Conditionnement d'intensité réduite à base de fludarabine dans l'allogreffe de cellules souches hématopoïétiques pour anémie de Fanconi (résultats d'une série pédiatrique de 17 patients)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Bordetella parapertussis Bacteremia: Clinical Expression and Bacterial Genomics

International audienceWhooping cough's primary etiological agent is Bordetella pertussis. The closely related Bordetella parapertussis rarely causes severe disease. Here we report an unusual case of bacteremia caused by B. parapertussis, review the literature, and characterize the genomic sequence of the bacterial isolate in comparison with B. parapertussis isolates from respiratory infections

Novel variants in the BLOC1S3 gene in patients presenting a mild form of Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) associates oculocutaneous albinism and systemic affections including platelet dense granules anomalies leading to bleeding diathesis and, depending on the form, pulmonary fibrosis, immunodeficiency, and/or granulomatous colitis. So far, 11 forms of autosomal recessive HPS caused by pathogenic variants in 11 different genes have been reported. We describe three HPS-8 consanguineous families with different homozygous pathogenic variants in BLOC1S3 (NM_212550.3), one of which is novel. These comprise two deletions leading to a reading frameshift (c.385_403del, c.338_341del) and one in frame deletion (c.444_467del). All patients have moderate oculocutaneous albinism and bleeding diathesis, but other HPS symptoms are not described. One patient diagnosed with HPS-8 suffered from lymphocyte-predominant Hodgkin lymphoma. The mild severity of HPS-8 is consistent with other HPS forms caused by variants in BLOC-1 complex coding genes (HPS-7, DTNBP1; HPS-9, BLOC1S6, HPS-11, BLOC1S5)

Two Monogenetic Disorders, Activated PI3-Kinase-δ Syndrome 2 and Smith–Magenis Syndrome, in One Patient: Case Report and a Literature Review of Neurodevelopmental Impact in Primary Immunodeficiencies Associated With Disturbed PI3K Signaling

International audienceActivated PI3-kinase-δ syndrome 2 (APDS2) is caused by autosomal dominant mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits. Most diagnosed APDS2 patients carry mutations affecting either the splice donor or splice acceptor sites of exon 11 of the PIK3R1 gene responsible for an alternative splice product and a shortened protein. The clinical presentation of APDS2 patients is highly variable, ranging from mild to profound combined immunodeficiency features as massive lymphoproliferation, increased susceptibility to bacterial and viral infections, bronchiectasis, autoimmune manifestations, and occurrence of cancer. Non-immunological features such as growth retardation and neurodevelopmental delay have been reported for APDS2 patients. Here, we describe a patient suffering from an APDS2 associated with a Smith–Magenis syndrome (SMS), a complex genetic disorder affecting, among others, neurological manifestations and review the literature describing neurodevelopmental impacts in APDS2 and other PIDs/monogenetic disorders associated with dysregulated PI3K signaling

Seconde allogreffe : recommandations de la Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Après allogreffe de cellules souches hématopoïétiques (allo-CSH), la rechute de la maladie initiale et le dysfonctionnement du greffon restent aujourd’hui parmi les causes majeures d’échec de cette thérapeutique tant pour les hémopathies malignes que non malignes. Une seconde allo-CSH est une option pour pallier ces situations. Dans le cadre des 8e ateliers d’harmonisation des pratiques de greffe de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC), le groupe de travail s’est basé sur les données de la littérature, afin d’élaborer des recommandations concernant la faisabilité, les indications, le choix du donneur et le conditionnement de la seconde allo-CSH. En cas de rechute de la maladie, une seconde allogreffe avec conditionnement à intensité réduite ou non myéloablatif est une option raisonnable, en particulier chez les patients en bon état général (Karnofsky/Lansky > 80 %), avec un faible score de comorbidités (score EBMT ≤ 3), ayant une longue rémission après la première greffe (> 6 mois) et une faible masse tumorale au moment de seconde allogreffe. Un donneur géno-identique tend à donner une meilleure survie globale. En cas de dysfonctionnement du greffon (rejet primaire et secondaire), un conditionnement immunoablatif est recommandé. Un changement de donneur reste une option valide, en particulier, en l’absence de maladie du greffon contre l'hôte après la première allo-CSH.[Second allogeneic hematopoietic stem cell transplant: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. Disease recurrence and graft dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) currently remain among the major causes of treatment failure in malignant and non-malignant hematological diseases. A second allo-HSCT is a valuable therapeutic option to salvage those situations. During the 8th annual harmonization workshops of the french Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines on feasibility, indications, donor choice and conditioning in the case of a second allo-HSCT. In case of relapse, a second allo-HSCT with reduced intensity or non-myeloablative conditioning is a reasonable option, particularly in patients with a good performance status (Karnofsky/Lansky>80%), low co-morbidity score (EBMT score≤3), a longer remission duration after the first allo-HSCT (>6 months), and who present low disease burden at the time of second allo-HSCT. Matched related donors tend to be associated with better outcomes. In the presence of graft dysfunction (primary and secondary graft rejection), an immunoablative conditioning regimen is recommended. A donor change remains a valid option, especially in the absence of graft-versus-host disease after the first allo-HSCT

Ontogeny of human mucosal-associated invariant T cells and related T cell subsets.

Mucosal-associated invariant T (MAIT) cells are semi-invariant V alpha 7.2(+) CD161(high)CD4(-)T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied V alpha 7.2(+) CD161(high) T cell and related subset levels in infancy and after cord blood transplantation. We show that V alpha 7.2(+) and V alpha 7.2(-) CD161(high) T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood V alpha 7.2(+) CD161(high) T cells, the minority recognizing MR1 : 5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1 : 5-OP-RU reactive V alpha 7.2(+) CD161(high) T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other V alpha 7.2(+) CD161(high) and V alpha 7.2(-) CD161(high) populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCR alpha beta chains recognizing MR1-restricted microbial antigens

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation : A multicenter study

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p < 0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p < 0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (N° Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered)

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation : A multicenter study

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p < 0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p < 0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (N° Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered)