Long-term follow-up of children with risk organ-negative Langerhans cell histiocytosis after 2-chlorodeoxyadenosine treatment

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO−) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO− LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3–19·7 years) and the median follow-up after was 5·4 years (range, 0·6–15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO− LCH. Appropriate management of induced immune deficiency is mandatory.     

A new efficient tool for non-invasive diagnosis of fetomaternal platelet antigen incompatibility

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the consequence of platelet destruction by maternal alloantibodies against fetal human platelet antigens (HPA). This may result in intracranial haemorrhages (ICH) or even fetal death. Currently, fetal HPA genotyping is performed using invasive procedures. Here, we carried out a proof-of-concept study for non-invasive prenatal diagnosis of fetal platelet genotyping in four HPA systems (HPA-1, -3, -5 and-15) by droplet digital polymerase chain reaction (ddPCR) using cell-free DNA extracts from the plasma of 47 pregnant women with suspected, or history of, FNAIT. Results showed that 74% (35/47) of pregnant women presented incompatibility in at least one HPA system, and 38% (18/47) of cases presented HPA-1 incompatibility, including nine women with multiple incompatibilities. ICH occurred in one case of profound fetal thrombocytopenia with HPA-15 incompatibility, confirming the need for non-invasive prenatal genotyping in systems other than HPA-1. Fetal HPA genotypes predicted by ddPCR were confirmed in all FNAIT cases after amniocentesis or delivery. Fetal HPA genotyping on maternal plasma based on ddPCR is a fast, safe and reliable non-invasive method. This technique will be useful for the early identification of pregnancies at high risk of FNAIT requiring antenatal management to minimize the risk of fetal/neonatal haemorrhage.     

A randomized controlled trial of a physiology-guided percutaneous coronary intervention optimization strategy: Rationale and design of the TARGET FFR study

Post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) ≥0.90 confers an improved cardiac prognosis. There are currently limited data available to determine how often it is possible to improve an angiographically acceptable but physiologically suboptimal result. A physiology-guided optimization strategy can achieve a clinically meaningful increase in the proportion of patients achieving a final post-PCI FFR ≥0.90 compared to standard care. Following angiographically successful PCI procedures, 260 patients will be randomized (1:1) to receive either a physiology-guided incremental optimization strategy (intervention group) or blinded post-PCI coronary physiology measurements (control group). Patients undergoing successful, standard-of-care PCI for either stable angina or non-ST-segment-elevation myocardial infarction who meet the study's inclusion and exclusion criteria will be eligible for randomization. The primary endpoint is defined as the proportion of patients with a final post-PCI FFR result ≥0.90. Secondary endpoints include change from baseline in Seattle Angina Questionnaire and EQ-5D-5L scores at 3 months and the rate of target vessel failure and its components (cardiac death, myocardial infarction, stent thrombosis, unplanned rehospitalization with target vessel revascularization) at 3 months and 1 year. 260 individual patients were successfully randomized between March 2018 and November 2019. Key baseline demographics of the study population are reported within. TARGET FFR is an investigator-initiated, prospective, single-center, randomized controlled trial of an FFR-guided PCI optimization strategy. The study has completed recruitment and is now in clinical follow-up. It is anticipated that primary results will be presented in Autumn 2020. ClinicalTrials.gov Identifier: NCT03259815. [Correction added on Apr 3 2020, after first online publication: Clinical Trials identifier added.]     

Brain networks disconnection in early multiple sclerosis cognitive deficits: An anatomofunctional study

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large‐scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3–5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age‐matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage. Hum Brain Mapp 35:4706–4717, 2014. © 2014 Wiley Periodicals, Inc .     

Synthesis and Biological Evaluation of New Quinoxaline Derivatives of ICF01012 as Melanoma-Targeting Probes

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Single-Center Outcome Analysis Comparing Reintervention Rates of Surgical Arterioplasty With Stenting for Branch Pulmonary Artery Stenosis in a Pediatric Population

Although catheter-based intervention is generally accepted as the treatment of choice for branch pulmonary artery (PA) stenosis, there are no data directly comparing both the need for reintervention and time to reintervention in patients undergoing transcatheter stenting versus surgical arterioplasty. We compared children who underwent surgical branch pulmonary arterioplasty and branch PA stent placement between January 2008 and May 2012 at a single tertiary center. Need for reintervention and mean time to reintervention were assessed using chi-square and independent sample Student t test. Thirty-seven patients were included (surgery n = 18, stent n = 19). Mean weight at initial intervention was 11.3 ± 8.8 kg for surgical and 20.1 ± 15.5 kg for stent (p = 0.041). Intervention was performed on the left PA in 17 patients, the right PA in 12 patients, and both PAs in 8 patients. Five patients had undergone previous intervention. On mean follow-up of 807 ± 415 days, 50 % (9 of 18) of the surgery cohort and 5.3 % (1 of 19) of the stent cohort required reintervention (p = 0.002). In all but one case reintervention was catheter-based. Mean time to reintervention for the surgery cohort was 272 ± 162 days and for the single stent cohort it was 150 days. When comparable age and weight groups were analyzed, reintervention was still more common in the surgery cohort (p = 0.007). Children undergoing surgical branch pulmonary arterioplasty are more likely to require reintervention than those undergoing stent placement.