Echocardiography to predict left ventricular filling pressure for long-term paediatric heart transplant patients.

OBJECTIVES: Left ventricular diastolic dysfunction is a recognised sequela following transplantation in paediatric heart transplant patients. Traditional echocardiographic indices do not correlate well with left ventricular filling pressure immediately after transplantation. This study aimed to assess whether these indices have any long-term correlation after transplantation in paediatric patients. METHODS: A retrospective chart review of 41 patients who had a heart transplant before the age of 24 years was performed. The median time since the transplantation was 11 years. Data obtained from surveillance cardiac catheterisation and echocardiographic examination were reviewed. Traditional echocardiographic indices of diastolic function were compared with the pulmonary capillary wedge pressure and left ventricular end-diastolic pressure obtained from cardiac catheterisation. RESULTS: The median age at transplant was 12.1 years, and the median time since transplant was 11 years. Eighteen patients (43%) had a history of at least one rejection episode and 12 patients (29%) had a history of cardiac allograft vasculopathy. There was no correlation between mitral inflow E velocity, mitral E/A ratio, tissue Doppler velocities, mitral E/e' (mitral inflow E velocity to mitral annular velocity), and elevated pulmonary capillary wedge pressure or elevated left ventricular end-diastolic pressure. There was no correlation between mitral valve deceleration time or isovolumetric relaxation time with elevated pulmonary capillary wedge pressure or elevated left ventricular end-diastolic pressure. CONCLUSION: Our findings suggest that traditional echocardiographic indices of diastolic function do not correlate well with elevated invasive pulmonary capillary wedge pressure or elevated left ventricular end-diastolic pressure in paediatric heart transplant patients' long-term post-transplantation.

Patent foramen ovale: is it an incidental finding to ignore or a disease to follow?

The authors briefly present two clinical cases and discuss the approach to the management of an incidental finding of patent foramen ovale (PFO) in a young child. We discuss the current controversies in the management of PFO in this age group.

Border Medicine: The Pediatric Cardiology Perspective.

Pediatric cardiology and cardiovascular surgery have witnessed significant advancements over the last two decades. In spite of this progress, congenital heart disease (CHD) still remains as one of the major causes of death in infants and young children in the United States. Many patient-related and patient-independent factors influence the outcomes in patients with CHD, one of which is the geographical location. In the US-Mexico border, management and outcomes of patients with CHD are further complicated by additional problems stemming from complex interplay between two different health systems, and socioeconomic disparities. In this article, the authors evaluate the various interplaying factors and describe the difficulties facing the practicing pediatric cardiologists in a US-Mexico border city.

Establishment of Myocardial Strain Measurement Data in Pediatric Patients Without Structural Heart Disease: A Single Center Study.

Accurate assessment of LV systolic function remains a challenge, especially in the pediatric population. Myocardial strain measurement by 2D speckle tracking echocardiography (2DSTE) is a relatively new modality for assessment of regional and global myocardial wall motion. This study aims to establish the normative value among various pediatric age groups at a large pediatric tertiary care institution and to describe the challenges encountered in establishing such strain data. Transthoracic echocardiograms were acquired in 121 healthy children (age 0-21 years) and were retrospectively analyzed. The global longitudinal strain (GLS) was obtained by 2D speckle tracking using Philips Epiq7® and QLAB post processing software. The normative value for left ventricular GLS (%) obtained in our study was - 20.8 ± 2.3 (< 1 year); - 21.4 ± 2.2 (1-4 years); - 19.6 ± 2.4 (5-9 years); - 19.4 ± 2.6 (10-14 years); - 18.9 ± 3.0 (15-21 years). There was a statistically significant difference in GLS between the different age groups. The BMI (kg/m2) of assessed subjects were 14.6 ± 2.3 (< 1 year); 16.3 ± 1.5 (1-4 years); 16.7 ± 2.3 (5-9 years); 21.3 ± 4.6 (10-14 years); 23.9 ± 5.9 (15-21 years). There was no significant difference in GLS by gender or by BMI found in our study. We present our experience with establishment of normative values of 2DSTE in our pediatric echocardiography lab. This study shows that age is the major determinant of variation in peak GLS in healthy subjects, emphasizing the importance of establishment of normative data among various age groups in pediatrics.

Congenital ductus arteriosus aneurysm in association with MYH11 mutation: a case report.

Congenital ductus arteriosus aneurysms develop in the third trimester of fetal life, possibly due to abnormal intimal cushion formation or elastin expression in the ductal wall. It is often diagnosed in infants before 2 months of age. Most have a benign course and resolve spontaneously. However, life-threatening complications have been reported. We report a case of large ductal aneurysm diagnosed incidentally in a neonate, in whom there was a novel mutation in the smooth muscle myosin protein gene-MYH11.

Comparison of echocardiographic changes in children with primary hypertension and hypertension due to mild to moderate chronic kidney disease.

BACKGROUND: Chronic systemic hypertension has a well-known association with increased cardiovascular morbidity and mortality. One of the most important target organs affected in systemic hypertension is the heart. In addition, chronic kidney disease (CKD) further increases the mortality from cardiovascular disease. The aim of this study was to evaluate the differences in the cardiovascular changes in pediatric patients with primary hypertension (pHTN) vs. those with secondary hypertension from chronic kidney disease (CKD-HTN). METHODS: This was a retrospective chart review of patients with CKD-HTN and pHTN. The medical records were reviewed for anthropometric data, biochemical assessment of renal function, and for cardiovascular changes on echocardiogram. RESULTS: Twenty-three patients with pHTN and 29 patients with CKD-HTN were included in the study. There were no differences in age, gender, weight, height, body mass index, and blood pressure between the 2 groups. There was a high prevalence of left ventricular diastolic dysfunction among both the groups (CKD-HTN 25 vs. pHTN 26%). Reduced mitral valve inflow Doppler E/A ratio, a marker of left ventricular diastolic dysfunction in echocardiogram, was more pronounced in CKD-HTN patents, in comparison to those with pHTN (p = 0.042). Also, diastolic function worsened with declining glomerular filtration rate in patients with CKD-HTN. Similarly, patients with CKD-HTN had a larger aortic root dimension when compared to patients with pHTN (p = 0.049). CONCLUSIONS: The prevalence of left ventricular diastolic dysfunction is similar in patients with pHTN and CKD-HTN. Patients with CKD-HTN appear to have more severe diastolic dysfunction and larger aortic root dimensions.

Does myocardial strain remain abnormal long after normalization of ejection fraction in patients with acute myocarditis?

Myocarditis is a common cause for acute heart failure in the pediatric population. Various imaging modalities have evolved over the past 3 decades in order to noninvasively image the myocardium in this patient population. These include standard 2-dimensional echocardiographic imaging, tissue Doppler imaging, and magnetic resonance imaging of the heart. More recently, myocardial speckle tracking also known as strain imaging has been utilized to assess regional wall motion abnormalities with increasing accuracy. We report a case of acute myocarditis in a teenage female in whom progression of myocardial strain findings correlated with the rapidly evolving clinical course of the patient.

Emerging trends in the prenatal diagnosis of complex CHD and its influence on infant mortality in this cohort.

BACKGROUND: Fetal echocardiography is the main modality of prenatal diagnosis of CHD. This study was done to describe the trends and benefits associated with prenatal diagnosis of complex CHD at a tertiary care centre. METHODS: Retrospective chart review of patients with complex CHD over an 18-year period was performed. Rates of prenatal detection along with early and late infant mortality outcomes were studied. RESULTS: Of 381 complex CHD patients born during the study period, 68.8% were diagnosed prenatally. Prenatal detection rate increased during the study period from low-50s in the first quarter to mid-80s in the last quarter (p=0.001). Rate of detection of conotruncal anomalies increased over the study period. No infant mortality benefit was noted with prenatal detection. CONCLUSIONS: Improved obstetrical screening indications and techniques have contributed to higher proportions of prenatal diagnosis of complex CHD. However, prenatal diagnosis did not confer survival benefits in infancy in our study.

Incidence and Outcome of Pericardial Effusion in Pediatric Patients After Hematopoietic Stem Cell Transplant: A Single-institution Experience.

BACKGROUND: Pericardial effusion (PE) is a known complication after hematopoietic stem cell transplant (HSCT). Limited data is currently available regarding the incidence and outcomes of PE in pediatric HSCT. METHODS: We conducted a retrospective study on a cohort of patients who underwent HSCT between 2004 and 2015. Risk factors associated with development of PE were evaluated. RESULTS: In 111 HSCT, stem cell source was bone marrow in 37 (33.3%), peripheral blood-42 (37.8%) and cord blood-32 (28.8%). Incidence of PE after HSCT was 37.8%. Insignificant effusion (trivial or small) was noted in 30 (27.0%) transplants, and significant (moderate or large) PE in 12 (10.8%). There were no associations between incidence of effusion and stem cell source, graft versus host disease or CMV infection. Risk factors associated with development of PE included systemic hypertension (P<0.05), total body irradiation (P<0.05), and sinusoidal obstruction syndrome formerly known as venoocclusive disease (P=0.03). Overall mortality was 22.5% after HSCT, but 38.1% among those with effusion (P<0.05). None of these deaths were attributed to primary cardiac etiologies. CONCLUSIONS: The incidence of PE in this cohort of pediatric HSCT recipients is high and associated with higher morbidity and mortality.

Impact of prenatal diagnosis of complex congenital heart disease on neonatal and infant morbidity and mortality.

OBJECTIVES: The objective of this study was to analyze the benefits associated with prenatal diagnosis of complex congenital heart disease (CHD) on preoperative morbidity, 30-day and 1-year mortality in this population. METHOD: This was a retrospective review of patients with complex CHD born at our tertiary care center over a 10-year period. Date analysis using Student t test and chi-square test. RESULTS: The overall rate of prenatal detection of complex CHD was 68.1%. A steady increase in the number of complex CHD diagnosed prenatally was noted during the study period. The prenatal diagnosis of complex CHD was associated with significant reduction in the incidence of the following preoperative parameters: antibiotic use, mechanical ventilation, inotropic support, hepatic and renal dysfunction, and acidosis. These beneficial effects were more significant in ductal-dependent cardiac anomalies. However, there were no neonatal and infant survival benefits in association with prenatal diagnosis. CONCLUSION: Prenatal diagnosis of complex CHD leads to improved preoperative morbidity, especially in patients with ductal-dependent cardiac anomalies. No survival benefits were noted with prenatal diagnosis of complex CHD.

Sinus node dysfunction masquerading as complete atrioventricular block in the setting of atrial parasystole after heart transplantation.

Heart transplantation is the gold standard for treatment of end stage heart failure. Atrial parasystole (AP), defined as the presence of an additional dissociated atrial pacemaker on a surface electrocardiogram, has been described to be seen after heart transplantation using biatrial surgical technique. AP may pose a challenge in diagnosing underlying rhythm disturbances in these patients. Here, we report a rare phenomenon of junctional escape rhythm with sinus node dysfunction, mimicking as complete atrioventricular block due to the presence of an AP, in a heart transplant recipient.

Association of left atrial pressure with left atrial volume and N-terminal prohormone brain natriuretic peptide in children with cardiomyopathy.

BACKGROUND: Enlargement of the left atrium is a non-invasive marker of diastolic dysfunction of the left ventricle, a determinant of prognosis in children with cardiomyopathy. Similarly, N-terminal prohormone brain natriuretic peptide is a useful marker in the management of children with cardiomyopathy and heart failure. The aim of this study is to evaluate the association of left atrial pressures with left atrial volume and N-terminal prohormone brain natriuretic peptide in children with cardiomyopathy. METHODS: This was a retrospective study reviewing the medical records of patients <18 years of age, who were diagnosed with cardiomyopathy or acute myocarditis with eventual development of cardiomyopathy. Left atrial volume by transthoracic echocardiogram and pulmonary capillary wedge pressure, a surrogate of left atrial pressure, obtained by means of cardiac catheterisation were analysed. In addition, N-terminal prohormone brain natriuretic peptide levels obtained at the time of the cardiac catheterisation were also reviewed. Statistical analysis was performed to evaluate the association of left atrial pressures with left atrial volume and N-terminal prohormone brain natriuretic peptide levels. RESULTS: There was a linear correlation of left atrial pressure estimated in the cardiac catheterisation with indexed left atrial volume (r=0.63; p<0.001) and left atrial volume z-scores (r=0.59; p<0.001). We found no statistically significant association between the left atrial pressure and N-terminal prohormone brain natriuretic peptide levels. CONCLUSIONS: Left atrial volume measured non-invasively by echocardiography can be used as a surrogate for left atrial pressure in assessing diastolic dysfunction of the left ventricle in children with cardiomyopathy. The larger the size of the left atrium, worse is the diastolic function of the left ventricle.

Intermediate-Term Results After Extracardiac Conduit Fontan Palliation in Children and Young Adults with Single Ventricle Physiology-A Single-center Experience.

The Fontan operation and its modifications are currently the standard palliation in patients with single ventricle physiology. The advantages of extracardiac conduit Fontan operation (ECF) have previously been described. We evaluated the outcome of patients who underwent ECF operation at our center since the year 2000 to assess morbidity, mortality and New York Heart Association (NYHA) functional class in the current era. Medical records of 97 patients who underwent ECF operation from November 2000 till October 2013 were reviewed to determine the diagnosis, age at surgery, surgical technique, postoperative complications, NYHA class at last follow-up, echocardiographic parameters, and most recent Holter monitor results. The median age at surgery was 3.4 years with 4 total deaths until last follow-up (hospital mortality was 1 %, and mortality after hospital discharge was 3 %). Seventy-eight of the 97 patients (80 %) underwent fenestrated Fontan surgery. Median duration of follow-up was 3.9 years (IQR 0.2-12.2 years). At the latest follow-up, 62 patients (67 %) were determined to be in NYHA class I, 25 patients (27 %) in NYHA class II, and 6 (6 %) patients in NYHA class III, and the median oxygen saturation was 92 % (IQR 86-96). There were 15 patients with history of preoperative arrhythmias and 6 of them required pacemaker placement at the time of surgery. One patient developed ectopic atrial tachycardia, and 1 patient had clinical thromboembolism on follow-up. Systolic function of the single ventricle by transthoracic echocardiogram at the latest follow-up was described as normal in 77 patients (83 %), fair in 15 patients (16 %), and poor in 1 patient (1 %). The results of our study show that patients who undergo extracardiac conduit Fontan operation in the modern era may have significantly less morbidity and mortality when compared to earlier years.

Pleiotropic Role of Dietary Phytochemicals in Cancer: Emerging Perspectives for Combinational Therapy.

Cancer is considered a complicated health issue worldwide. The mean cancer survival through standard therapeutic strategies has not been significantly improved over the past few decades. Hence, alternate remedies are needed to treat or prevent this dreadful disease being explored. Currently, it has been recognized that repeated treatment with chemotherapeutic agents has been largely ineffective due to multidrug resistance and further conventional treatment possesses limited drug accessibility to cancerous tissues, which in turn necessitates a higher dose resulting in increased cytotoxicity. Drug combinations have been practiced to address the problems associated with conventional single drug treatment. Recently, natural dietary agents have attracted much attention in cancer therapy because of their synergistic effects with anticancer drugs against different types of cancer. Natural phytochemicals may execute their anticancer activity through targeting diverse cancer cell signaling pathways, promoting cell cycle arrest and apoptosis, regulating antioxidant status and detoxification. This review focuses mainly on the anticancer efficacy of dietary phytochemicals in combination with standard therapeutic drugs reported from various in vitro and in vivo experimental studies apart from clinical trials. This review adds knowledge to the field of intervention studies using combinational modalities that opens a new window for cancer treatment/chemoprevention.

Novel epithelial cell adhesion molecule antibody conjugated polyethyleneimine-capped gold nanoparticles for enhanced and targeted small interfering RNA delivery to retinoblastoma cells.

BACKGROUND: Several nanoconjugates have been designed to deliver nucleic acids such as small interfering RNA (siRNA) and DNA to cells to study silencing and expression efficacies. In the present study, we prepared novel epithelial cell adhesion molecule (EpCAM) monoclonal antibody conjugated polyethyleneimine (PEI) capped gold nanoparticles (AuNPs) loaded with EpCAM-specific siRNA molecules to knock-down the EpCAM gene in retinoblastoma (RB) cells. We chose EpCAM as a target moiety to deliver siRNA because this molecule is highly expressed in various epithelial cancers and is an ideal target as it is highly expressed in the apical surface of tumor cells while showing basolateral expression in normal cells. METHODS: The EpCAM antibody was conjugated to AuNP-PEI loaded with siRNA molecules to specifically deliver siRNA to EpCAM-expressing RB cells. Conjugation efficiencies were confirmed with ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy, and agarose and SDS-polyacrylamide gel electrophoresis. The size and zeta potential were measured using a Zeta sizer analyzer. Nanoparticle internalization and uptake were studied using fluorescent microscopy and flow cytometry. Gene silencing efficacy was monitored with western blot analysis and real-time quantitative PCR. RESULTS: Optimal size and neutral zeta potential properties of the AuNP-PEI- EpCAM antibody (EpAb) antibody were achieved for the transfection studies. The AuNP-PEI nanoparticles did not show any cytotoxicity to the cells, which means these nanomaterials are suitable for intracellular delivery of siRNA for therapeutic interventions. With EpCAM antibody conjugation, PEI-capped AuNPs loaded with EpCAM siRNA were significantly internalized in the Y79 cells as observed with fluorescence microscopy and flow cytometry and induced a highly significant reduction in the cell viability of the Y79 cells. Through increased binding of EpCAM antibody-conjugated AuNP-PEI nanoparticles, significant downregulation of EpCAM gene was observed in the Y79 cells when compared to the cells treated with the antibody-unconjugated AuNP-PEI nanoparticles. CONCLUSIONS: Thus, a novel antibody conjugated nanocarrier designed to deliver siRNA holds promise as an effective gene therapy strategy for retinoblastoma in the near future. In addition to serving as an siRNA delivery tool for therapy, gold nanoparticles can also serve as imaging modality in diagnosis.

EpCAM is a putative stem marker in retinoblastoma and an effective target for T-cell-mediated immunotherapy.

PURPOSE: The molecular markers cluster of differentiation (CD)24, CD44, adenosine tri-phosphate (ATP) binding cassette protein G2 (ABCG2), and epithelial cell adhesion molecule (EpCAM) are widely used, individually or in combination, to characterize some types of cancer stem cells. In this study we characterized the EpCAM+ retinoblastoma (RB) cells for their cancer stem-like properties in vitro. Additionally, we targeted RB tumor cells via redirecting T cells using bispecific EpCAM×CD3 antibody. METHODS: Flow cytometry was used to study the co-expression of EpCAM with putative cancer stem cell markers, such as CD44, CD24, and ABCG2, in RB primary tumors. In vitro methyl thiazol tetrazolium (MTT) assay, invasion assay, and neurosphere formation assay were performed to characterize EpCAM+ cells for their cancer stem/progenitor cell-like properties. We assessed the in vitro efficacy of bispecific EpCAM×CD3 antibody on RB tumor cell proliferation and validated the results by evaluating effector cytokine production in the culture medium with the ELISA method. RESULTS: EpCAM was co-expressed with all cancer stem cell markers (CD44, CD24, and ABCG2) in primary RB tumors. EpCAM+ cells showed significantly higher proliferative invasive potential and neurosphere formation in vitro compared to EpCAM⁻ Y79 cells. EpCAM+ cells showed higher ß-catenin expression compared to EpCAM- cells. EpCAM×CD3 significantly retarded proliferation of RB primary tumor cells. EpCAM×CD3 effectively induced the secretion of effector cytokines, such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-10, IL-2, and transforming growth factor (TGF)-ß1, and also perforin levels by pre-activated lymphocytes. CONCLUSIONS: EpCAM might be a novel cancer stem cell marker in RB. EpCAM×CD3 antibody redirecting T cells to attack RB tumor cells may prove effective in RB management. Further preclinical studies are needed to confirm the initial findings of our study.

Pediatric Heart Failure Inpatient Mortality: A Cross-Sectional Analysis.

Background Heart failure constitutes significant morbidity and mortality among the pediatric population. Few data exist on the prevalence and mortality rate of pediatric heart failure (pHF) in the United States. Objectives This study aimed to determine the in-hospital mortality and the principal diagnoses in pediatric patients with heart failure who died while being hospitalized in the United States. Methods This is a retrospective cross-sectional study using data from the 2019 Kid Inpatient Database (KID). The KID contained data on hospitalized children below 21 years of age. Using Stata 17 software (StataCorp LLC, College Station, Texas), the data were searched for heart failure diagnoses using International Classification of Diseases 10th revision Clinical Modification (ICD-10-CM) codes. By using the "rank" command in Stata, the most common principal diagnoses were placed in descending order of frequency, and these were further divided into different ICD-10 code categories. Results There were 16,206 pHF admissions in 2019. Of these admissions, 1,023 (6.31%) patients died. The top five principal ICD 10 code categories among all pHF deaths in descending order were circulatory system (17.95%), congenital/chromosomal abnormalities (17.43%), respiratory system (10.28%), infectious diseases (9.24%, and perinatal diseases (7.90%). Among all pHF deaths, sepsis of unspecified organisms (5.14%), hypoplastic left heart syndrome (HLHS) (3.19%), and acute respiratory failure with hypoxia (3.14%) were the most common primary diagnoses. Conclusion and significance Pediatric heart failure in-hospital overall mortality is 6.31%, and sepsis of unspecified organisms, HLHS, and acute respiratory failure are the most common principal diagnoses among these children. Preventive measures and prompt treatment of infections are paramount to reducing pHF mortality.

Case report: Bordetella holmesii: A rare pathogen causing infective endocarditis associated glomerulonephritis.

Infective endocarditis (IE) can cause multiorgan dysfunction and chronic kidney disease, in addition to cardiac sequelae. The presentation may be vague and can manifest as acute glomerulonephritis. While the most common pathogens of infective endocarditis are Staphylococcus and Streptococcus species, we report a rare pathogen Bordetella holmesii causing infective endocarditis associated glomerulonephritis. A 20-year-old male patient with tetralogy of Fallot with pulmonary atresia and aortopulmonary collaterals underwent several cardiac surgeries including prosthetic pulmonary valve replacement in the past. He was admitted for 3 days at an outside hospital for fever, cough, and hemoptysis, and diagnosed with streptococcal pharyngitis, for which he received antibiotics. Five weeks later, he presented to our institution with lower extremity edema and gross hematuria. On examination, he was afebrile, normotensive, had a 7-kg weight gain with anasarca, and a systolic murmur, without rash. Investigations revealed elevated serum creatinine, nephrotic range proteinuria, hematuria, and hypocomplementemia, consistent with acute glomerulonephritis. Given his cardiac history, blood cultures were collected from three sites. Broad-spectrum antibiotics were initiated when he subsequently developed fever. Renal pathology on biopsy showed diffuse proliferative immune complex-mediated glomerulonephritis. Transesophageal echocardiogram visualized a vegetation on the pulmonary valve. Bordetella holmesii was ultimately cultured from the prior and current hospitalization. A serum sample detecting microbial cell-free DNA sequencing confirmed Bordetella holmesii at very high levels. After completing 6 weeks of intravenous antibiotics with concurrent angiotensin receptor blockade, his kidney function recovered with improvement in hypocomplementemia and proteinuria. This case report highlights the early recognition and comprehensive evaluation of a rare organism causing IE-associated GN, which allowed for renal recovery and preserved cardiac function.

Patent foramen ovale in children: Unique pediatric challenges and lessons learned from adult literature.

A patent foramen ovale (PFO) is a frequent incidental finding during echocardiography in otherwise healthy children. In most healthy children with a diagnosis of isolated incidental PFO, no further follow-up or intervention is necessary. In some children, PFO is associated with certain clinical syndromes such as cryptogenic stroke, decompression sickness, migraine, and platypnea-orthodeoxia syndrome. This review discusses PFO anatomy, diagnostic imaging, PFO-associated clinical situations, management options, and the role of PFO in certain congenital heart disease. This review also highlights the current deficiency of pediatric data guiding management of these uncommon but important PFO-associated conditions. Future multicenter randomized controlled studies are necessary to guide the management of these unique and challenging PFO-associated conditions.

Rapid Involution of Large Cardiac Rhabdomyomas With Everolimus Therapy.

Rhabdomyoma of the fetal heart is a rare disease accounting for about 1% of all fetal cardiac structural anomalies. They are often found in association with tuberous sclerosis complex. Large cardiac rhabdomyomas can compromise the cardiac function. We report a case of multiple large rhabdomyomas of the right and left ventricles, affecting the cardiac function, which was successfully treated with the chemotherapeutic and immunosuppressive medication everolimus, in a neonate with genetically confirmed tuberous sclerosis complex with multisystem manifestations. There was rapid involution of the tumors in response to everolimus therapy in this infant.