Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report.

Hematopoietic stem cell transplantation (HSCT) is an established procedure for many acquired and congenital disorders of the hematopoietic system. A record number of 42 171 HSCT in 37 626 patients (16 030 allogeneic (43%), 21 596 autologous (57%)) were reported by 655 centers in 48 countries in 2015. Trends include continued growth in transplant activity over the last decade, with the highest percentage increase seen in middle-income countries but the highest absolute growth in the very-high-income countries in Europe. Main indications for HSCT were myeloid malignancies 9413 (25%; 96% allogeneic), lymphoid malignancies 24 304 (67%; 20% allogeneic), solid tumors 1516 (4%; 3% allogeneic) and non-malignant disorders 2208 (6%; 90% allogeneic). Remarkable is the decreasing use of allogeneic HSCT for CLL from 504 patients in 2011 to 255 in 2015, most likely to be due to new drugs. Use of haploidentical donors for allogeneic HSCT continues to grow: 2012 in 2015, a 291% increase since 2005. Growth is seen for all diseases. In AML, haploidentical HSCT increases similarly for patients with advanced disease and for those in CR1. Both marrow and peripheral blood are used as the stem cell source for haploidentical HSCT with higher numbers reported for the latter.Bone Marrow Transplantation advance online publication, 13 March 2017; doi:10.1038/bmt.2017.34

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

Several human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome

XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency

Background Nonhomologous end-joining (NHEJ) is the major DNA double-strand break (DSB) repair mechanism in human cells. The final rejoining step requires DNA ligase IV (LIG4) together with the partner proteins X-ray repair cross-complementing protein 4 (XRCC4) and XRCC4-like factor. Patients with mutations in genes encoding LIG4, XRCC4-like factor, or the other NHEJ proteins DNA-dependent protein kinase catalytic subunit and Artemis are DSB repair defective and immunodeficient because of the requirement for NHEJ during V(D)J recombination. Objective We found a patient displaying microcephaly and progressive ataxia but a normal immune response. We sought to determine pathogenic mutations and to describe the molecular pathogenesis of the patient. Methods We performed next-generation exome sequencing. We evaluated the DSB repair activities and V(D)J recombination capacity of the patient's cells, as well as performing a standard blood immunologic characterization. Results We identified causal mutations in the XRCC4 gene. The patient's cells are radiosensitive and display the most severe DSB repair defect we have encountered using patient-derived cell lines. In marked contrast, a V(D)J recombination plasmid assay revealed that the patient's cells did not display the junction abnormalities that are characteristic of other NHEJ-defective cell lines. The mutant protein can interact efficiently with LIG4 and functions normally in in vitro assays and when transiently expressed in vivo. However, the mutation makes the protein unstable, and it undergoes proteasome-mediated degradation. Conclusion Our findings reveal a novel separation of impact phenotype: there is a pronounced DSB repair defect and marked clinical neurological manifestation but no clinical immunodeficiency

Hematopoietic Stem Cell Transplantation for Primary Immunodeficiencies

The field of primary immunodeficiencies has pioneered many of the advances in haematopoietic stem cell transplantation and cellular therapies over the last 50 years. The first patients to demonstrate sustained benefit and prolonged cure from the primary genetic defect following allogeneic haematopoietic stem cell transplantation were patients with primary immunodeficiencies. Although primary immunodeficiency patients began the modern era of haematopoietic stem cell transplantation, the history is nevertheless short-in answer to the question "what is the long term outcome of patients transplanted for primary immunodeficiencies?" we often have to say that we do not know. We believe that most patients who undergo haematopoietic stem cell transplantation for primary immunodeficiencies should live a normal lifespan with a fully corrected immune system. We are now beginning to understanding long term outcomes, the relationship to the underlying genetic defect, age, and pre-morbid condition of the patient at time of transplantation, stem cell source and donor, and effect of pre-transplant cytoreductive chemotherapy conditioning. The long term consequences of post-transplant complications such as graft vs. host disease, veno-occlusive disease, or immune dysregulation are also being recognized. Additionally, some genetic defects have a systemic distribution, and we are learning the natural history of these defects once the immunodeficiency has been removed

Controlo químico de infestantes

Uma planta é considerada infestante quando nasce espontaneamente num local e momento indesejados, podendo interferir negativamente com a cultura instalada. As infestantes competem com as culturas para o espaço, a luz, água e nutrientes, podendo atrasar e prejudicar as operações de colheita, depreciar o produto final e assegurarem a reinfestação nas culturas seguintes. Dado o modo de propagação diferenciado das diversas espécies de infestantes, com as anuais a propagarem-se por semente e as perenes ou vivazes a assegurarem a sua propagação através de órgãos vegetativos (rizomas, bolbos, tubérculos, etc.), assim, também o seu controlo quer químico, quer mecânico terá que ser diferenciado, ou seja, para controlar infestantes anuais será suficiente destruir a sua parte aérea, enquanto para controlar infestantes perenes teremos que destruir os seus órgãos reprodutivos. O controlo de infestantes poderá ser químico, através da utilização de herbicidas, ou mecânico pela utilização de alfaias agrícolas, tais como a charrua de aivecas, a charrua de discos, a grade de discos, o escarificador e a fresa. Quando a técnica utilizada na instalação das culturas é a sementeira directa, o controlo das infestantes terá que ser obrigatoriamente químico, enquanto se o recurso à mobilização do solo for a técnica mais utilizada (sistema de mobilização tradicional ou sistema de mobilização reduzida), o controlo das infestantes tanto poderá ser químico como mecânico. Neste trabalho iremos abordar apenas, o controlo químico de infestantes

Too much of a good thing: a review of primary immune regulatory disorders

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity caused by a loss in the regulatory mechanism of the inflammatory or immune response, leading to impaired immunological tolerance or an exuberant inflammatory response to various stimuli due to loss or gain of function mutations. Whilst PIRDs may feature susceptibility to recurrent, severe, or opportunistic infection in their phenotype, this group of syndromes has broadened the spectrum of disease caused by defects in immunity-related genes to include autoimmunity, autoinflammation, lymphoproliferation, malignancy, and allergy; increasing focus on PIRDs has thus redefined the classical ‘primary immunodeficiency’ as one aspect of an overarching group of inborn errors of immunity. The growing number of genetic defects associated with PIRDs has expanded our understanding of immune tolerance mechanisms and prompted identification of molecular targets for therapy. However, PIRDs remain difficult to recognize due to incomplete penetrance of their diverse phenotype, which may cross organ systems and present to multiple clinical specialists prior to review by an immunologist. Control of immune dysregulation with immunosuppressive therapies must be balanced against the enhanced infective risk posed by the underlying defect and accumulated end-organ damage, posing a challenge to clinicians. Whilst allogeneic hematopoietic stem cell transplantation may correct the underlying immune defect, identification of appropriate patients and timing of transplant is difficult. The relatively recent description of many PIRDs and rarity of individual genetic entities that comprise this group means data on natural history, clinical progression, and treatment are limited, and so international collaboration will be needed to better delineate phenotypes and the impact of existing and potential therapies. This review explores pathophysiology, clinical features, current therapeutic strategies for PIRDs including cellular platforms, and future directions for research

Reprint of “The clinical impact of deficiency in DNA non-homologousend-joining”

DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway inmammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models,since radiation potently induces DSBs. The process of V(D)J recombination functions during the devel-opment of the immune response, and involves the introduction and rejoining of programmed DSBs togenerate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJdeficiency confers (severe) combined immunodeficiency – (S)CID – due to a failure to carry out V(D)Jrecombination efficiently. NHEJ also functions in class switch recombination, another step enhancing Tand B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patientsrevealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syn-dromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have beenidentified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCIDpatients frequently display additional characteristics including microcephaly, dysmorphic facial featuresand growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our currentunderstanding of the underlying biology

Recommendations for uniform definitions used in newborn screening for severe combined immunodeficiency

BACKGROUND: Public health newborn screening (NBS) programs continuously evolve, taking advantage of international shared learning. NBS for severe combined immunodeficiency (SCID) has recently been introduced in many countries. However, comparison of screening outcomes has been hampered by use of disparate terminology and imprecise or variable case definitions for non-SCID conditions with T-cell lymphopenia. OBJECTIVES: This study sought to determine whether standardized screening terminology could overcome a Babylonian confusion and whether improved case definitions would promote international exchange of knowledge. METHODS: A systematic literature review highlighted the diverse terminology in SCID NBS programs internationally. While, as expected, individual screening strategies and tests were tailored to each program, we found uniform terminology to be lacking in definitions of disease targets, sensitivity, and specificity required for comparisons across programs. RESULTS: The study’s recommendations reflect current evidence from literature and existing guidelines coupled with opinion of experts in public health screening and immunology. Terminologies were aligned. The distinction between actionable and nonactionable T-cell lymphopenia among non-SCID cases was clarified, the former being infants with T-cell lymphopenia who could benefit from interventions such as protection from infections, antibiotic prophylaxis, and live-attenuated vaccine avoidance. CONCLUSIONS: By bringing together the previously unconnected public health screening community and clinical immunology community, these SCID NBS deliberations bridged the gaps in language and perspective between these disciplines. This study proposes that international specialists in each disorder for which NBS is performed join forces to hone their definitions and recommend uniform registration of outcomes of NBS. Standardization of terminology will promote international exchange of knowledge and optimize each phase of NBS and follow-up care, advancing health outcomes for children worldwide