Cardiac MRI six months after the onset of multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19: A retrospective follow-up study.

BACKGROUND: In 2020, reports revealed cases called multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19 or multisystem inflammatory syndrome in children. A small proportion of patients suffer from persistent left ventricular dysfunction at discharge. The primary aim was to investigate if myocardial impairment persists during follow-up in these patients. METHODS: Children fulfilling the criteria for multisystem inflammatory syndrome in children with cardiac involvement hospitalized between December 2020 and February 2022 were included in this retrospective single centre study. Cardiac MRI was performed six months after the onset of symptoms to evaluate possible persistent myocardial damage. RESULTS: Fifteen patients (80% male) with a median age of 8 years (interquartile range 4.5 - 13.5 years) were included. Upon admission, eight patients (53%) presented with reduced left ventricular function, with a median left ventricular ejection fraction of 54% (interquartile range 49.5%-61.5%) on transthoracic echocardiography. Elevated levels of cardiac-specific markers were found in 14 patients (93%). Cardiac MRI was performed in 12 patients at a median of 190.5 days after the onset of symptoms. Nine patients (75%) had normal left ventricular function, with a median left ventricular ejection fraction of 59.45%, while the remaining patients showed mildly to moderately reduced values. None of the patients showed signs of late gadolinium enhancement, indicating the absence of persistent myocardial scarring. CONCLUSION: During a follow-up of 6.2 months, mild to moderate cardiac impairment was revealed in 25% of patients evaluated by cardiac MRI. Although a majority of patients do not show signs of cardiac impairment, close follow-ups should be performed in a proportion of patients.

Non-Contrast MR Lymphography and Intranodal Dynamic Contrast MR Lymphangiography in Children with Congenital Heart Disease-Imaging Findings as well as Impact on Patient Management and Outcome.

Lymphatic flow disorders are rare but devastating complications in children with congenital heart disease. T2-weighted magnetic resonance lymphography and intranodal dynamic contrast magnetic resonance lymphangiography are imaging modalities that can depict central lymphatic anatomy and flow pattern. Our objective was to describe the technical aspects and our imaging findings of central lymphatic abnormalities and their impact on patient management and outcomes: We conducted a retrospective review of 26 children with congenital heart disease who presented for lymphatic imaging between 2015 and 2020 at our institution. Eleven had postoperative chylothorax, six had plastic bronchitis, seven had protein-losing enteropathy and three had Noonan syndrome. Our lymphatic imaging demonstrated severely abnormal lymphatic flow in all of the children, but only minor abnormalities in protein-losing enteropathy. No major procedure-related complication occurred. Lymphatic interventions were performed in six patients, thoracic duct decompression in two patients and chylothorax revision in three patients. This led to symptomatic improvements in all of the patients: Lymphatic imaging is safe and essential for the diagnosis of lymphatic flow disorders and therapy planning. Our intranodal lymphangiography depicts an abnormal lymphatic flow pattern from the central lymphatics but failed to demonstrate an abnormal lymphatic flow in protein-losing enteropathy. These imaging techniques are the basis for selective lymphatic interventions, which are promising to treat lymphatic flow disorders.

Current diagnostic and therapeutic strategies for the management of lymphatic insufficiency in patients with hypoplastic left heart syndrome.

Children with hypoplastic left heart syndrome share unique hemodynamic features that alter lymphatic integrity at all stages of palliation. Lymphatic congestion is almost universal in this patient group to some extent. It may lead to reversal of lymphatic flow, the development of abnormal lymphatic channels and ultimately decompression and loss of protein rich lymphatic fluid into extra lymphatic compartments in prone individuals. Some of the most devastating complications that are associated with single ventricle physiology, notably plastic bronchitis and protein losing enteropathy, have now been proven to be lymphatic in origin. Based on the new pathophysiologic concept new diagnostic and therapeutic strategies have recently been developed. Dynamic contrast magnetic resonance lymphangiography is now mainstay in diagnosis of lymphatic insufficiency and allows a thorough assessment of anatomy and function of the main lymphatic compartments through intranodal, intrahepatic and intramesenteric lymphatic imaging. Contrast enhanced ultrasound can evaluate thoracic duct patency and conventional fluoroscopic lymphangiography has been refined for evaluation of patients where magnetic resonance imaging cannot be performed. Novel lymphatic interventional techniques, such as thoracic duct embolization, selective lymphatic duct embolization and liver lymphatic embolization allow to seal abnormal lymphatic networks minimally invasive and have shown to resolve symptoms. Innominate vein turn-down procedures, whether surgical or interventional, have been designed to reduce lymphatic afterload and increase systemic preload effectively in the failing Fontan circulation. Outflow obstruction can now be managed with new microsurgical techniques that create lympho-venous anastomosis. Short term results for all of these new approaches are overall promising but evidence is sparse and long-term outcome still has to be defined. This review article aims to summarize current concepts of lymphatic flow disorders in single ventricle patients, discuss new emerging diagnostic and therapeutic strategies and point out lacks in evidence and needs for further research on this rapidly growing topic.

Spontaneous reshaping of vertebral fractures in an adolescent with osteogenesis imperfecta.

Background: Vertebral compression fractures (VFs) are a common and severe finding in patients with osteoporosis. In children, VFs have the unique potential to reshape and regain their original configuration. Spontaneous vertebral body reshaping (i.e., medication-unassisted) has been reported in secondary osteoporosis. Here we describe a previously unreported spontaneous vertebral reshaping in an adolescent with osteogenesis imperfecta (OI) with multiple vertebral fractures. Case report: A 17-year-old female was diagnosed with OI type I at 5 years of age caused by a novel frameshift variant in COL1A1 (NM_000088.4: c.540delC; p.Met181TrpfsTer84). Due to parental reservations about medication, she had never received bisphosphonate or any other bone active therapy. A lateral spine X-ray demonstrated transparent bones and no VF. However, previous spine X-rays taken at age of 6 years at an external institution showed VFs in T5-7 (Genant semiquantitative method grade I-II). The two lateral spine x-rays, taken 11 years apart, demonstrate that substantial spontaneous vertebral reshaping occurred without bone active therapy during puberty. Discussion: Vertebral reshaping is explained by the stabilization of bone mineral density (BMD) and the remaining growth capacity the children. We hypothesize that spontaneous reshaping may occur in milder forms of OI, and that puberty may be a key mediator of the phenomenon. In all children with OI and vertebral fractures, we nevertheless recommend bisphosphonate therapy since it improves bone mass, BMD, vertebral shape, physical activity and reduces fracture rates.

Vascular Anatomy in Congenital Lung Lesions-Description and Classification.

Background: Bronchopulmonary sequestration (BPS) and hybrid lesion of congenital pulmonary airway malformation (CPAM) are congenital lung lesions typically presenting with systemic vascular connection. We describe and categorize this atypical systemic vascular anatomy in congenital lung lesions. Methods: In a medical chart review from 2005 to 2020 patients with systemic vascular connection of congenital lung lesions were identified. Clinical and radiological data were collected and compared. Two experienced pediatric radiologists reviewed postnatal thoracic contrast-enhanced computed tomography scans to describe and categorize atypical vascular anatomy. We completed our findings with a review on vascular anatomy in congenital lung lesions. Results: A total of 21 patients with congenital lung lesions (nine extralobar BPS, five intralobar BPS, seven hybrid lesions) had systemic arterial supply; with seven of these additionally having systemic venous drainage. Origin of the feeding arteries from the aorta or aortic main branches was described as supra-diaphragmatic (descending thoracic aorta) in nine and infra-diaphragmatic in ten patients (abdominal aorta, celiac trunk). In two patients with hybrid lesions both supra- and infra-diaphragmatic arterial feeders were found. Additional systemic venous connection of supra-diaphragmatic type drains into the azygos-hemiazygos system (4/21) while the infra-diaphragmatic type (3/21) drains into caval vein, portal or splenic vein. Conclusion: Various variants of systemic arterial and venous connection of congenital lung lesions can be found. Classification of systemic arterial connection as well as venous drainage of congenital lung lesions as supra-diaphragmatic and infra-diaphragmatic types is intuitive, simple and may be important for the surgeon to avoid unanticipated situations and to perform safe resections.

Serum Tumor Marker Dynamics as Predictive Biomarkers in NSCLC Chemo-Immunotherapy and Mono-Immunotherapy Maintenance: A Registry-Based Descriptive Study.

OBJECTIVE: To evaluate serum tumor markers (STM) as predictive biomarkers in advanced non-small cell lung cancer (NSCLC) treated with chemo-immunotherapy. METHODS: Patients having received platinum-based chemo-(CHT) and PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) combination therapy were retrospectively followed. Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis. The marker with the highest relative elevation was defined "leading STM", its change was assessed between CHT-ICI as well as mono-ICI maintenance initiation and the respective subsequent restaging. Corresponding computed tomography evaluations were analyzed using response evaluation criteria in solid tumors (RECIST). For CHT-ICI combination and subsequent mono-ICI-maintenance therapy, leading STM and RECIST response were evaluated regarding progression-free (PFS) and overall survival (OS) in Kaplan-Meier analyses. RESULTS: Among 80 CHT-ICI patients (41% women, mean age 63 years), median PFS was 5 months (M;4,9), median OS was 15M (10,/). PFS was significantly (p=0.042) longer, when the leading STM had decreased at first restaging under CHT-ICI combination therapy (9M (5,12; n=41) vs 5M (3,6; n=16)). In the 54 (67.5%) patients who received subsequent mono-ICI maintenance therapy, STM decrease was similarly associated with significantly (p<0.001) longer PFS (16M (7,/; n=16) vs 3.5M (2,6; n=22)). Patients with radiologically stable or progressive disease and concomitant leading STM decrease had similar PFS in the CHT-ICI combination phase (4M (3,7; n=16) vs 4.5M (2,6; n=14)), but longer PFS in the mono-ICI maintenance setting (13M (7,16; n=10) vs 3M (2,4; n=17)). Median OS was not reached in most subgroups. CONCLUSION: Leading STM dynamics provide predictive biomarker information additional to radiological response evaluation patients receiving CHT-ICI combination therapy, especially in the mono-ICI maintenance setting.

Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC-A retrospective cohort study.

OBJECTIVES: To evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics. RESULTS: Among 84 patients (61% men, mean age 68 years), median PFS was significantly (p < 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (<2-fold: 6 M (3,8) N = 31; ≥2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p < 0.001) median OS (not reached) than with STM increase (<2-fold: 14 M (12,26); ≥2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p < 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p < 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p < 0.001), presence of cerebral metastases (p = 0.036) and therapy line ≥3 (p = 0.001) were identified. CONCLUSION: Decreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.

A Pharmacokinetics, Efficacy, and Safety Study of Gadoterate Meglumine in Pediatric Subjects Aged Younger Than 2 Years.

OBJECTIVES: The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety. MATERIAL AND METHODS: This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium-enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization. RESULTS: Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2ß) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 µmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1 subject (2.2%). One subject (2.2%) experienced 1 rash of moderate intensity considered as related to gadoterate meglumine. CONCLUSIONS: The pharmacokinetic profile of gadoterate meglumine after a single intravenous injection of 0.1 mmol/kg was appropriately described in newborns and infants younger than 2 years, for whom no dose adjustment is required. The improved efficacy of gadoterate meglumine for contrast-enhanced MRI examination of brain, spine, and associated tissues, as well as its good safety profile, was also demonstrated in this population.