Postnatal outcome following fetal aortic valvuloplasty for critical aortic stenosis.

OBJECTIVE: To report our experience of fetal aortic valvuloplasty (FAV) for critical aortic stenosis (AS), with a focus on the postnatal evolution of the patients. METHODS: This was a retrospective study including all fetuses with critical AS which underwent FAV in a single center between January 2011 and June 2022. FAV was performed under ultrasound guidance. Technical success was based upon balloon inflation across the aortic valve and improvement of the antegrade aortic flow across the aortic valve. At birth, a biventricular circulation (BVC) strategy was decided assuming the left ventricular (LV) systolic and diastolic function would ensure the systemic circulation. RESULTS: Sixty-three FAV procedures were performed in 58 fetuses, at a median (range) gestational age of 26.2 (20.3-32.2) weeks. The procedure was technically successful in 50/58 (86.2%) fetuses. There were 11/58 (19.0%) cases of in-utero demise and 9/58 (15.5%) terminations of pregnancy. No patient was liveborn after an unsuccessful procedure. Thirty-eight (65.5%) infants were liveborn, at a median (range) gestational age of 38.1 (29.0-40.6) weeks, of whom 21 (55.3%) required prostaglandin treatment. Twenty-eight of the 38 (73.7%) liveborn children (48.3% of the study population) entered the BVC pathway at birth. Among them, 20 (71.4%) required an aortic valvuloplasty procedure at birth (11 (55.0%) percutaneous balloon, nine (45.0%) surgical) and eight (28.6%) did not require any treatment at birth, but, of these, five (62.5%) underwent surgical valvuloplasty between day 26 and day 1200 of age. Eleven (39.3%) of the infants with BVC at birth required a second intervention and four (14.3%) of them required a third intervention. Two (7.1%) infants who entered the BVC pathway at birth underwent conversion to univentricular circulation (UVC). None of the surviving children with BVC developed pulmonary hypertension. The overall survival rate in those with BVC at birth was 22/28 (78.6%) at a median (range) follow-up of 23.3 (2.0-112.6) months. Ten of the 58 (17.2%) patients had UVC at birth. Among these, six (60.0%) received compassionate care from birth and four (40.0%) underwent surgery. Three of the 10 patients who had UVC at birth were still alive at the latest follow-up assessment, at a median (range) gestational age of 24.3 (8.3-48.7) months. CONCLUSIONS: FAV for critical AS led to increase of antegrade aortic flow in 86.2% of fetuses, with BVC being achieved in 48.3% (73.7% of the liveborn cases). Among patients with BVC at birth, the rate of reintervention was high, but 78.6% of these children were alive at the latest evaluation. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence.

The specific niche adaptations that facilitate primary disease and Acute Lymphoblastic Leukaemia (ALL) survival after induction chemotherapy remain unclear. Here, we show that Bone Marrow (BM) adipocytes dynamically evolve during ALL pathogenesis and therapy, transitioning from cellular depletion in the primary leukaemia niche to a fully reconstituted state upon remission induction. Functionally, adipocyte niches elicit a fate switch in ALL cells towards slow-proliferation and cellular quiescence, highlighting the critical contribution of the adipocyte dynamic to disease establishment and chemotherapy resistance. Mechanistically, adipocyte niche interaction targets posttranscriptional networks and suppresses protein biosynthesis in ALL cells. Treatment with general control nonderepressible 2 inhibitor (GCN2ib) alleviates adipocyte-mediated translational repression and rescues ALL cell quiescence thereby significantly reducing the cytoprotective effect of adipocytes against chemotherapy and other extrinsic stressors. These data establish how adipocyte driven restrictions of the ALL proteome benefit ALL tumours, preventing their elimination, and suggest ways to manipulate adipocyte-mediated ALL resistance.

Respiratory morbidity in children with congenital heart disease.

OBJECTIVE: To evaluate the respiratory outcome in children with congenital heart disease (CHD), considering recent management procedures and the CHD pathophysiology. DESIGN AND SETTING: Clinical and functional respiratory outcome were evaluated in 8-year-old children with isolated CHD followed up from birth in the prospective population-based EPICARD cohort. PATIENTS: Children were assigned to two groups, based on the pathophysiology of the CHD: CHDs with left-to-right shunt (n = 212) and CHDs with right outflow tract obstruction (n = 113). RESULTS: Current wheezing episodes were observed in 15% of the children with isolated CHD and left-to-right shunt, and 11% of the children with isolated CHD and right outflow tract obstruction (not significant). Total lung capacity (TLC) was the only respiratory function parameter that significantly differed between the two groups. It was lower in children with left-to-right shunt (88.72 ± 0.65% predicted) than in those with right outflow tract obstruction (91.84 ± 0.96, p = 0.006). In multivariate analysis, CHD with left-to-right shunt (coeff. [95% CI]: -3.17 [-5.45; -0.89]) and surgery before the age of 2 months (-6.52 [-10.90; -2.15]) were identified as independent factors associated with significantly lower TLC values. CONCLUSION: Lower TLC remains a long-term complication in CHD, particularly in cases with left-to-right shunt and in patients requiring early repair. These findings suggest that an increase in pulmonary blood flow may directly impair lung development.

Multifactorial origin of pulmonary hypertension in a child with congenital heart disease, Down syndrome, and BMPR-2 mutation.

A late preterm infant had pulmonary hypertension caused by a variety of mechanisms leading to complex management. This child had complete atrioventricular septal defect associated with mild left ventricular hypoplasia and Down syndrome diagnosed prenatally. The mother had been treated by antiretroviral HIV treatment during pregnancy. Aortic coarctation was diagnosed and rapidly repaired. After surgery, he required noninvasive ventilation for persisting elevated PCO2. Pulmonary CT scan showed normal bronchial tree, lung parenchymal abnormalities with mosaic aspect and hyperlucent zones, and indirect signs of lung hypoplasia with peripheral microbubbles. During follow-up, severe pulmonary hypertension was diagnosed on echocardiography without recoarctation, significant intracardiac shunting or diastolic dysfunction. The patient died after four months unable to be weaned from noninvasive ventilation. Post mortem lung biopsy showed abnormally muscularized arterioles with intimal fibrosis and pulmonary immaturity. Gentetic screening identified a BMPR-2 mutation. This patient illustrates the multifactorial origin of pulmonary hypertension in the neonatal period. The respective contribution of left-to-right shunt, post-capillary obstruction, and abnormally elevated pulmonary vascular resistances led to perform right heart catheterization to exclude excessive shunting and restrictive physiology of the left heart. Subjects with Down syndrome are also highly susceptible to decreased lung vascular and alveolar growth, which may increase the risk for pulmonary hypertension and lung hypoplasia. This case highlights two issues. The first one is that right heart catheterization should be discussed in neonates with unexplained pulmonary hypertension and the second is to extend indications of genetic testing for pulmonary hypertension genes in neonates who have unusual course of neonatal pulmonary hypertension, particularly in the setting of associated congenital heart disease (CHD).

[Prenatal path of care following the diagnosis of a malformation for which a novel prenatal therapy is available]. / Parcours prénatal devant une malformation pour laquelle un traitement in utero émergent est disponible.

OBJECTIVES: Fetal therapy is part of the available care offer for several severe malformations. The place of these emergent prenatal interventions in the prenatal path of care is poorly known. The objective of this study is to describe the decision-making process of patients facing the option of an emergent in utero intervention. METHODS: We have conducted a retrospective monocentric descriptive study in the department of maternal-fetal medicine of Necker Hospital. We collected data regarding eligibility or not for fetal surgery and the pregnancy outcomes of patients referred for myelomeningocele, diaphragmatic hernia, aortic stenosis and low obstructive uropathies. RESULTS: All indications combined, 70% of patients opted for fetal surgery. This rate was lower in the case of myelomeningocele with 21% consent, than in the other pathologies: 69% for diaphragmatic hernias, 90% for aortic stenoses and 76% for uropathy. When fetal intervention was declined, the vast majority of patients opted for termination of pregnancy: 86%. In 14% of the considering fetal surgery, the patient was referred too far. CONCLUSION: The acceptance rate for fetal surgeries depends on condition. It offers an additional option and is an alternative for couples for which termination of pregnancy (TOP) is not an option. Timely referral to an expert center allows to discuss the place of a fetal intervention and not to deprive couples of this possibility.

Activation of the receptor tyrosine kinase RET improves long-term hematopoietic stem cell outgrowth and potency.

Expansion of human hematopoietic stem cells (HSCs) is a rapidly advancing field showing great promise for clinical applications. Recent evidence has implicated the nervous system and glial family ligands (GFLs) as potential drivers of hematopoietic survival and self-renewal in the bone marrow niche; how to apply this process to HSC maintenance and expansion has yet to be explored. We show a role for the GFL receptor, RET, at the cell surface of HSCs in mediating sustained cellular growth, resistance to stress, and improved cell survival throughout in vitro expansion. HSCs treated with the key RET ligand/coreceptor complex, glial-derived neurotrophic factor and its coreceptor, exhibit improved progenitor function at primary transplantation and improved long-term HSC function at secondary transplantation. Finally, we show that RET drives a multifaceted intracellular signaling pathway, including key signaling intermediates protein kinase B, extracellular signal-regulated kinase 1/2, NF-κB, and p53, responsible for a wide range of cellular and genetic responses that improve cell growth and survival under culture conditions.

Germline mutation p.N363K in POLE is associated with an increased risk of colorectal cancer and giant cell glioblastoma.

Germline mutations of the POLE gene are responsible for polymerase proofreading-associated polyposis syndrome (PPAP). These mutations were hypothesised to predispose to extra-gastrointestinal tumours (ovary, endometrium, brain), but this association has not been confirmed so far. We report a family with an autosomal dominant inheritance of PPAP due to a c.1089C>A; p.Asn363Lys mutation in the proofreading exonuclease domain of POLE. Ten patients presenting a history of colorectal tumours and three patients with polyposis are indexed in this family. Three carriers (including siblings and a distant cousin at 30, 45 and 52 respectively) and another member (at 37 not tested) presented glioblastoma. This is the second family reported to carry this mutation. Among the four glioblastomas in the family that we report, both show similar pathology: giant cell glioblastoma. These cases suggest that the c.1089C>A germline POLE mutation may confer an increased risk of brain cancer [incidence 17.4% (4/23) in mutation carriers combining the two families]. More observations are needed to support this hypothesis. It seems that not all mutations of POLE are equally associated with extra-gastrointestinal tumours. Although carriers of a mutation responsible for PPAP should benefit from screening for colorectal and uterine cancer, due to the rapid evolution of glioblastoma the value of neurological follow-up and brain imaging screening remains questionable. Nevertheless, considering the limitations of standard therapy for glioblastoma, mutation status could be useful for targeting therapy. The biological mechanism linking POLE mutation to glioblastoma remains to be determined.

Reliability of Peak Exercise Stroke Volume Assessment by Impedance Cardiography in Patients with Residual Right Outflow Tract Lesions After Congenital Heart Disease Repair.

Global ventricular response to exercise may be useful in follow-up of patients with residual right outflow tract lesions after congenital heart disease repair. In this context, impedance cardiography is considered accurate for stroke volume (SV) measurement during exercise testing, however, to date, only partial assessment of its reliability has been reported. We retrospectively evaluated relative and absolute reliability of peak SV by impedance cardiography during exercise using intraclass correlation (ICC) and standard error of measurement (SEM) in this population. Peak SV was measured in 30 young patients (mean age 14.4 years ± 2.1) with right ventricular outflow tract reconstruction who underwent two cardiopulmonary exercise tests at a mean one-year interval. SV was measured using a signal morphology impedance cardiography analysis device (PhysioFlow®) and was indexed to body surface area. ICC of peak indexed SV measurement was 0.80 and SEM was 10.5%. High heterogeneity was seen when comparing patients according to peak indexed SV; in patients with peak SV < 50 ml/m2 (15 patients), ICC rose to 0.95 and SEM dropped to 2.7%, while in patients with a peak SV > 50 ml/m2 relative and absolute reliability decreased (ICC = 0.45, SEM = 12.2%). Peak exercise SV assessment by a PhysioFlow® device represents a highly reliable method in patients with residual right outflow tract lesions after congenital heart disease repair, especially in patients with peak SV < 50 ml/m2. In this latter group, a peak SV decrease > 7.3% (corresponding to the minimum "true" difference) should be considered a clinically-relevant decrease in global ventricular performance and taken into account when deciding whether to perform residual lesion removal.

Preclinical modeling of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematological clonal disorders. Here, we have tested the bone marrow (BM) cells from 38 MDS patients covering all risk groups in two immunodeficient mouse models: NSG and NSG-S. Our data show comparable level of engraftment in both models. The level of engraftment was patient specific with no correlation to any specific MDS risk group. Furthermore, the co-injection of mesenchymal stromal cells (MSCs) did not improve the level of engraftment. Finally, we have developed an in vitro two-dimensional co-culture system as an alternative tool to in vivo. Using our in vitro system, we have been able to co-culture CD34+ cells from MDS patient BM on auto- and/or allogeneic MSCs over 4 weeks with a fold expansion of up to 600 times. More importantly, these expanded cells conserved their MDS clonal architecture as well as genomic integrity.

Follow-up of children exposed to ionising radiation from cardiac catheterisation: the Coccinelle study.

Cardiac catheterisation has become an essential tool in the diagnosis and treatment of children with a wide variety of congenital and acquired forms of cardiovascular disease. Despite the clear clinical benefit to the patient, radiation exposure from paediatric cardiac catheterisation procedures (CCPs) may be substantial. Given children's greater sensitivity to radiation and the longer life span during which radiation health effects can develop, an epidemiological cohort study, named Coccinelle or 'Ladybird' (French acronym for 'Cohorte sur le risque de cancer après cardiologie interventionnelle pédiatrique'), is carried out in France to evaluate the risks of leukaemia and solid cancers in this population. A total number of 8000 included children are expected. Individual CCP-related doses will be assessed for each child included in the cohort. For each CCP performed, dosimetric parameters (dose-area product, fluoroscopy time and total number of cine frames) are retrieved retrospectively. Organ doses, especially to the lung, the oesophagus and the thyroid, are calculated with PCXMC software. The cohort will be followed up through linkage with French paediatric cancer registries.

Markers of a recent bocavirus infection in children with Kawasaki disease: "a year prospective study".

BACKGROUND: Retrospective studies and case-reports have suggested the possible role of various viruses in the pathogenesis of the Kawasaki disease. OBJECTIVES: To determine prospectively the incidence of Kawasaki diseases associated with a recent bocavirus infection in the course of a year. STUDY DESIGN: Thirty-two children with Kawasaki disease were enrolled in a 13 months prospective study to assess the frequency of human bocavirus type 1 infections. Seasonal shedding of virus, markers of recent infection such as viraemia, viral load, and serum interferon alpha were analyzed. RESULTS: Three of 32 (9%) children had HBoV-DNA in the serum suggesting a recent infection. HBoV-DNA was detected in naso-pharyngeal aspiration of 7/32 (21.8%) children with Kawasaki Disease and six of them (18%) had an increased viral load. No common respiratory viruses were isolated from the 32 patients with the exception of one adenovirus. The seven bocaviruses were identified during the winter-spring season. In addition, 4 of 7 of Kawasaki disease patients shedding bocavirus had detectable interferon alpha in the blood, indicating a possible active or recent viral infection. CONCLUSIONS: This study shows that a recent bocavirus infection is concomitant with the onset of some cases of Kawasaki disease. Bocavirus may be a cofactor in the pathogenesis of this disease as previously reported for other infectious agents.

Local reference levels and organ doses from pediatric cardiac interventional procedures.

Interventional cardiology (IC) procedures can be responsible for relatively high radiation doses compared to conventional radiology especially for young patients. The aim of this study was to assess current exposure levels in a French reference centre of pediatric IC. Dosimetric data including dose area product (DAP), fluoroscopy time (FT) and number of cine frame (NF) were analysed taking into account patient weight. Doses to the lungs, esophagus, breast and thyroid were evaluated using anthropomorphic phantoms and thermoluminescent dosimeters. Finally, effective doses (E) were calculated using DAP and conversion factors calculated with PCXMC 2.0 software. 801 IC procedures performed between 2010 and 2011 were analysed. Large variations were observed for DAP, FT and NF values for a given procedure and a given weight group. The assessment of organ doses showed high levels of dose to the lungs and esophagus especially in new-born babies. For diagnostic procedures, E varied from 0.3 to 23 mSv with a mean value of 4.8 mSv and for therapeutic procedures, values ranged from 0.1 to 48.4 mSv with a mean value of 7.3 mSv. The highest values were recorded for angioplasty procedures (mean 13 mSv, range 0.6-48.4 mSv). The increasing use of IC in pediatric population stresses the need of setting up reference levels and keeping doses to children as low as possible.

Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo.

As significant numbers of acute myeloid leukemia (AML) patients are still refractory to conventional therapies or experience relapse, immunotherapy using T cells expressing chimeric antigen receptors (CARs) might represent a valid treatment option. AML cells frequently overexpress the myeloid antigens CD33 and CD123, for which specific CARs can be generated. However, CD33 is also expressed on normal hematopoietic stem/progenitor cells (HSPCs), and its targeting could potentially impair normal hematopoiesis. In contrast, CD123 is widely expressed by AML, while low expression is detected on HSPCs, making it a much more attractive target. In this study we describe the in vivo efficacy and safety of using cytokine-induced killer (CIK) cells genetically modified to express anti-CD33 or anti-CD123 CAR to target AML. We show that both these modified T cells are very efficient in reducing leukemia burden in vivo, but only the anti-CD123 CAR has limited killing on normal HSPCs, thus making it a very attractive immunotherapeutic tool for AML treatment.

F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity.

Chemotherapy remains mainly used for the treatment of acute myeloid leukemia (AML). However, in the past 3 decades limited progress has been achieved in improving the long-term disease-free survival. Therefore the development of more effective drugs for AML represents a high level of priority. F14512 combines an epipodophyllotoxin core targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine moiety facilitates F14512 selective uptake by tumour cells via the polyamine transport system, a machinery overactivated in cancer cells. F14512 has been characterized as a potent drug candidate and is currently in Phase I clinical trials. Here, we demonstrated marked survival benefit and therapeutic efficacy of F14512 treatments in a series of human AML models, established either from AML cell lines or from patient AML samples. Furthermore, we reported in vitro synergistic anti-leukemic effects of F14512 in combination with cytosine arabinoside (Ara-C), doxorubicin, gemcitabine, bortezomib or SAHA. In vivo combination of suboptimal doses of F14512 with Ara-C also resulted in enhanced anti-leukemic activity. We further showed that F14512 triggered both senescence and apoptosis in vivo in primary AML models, but not autophagy. Overall, these results support the clinical development in onco-hematology of this novel promising drug candidate.