) n Response Rate (Confirmed) Median Duration of Response (months) 2 183 51% 8.0 27 74% 14.4 3 145 52% 5.0 44 64% 47.2 4 98 45% 5.0 54 52% 10.8 5 45 40% 4.0 48 54% 11.0 6 33 36% 4.0 21 52% 27.0 7 or more 48 19% 3.5 36 42% 9.6
Delayed Severe Neutropenia after Rituximab Therapy in 18 among 293 Patients with B-Cell Malignancies Treated in a Single Institution. an Adverse Event of Unknown Mechanism.
Authors: Belhadj Karim , El Gnaoui Taoufik , Doghmi Kamal , Joly Bertrand , Lee Ketty , Plonquet Anne , Jouault Hélène , Gourlain Karine , Delfau-Larue Marie-Hélène , André Chantal , Reyes Felix , Haioun Corinne 
Published: April 2020

Abstract
The characteristics of severe neutropenia with delayed onset following administration of rituximab were evaluated in 293 consecutively patients treated for B-cell malignancies between Oct. 1996 and Feb. 2004. Eighteen episodes of severe neutropenia were identified between 2 to 36 weeks after rituximab, delivered alone in 4 cases or combined to chemotherapy in 14 other cases. At the time of occurrence of neutropenia, 10 patients had completed treatment and were in complete remission and 8 were still on therapy. All patients had a normal neutrophil count before rituximab treatment. In 4 cases, neutropenia was complicated by fever requiring hospitalisation. Among the18 patients [diffuse large B-cell lymphoma: 12, follicular lymphoma: 3, mantle cell lymphoma: 1, post transplant lymphoproliferative disorder: 1, chronic lymphocytic leukemia (CLL): 1], 8 had previouly been treated with high-dose therapy followed by autologous stem-cell transplantation. None of the known causes of neutropenia were found. Neutropenia was associated with selective marrow depletion of neutrophil precursors in all episodes. The peripheral blood lymphocyte subset repartition was documented in 16 cases; a severe B lymphopenia was observed in all except one - patient with CLL - and CD4+ lymphopenia was seen in 13. T-cell clonality was studied in 8 cases and was positive in 5. Parvovirus B19 DNA was not detected in the 11 tested cases. Tests for antineutrophil antibodies were positive in 5 cases; no hemolytic anemia, autoimmune thrombocytopenia or large granular natural killer lymphocytosis were observed. Filgrastim was given to 4 patients only. The median time of neutrophil recovery for the entire group was 14 days (range: 2–180).
The mechanism of this rare event already reported (Saikia et al. Ann. Oncol 2002, Voog et al. NEJM 2003, Chaiwatanatorn et al. BJH 2003, Lemieux et al. BMT 2004) remains to be established. Since it seems to be more frequent in patients who have received extensive prior chemotherapy (8/18), it is tempting to speculate that cumulative immunosuppression might favor the development of such an event.
Treatment of Complete DiGeorge Syndrome by Repeat Transfusions of Blood Lymphocytes from an HLA-Identical Sibling Donor.
Authors: Hoenig Manfred , Schulz Ansgar , Schuetz Catharina , Debatin Klaus-Michael , Friedrich Wilhelm 
Published: April 2020

Abstract
DiGeorge syndrome (DGS) is a congenital disorder characterized by facial dysmorphies, hypoparathyroidism, cardio-vascular malformations and variable T-cell deficiency due to thymic hypoplasia. We present a male infant with complete absence of T-cells and thymus successfully treated by repeat blood lymphocyte transfusions. According to previous experience of bone marrow transplantation in a similar patient, T-cell reconstitution is possible by peripheral expansion of mature donor cells, independent of stem cell engraftment. Our patient received at the age of four months an initial transfusion of blood lymphocytes from his HLA-identical brother, containing 1x108 T-cells/ kg. Ten days later he developed mild cutaneous GvHD, which resolved spontaneously without immunosuppressive therapy. Lymphocyte transfusions were repeated three times at 4 weeks intervals without reappearance of GvHD. T-cells developed within two months after the first transfusion and since then remain at levels between 500–1000/μl with a proportion of 25% disclosing a CD45RA+ phenotype. In chimerism analysis T-cells are exclusively of donor origin. The T-cell receptor repertoire is similarly diverse as in the donor. After more than 2 years of follow up the boy is not suffering from severe infections and shows no signs of autoimmune disease. Following immunization, antibody titres normalized. Conclusion: In infants with complete DGS transfusions of blood lymphocytes from a matched family donor may lead to long-lasting engraftment of functional T cells and stable chimerism and represents a potentially helpful therapeutic option.
UNC13D and PRF1 Mutations in Childhood Patients with Hemophagocytic Lymphohistiocytosis.
Authors: Stadt Udo zur , Beutel Karin , Oyen Florian , Diler A. Sarper , Kabisch Hartmut , Schneppenheim Reinhard , Hennies Hans-Christian , Janka Gritta 
Published: April 2020

Abstract
Introduction: Familial Hemophagocytic Lymphohistiocytosis (FHLH) is an autosomal recessive disease affecting young children. It manifests itself as a severe hyperinflammatory syndrome with activated macrophages and T-lymphocytes. Mutations in Perforin (PRF1) are responsible for FHL-2 in about 15 to 50 % of the patients. Defective granule exocytosis due to mutations in UNC13D have recently been described as the genetic defect underlying FHL-3. Both types are phenotypically not distinguishable from one another.
Patients and Methods: Genetic analysis was performed in either the 2 or the 32 exons of PRF1 and UNC-13D, respectively, in 61 patients with hemophagocytic lymphohistiocytosis (HLH) of different geographic origin (28 from Germany, 24 from Turkey and 9 from other countries).
Results: We identified mutations in 28 samples investigated (18 in PRF1, 10 in UNC-13D). Besides several known mutations novel deletions, missense and nonsense mutations were detected in both genes scattering the whole coding regions. The Trp374stop mutation (11/13 patients with a PRF1 mutation from Turkey) was the only single mutation repeatedly observed in several patients with a common geographic origin. In HLH patients from Germany, 7/28 patients showed homozygous or compound heterozygous mutations in either PRF1 (3) or UNC13D (4). In 24 HLH patients from Turkey 13 patients with a mutation in PRF1 and 4 patients with a mutation in UNC13D were identified. In addition, four out of 9 patients with a different geographic origin showed mutations in one of this genes. In 10 patients only one heterozygous mutation in UNC13D was detected so far. In these cases, control samples or regulatory regions of the gene have to be analysed to ascertain the relevance of the underlying mutation.
Defect Turkey German Other All UNC13D 4 4 2 10 PRF1 13 3 2 18 Unknown 7 21 5 33
Discussion: Overall, UNC-13D and PRF1 mutations were detectable in 45% of the cases. Our results indicate that FHL-2 and FHL-3 account for more than 60% of the HLH cases of Turkish origin with only a small number involving UNC-13D. In contrast, gene defects were identified in only 25% of the patients with a German ancestry. This work was supported by the Foerdergemeinschaft Kinderkrebszentrum Hamburg e. V.
The Significant Decrease of Recent Thymic Output Function in Patients with Benzene-Poisoned Aplastic Anemia.
Authors: Li Yangqiu , Han Sufang , Yang Lijian , Chen Shaohua , Zhou Yubing , Chen Jiayu , Liu WeiWei 
Published: April 2020

Abstract
It has been known for many years that benzene causes hematotoxicity, as well as the toxicity in lymphopoiesis, and it associated with aplastic anemia and leukemia. The aim of the present study was to investigate the level of T-cell receptor excision DNA circles (TRECs) within peripheral blood mononuclear cells (PBMCs) in patients with benzene-poisoned aplastic anemia (AA), thereby to evaluate the content of naive T cells and the recent thymic output function. Quantitative detection of TRECs in DNA of PBMCs from 16 normal individuals and 7 cases with benzene-poisoned AA was preformed by real-time PCR using TaqMan technique. The results showed that TRECs level was 6.69±4.79/1000 PBMCs in normal individuals, it was significant decrease in patients with benzene-poisoned AA (2.24±1.57/1000 PBMCs, p&lt;0.05). The TRECs levels in 2 cases with benzene-poisoned AA were followed up in different time points up to 55 weeks. The TRECs level was persistent decrease after diagnosis of benzene-poisoned and leaving the benzene exposure workplaces and undergoing clinic specific treatment, even if peripheral blood cell counts were became normal levels. The TRECs levels were 1.35±0.87/1000 PBMCs (at 5 time points) and 0.61±0.45/1000 PBMCs (at 4 time pionts) in two cases respectively. The results indicated that the recent thymic output function was remarkable decrease in patients with benzene-poisoned AA. It may obviously damage the T cell immune function in benzene poisoning.
Proliferation of CD8+ T-Cells Specific for CMV and EBV in Response to TCR Mediated Recognition of Cognate Antigen Is Inhibited by Imatinib in a Dose-Dependent Manner.
Authors: Seggewiss Ruth , Lore Karin , Greiner Elisabeth , Magnusson Magnus K. , Price David A. , Douek Daniel C. , Dunbar Cynthia E. , Wiestner Adrian 
Published: April 2020

Abstract
We and others have shown that the tyrosine kinase inhibitor imatinib (STI571, Gleevec®) inhibits T-cell proliferation and activation at concentrations achieved in vivo. At 10μM, imatinib inhibited T-cell receptor (TCR)-mediated proliferation of purified peripheral blood T-cells almost completely. Up-regulation of the activation markers CD25 and CD69 at 24h in response to TCR cross-linking was suppressed by imatinib at a mean IC50 of 5.4μM and 7.3μM, respectively and IL-2 production was also severely impaired. However, these assays may not fully reflect the response to clinical relevant antigens. Therefore, we chose to investigate the antigen-triggered proliferation of memory CD8+ T-cells specific for immunodominant CMV and EBV HLA-A2 peptide epitopes. We used HLA-peptide tetramers to identify healthy blood donors with detectable CMV- or EBV-specific CD8+ T-cell populations. Purified T-cells from these donors were then stimulated with the CMV peptide pp65495–503 or the EBV peptide BMFLI259–267. Antigen-induced proliferation was measured by dilution of the vital dye CFSE over a period of 4 or 8 days. The magnitude of the virusspecific CD8+ T-cell population ranged from 0.5 % to 7.1% of CD8+ T-cells for CMV and from 0.05% to 0.35% of CD8+ T-cells for EBV. Antigen-specific CD8+ T-cells from all 10 donors studied proliferated in response to the CMV peptide. In 8 from 10 donors, imatinib reduced CMV peptide induced proliferation. With increasing imatinib concentrations (range: 5 – 10μM), we observed dose dependent reduction of both the number of cells undergoing cell division and the average number of divisions completed per cell. Comparable inhibition of specific T-cell proliferation in response to the EBV-derived peptide was observed in two donors. Immunoblots demonstrated that imatinib substantially reduced tyrosine phosphorylation of ZAP70 and LAT in response to TCR-mediated activation in Jurkat T-cells. Sequence comparisons of all 90 tyrosine kinase genes in the human genome for homology in the ATP binding pocket identified Lck, which is required for ZAP70 activation, as a likely target for imatinib. Our results indicate that imatinib may interfere with clinically important T-cell effector functions. As concentrations sufficient for half-maximal inhibition of TCR signalling are achieved in vivo, imatinib could increase the risk of opportunistic infections and impact on GVH and GVL reactions post-transplantation especially when used in conjuction with other immunosuppressive agents. Therefore, close monitoring of patients on imatinib for CMV reactivation or EBV-induced lymphoproliferative diseases, especially in stem cell transplant recipients, appears warranted.