Vesico-ureteral reflux diagnosis after initial kidney abscess: Results from a Paediatric Tertiary Hospital.

AIMS: Guidelines regarding voiding cystourethrogram (VCUG) indications following a paediatric kidney abscess are lacking. This study evaluates vesicoureteral reflux (VUR) prevalence and outcome after a first kidney abscess. METHODS: This retrospective study included all children presenting to a tertiary paediatric reference centre with de-novo kidney abscesses from 2011 to 2022, diagnosed through imaging (ultrasonography or computed tomography). VCUG's clinical utility was assessed by exploring outcomes related to interventions. RESULTS: Among the 17 patients (median age 9 months, IQR; 6 months-6 years), VCUG identified VUR in 7 (41%; 95% CI: 18-65%), including two with grade IV-V. Median abscess size was 19 mm (IQR; 14-27). 7/8 (88%) children with DMSA scan presented scars, including 4 with hypofunctioning (20%-44%), and one with a non-functioning kidney. Scarring on the DMSA scan was similar regardless of identified VUR. Six children had subsequent pyelonephritis. Three of the remaining 11 had grade I-III and two IV-V VUR. Surgery was required in four children overall: three for recurrent pyelonephritis and one for high-grade VUR and scars. CONCLUSION: Among initial kidney abscess cases, 41% had VUR, similar to children experiencing their first uncomplicated pyelonephritis. VCUG results guided antibiotic prophylaxis but not surgical decisions. We suggest considering VCUG following recurrent pyelonephritis/kidney abscess and/or kidney scarring.

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.

Clinical, pathologic, and molecular features of inflammatory myofibroblastic tumors in children and adolescents.

BACKGROUND: Inflammatory myofibroblastic tumors (IMT) are rare, intermediate malignant tumors harboring frequent somatic molecular rearrangements. The management of IMT has not been standardized. METHODS: A retrospective multicenter study was conducted on all pediatric patients treated for IMT between 2000 and 2019. RESULTS: This series included 39 cases of IMT, with a median age at diagnosis of 7 years (range 20 days to 16 years). Tumor location included pelvis-abdomen (n = 16), thorax (n = 14), head and neck (n = 7), and limbs (n = 2). One patient had metastatic disease. Immunochemistry showed 21/39 (54%) anaplastic lymphoma kinase (ALK)-positive tumors. Somatic tyrosine kinase rearrangement was present in 31/36 (86%) of the tumors analyzed: 21 ALK, five ROS1, and five NTRK. Immediate surgery was performed in 24 patients (62%), with adjuvant therapy for three patients. Delayed surgery after neoadjuvant therapy was possible in 10 cases. Exclusive systemic therapy was delivered to four patients; one patient with orbital IMT was managed by watchful waiting. After a median follow-up of 33 months (range 5-124), eight (20%) recurrences/progressions occurred after surgery (seven after primary surgery and one after delayed surgery), after a median interval of 7 months (range 2-21), all in thoracic locations. The 3-year overall and disease-free survivals were 96.8% (95% CI: 79.2%-94.0%) and 77.4% (95% CI: 59.6%-88.1%), respectively. Relapses/progressions were more common in patients with a thoracic primary (p < .001) or after incomplete surgery with no adjuvant therapy (p = .027). CONCLUSION: Surgery is effective in most cases of pediatric IMT. Systematic analysis of tyrosine kinase rearrangement is recommended. When the tumor is deemed only partially resectable to preserve organs and function, neoadjuvant therapy may be proposed to allow adequate conservative surgery.

Cystic fibrosis-related liver disease: Clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies.

Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. Cystic fibrosis-related liver disease (CFLD) is defined as the pathogenesis related to the underlying CFTR defect in biliary epithelial cells. CFLD needs to be distinguished from other liver manifestations that may not have any pathological significance. The clinical/histological presentation and severity of CFLD vary. The main histological presentation of CFLD is focal biliary fibrosis, which is usually asymptomatic. Portal hypertension develops in a minority of cases (about 10%) and may require specific management including liver transplantation for end-stage liver disease. Portal hypertension is usually the result of the progression of focal biliary fibrosis to multilobular cirrhosis during childhood. Nevertheless, non-cirrhotic portal hypertension as a result of porto-sinusoidal vascular disease is now identified increasingly more frequently, mainly in young adults. To evaluate the effect of new CFTR modulator therapies on the liver, the spectrum of hepatobiliary involvement must first be precisely classified. This paper discusses the phenotypic features of CFLD, its underlying physiopathology and relevant diagnostic and follow-up approaches, with a special focus on imaging.

Lumacaftor-ivacaftor effects on cystic fibrosis-related liver involvement in adolescents with homozygous F508 del-CFTR.

BACKGROUND: The effects of lumacaftor-ivacaftor on cystic fibrosis transmembrane conductance regulator (CFTR)-associated liver disease remain unclear. The objective of the study was to describe the effect of this treatment on features of liver involvement in a cystic fibrosis (CF) adolescent population homozygous for F508del. METHODS: Clinical characteristics, liver blood tests, abdominal ultrasonography (US), and pancreas and liver proton density fat fraction (PDFF) by magnetic resonance imaging, were obtained at treatment initiation and at 12 months for all patients. Biomarkers of CFTR activity (sweat chloride test, nasal potential difference, and intestinal current measurement) were assessed at initiation and at 6 months therapy. RESULTS: Of the 37 patients who started ivacaftor/lumacaftor treatment, 28 were eligible for analysis. In this group, before treatment initiation, 4 patients were diagnosed with multinodular liver and portal hypertension, 19 with other forms of CF liver involvement, and 5 with no signs of liver involvement. During treatment, no hepatic adverse reactions were documented, and no patient developed liver failure. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyl transferase (GGT) decreased significantly following initiation of lumacaftor-ivacaftor, and remained so after 12 months treatment. This was not correlated with changes in clinical status, liver and pancreas US and PDFF, fecal elastase, or lumacaftor-ivacaftor serum levels. The most "responsive" patients demonstrated a significant increase in biomarkers of CFTR activity. CONCLUSIONS: These results may suggest a potential beneficial effect of CFTR modulators on CF liver disease and warrant further investigation in larger, prospective studies.

Robotic Surgery in Pediatric Oncology: Lessons Learned from the First 100 Tumors-A Nationwide Experience.

BACKGROUND: While robotics has become commonplace in adult oncology, it remains rare in pediatric oncology due to the rarity of childhood cancers. We present the results of a large nationwide experience with robotic oncology, with the aim of providing practical and feasible guidelines for child selection. METHODS: This was a prospective analysis performed over a period of 4 years. Treatment was delivered according to the Société Internationale d'Oncologie Pédiatrique/International Society of Paediatric Oncology Europe Neuroblastoma Group (SIOP/SIOPEN) protocols. Indications were approved by a certified tumor board. RESULTS: Overall, 100 tumors were resected during 93 procedures (abdomen, 67%; thorax, 17%; pelvis, 10%; retroperitoneum, 6%) in 89 children (56 girls). The median age at surgery was 8.2 years (range 3.6-13); 19 children (21%) harbored germinal genetic alterations predisposing to cancer. No intraoperative tumor ruptures occurred. Seven conversions (8%) to an open approach were performed. Neuroblastic tumors (n = 31) comprised the main group (18 neuroblastomas, 4 ganglioneuroblastomas, 9 ganglioneuromas) and renal tumors comprised the second largest group (n = 24, including 20 Wilms' tumors). The remaining 45 tumors included neuroendocrine (n = 12), adrenal (n = 9), germ-cell (n = 7), pancreatic (n = 4), thymic (n = 4), inflammatory myofibroblastic (n = 4), and different rare tumors (n = 5). Overall, 51 tumors were malignant, 2 were borderline, and 47 were benign. The median hospital stay was 3 days (2-4), and five postoperative complications occurred within the first 30 days. During a median follow-up of 2.4 years, one child (Wilms' tumor) presented with pleural recurrence. One girl with Wilms' tumor died of central nervous system metastasis. CONCLUSIONS: Robotic surgery for pediatric tumors is a safe option in highly selected cases. Indications should be discussed by tumor boards to avoid widespread and uncontrolled application.

Comparison of Transient Elastography, ShearWave Elastography, Magnetic Resonance Elastography and FibroTest as routine diagnostic markers for assessing liver fibrosis in children with Cystic Fibrosis.

BACKGROUND AND OBJECTIVE: Reliable markers are needed for early diagnosis and follow-up of liver disease in Cystic Fibrosis (CF). The objective was to evaluate the diagnostic performance of Transient Elastography (TE), Real-Time ShearWave Ultrasound Elastography (SWE), Magnetic Resonance Elastography (MRE) and the FibroTest as markers of Cystic Fibrosis Liver Disease (CFLD). METHODS: A monocentric prospective cross-modality comparison study was proposed to all children (6 to 18 years of age) attending the CF center. Based on liver ultrasound findings, participants were classified into 3 groups: multinodular liver or portal hypertension (Nodular US/PH, advanced CFLD), heterogeneous increased echogenicity (Heterogeneous US, CFLD) or neither (Normal/Homogeneous US, no CFLD). The 4 tests were performed on the same day. The primary outcome was the FibroTest value and liver stiffness measurements (LSM). RESULTS: 55 participants (mean age 12.6 ± 3.3 years; 25 girls) were included between 2015 and 2018: 23 in group Nodular US/PH, 8 in group Heterogeneous US and 24 in group Normal/Homogeneous US (including 4 with steatosis). LSM on TE, SWE and MRE were higher in participants with CFLD (groups Nodular US/PH and Heterogeneous US) compared to others (group Normal/Homogeneous US) (p<0.01), while FibroTest values did not differ (p = 0.09). The optimal cut-off values for predicting CFLD on TE, SWE and MRE were 8.7 (AUC=0.83, Se=0.71, Sp=0.96), 7.8 (AUC=0.85, Se=0.73, Sp=0.96) and 4.15 kPa (AUC=0.68, Se=0.73, Sp=0.64), respectively. LSM predicted the occurrence of major liver-related events at 3 years. TE and SWE were highly correlated (Spearman's ρ=0.9) and concordant in identifying advanced CFLD (Cohen's κ=0.84) while MRE was moderately correlated and concordant with TE (ρ=0.41; κ=36) and SWE (ρ=0.5; κ=0.50). CONCLUSION: This study demonstrated excellent diagnostic performance of TE, SWE and MRE for the diagnosis of CFLD.

Alternative pathways for the development of lymphoid structures in humans.

Lymphoid tissue inducer (LTi) cells are critical for inducing the differentiation of most secondary lymphoid organs (SLOs) in mice. In humans, JAK3 and γc deficiencies result in severe combined immunodeficiency (SCIDs) characterized by an absence of T cells, natural killer cells, innate lymphoid cells (ILCs), and presumably LTi cells. Some of these patients have undergone allogeneic stem cell transplantation (HSCT) in the absence of myeloablation, which leads to donor T cell engraftment, while other leukocyte subsets are of host origin. By using MRI to look for SLOs in nine of these patients 16 to 44 y after HSCT, we discovered that SLOs were exclusively found in the three areas of the abdomen that drain the intestinal tract. A postmortem examination of a child with γc-SCID who had died 3.5 mo after HSCT showed corticomedullary differentiation in the thymus, T cell zones in the spleen, and the appendix, but in neither lymph nodes nor Peyer patches. Tertiary lymphoid organs were observed in the lung. No RAR-related orphan receptor-positive LTi cells could be detected in the existing lymphoid structures. These results suggest that while LTi cells are required for the genesis of most SLOs in humans, SLO in the appendix and in gut-draining areas, as well as tertiary lymphoid organs, can be generated likely by LTi cell-independent mechanisms.

Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.

Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.

Endovascular stenting of blunt aortic isthmus rupture in a 5-year-old child.

Blunt traumatic aortic tear is an extremely rare and life-threatening paediatric emergency. Percutaneous repair is highly debateable in children due to anatomic limitations. Herein, we report an important case of a 5-year-old boy diagnosed with grade 3 aortic isthmus disruption following fifth-floor defenestration. The 96-h control computerized tomography (CT) scan showed an increase in the pseudoaneurysm size with small active bleeding motivating endovascular covered stenting that was safely and efficiently performed with good outcomes.

Ultrasound detected prenatal hyperechoic lung lesions and concordance with postnatal findings: A common aspect for multiple diagnoses.

OBJECTIVE: Hyperechoic lung lesions are largely detected prenatally but their underlying etiology is still poorly defined. The aim of the study was to determine the concordance between pre and postnatal diagnosis of hyperechoic lung lesions. METHODS: Prenatal ultrasound (US) evaluation was performed by a fetal medicine specialist. Postnatal diagnosis was based on CT-scan. Pre- and postnatal features were retrieved from medical charts. RESULTS: Seventy five patients were included from January 2009 to December 2018. Main prenatal diagnoses were bronchopulmonary sequestrations (BPS) (n = 24%-32%), pulmonary cystic malformations (PCM) (n = 19%-25%), congenital lobar emphysemas (CLE) (n = 15%-20%). Mediastinal shift was observed in 18 cases (24%). The prenatal detection of a systemic arterial supply had a diagnostic accuracy of 90%, while the prenatal detection of a cystic component had a diagnostic accuracy of 76.5%. All 16 neonates with prenatal isolated mediastinal shift were asymptomatic at birth. Seven neonates showed respiratory distress that was not predicted prenatally. CONCLUSIONS: Hyperechoic lung malformations reflect a heterogeneous group of lesions with a good concordance for bronchopulmonary sequestration, but not a satisfying prediction for cystic lesions.

The "salt and pepper" pattern on renal ultrasound in a group of children with molecular-proven diagnosis of ciliopathy-related renal diseases.

BACKGROUND: While typical ultrasound patterns of ciliopathy-related cystic kidney diseases have been described in children, ultrasound findings can overlap between different diseases and atypical patterns exist. In this study, we assessed the presence of the "salt and pepper" pattern in different renal ciliopathies and looked for additional ultrasound features. METHODS: This single-center, retrospective study included all patients with a molecular-proven diagnosis of renal ciliopathy, referred to our center between 2007 and 2017. Images from the first and follow-up ultrasound exams were reviewed. Basic ultrasound features were grouped into patterns and compared to genetic diagnoses. The "salt and pepper" aspect was described as enlarged kidneys with heterogeneous, increased parenchymal echogenicity. RESULTS: A total of 41 children with 5 different renal ciliopathies were included (61% male; median age, 6 years [range, 3 days to 17 years]). The "salt and pepper" pattern was present in 14/15 patients with an autosomal recessive polycystic kidney disease (ARPKD). A similar pattern was found in 1/4 patients with an autosomal dominant polycystic kidney disease and in 1/11 patients with HNF1B mutation. Additional signs found were areas of cortical sparing, comet-tail artifacts, and color comet-tail artifacts. CONCLUSION: Although the "salt and pepper" ultrasound pattern is predominantly found in ARPKD, it may be detected in other ciliopathies. The color comet-tail artifact is an interesting sign when suspecting a renal ciliopathy in case of enlarged hyperechoic kidneys with no detectable microcysts on B-mode grayscale ultrasound.

Comprehensive Review of 3D Segmentation Software Tools for MRI Usable for Pelvic Surgery Planning.

Patient-specific 3D modeling is the first step towards image-guided surgery, the actual revolution in surgical care. Pediatric and adolescent patients with rare tumors and malformations should highly benefit from these latest technological innovations, allowing personalized tailored surgery. This study focused on the pelvic region, located at the crossroads of the urinary, digestive, and genital channels with important vascular and nervous structures. The aim of this study was to evaluate the performances of different software tools to obtain patient-specific 3D models, through segmentation of magnetic resonance images (MRI), the reference for pediatric pelvis examination. Twelve software tools freely available on the Internet and two commercial software tools were evaluated using T2-w MRI and diffusion-weighted MRI images. The software tools were rated according to eight criteria, evaluated by three different users: automatization degree, segmentation time, usability, 3D visualization, presence of image registration tools, tractography tools, supported OS, and potential extension (i.e., plugins). A ranking of software tools for 3D modeling of MRI medical images, according to the set of predefined criteria, was given. This ranking allowed us to elaborate guidelines for the choice of software tools for pelvic surgical planning in pediatric patients. The best-ranked software tools were Myrian Studio, ITK-SNAP, and 3D Slicer, the latter being especially appropriate if nerve fibers should be included in the 3D patient model. To conclude, this study proposed a comprehensive review of software tools for 3D modeling of the pelvis according to a set of eight criteria and delivered specific conclusions for pediatric and adolescent patients that can be directly applied to clinical practice.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Hemodynamic Shock Caused by Tension Pneumoperitoneum in a 5-Year-Old Girl.

Tension pneumoperitoneum is a relatively rare occurrence in the pediatric population. However, tension pneumoperitoneum is associated with significant morbidity and mortality if it is not promptly diagnosed and treated. A 5-year-old girl was admitted to emergency department with abdominal pain. She was in shock, and the radiograph film of the abdomen revealed a voluminous tension pneumoperitoneum. Aggressive fluid challenges were performed in intensive care followed by urgent laparotomy. Primary abdominal compartment due to trapped gas caused a decreased venous return and visceral perfusion. In the absence of hemodynamic improvement after vascular filling, needle decompression was performed before surgery.

Bronchopulmonary sequestrations in a paediatric centre: ongoing practices and debated management.

OBJECTIVES: Bronchopulmonary sequestration (BPS) is the second most common congenital lung malformation, with an estimated incidence ranging from 0.15% to 1.8%. Surgical treatment is elective in patients with symptoms, but the management of asymptomatic patients remains controversial. METHODS: We retrospectively reviewed the medical records of 99 patients treated for BPS in our institution from January 2000 to December 2015. BPS was diagnosed prenatally in 86 (87%) cases. Management throughout this 16-year period was based on 3 interventions: resection by open surgery, resection by thoracoscopy and embolization. RESULTS: Among the 86 patients with a prenatal diagnosis of BPS, 14% had symptoms at birth and 10% had delayed symptoms at a median delay of 8 months (4.5-42 months). For the other 13 patients, symptoms occurred at a median age of 34 months (range 3-96 months). Embolization of the feeding vessel was performed in 46 patients with 6 secondary surgical resections (13%). A total of 59 patients were operated on: 23 cases by open surgery and 36 cases by thoracoscopy. The mean hospitalization stay was significantly longer for open surgery: 4.8 ± 1.3 days vs 4.1 ±1.5 days, respectively (P = 0.03). Differences in hospitalization stay were also found between asymptomatic and symptomatic patients: 3.5 ± 1.2 vs 5.1 ±1.6 days, respectively (P = 0.002). Two of the operated patients died. CONCLUSIONS: When surgery is chosen, thoracoscopy appears to be a valuable procedure. A better understanding of the natural history of BPS is still needed to define the optimal management and the respective roles of surgery, embolization or non-interventional follow-up.

Associations Among Mucosal and Transmural Healing and Fecal Level of Calprotectin in Children With Crohn's Disease.

BACKGROUND & AIMS: Bowel healing is an important goal of therapy for patients with Crohn's disease (CD). Although there have been many studies of mucosal healing, transmural healing (ie, in the bowel wall) has not been investigated in children. We analyzed data from the ImageKids study to determine associations among mucosal, transmural healing and levels of calprotectin and C-reactive protein in children with CD. METHODS: We collected data from a multi-center study designed to develop 2 magnetic resonance enterography (MRE)-based measures for children with CD (6-18 years old). In our analysis of 151 children (mean age, 14.2 ± 2.4 years), all patients underwent MRE and a complete ileocolonoscopic evaluation; fecal levels of calprotectin and blood levels of C-reactive protein were measured. Mucosal healing was defined as simple endoscopic severity index in CD score below 3, transmural healing as an MRE visual analogue score below 20 mm, and deep healing as a combination of transmural and mucosal healing. RESULTS: We identified mucosal healing with transmural inflammation in 9 children (6%), transmural healing with mucosal inflammation in 38 children (25%), deep healing in 21 children (14%), and mucosal and transmural inflammation in 83 children (55%). The median level of calprotectin was lowest in children with deep healing (mean level, 10 µg/g; interquartile range, 10-190 µg/g), followed by children with either transmural or mucosal inflammation, and highest in children with mucosal and transmural inflammation (810 µg/g; interquartile range, 539-1737 µg/g) (P < .001). Fecal level of calprotectin identified children with deep healing with an area under the receiver operating characteristic curve value of 0.93 (95% CI, 0.89-0.98); level of C-reactive protein identified children with deep healing with an area under the receiver operating characteristic curve value of 0.81 (95% CI, 0.71-0.9). A calprotectin cutoff value of 100 µg/g identified children with deep healing with 71% sensitivity and 92% specificity; a cutoff value of 300 µg/g identified children with mucosal healing with 80% sensitivity and 81% specificity. CONCLUSIONS: In a prospective study of children with CD, we found that one-third have healing in only the mucosa or the bowel wall (not both). Levels of fecal calprotectin below 300 µg/identify children with mucosal healing, but a lower cutoff value (below 100 µg/g) is needed to identify children with deep healing. Clinicaltrials.gov no: NCT01881490.