bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Prognostic Factors in Patients with Early Stage Unfavorable Hodgkin’s Lymphoma: An Individual Patient Data Meta-Analysis.
Authors: Bohlius Julia , Haverkamp Heinz , Diehl Volker , Eghbali Houchingue , Franklin Jeremy , Pfistner Beate , Raemaekers John , Engert Andreas , Henry-Amar Michel 
Published: April 2020

Abstract
Background: In patients with early stage unfavorable Hodgkin’s lymphoma (HL) event-free-survival (EFS) is low compared to patients with early favorable or advanced stage disease. An international collaborative study was initiated to identify prognostic factors that could help to define among early stage unfavorable patients those who might benefit from more intensive treatment.
Methods: Medline and Cochrane Library were systematically searched for randomized controlled trials in stage I/II HL. Trials should concern patients with one or more risk factors (age, sex, stage, B-symptoms, bulky disease, number of areas involved, laboratory parameters) receiving 4–6 cycles of ABVD or similar chemotherapy and radiotherapy. Only trials with ≥ 100 patients per study arm were considered. Individual patient data were collected.
Results: Six studies were identified: GHSG: HD5, HD8, HD11; EORTC: H6U, H7U, H8U. Data from 4,235 patients enrolled between 08/1982 and 01/2003 were available for analysis. The proportion of missing data was very low for demographic and clinical characteristics (&lt; 1%); it was acceptable (1.5–9%) for laboratory parameters with the exception of albumin (41% missing values, not recorded in 3 trials). Patient characteristics are listed below. The median follow up was 58.4 months (95% CI 56–61). At the time of analysis 612 patients had experienced an event (disease progression, relapse or death) leading to a 5-year EFS rate of 85%. Using an univariate Cox-regression stratified by study and treatment arm several parameters showed significant influence on EFS.
Conclusion: The data set available is sufficiently powered to identify relevant prognostic factors. A multivariate analysis using updated data will be presented.
Baseline parameter of inlcuded studies Age (median years) Male sex Sage (I/II) B symptoms Bulky disease Hb (median g/dL) All patients, n=4,325 32 2,039 (48.1%) I: 546 (12.9%), II: 3,688 (87.1%) 1,490 (35.2%) 1,936 (45.7%) 12.9 Missing data 1 (&lt; 1%) 0 1 (&lt; 1%) 35 (&lt; 1%) 0 82 (1.9%)
The Mechanism of Rh-Immune Globulin Prophylaxis Involves Significant Increases in the Immunosuppressive Cytokines TGFβ and PGE2.
Authors: Branch Donald R. , Lund Nicole , Shabani Fariba , Denomme Gregory A. 
Published: April 2020

Abstract
For more than 40 years, hemolytic disease of the newborn (HDN) caused by anti-Rh(D) antibody produced by a pregnant mother to her Rh(D)+ baby has been prevented by Rh(D)-immune globulin prophylaxis. Surprisingly, although a number of theories have been proposed, the mechanism of action of this immunosuppressive treatment remains completely unknown (Kumpel BM, Immunol Lett.2002;82:67–73). One potential mechanism of action is the production of one or several strongly immunosuppressive cytokines capable of blocking a primary immune response. Thus, to begin to unravel the possible mechanism(s) of the immunosuppression induced by administration of Rh(D)-immune globulin, we have examined production of a number of immunomodulatory cytokines following administration of Rh(D)-immune globulin. After informed consent, we measured levels of 17 different cytokines pre- and 48 hours post-administration of 300 μg of anti-Rh(D)(WinRhoSDF) in 10 healthy women candidates for Rh(D)-immune globulin prophylaxis. We used platelet-poor plasma from citrated whole blood and quantitative ELISA having the most sensitive detection limits. We observed no striking changes in levels of the cytokines IL-1 sRII, IL-12 p40, IL-16, or MCP-1. Levels of IL-4, IL-5, IL-10, IL-13, IL-17, MIP-1α, GM-CSF, TNFβ, and IFNγ remained below detection levels both pre- and post-testing. However, IL-1ra levels showed a slight to moderate decrease in 7 of 10 women after Rh(D)-immune globulin administration. In contrast, levels of TGFβ-1 increased, &gt;1.3-fold in 7 of 10 women and &gt;2-fold in 4 of 10 women. In one instance, the increase in TGFβ-1 (42, 855 pg/mL) was &gt;5-fold and this woman also had a significant increase in TGFβ-2 (352 pg/mL). In addition to TGFβ, 4 of 10 women had increases of &gt;1.5-fold in PGE2. Statistical analyses using ANOVA, paired Student’s t-test, and Wilcoxon signed-rank, for the combined results of all 10 women receiving Rh(D)-immune globulin indicated that only TGFβ and PGE2 were significantly elevated post administration of Rh(D)-immune globulin. These results indicate that Rh(D)-immune prophylaxis can induce high levels of the strongly immunosuppressive cytokines TGFβ and PGE2. Both of these molecules have been shown to induce profound immunosuppression including prevention of primary immune responses (Ludviksson BR, et al., Eur J Immunol.2000;30:2101–2111; Zhou H, Lamont SJ, Int J Fertil.1986;31:305–310). Our findings represent the first clear evidence for a mechanism of action of Rh(D)-immune prophylaxis.
Incidence of Aplastic Anemia and Agranulocytosis in Brazil and Argentina - The LATIN Study.
Authors: Hamerschlak Nelson , Maluf Eliane , Pasquini Ricardo , Moreira Frederico R. , Cavalcante Alexandre B. , Okano Iria R. , Falcao Roberto P. , Pita Marimilia T. , Looggetto Sandra R. , Rosenfeld Luiz G. , Irene Lorand-Metze G. , Jose Eluf Neto 
Published: April 2020

Abstract
CONTEXT: Aplastic anemia and agranulocytosis are rare but life-threatening disorders, often caused by drugs and other environmental exposures. Reported incidences of these diseases seem to vary between different geographic regions, and few data on the incidence are available for Latin American countries.
OBJECTIVE: To determine the incidence of agranulocytosis and aplastic anemia in Brazil and Argentina.
TYPE OF STUDY: Incidence study.
SETTING: Seven centers in Brazil and one in Argentina took part in the study.
METHODS: Each center conducted active search for new cases in a defined region by means of regular contacts with all hematologists, main clinical laboratories and clinicians in hospitals of the region.
RESULTS: 191 patients with aplastic anemia and 63 with agranulocytosis were identified from 2002 to 2005. The incidence of agranulocytosis was estimated to be 0.6 cases per million people per year. The incidence of aplastic anemia was 1.5 cases per million people per year.
DISCUSSION: Aplastic anemia and agranulocytosis are rare diseases in Brazil and Argentina. The overall incidence of agranulocytosis was lower than generally reported for other countries, while the incidence of aplastic anemia was similar to previous studies. However, there was considerable incidence variability among the regions involved in the study, more markedly for agranulocytosis.
Incidence of Agranulocytosis and Aplastic Anemia/region Region Agranulocyyosis Aplastic Anemia a Rate calculated as population-weighted average of the region specific rates Parana 0.6 1.5 Ribeirao Preto 0.8 0.8 Uberaba e Juiz de Fora 0.7 1.4 Recife 0.3 2.0 Manaus 0.3 1.5 Goiania 0.1 1.6 Buenos Ayres 2.5 1.5 Total a 0.6 1.5
The Use of a Bone Marrow Transplant Program Public Website for Patient Education and Reporting of Outcomes: Increased Use Resulting in Improved Patients’ Trust and Assurance.
Authors: Malcolm Elissa F. , Patchett Linda J. , Fitzmaurice Thomas F. , Hill John M. , Meehan Kenneth R. 
Published: April 2020

Abstract
To promote patient education, the Dartmouth Bone Marrow Transplant (BMT) Program created a website focusing on Quality Reports, highlighting outcomes and patient satisfaction data. In an attempt to address areas most important to potential patients, the development of the website involved Transplant physicians and nurses, outside reviewers and recently transplanted patients. Based on these assessments and interviews, the BMT website was designed to provide various outcome data, including disease-specific overall- and disease-free survival, length of stay, and incidence of nausea. The website became public in January 2004. The use of the public website was evaluated 18 months after initiation. There was a 300% increase in external user visits to the Dartmouth BMT Website (comparing 3 month averages). Eighty percent of the information accessed was in the topic of “Safe and Effective Care”, which addresses patient-specific data, including survival statistics, length of stay, or toxicities during the transplant. The remaining 20% of interest was satisfaction measures addressing patients’ view of their overall care, opinions addressing nursing care or physician interaction. Of the top ten measures that were evaluated by users, the first 9 were disease-specific survival statistics and the remaining was “Average Length of Hospital Stay”. Individual interviews with patients (n=16) indicate that the information provided on the web site increased the trust of the institution. In addition, patients felt re-assured concerning their selection of our institution. In conclusion, the initiation of the Dartmouth BMT Quality Reports Website (http://www.dhmc.org/QualityReports) that focuses on outcome data resulted in a marked increased use of the Dartmouth BMT Website within 18 months. Patients were most interested in disease-specific survival statistics, followed by transplant patients’ opinions of their care. Patients report that the “transparency” of outcome results and the patient education provided by the website improve their trust of our BMT program/hospital and foster assurance of our institution’s reputation.
Prognostic Factors in Patients with Fanconi Anemia (FA) after Alternate Donor (AD) Hematopoietic Cell Transplantation (HCT).
Authors: Alsweedan Suleimman A. , Wagner John E. , Tan Ye , DeFor Todd E. , MacMillan Margaret L. 
Published: April 2020

Abstract
The treatment of choice for the hematological complications in FA patients is a histocompatible sibling donor HCT. However, as FA is inherited disorder, most patients do not have an HLA-matched non-affected sibling donor and therefore require AD (HLA-mismatched sibling or unrelated) HCT with inherent increased morbidity and mortality. To identify prognostic factors for survival after AD HCT, we evaluated outcomes in 83 FA patients transplanted at the University of Minnesota from 1990 to 2004. Median age at HCT was 11.8 years (range, 0.8–48.5). 82% received bone marrow (BM) grafts and 18% received unrelated cord blood (UCB). In univariate analysis, factors associated with significantly higher 3-year survival included: age [42% (&lt;18 years, n=67) vs 16% (&gt;18 years, n=16) p=0.01]; recipient CMV serostatus [45% (negative, n=55) vs 19% (positive) p=0.01]; blood product transfusion 82% [(none, n=11) vs 28%(any, n= 67) p= 0.03], prior infection (gram negative bacteria or fungal) [46% (absent, n=62) vs 8%(present, n=19) p= 0.01], and use of fludarabine (FLU) in preparative regimen [45% (present, n=54) vs 24% (absent, n=29) p=0.03]. In multivariate analysis, factors associated with improved survival were young age, negative recipient CMV serostatus, no prior infections and no severe acute GVHD (Table 1). If age &lt;18 yrs, CMV negativity, and absence of prior infections defines ‘standard risk’, 3 year survival is 68% (95% CI, 50–85%) compared to 20% (95% CI, 7–32%) for those with ‘high risk’ disease (p =0.01). Disease status at HCT, androgen use, number of malformations, gender, donor source and HLA disparity did not have a demonstrable effect on survival.
Table 1: Cox regression on survival Factors Relative Risk(95% CI) P-value Note:*-reference category Model(X2=33.5, p&lt;0.01) Age at transplant(X10) 1.62 (1.15-2.28) &lt;0.01 Recipient CMV Negative 1.0 * Positive 3.41(1.82-6.37) &lt;0.01 Prior Infection No 1.0 * Yes 2.33 (1.24-4.36) &lt;0.01 Grade 3-4 acute GvHD No 1.0 * Yes 5.04 (2.34-10.88) &lt;0.01
These data suggest that patients with FA should receive AD HCT before the development of preventable high risk features, namely older age and serious infections. FLU based preparative regimens and measures to prevent acute GVHD should also be used to improve survival. Mismatched BM and UCB donor may provide greater donor options for timely transplants in FA patients.
Enzymatically-Active ADAMTS13 Variants Are Not Inhibited by Anti-ADAMTS13 Autoantibodies - A Potential Novel Therapeutic Strategy.
Authors: Zhou Wenhua , Dong Lingli , Motto David , Ginsburg David , Bouhassira Eric , Tsai Han-Mou 
Published: April 2020

Abstract
ADAMTS13, a reprolysin-type zinc metalloprotease consisting of a metalloprotease (MP), a disintegrin, a thrombospondin-1 (TSP), a cysteine-rich region (Cys), a spacer, seven additional TSP, and two CUB domains, is critical for preventing unwarranted VWF-platelet interaction in the circulation. Profound deficiency of ADAMTS13, due to genetic mutations of the ADAMTS13 gene or autoimmune inhibitors of the protease, causes microvascular thrombosis characteristic of TTP. Plasma exchange is a conventional but complex therapy of TTP that may be ineffective for patients with high inhibitor titers. In this study we produce recombinant ADAMTS13 variant proteins and analyze their binding with and suppression by TTP inhibitors. TTP IgG binds the ADAMTS13 variants ending downstream of the spacer domain but not those truncated upstream, consistent with recent reports that the spacer domain is essential for interaction between TTP IgG and ADAMTS13. Nevertheless, the spacer domain sequence alone may be insufficient since TTP IgG does not bind a fragment consisting solely of the spacer domain sequence but binds a fragment encompassing the sequence between the distal 2/3 of the MP and the spacer. ADAMTS13 ending at the TSP#1 or downstream are proteolytically active in cleaving either VWF multimers or a 73-amino acid fragment of the VWF A2 domain. Mixing studies show that each of ten TTP plasma samples tested suppresses the protease activity of ADAMTS13 ending downstream of the spacer domain, but not the activity of the variants truncated at the TSP#1 or Cys domain. The variant proteins truncated at TSP#1, when added to a series of plasma samples from a TTP patient with rising inhibitor titers, consistently yield the expected protease activity levels, even in those samples whose high inhibitor titers abolish the activity of the full-length ADAMTS13 at 15x of its concentration. These findings indiate that it is feasible to design ADAMTS13 variant proteins that are proteolytically active yet refractory to suppression by inhibitors of TTP. Such ADAMTS13 variants may be exploited to circumvent the inhibitors of TTP, potentially eliminating the need of performing plasma exchanges in the future.
The Fate of Human Langerhans Cells in Hematopoietic Stem Cell Transplantation.
Authors: Collin Matthew P. , Hart Derek N. , Jackson Graham H. , Cook Gordon , Cavet James , Mackinnon Stephen , Dickinson Anne M. 
Published: April 2020

Abstract
The fate of Langerhans cells (LC) and other antigen-presenting cells (APC) in haematopoietic stem cell transplantation (HSCT), their depletion by conditioning regimens, reconstitution and chimerism are important factors in understanding graft versus host disease and the outcome of transplantation. Hitherto untested predictions in humans state that depletion of recipient LC may prevent acute graft versus host disease (GVHD), the acquisition of donor chimerism in LC may drive the evolution of clinical GVHD from acute to chronic and the persistence of recipient LC may explain late acute GVHD phenomena and donor lymphocyte infusion toxicity.
Between April 2003 and June 2005 we obtained 184 skin biopsies from 76 patients at 4 UK centres. Using confocal microscopy of intact epidermal sheets to image up to 2000 LC at a time, we find that full intensity transplant (FIT) conditioning with TBI-based regimens or busulfan and cyclophosphamide depletes 55% of LC at day 0 (n 14; p 0.001). In contrast, fludarabine-based reduced intensity transplant (RIT) depletes only 9% of LC (n 23; p 0.061). A minimum LC density is reached at 14-21 days in both regimes with little difference at the nadir, suggesting that the effect on density at day 0 is primarily kinetic. Rapid recovery occurs by 40 days in the absence of acute cutaneous GVHD but is delayed beyond 100 days in the presence of GVHD (n 50; p 0.006)
We assessed LC chimerism in sex-mismatched transplants by allowing single cells to migrate from small epidermal sheets in vitro and applying a two-step Giemsa/FISH assay. At 40 days median LC donor chimerism is 97% after FIT and 36.5% after RIT (n 11; p 0.004). At 100 days median donor chimerism is 100% after FIT and 97.5% after RIT (n 28; p 0.133.). The majority of transplants - 16/28 (57%) - achieve 100% LC donor chimerism at day 100 and all are at least 90%. Attainment of full donor chimerism at 100 days shows only a trend with FIT (p 0.133), and with complete myeloid chimerism in the blood (p 0.080) but is strongly associated with prior acute cutaneous GVHD (p 0.002). At one year post transplant it is possible to detect rare recipient cells in a minority of transplants (12/1746 interphase nuclei - less than 1%), confirming that LC may regenerate in the skin under quiescent conditions.
In conclusion we find that: 1) recipient LC survive conditioning, especially after RIT, suggesting that targeted APC depletion might have potential as a novel means of preventing acute GVHD; 2) LC turnover is accelerated by full conditioning, complete myeloid chimerism and acute GVHD; 3) the majority of LC are donor-derived in all transplants at 100 days, consistent with the hypothesis that donor engraftment of APC drives the transition of acute to chronic GVHD. 4) there is little evidence using these conditioning regimens that acute GVHD or DLI-toxicity occurring after 100 days is related to the persistence of recipient APC.
CD4+ Effector Memory and Naive T Cells Mediate Graft-Versus-Leukemia Via Direct Recognition of MHCII on Leukemic Cells.
Authors: Zheng Hong , Matte Catherine C. , Venkatesan Srividhya , Anderson Britt E. , Shlomchik Mark J. , Shlomchik Warren D. 
Published: April 2020

Abstract
One of the major challenges in allogeneic stem cell transplantation (alloSCT) is to separate graft-versus-host-disease (GVHD) from graft-versus-leukemia (GVL). We and others have previously demonstrated, in both major histocompatibility complex (MHC)-compatible/multiple minor histocompatibility antigen-mismatched and MHC-mismatched murine models of alloSCT, that spontaneous effector memory (EM) CD4+T cells depleted of regulatory CD25+ cells (CD4+CD44+CD62L-CD25-) do not cause GVHD. We have also shown that these EM CD4+ T cells can mediate GVL against a model of murine chronic phase of CML (mCP-CML) induced via retroviral transduction of BM cells with the bcr-abl fusion cDNA without causing GVHD (Zheng, et al ASH meeting 2004). In the present study we analyzed the effector mechanisms of these EM CD4+ cells in the B6bm12 → B6 MHCII disparate bone marrow transplantation (BMT) model. First, we demonstrated that the GVL activity of both EM and naïve CD4+ T cells required cognate interactions with CML targets as GVL was ineffective against mCP-CML induced in bone marrow from B6.I-Ab−/− (MHCII−) mice. Recipients of MHCII− mCP-CML died from mCP-CML between day 15-20 post BMT, regardless of whether they received EM or naïve CD4+ cells or no T cells at all. In light of data in the same model that parenchymal MHCII expression is not required for GVHD (Teshima et al, 2002), these data demonstrate distinct mechanisms for the cytotoxicity by CD4+ cells in GVL and GVHD—direct in the former and indirect in the latter. To further investigate the specific mechanisms of T cell killing, we tested the effectiveness of EM CD4+ cells in eradicating mCP-CML induced in bone marrow cells from Fas−/− and TNFR1/R2−/− mice. Both EM and naïve CD4+ cells mediated GVL against these gene deficient leukemias that was similar to that against wild type mCP-CML. In summary, these results suggest that EM and naive CD4+ cells mediate GVL via direct cognate engagement with targets. Their killing, however, does not depend on either FasL or TNF-α which suggests a dominant role for perforin, TRAIL, or both. Interestingly, although the mechanisms of recognition and killing of mCP-CML by either naïve or EM CD4+ T cells are so far indistinguishable, whereas only the naïve cells cause GVHD. Whereas a number of investigators have been able to separate mechanisms of killing in GVHD vs. GVL, this is to our knowledge the first clear demonstration of a difference in the mechanism of recognition between GVHD and GVL.
Bone Marrow Derived, De Novo Generated CD4+ T Cells Are Previously Unsuspected Participants in CD8+ T Cell-Mediated Graft-Versus-Host Disease.
Authors: Zhang Yi , Hexner Elizabeth , Frank Dale , Gerard Joe , Kung Frank , Emerson Stephen G. 
Published: April 2020

Abstract
Although mature CD8+ T cells are known to be major effectors of acute GVHD, patients receiving T cell-depleted allografts remain at high risk for chronic GVHD. To what extent CD8+, CD4+ or both T cell subsets contribute to this chronic immunopathology is not known. We have recently demonstrated that alloreactive memory T cells develop in mice with acute GVHD and account for the persistence of host tissue injury (Journal of Immunology, 2005;174:3051). Based on these findings, we now ask whether de novo generated donor T cells from engrafted T-BM themselves contribute to persistent host tissue injury in GVHD. Confirming previous observations, we found that transplantation of lethally irradiated C57BL/6SJL (B6, CD45.1) mice with highly purified C3H.SW (CD45.2) CD4+ naïve T cells did not cause GVHD, but mice receiving highly purified CD8+ naïve T cells together with C3H.SW T-BM, suffered severe acute GVHD. Surprisingly, in these mice receiving only CD8+ T cells, a substantial number of donor CD4+ T cells as well as CD8+ T cells were detected in GVHD target tissues, indicating that these infiltrating CD4+ T cells had arisen de novo from the transplanted T-BM. Donor CD4+ T cells recovered from GVHD mice expressed surface markers of activated effector/effector memory T cells, including CD25, CD69, CXCR3, and CD44hiCD62Llo. In response to host DCs, purified GVHD CD4+ T cells proliferated and expanded 4-5X more, and produced 10X higher levels of IFN-γ than did CD4+ T cells derived from B6 mice receiving C3H.SW T-BM alone. Furthermore, adoptive transfer of these in vivo generated GVHD CD4+ T cells, without CD8+ T cells, into secondary irradiated B6 recipients induced clinical GVHD characterized by delayed onset, weight loss, diarrhea, and lymphopenia, but without cutaneous inflammation. Histologic examination demonstrated chronic inflammation in the liver and intestinal tract, including epithelial apoptosis. Thymic pathology was dramatic in secondary B6 recipients of GVHD CD4+ T cells, including thymic atrophy, loss of thymic cortex, and infiltration of large amount of tingible macrophages. Taken together, these results demonstrate that donor bone marrow derived, de novo generated CD4+ T cells also contribute to GVHD together with transferred mature CD8+ T cells. Moreover, they suggest that these CD4+ T cells, in concert with alloreactive memory CD8+ T cells that develop during the evolution of GVHD, cause the persistence of acute GVHD and its subsequent progression into chronic GVHD. Thus, donor BM-derived, de novo generated CD4+ T cells are the “Hidden Dragon” of CD8+ T cell-mediated GVHD. Understanding how these CD4+ T cells are generated and regulated will prove to be critical to the prevention and treatment of both acute and chronic GVHD.