bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Bortezomib on the Autonomic Nervous System.
Authors: Crocchiolo Roberto , Ferrari Stefania , Calbi Valeria , Marcatti Magda , Guggiari Elena , Servida Paolo , Bernardi Massimo , Carro Ubaldo Del , Bonini Chiara , Tresoldi Moreno , Peccatori Jacopo , Ciceri Fabio , Sora Maria Grazia Natali 
Published: October 2019

Abstract
Background
Peripheral neuropathy is one of the most frequent adverse events associated to bortezomib therapy; among neuropathic syndromes, postural hypotension is described as well. However, information on disautonomic toxicity are limited and there are no studies addressed to this particular issue so far.
Before starting this study we had observed a case of dramatic acute autonomic failure during bortezomib treatment in a patient with advanced multiple myeloma, who developed severe orthostatic hypotension, tachycardia and impairment to tolerate the sitting and orthostatic posture for several weeks.
Methods
We prospectively studied 12 consecutive patients, treated with bortezomib at our Institution between February 2005 and July 2006. Assessment included neurological examination, INCAT Disability scale, INCAT sensory sum score, MRC sum score, nerve conduction studies, and standard cardiovascular autonomic tests including Lying to standing, Deep breathing and Postural hypotension. These tests were conducted baseline and after each bortezomib 21-days cycle up to three consecutive cycles.
Results
Two pts showed a clinically evident autonomic involvement with orthostatic hypotension; a change to a pathological score in 2 out of 3 tests anticipated clinical disautonomic signs in 1 and 11 weeks respectively. Clinical impairment showed to be reversible in both cases. Four pts presented only 1 pathological test (without any clinical sign or symptom of postural hypotension) and 6 patient had normal results. There was no apparent correlation between autonomic impairment and disease response to therapy or patients baseline characteristics (disease stage, Ig class, previous anti-myeloma therapies, concomitant thalidomide or anti-hypertensive treatment); furthermore, none had evidence of amyloidosis.
Conclusions
Our prospective study confirms that autonomic dysfunction is a potential adverse effect of bortezomib. Autonomic, non invasive, cardiovascular testing may reveal subclinical involvement and precede clinical evidence of disautonomic neuropathy. Further studies in larger cohorts of patients are needed to clarify the interactions between proteasome inhibitor activity and autonomic nervous system, in order to assess the frequency, the ability of available test in early pre-clinical diagnosis and the potential of the reversibility of neuropathic signs after drug discontinuation.
Conditioning with Treosulfan and Cyclophosphamide without Application of Antibodies in MHC Mismatch Transplantations in Mice.
Authors: Nogai Axel , Thiele Marc , Heimesaat Markus M. , Thiel Eckhard , Goebel Ulf B. , Uharek Lutz 
Published: October 2019

Abstract
BACKGROUND: Treosulfan is increasingly used in clinical conditioning regimens because of its myeloablative and immunosuppressive effects and the low hepatotoxicity compared to busulfane. The myeloablative and immunosuppressive characteristics of treosulfane was investigated in a murine MHC mismatch transplantation model.
METHODS: C57BL/10 (H-2Db) female mice were treated with treosulfan (2000 mg/kg) on day -3 to -1 and increasing doses of cyclophosphamide (without, 100 or 200mg/kg) at day -1, or 3000 mg/kg treosulfan with and without 200 mg/kg cyclophosphamide at day -1. Some mice were not transplanted to examine the myeloablative effect of the regimens, the rest of mice were transplanted with 10 × 10^6 marrow cells from Balb/c mice (H-2Dd) donors and monitored for donor-type chimerism determined by flow cytometry.
RESULTS: Mice treated with treosulfan and cyclophosphamid without transplantation died, indicating the myeloablative effect of the regimens. Ca. 50% of mice treated with 3000 mg/kg treosulfan and 200 mg/kg cyclophosphamide at day -1 died. Analysis of bone marrow cells in the remaining mice showed a complete rejection at day 55. Approximately 90% of the recipients of three daily doses of treosulfan and increasing doses of cyclophosphamide survived until the end of experiment (day +100). All hosts engrafted when 200 mg/kg cyclophosphamide was applied. 85% of mice engrafted after 100mg/kg cyclophosphamide. 100% of grafts were rejected in the group with treosulfan alone (2000 mg/kg).
CONCLUSION: A chemotherapeutic regimen for achieving a long term survival in a MHC-mismatch situation without additional need of antibodies was established in mice. While investigated for the practicability in an animal model as alternative to TBI, the high rate of engraftments in a MHC mismatch situation makes the chemotherapeutic regimen suitable for clinical situations.
Low-Dose Cyclosporin A Does Not Abrogate the Suppressive Function of In Vitro Expanded Human CD4+CD25+ Regulatory T Cells.
Authors: Piseshka Biserka , Eder Ruediger , Boeld Tina J. , Andreesen Reinhard , Holler Ernst , Hoffmann Petra , Edinger Matthias 
Published: October 2019

Abstract
Graft-versus-host disease (GVHD) is a major complication after allogeneic stem cell transplantation caused by donor T cells in the stem cell graft. Prophylactic treatment of GVHD usually comprises immunosuppressive medication including cyclosporin A (CsA) that blocks calcineurin phosphatase activity and thereby inhibits nuclear factor of activated T cells (NFAT)-mediated cytokine production. CD4+CD25+ natural regulatory T (Treg) cells have been shown to suppress the proliferation and cytokine secretion of conventional CD4+ and CD8+ T cells in vitro and to protect from GVHD lethality in murine models of allogeneic BMT. As the adoptive transfer of human CD4+CD25+ Treg cells as a means of GVHD prophylaxis is currently under investigation, we aimed to explore the influence of CsA on survival, cytokine production and suppressive activity of this T cell subpopulation. To this end, in vitro expanded human CD4+CD25high and CD4+CD25− T cells were stimulated with anti-CD3 and anti-CD28 antibodies and simultaneously exposed to various concentrations of CsA. While T cell death occurred in both in vitro expanded subpopulations at high CsA concentrations of 1000 ng/ml, with only 10 to 20% viable cells after 72h exposure, CD4+CD25high T cells showed significantly enhanced resistance to lower CsA concentrations of 100 ng/ml with still approx. 60% viable cells, as compared to only 20% viability in expanded CD4+CD25− T cells. At this lower concentration, CsA also blocked the proliferation of the two subpopulations in response to anti-CD3/CD28 stimulation, as determined by CFSE-dilution, and inhibited the IL-2 and IFN-γ production of CD4+CD25− T cells as well as the IL-10 production by expanded CD4+CD25high Treg cells, as shown by intracellular staining after stimulation with PMA/ionomycin. Addition of exogenous IL-2 protected both subpopulations from CsA-induced cell death and restored their proliferative capacity but was unable to abrogate the block in cytokine production. Surprisingly, the suppressive activity of in vitro expanded CD4+CD25high Treg cells was neither affected by a pre-incubation of the cells with 100 ng/ml CsA, nor by its presence during the suppression assay. These results indicate that in vitro expanded CD4+CD25+ Treg cells are less sensitive to CsA-induced apoptosis and that their yet unknown mechanism of suppression does not involve the calcineurin pathway.
Human CD4+CD25+CD127− T Cells Show Potent Dose-Dependent Inhibition of Allogeneic DC-Driven MLRs.
Authors: Protheroe Rachel E. , Steward Colin G. , Mazza Graziella , Wraith David C. 
Published: October 2019

Abstract
Graft versus host disease (GVHD) is the primary cause of transplant related morbidity and mortality, limiting the widespread application of haemopoietic stem cell transplantation (HSCT). Evidence from murine models supports the role of CD4+CD25+ regulatory T cells in the suppression of GVHD. Human evidence regarding the role of regulatory T cells in alloresponses is conflicting and may reflect the difficulty in defining and isolating the regulatory T cell population in humans. We have investigated the use of peripheral blood monocyte-derived dendritic cells (DCs) as stimulator cells in allogeneic mixed lymphocyte reactions (MLRs), as a means of assessing the in vitro suppressive function of regulatory T cells in human alloresponses. Peripheral blood mononuclear cells (PBMCs) were obtained from healthy adult volunteers. Magnetically isolated CD4+CD25+ T cells were combined with 50×103 autologous PBMCs or 20×103 autologous CD4+ T cells as responders, and 5×103 allogeneic irradiated DCs. Proliferation was assessed by tritiated thymidine incorporation. The CD4+CD25+ cells were anergic and demonstrated dose-dependent suppression of responder cell proliferation in the DC-driven allogeneic MLR. Greater than 50% suppression was seen with CD4+CD25+ T cells co-cultured with responder PBMCs at ratios of 1:4 to 1:32. Furthermore, depletion of CD4+CD25+ T cells from whole CD4+ responder cells resulted in enhanced proliferation and an increase in the amplitude of the MLR. Flow cytometry indicated that the majority of the magnetically isolated CD4+CD25+ T cells were FoxP3+ on intracellular staining and demonstrated down-regulation of cell surface expression of the IL-7 receptor (CD127). The potent suppression demonstrated here by CD4+CD25+CD127− T cells at ratios of 1:32 responder cells, suggests that these cells have a potential role for suppressing alloresponses at physiological levels. Moreover, this assay provides the basis for future investigation into regulatory T cell function in patients post-HSCT.
Decitabine Induces Responses in Patients with Myelodysplastic Syndrome (MDS) after Failure of Azacitidine Therapy.
Authors: Borthakur Gautam , Ravandi-Kashani Farhad , Cortes Jorge , Jabbour Elias , Faderl Stefan , O’Brien Susan , Verstovsek Srdan , Garcia-Manero Guillermo , Newman Beth Ann , Giles Francis , Issa Jean-Pierre , Kantarjian Hagop M. 
Published: October 2019

Abstract
Background
The hypomethylating agents azacitidine and decitabine are active in MDS and approved in the U.S.A. for this indication. The comparative efficacy of these two agents is not established. Responses to one drug after treatment failure with the other may offer evidence for superior efficacy.
Study Aims
Evaluate the efficacy of decitabine in MDS after failure of azacitidine therapy.
Study Group and Treatment
Adults with MDS who have progressed or failed to respond after at least three courses of azacitidine were eligible. Other entry criteria were standard including performance status 0–2, normal liver, kidney, and cardiac functions, and informed consent. Patients received decitabine 20 mg/m2 IV/D x 5 every four weeks. Response was evaluated by the modified IWG criteria (Cheson, Blood 2006).
Results
Fourteen patients have been treated to date. Their median age was 74 years (range 58–85 years). Patients had received prior azacitidine for a median of 4 courses (range 1 to 9); number of azacitidine courses 3 or more in 12 patients (86%); hemoglobin less than 10 g/dL in 7 (50%); thrombocytopenia < 100 x 109/L in 11 (78%); chromosomal abnormalities in 6 (43%); marrow or peripheral blast 5% or more in 13 (93%). Overall, 5 patients (36%) achieved IWG response: CR in 3 (21%), PR in 1 (7%), marrow CR +/− other hematologic improvements (HI) in 1 (7%). Improvement of thrombocytopenia was noted in 2/5 patients (40%) with pretreatment platelets < 50 x 109/L. Median remission duration was 5.3 months; median survival was 6.0 months. Extramedullary toxicities were minimal.
Conclusions
Decitabine is active in MDS following failure of azacitidine therapy. Comparative randomized studies of decitabine versus azacitidine in MDS may be indicated.
Enhancement of Dendritic Cell Therapy for Malignancy by Co-Activation of CD1d Restricted NKT Cells, NK Cells, and Antigen CTL.
Authors: Hagi Tomomi , Truong Vy , So Hang-Fai , Wang Qiao , Morley Jacqueline S. , Nieda Mie , Nicol Andrew 
Published: October 2019

Abstract
Human Vα24+ Natural Killer T (NKT) cells are cytotoxic against a range of malignancies, including human lymphoma and myeloid leukaemia in vitro and in murine models in vivo. Human NKT cells are activated by α-galactosylceramide (KRN7000) when presented by the MHC Class I-like molecule, CD1d, expressed by antigen presenting cells, particularly dendritic cells (DCs). Successful activation of human NKT cell antitumor activity in a clinical setting, particularly if this also activates natural killer (NK) cells and enhances tumor-specific cytotoxic T lymphocyte (CTL) activity, has the potential to be more potent and effective than current strategies focusing entirely on activation of peptide antigen specific CTL. In order to evaluate this we initiated a clinical study aiming to determine whether all three cell types could be activated with a single therapy. Melanoma was evaluated because of the known responsiveness to DC based immune therapy and the availability of well-defined peptide tumor antigens amenable to evaluation in a large number of subjects. Subjects with stage IV metastatic melanoma who were HLA-A*0201 were randomized to receive multiple intradermal or intravenous treatments with autologous mature monocyte derived DC pulsed with KRN7000, 4 peptide antigens (Mart-1, gp100, tyrosinase and Mage 3) or both. Peripheral blood NKT cells, NK cells and CD8+ CTL specific for the four melanoma antigens were monitored before, during, and after the series of treatments using 5 color flow cytometry. Antigen specific CTL were monitored using tetramers obtained from Beckman Coulter. Our results were that DC pulsed with KRN7000 + peptide were able to activate NKT cells and NK cells as well as increase the number of tumour antigen specific CTL. Activation of NKT and NK cells was most marked after intravenous treatment. However increased tumor antigen specific CTL were observed after treatment by both routes. Minor disease responses and stabilization were noted in subjects with non-bulky disease. We conclude that activation of NKT, NK and antigen specific CTL is possible with a single modality of immune therapy and that this is associated with disease responses.
Prospective Evaluation of Procalcitonin in Adults after Prolonged Neutropenia.
Authors: Cornillon Jerome J. , Bouteloup Marie M. , Lambert Claude C. , Devanlay Camille C. , Guyotat Denis D. 
Published: October 2019

Abstract
Infectious disease are persisting problem in patients with prolonged aplasia and a main cause to death. Determination of localization and germ remains difficult. The clinical presentation is poor and C Reactive Protein (CRP) is not specific. Treatment is empirical and uses broad spectrum antibiotic and antifungal therapy with sometimes moderate efficacy. Monotherapy or bitherapy in intial fewer are frequently discussed and no consensus exists. However, in sepsis, it is recommanded to use bitherapy in initial phase. Procalcitonin (PCT) is a pro-peptide of calcitonin produced mainly but not only in the C-cells of the thyroid glands. Several studies show PCT levels in plasma increase during infectious diseases in immunocompetent patients. In febrile neutropenia, data of PCT is scare and controversal. To determine the diagnostic and prognostic values of PCT, we assessed daily PCT level before and during the first febrile episode in 58 consecutive adults. Between November 2004 - April 2006, 32 patients received induction, or consolidation treatment for acute leukemia and 26 patients allogeneic or autologous hematopoietic stem cells transplantation. The mean duration of neutropenia was 17 days (range 5–43). Patients were treated with imipen only in first line except when clinical criteria of severity were presents (14 patients). Twenty-six percent had a clinically localized infectious (LI) which was documented in 14/15 patients, 45% had non documented fever and 29% bacteriemia. Twenty-one percent had a gram - bacillus and 29% gram+. No death was noted in this period. Mean duration of fever is 3.3 days (1–11). The means of CRP and PCT at day 0 and day 1 are presented in table 1. No difference exists in PCT before the first day of fewer (day -1). Not correlation was noted between different etiologies of fever and PCT or CRP. However, a trend of PCT values in bacteriemia was noted at day 1 (p=.07). The predictive value of PCT level at day 1 was calculated for bacteriemia. With a cut-off at 0.03, the negative predictive value was 78% (positive predictive value: 55%). In conclusions, neither PCT nor CRP levels can anticipate infections. Nevertheless, at day +1, PCT level < 0.03 could exclude the possibility of bacteriemia and therefore avoid the use of bitherapy before bacteriologic results. More patients are necesseray to confirm these preliminary results.
Table 1 PCT D−1 PCT H0 PCT D+1 CRP H0 CRP D+1 localized infections .11 .13 .17 49.33 94.14 SIRS .20 .23 .25 49.56 94.73 sepsis .15 .19 .95 52.69 104.54 Total .16 .19 .44 50.57 97.92
Split-Liver Transplantation in a Child with Liver Failure Based on Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from the Same Donor.
Authors: Englert Cornelia Nicole , Ganschow Rainer , Beckmann Matthias , Janka-Schaub Gritta , Burdelski Martin 
Published: October 2019

Abstract
We report a case of a 6-year-old boy who developed chronic graft-versus-host-disease (GVHD) of the liver, the intestines and the skin following allogeneic hematopoietic stem cell transplantation.
The boy received allogeneic hematopoietic stem cell transplantation by the age of two years because of early recurrence of acute lypmphoblastic leukemia. The chimerism analysis showed complete chimerism. In the following year he developed GVHD despite adequate immunosuppressive therapy. Liver biopsy showed liver-GVHD resulting in liver cirrhosis by the age of five years.
Liver transplantation was performed with a split liver segment from the same unrelated donor as of the stem cells. Immunosuppressive therapy consisted of low dose steroids and low dose cyclosporine. The postoperative course was uneventful. Graft function was excellent and we performed protocol biopsies seven days and three weeks after transplantation which did not show any signs of rejection or GVHD.
To our knowledge this is the first report on a liver transplantation following allogeneic hematopoietic stem cell transplantation from the same unrelated donor.
In the latest liver biopsy three months after liver transplantation slight signs of GVHD could not be ruled out completely so that the low dose cyclosporine therapy is still continued.
Further biopsies will show if the immunosuppressive therapy can be discontinued.
Does Polyoma (BK) Virus Contribute to Development of Hemorrhagic Cystitis (HC) in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (UD HSCT) Recipients? A Prospective Evaluation.
Authors: Patah Poliana A. , Szewczyk Nicholas A. , Gilman Lisa , Gulbis Alison , Neumann Joyce , Walker Julia A. , Petropoulos Demetrios , El-Zimaity Maha , Anderlini Paolo , Tarrand Jeffrey , Champlin Richard E. , de Lima Marcos 
Published: October 2019

Abstract
BK virus infection is highly prevalent in humans, and has been associated with development of HC after HSCT. Previously we determined that UD HSCT is independently associated with higher prevalence of HC (El-Zimaity et al. Blood 2004). In order to further investigate the association of BK with HC, we hypothesized that patients who have positive urine PCR for BK virus before UD transplant have a higher incidence of HC.
Methods: we studied 62 consecutive patients transplanted from 09/05 to 05/06. Preparative regimens were ablative (n=26) or reduced intensity (n=36); 15 patients (23%) received cyclophosphamide-containing regimens. GVHD prophylaxis was tacrolimus and mini-methotrexate. Stem cell source was bone marrow (n=28), peripheral blood (n=25) or umbilical cord (n=9). BK virus quantitative PCR was performed on urine samples collected upon admission.
Results: Median age was 53 years (range, 19–67). Diagnoses were leukemias (n=36), multiple myeloma (n=2), Hodgkin’s disease (n=4), non-Hodgkin’s lymphomas (n=16), and other (n=4). Median time to platelet engraftment was 16 days (range, 0–62; n=51). Median follow-up is 97 days. BK PCR was positive in 28 patients (45%). Number of viral copies ranged from 300 to > 200 million copies. Eleven patients (18%) developed HC, at a median of 25 days after HSCT. HC was of grade 1 (n=1), grade 2 (n=4), grade 3 (n=5), grade 4 (n=1; required bilateral nephrostomies). In the PCR positive group, 7 patients (25%) had HC, versus 4 (12%) in the PCR-negative group (hazard ratio = 3.4 for a positive PCR; log-rank p = 0.057). 100-day cumulative incidence of HC is shown in the figure. 45% of CB recipients developed HC.
Incidence of HC was not statistically significantly increased among recipients of ablative or cyclophosphamide-containing regimens. Likewise, development of grade II-IV acute GVHD (n=18, 29%) was not associated with higher rates of HC. Six patients developed HC before platelet engraftment. Viral load did not correlate with development of HC. Four patients had viruria of 50–200million/mL; only one developed HC.
Conclusion: BK viruria pre-HSCT may be a risk factor for development of HC; further study is needed in a large cohort of patients.
Figure Figure