Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPβ expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode

Évaluation de la gastrostomie précoce dans la prise en charge des tumeurs osseuses primitives malignes de l’enfant. Expérience du groupe Grand Ouest Cancer de l’Enfant (GOCE) sur 10 ans [Assessment of early gastrostomy in the treatment of primary malignant bone tumors in children. A report from the French children's oncology study Group GOCE]

International audiencePurpose. - Patients in pediatric oncology are at high risk of undernourishment, especially during intensive treatment such as malignant primary bone tumors. Many consequences of malnutrition have been highlighted, yet the nutritional care is not standardized. We evaluated the nutritional benefits and the feasibility of enteral nutrition on early gastrostomy, by comparison to other methods of nutritional support during the treatment of malignant primary bone tumor in children. Methods. - The characteristics of patients with malignant primary bone tumors have been retrospectively analyzed in Western regions of France from 2003 to 2013. The census of complications of early gastrostomy and the nutritional parameters of patients (Z-scores weight for height and height for age and body mass index) allowed the evaluation of its feasibility and effectiveness. Complications data, nutritional status and oncology treatment were also analyzed in the groups of patients who received enteral nutrition through nasogastric tube and those who did not receive it. Results. - Early gastrostomy was inserted in 58 patients, a nasogastric tube in 20 and 60 did not receive any of these two nutritional supports. Early gastrostomy is a purveyor of complications (82 for 58 patients) but they are minor and not specific (92.7%). No difference between the three groups has been demonstrated about the frequency of complications, the number of hospitalization or their duration. Early gastrostomy avoided a deterioration of the nutritional status as soon as the preoperative stage unlike the two other groups. No significant difference in survival at 4 years was found between the three groups. Conclusion. - Early gastrostomy is an effective nutritional support which does not increase complications and which does not affect the oncologic prognosis. Its psychological evaluation and nutritional impact in the long term are to be assessed on a prospective group. (C) 2017 Elsevier Masson SAS. All rights reserved

Keep in mind quality of life: outcome of a 10-year series of post-transplant early relapses in childhood acute lymphoblastic leukemia A report from the GOCE, the Grand Ouest oncology study group for children in France

International audienceAcute lymphoblastic leukemia (ALL) relapses early after hematopoietic stem-cell transplants in children are uncommon, but associated with a very poor prognosis. Whereas there are no current recommendations for the management of these relapses, the children’s quality of life is an important issue. We studied the outcomes, including one-year overall survival, complete remission and quality of life, of 19 children with ALL who relapsed within the year following their transplant treated in the 5 participating centers between 2000 and 2011 Patients were distributed as follows: supportive care only (group A), outpatient treatment (mainly steroid and vincristine; group B) or intensive inpatient treatment (group C). There were no significant differences in one-year overall survival (31.5% for the entire cohort) or remission rate for time between transplant and relapse (<6 months or 6–12 months), transplant or disease characteristics or treatment group. However, time spent in hospital (for treatment and complications) significantly differed between treatment groups B and C (20.8%+/-13.0 versus 59.1% +/-32.9, respectively; p<0.05). No differences in organ toxicities, school attendance or Lansky score were found between treatment groups. Our sample size-limited data indicate, in a pre-personalized medicine era, that children treated with steroid and vincristine have the same prognosis as those treated with intensive therapy, but may benefit from improved quality of life. Nevertheless, new therapeutic strategies are required and future prospective trials would help to establish recommendation

Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study.

International audiencePURPOSE: Antibiotic prophylaxis is given to children at risk for urinary tract infection. However, evidence concerning its effectiveness in grade I to III vesicoureteral reflux is lacking. The objective of this study was to determine whether antibiotic prophylaxis reduces the incidence of urinary tract infection in young children with low grade vesicoureteral reflux. MATERIALS AND METHODS: Children 1 month to 3 years old with grade I to III vesicoureteral reflux were assigned randomly to receive daily cotrimoxazole or no treatment, and followed for 18 months. A urinary tract infection constituted an exit criterion. Infection-free survival rates were calculated using the Kaplan-Meier method and compared using the log rank test. RESULTS: A total of 225 children were enrolled in the study. Distribution of gender, age at inclusion and reflux grade were similar between the 2 groups. There was no significant difference in the occurrence of urinary tract infection between the 2 groups (17% vs 26%, p = 0.2). However, a significant association was found between treatment and patient gender (p = 0.017). Prophylaxis significantly reduced urinary tract infection in boys (p = 0.013), most notably in boys with grade III vesicoureteral reflux (p = 0.042). CONCLUSIONS: These data suggest that antibiotic prophylaxis does not reduce the overall incidence of urinary tract infection in children with low grade vesicoureteral reflux. However, such a strategy may prevent further urinary tract infection in boys with grade III reflux

Treatment and outcome of congenital nephrotic syndrome

BACKGROUND: Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. METHODS: We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. RESULTS: The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9-52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. CONCLUSIONS: Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients

Dental Abnormalities in Schimke Immuno-osseous Dysplasia

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGF beta 1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD