Disease relapse is the commonest cause of treatment failure after allogeneic haematopoietic stem-cell transplantation. Adoptive immunotherapy based on donor lymphocyte infusions (DLI) has a prominent ...role in the management of disease recurrence. Although the highest remission rates are achieved in chronic myeloid leukaemia (CML), encouraging results have also been reported in chronic lymphoproliferative disorders. However, the experience of DLI in CML is not necessarily applicable to the management of lymphoproliferative diseases because of the heterogeneity of the conditioning regimens used in chronic lymphoid malignancies. We will review the role of DLI for different disease types in the context of conventional and reduced-intensity conditioning regimens. The factors influencing response and graft-versus-host disease as well as the optimal cell dose will be discussed. Finally, we will describe the main avenues currently being explored to improve the selectivity and efficacy of DLI.
The current nosography of eating disorders (ED) has various limitations in terms of validity and accuracy. The changes adopted in the DSM-5 limit some of the current problems, such as excessive ...prevalence of ED not otherwise specified (EDNOS) and the lack of longitudinal stability, but are unlikely to adequately capture the clinical complexity of ED. Many authors suggest the need for a thorough review of the current nosography to support evidence-based classification. In this paper, we discuss the validity of the current diagnostic categories and their possible reorganization. Furthermore, we review the main empirical models of classification and the diagnostic approach from a personality perspective, with particular attention to research and to the prognostic and therapeutic implications.
The MAGIC collaboration has studied the high-frequency-peaked BL Lac object 1ES 1218+30.4, at a redshift z = 0.182, using the MAGIC imaging air Cerenkov telescope located on the Canary Island of La ...Palma. A gamma-ray signal was observed with 6.4 s significance. The differential energy spectrum for an energy threshold of 120 GeV can be fitted by a simple power law, yielding F sub(E)(E) = (8.1 c 2.1) x 10 super(-7) E/(250 GeV) super(-3.0c0.4) TeV super(-1) m super(-2) s super(-1). During the 6 days of observation in 2005 January, no time variability on timescales of days was found within the statistical errors. The observed integral flux above 350 GeV is nearly a factor of 2 below the upper limit reported by the Whipple collaboration in 2003.
•Seventeen EBMT centers participated to a questionnaire on MSC manufacturing.•88% of centers manufacture MSC from bone marrow and only 2 centers from umbilical cord.•Human platelet lysate has ...replaced bovine serum as culture medium supplement.•Release criteria extensively differ among centers.•The results highlight the need to harmonize MSC manufacturing.
The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients’ stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufacturing as clinical products and the need for harmonization. Until more informative potency assays become available, a more homogeneous approach to cell production may at least reduce variability in clinical trials and improve interpretation of results.
Abstract Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase ...clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an “open-access” manner, such as through publication or database collection.
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