Developing a policy for paediatric biobanks: Principles for good practice

The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions

Real-World Insights on the Management of Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP) With Caplacizumab

peer reviewe

Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or r-chop consolidation in an international, prospective, multicenter Phase II trial

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective

Posttransplantation lymphoproliferative disorders (PTLD): towards an integrated approach

Prevention of organ rejection and graft-versus-host disease following solid organ and hematopoietic stem cell transplantation requires long term immunosuppressive therapy, leading to an increased risk of both infections and malignancies. Despite the fact that skin cancers are the most common malignancies, posttransplant lymphoproliferative disorder (PTLD) comprises one of the most serious complications following transplantation with high morbidity and mortality rates. Although the interest in diagnosis, pathogenesis, treatment and prevention of this disorder obviously has increased during the last decade, these different aspects have been characterized by a huge heterogeneity. In this work we tried to put some different pieces (illustrated by the large number of involved disciplines) of the PTLD puzzle together, aiming to obtain a global approach of this disorder. From a clinicopathological point of view we analysed a large cohort of transplant patients diagnosed with PTLD in our center. Although not randomized or prospective, the patient cohort is representative of the general PTLD population, providing a real life picture of the incidence, the clinic-pathological features, the therapeutic changes over the last decade and the outcome of patients diagnosed with PTLD. The results of this retrospective cohort study should enable clinicians, at least in part, to base their clinical management strategies for PTLD on systematically acquired evidence recovered from a representative large study population, in the absence of prospective studies. Based on this database we also analysed some specific rare subtypes of PTLD, in particular T-cel non-Hodgkin lymphoma PTLD and plasmablastic lymphoma PTLD. In a second part of our work we were able to show that 18F-fluorodeoxyglucose-positron emission tomography (PET scan) is highly sensitive for detecting PTLD and has an excellent ability to differentiate PTLD from non-malignant diseases. In addition, compared with CT scan PET may be more prefereable due to other reasons. As extranodal involvement is a frequent feature of PTLD, CT scan may not be the most appropriate staging tool. Another potential problem is the need for intravenous contrast with CT, which is relatively contra-indicated in transplant patients due to the relative frequent co-existing renal impairment. Based on this PET project our center was asked to organize the central PET review program of an upcoming international European PTLD trial. The pathogenesis of PTLD is only poorly understood and studied. In order to improve our knowledge we performed gene expression profiling on a large set of PTLD samples. This study revealed that the samples show clustering according to the underlying EBV status rather than to the immune state. A viral response signature clearly segregates EBV+ cases (PTLD) from EBV- cases (both PTLD and immune competent diffuse large B cell lymphomas) cases. In future we wil further try to integrate different molecular and cytogenetic techniques in an attempt to unravel the complex pathogenesis of the disorder. Finally we joined and actively participated in a European PTLD-1 Study Group, consisting of different experts in the field of PTLD. This Study Group initiated a European Phase II trial investigating the efficacy and safety of sequential immunochemotherapy in patients diagnosed with PTLD following solid organ transplantation. After an interim analysis the trial was amended in 2007 introducing risk stratification according to the response to rituximab. This trial is currently ongoing aiming to recruit 150 patients in the different participating European and Australian centers. In 2012 a scheduled interim analysis was presented of 91 patients treated with the risk stratification strategy, of which 18.7% were treated in Leuven. In the meantime the PTLD-1 Study Group is preparing a new trial (PTLD-2) integrating extended risk stratified sequential treatment, introducing PET scan in risk stratification and also focusing on new molecular techniques. Taken together, in this work, we tried to integrate clinical, diagnostic, pathogenic and therapeutic issues involved in PTLD. However, many more questions remain. Further research, translational and clinical studies are needed in this rapidly changing field with increasing transplant activities worldwide and the use of new and very potent immunosuppressive therapy. In the future we hope we can further contribute in this project.status: publishe

Management of post-transplant lymphoproliferative disorders

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The ABC of apheresis

Apheresis is a collective term for several activities in which a desirable specific blood component is separated and collected or a harmful component is removed. During the last decades the application of apheresis has expanded to a broad spectrum of diseases due to various studies on the clinical efficacy of this therapy as well as the innovation of new techniques. However, adverse events quite often occur during apheresis. In this article we will give a brief overview on general principles, indications and complications of apheresis.peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=yacb20status: publishe

Posttransplant lymphoproliferative disorders following liver transplantation: Where are we now?

Liver transplantation has emerged as a life-saving treatment for several patients with acute liver failure, end stage liver disease and primary hepatic malignancies. However, long term immunosuppressive therapy aiming to reduce the risk of transplant rejection increases the incidence of several complications including malignancies. This is illustrated by the observation of a high ratio between observed and expected cases of lymphoproliferative disorders following liver transplantation. Despite a huge heterogeneity in morphological appearance of these disorders ranging from reactive-like lesions to real lymphomas, they are collectively termed posttransplant lymphoproliferative disorders. In this review we will provide an overview of this rare but challenging disorder as a complication of liver transplantation.status: publishe