Search

We report the case of a female neonate admitted to the neonatal ICU with a rapid, narrow-complex tachyarrhythmia determined to be supraventricular tachycardia. Multimodality imaging and genetic testing confirmed a diagnosis of tuberous sclerosis complex with multiple cardiac rhabdomyomas. At 13 days of age, the patient was readmitted, exhibiting recurrent supraventricular tachycardia non-responsive to first-line treatment. Management required triple-drug therapy, whereafter the patient remained stable without recurrences. This is a rare report of supraventricular tachycardia in a functionally normal heart with the occurrence of supraventricular tachycardia due to structural abnormalities, with the possibility of multiple concealed accessory pathways.

The mammalian/mechanistic target of rapamycin (mTOR) is a protein kinase that plays a crucial role in regulating cellular growth, metabolism, and survival. Although there is no absolute contraindication for the use of mTOR inhibitors during pregnancy, the specific fetal effects remain unknown. Available data from the past 2 decades have examined the use of mTOR inhibitors during pregnancy in patients with solid organ transplantation, showing no clear link to fetal complications or structural abnormalities. Recently, a handful of case reports and series have described transplacental therapy of mTOR inhibitors to control symptomatic and complicated pathologies in the fetus. The effect of these agents includes a significant reduction in lesion size in the fetus and a reduced need for mechanical ventilation in neonates. In this context, we delve into the potential of mTOR inhibitors as in-utero therapy for fetal abnormalities, with a primary focus on lymphatic malformation (LM) and cardiac rhabdomyoma (CR). While preliminary reports underscore the efficacy of mTOR inhibitors for the treatment of fetal CR and fetal brain lesions associated with tuberous sclerosis complex, chylothorax, and LMs, additional investigation and clinical trials are essential to comprehensively assess the safety and efficacy of these medications., (© 2024 John Wiley & Sons Ltd.)

Everolimus is a mTOR inhibitor that has been increasingly used in high-risk cardiac rhabdomyomas in recent years. There are questions regarding the optimal dose and duration of therapy with everolimus for cardiac rhabdomyomas. The purpose of this study was to examine retrospectively the dosage-efficacy relationship in seven babies diagnosed with rhabdomyoma treated with different everolimus dose regimens retrospectively. Cardiac rhabdomyoma diagnosis was made in six of seven babies during the prenatal period. Indication of everolimus was an obstruction in six patients and supraventricular tachycardia which is resistant to antiarrhythmic drugs in the remaining one patient. The median age was 8 days (range; 2-105 days) at the time of starting everolimus. It was administered at a dose of 0.25 mg twice a day for two days a week in four patients; 0.1 mg/day in two and 0.4 mg/day in one patient. Serum everolimus level was kept between 5 and 15 ng/ml. All seven cases showed significant regression of cardiac rhabdomyoma within four weeks, and supraventricular tachycardia was controlled in two weeks after everolimus administration.This study demonstrates that everolimus was effective in accelerating regression of the cardiac rhabdomyoma. Dose with 2 × 0,25 mg/day, 2 days a week, seems appropriate. However, lower doses such as 0.1 mg/day are also effective. But dose adjustment should be made according to serum level monitoring.

Background: Primary cardiac tumors are extremely rare. Cardiac rhabdomyoma is the most common primary cardiac tumor. 50-80% of solitary rhabdomyomas and all multiple rhabdomyomas are associated with tuberous sclerosis complex. Due to spontaneous regression, surgery is necessary only in severe hemodynamic compromise and persistent arrhythmias. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, can be used in the treatment of rhabdomyomas seen in tuberous sclerosis complex. We aimed to evaluate the clinical progression of rhabdomyomas followed-up in our center between the years 2014-2019 and evaluate the efficacy and safety of everolimus treatment on tumor regression., Methods: Clinical features, prenatal diagnosis, clinical findings, tuberous sclerosis complex presence, treatment and follow-up results were evaluated retrospectively., Results: Among 56 children with primary cardiac tumors, 47 were diagnosed as rhabdomyomas, 28/47 patients (59.6%) had prenatal diagnosis, 85.1% were diagnosed before one year of age and 42/47 patients (89.3%) were asymptomatic. Multiple rhabdomyomas were present in 51% and median diameter of tumors was 16mm (4.5 - 52 mm). In 29/47 patients (61.7%) no medical or surgical treatment were necessary while 34% of these had spontaneous regression. Surgery was necessary in 6/47 patients (12.7%). Everolimus was used in 14/47 patients (29.8%). Indications were seizures (2 patients) and cardiac dysfunction (12 patients). Regression in size of rhabdomyomas was achieved in 10/12 patients (83%). Although, in the long-term, the amount of tumor mass shrinkage was not significantly different between patients who received everolimus and untreated patients (p=0.139), the rate of mass reduction was 12.4 times higher in patients who received everolimus. Leukopenia was not detected in any of the patients, but, hyperlipidemia was noted in 3/14 patients (21.4%)., Conclusions: According to our results, everolimus accelerates tumor mass reduction, but not amount of mass regression in the long term. Everolimus may be considered for treatment of rhabdomyomas which cause hemodynamic compromise or life-threatening arrhythmias before surgical intervention.

Background: Sirolimus constitutes a safe and effective treatment for cardiac manifestations of tuberous sclerosis complex (TSC) in children but only four cases describing prenatal treatment of rhabdomyomas with mTOR inhibitors have been published., Case: In this case, sirolimus was initiated at 26 weeks´ gestation in a pregnant woman with TSC with a fetus with a large rabdomyoma conditioning severe arrythmia. There was a significant reduction in the tumor size with ongoing treatment and a partial reversion of the arrythmia., Conclusion: m-TOR inhibitors can be considered for severe cases of fetal rhabdomyomas with poor prognosis given its potencial benefits.

Cardiac rhabdomyoma is the most common cardiac tumour in childhood, with a strong genetic association to tuberous sclerosis complex. Although most of the patients remain asymptomatic, a small proportion present with cardiac complications in the early neonatal period. Timely initiation of treatment can potentially reduce disease morbidity, and mammalian target of rapamycin (M-TOR) inhibitors play an effective role in promoting regression of these tumours. A healthy term newborn was diagnosed with a giant congenital cardiac rhabdomyoma at birth. He developed clinical signs of compromised cardiac function and progressive myocardial ischaemia, with echocardiography showing significant dyskinesia. He was treated with M-TOR inhibitors and clinical response was monitored via serial echocardiography. Remarkable regression of the tumour was visibly demonstrated within 4 months of sirolimus treatment. The infant continues to be reviewed by a multidisciplinary team of physicians and monitored for features of tuberous sclerosis complex., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In tuberous sclerosis, most cardiac rhabdomyomas regress spontaneously. In some cases, the tumors can cause life-threatening hemodynamic compromise requiring subsequent surgical resection. The mechanistic target of rapamycin inhibitors everolimus and sirolimus have shown to be effective treatments for multiple conditions. There are four reports of off-label treatment with transplacental sirolimus for fetal rhabdomyomas due to tuberous sclerosis complex. The optimal dosing regimen is unknown., Methods: We reviewed the medical records of all patients treated prenatally with sirolimus for rhabdomyomas. All fetuses had a clinical and molecular diagnosis of tuberous sclerosis complex (2012 Consensus Diagnostic Criteria, including a positive genetic test). Clinical history, mechanistic target of rapamycin inhibitor dosing and levels, outcome, and adverse events were reviewed after initiation of sirolimus treatment., Results: Three fetuses were treated with maternal sirolimus. Dosing regimens and subsequent trough levels differed from 1 mg/day to 6 mg/day and <1.0 ng/mL to 12.2 ng/mL. Cardiac rhabdomyomas gradually shrank in all patients. Growth restriction was noted in one patient. No severe adverse events occurred during the treatment period., Conclusions: Maternal sirolimus appears to be a safe treatment option in prenatally detected rhabdomyomas with possible need for intervention. Follow-up visits with fetal ultrasound, echocardiography, and laboratory work should be performed weekly during the treatment period. The optimal dosing and trough level timepoints remain unclear. Based on our results, we recommend a sirolimus starting dose of at least 2 mg/m 2 /day, preferably 3-3.5 mg/m 2 /day to achieve a target trough level of 10-12 ng/mL., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The association between cardiac rhabdomyoma and intraventricular tumors and/or subcortical nodules is characteristic of tuberous sclerosis complex (TSC). Patients with TSC may have refractory seizures, autistic behavior, and cognitive decline., Case Report: The patient received the fetal diagnosis of TSC at the age of 19 weeks of gestations, where presented at prenatal ultrasound cardiac and brain tumors. Fetal MRI showed a lesion in the right and left lateral ventricles near the foramen of Monro associated with subependymal lesions along the entire ependyma of the lateral ventricles and several subcortical tubercles, and the fetal Doppler echocardiogram revealed three cardiac lesions. The fetus underwent intrauterine treatment with everolimus and presented regression and subsequent stabilization of the cardiac and brain lesions; additionally, the patient did not develop seizures or autism and presented good neuropsychomotor development., Conclusion: It is the first evidence that mTOR inhibitors may help to prevent neurological complications associated with TSC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Tuberous sclerosis complex is a rare multisystem genetic disorder characterised by the growth of numerous tumour-like malformations in many parts of the body including skin, kidneys, brain, lung, eyes, liver, and heart. Mutations in the TSC1 or TSC2 genes have been reported to cause disruption in the TSC1-TSC2 intracellular protein complex, causing over-activation of the mammalian target of rapamycin protein complex. In this study, we present a 3-month-old male infant diagnosed with tuberous sclerosis, bilateral neurosensorial hearing loss, Wolff-Parkinson-White syndrome on electrocardiography, multiple cardiac rhabdomyomas with severe stenosis in the left ventricular outflow tract, who responded well to the Everolimus therapy.

Objectives: To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups., Study Design: The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described., Results: A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P = .027) and female patients (hazard ratio = 2.08, P = .015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6 months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis., Conclusions: Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cardiac rhabdomyomas (CRs) are the earliest sign of tuberous sclerosis complex (TSC). Most of them spontaneously regress after birth. However, multiple and/or large tumors may result in heart failure or cardiac arrhythmia. Recently, the attempts to treat CRs with mTOR inhibitors (mTORi) have been undertaken. We reviewed the current data regarding the effectiveness and safety of mTORi in the treatment of CRs in children with TSC., Methods: The review was conducted according to the PRISMA guidelines. Medline, Embase, Cochrane library, and ClinicalTrial.gov databases were searched for original, full-text articles reporting the use of mTORi (everolimus or sirolimus) in the treatment of CRs in children with TSC., Results: Thirty articles describing 41 patients were identified (mostly case reports, no randomized or large cohort studies). Thirty-three children (80.5%) had symptomatic CRs and mTORi therapy resulted in clinical improvement in 30 of them (90.9%). CRs size reduction was reported in 95.1%. Some CRs regrew after mTORi withdrawal but usually without clinical symptoms recurrence. The observed side effects were mostly mild., Conclusions: mTORi may be considered as a temporary and safe treatment for symptomatic CRs in children with TSC, especially in high-risk or inoperable tumors. However, high-quality, randomized trials are still lacking.

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.

Mammalian target of rapamycin inhibitors was found recently to be an effective treatment for manifestations of Tuberous sclerosis complex, including cardiac rhabdomyomas. Most cases with Cardiac rhabdomyoma treated with mammalian target of rapamycin inhibitors to date were diagnosed with Tuberous sclerosis. We report a case of cardiac rhabdomyoma and severe right ventricular outflow obstruction in a baby with negative genetics for Tuberous sclerosis that responded rapidly to Sirolimus.

Cardiac rhabdomyomas represent the most common primary paediatric cardiac tumour and typically regresses over time in the majority of patients. Among those who are symptomatic, surgical resection or catheterisation procedures have traditionally proven effective. More recently, those invasive or challenging tumours have been successfully treated with mammalian target of rapamycin inhibitors, typically everolimus and sirolimus. This review outlines the current medical literature of the state-of-the-art medical treatment of these tumours. We specifically focus on dosing regimens, duration of therapy, and side-effect profiles of mammalian target of rapamycin inhibitors among this population. Although the majority of cases responded to mammalian target of rapamycin inhibition, standardised guidelines for dosing and duration of treatment remain to be defined.

Introduction: Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma., Methods: ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure., Conclusions: ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

Objective: To review the pathophysiology of rhabdomyomas and the emerging option of prenatal treatment of fetal cardiac rhabdomyomas., Methods: We present a case of fetal rhabdomyomas causing significant hemodynamic compromise that received in utero treatment of maternal sirolimus. Genetic amniocentesis confirmed a TSC2 mutation. A treatment program was initiated with a 10-mg loading dose titrated to a goal maternal trough of 10 to 15 ng/dL. In order to follow fetal cardiac function, a sophisticated method of speckle tracking echocardiography was used before and after treatment. Obstetric ultrasound was used to monitor fetal growth, and clinical surveillance, echocardiography, and brain MRI were used to monitor postnatal growth and development through 6 months of neonatal life., Results: Sirolimus was initiated from 28 to 36 weeks of gestation with improvement of cardiac status. During this period, intrauterine growth restriction developed. Postnatally, the infant has had stable rhabdomyomas and cardiac function without reinitiating sirolimus. Brain MRI demonstrated scattered cortical tubers and subependymal nodules, and the infant has not had seizure-like activity. At 6 months of age, the infant has achieved appropriate developmental milestones., Conclusion: In counseling cases of prenatal onset large obstructing rhabdomyomas and cardiac compromise, in utero sirolimus treatment can be considered., (© 2019 John Wiley & Sons, Ltd.)

Cardiac rhabdomyoma is the most common neonatal cardiac tumor and is typically associated with tuberous sclerosis complex (TSC). Although these tumors may naturally regress, some patients require surgical resection because of cardiac instability. If not fully resected, patients may also require medical therapy to improve their hemodynamics. Everolimus, a mammalian target of rapamycin inhibitor, has shown promise in reducing rhabdomyoma in patients with TSC, but the drug's impact in patients without TSC has not been reported. Monitoring of tumor response has typically been limited to echocardiograms, which is not ideal given inherent difficulties in three-dimensional measurements. We report a case of sporadic cardiac rhabdomyoma in a neonate treated with everolimus resulting in tumor regression as documented by cardiac MRI. While on everolimus, our patient had an increased incidence of a preexisting arrhythmia, which resolved with planned cessation of therapy, suggesting that close monitoring is imperative in patients with arrhythmia., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Background: Tuberous Sclerosis Complex (TSC) is a rare multisystem disorder. In 2012 diagnostic criteria for TSC were revised. However, data on the incidence of TSC are limited., Methods: Prospective, national surveillance study in Germany over a 2-year-period (03/2015-02/2017) using current revised criteria for TSC. Patients up to the age of 18 years with a new diagnosis of definite or possible TSC (clinical and/or genetic) were included. The aims of this study were 1) to generate up-to-date data on the incidence of definite or possible TSC, 2) to assess age at first diagnosis, and 3) to compare these data with previous epidemiologic data., Results: In total, 86 patients met inclusion criteria (definite or possible TSC) with a median age at diagnosis of 6 months (range: 5 months before birth - 197 months of age). Among patients identified with features of TSC, 73.3% met criteria for definite diagnosis (median age: 7 months) and 26.7% met criteria for a possible diagnosis (median age: 3 months). 55.8% of patients were male. When excluding prenatally diagnosed patients, median age at diagnosis was 11 months with a range of 0 to 197 months. The 3 most common clinical features at diagnosis of TSC were central nervous system involvement in 73.3% patients (of these 95.2% experienced seizures), cutaneous involvement in 58.1% patients (with the most common lesion being hypomelanotic macules in 92%) and cardiac rhabdomyoma in half of the patients. Cardiac rhabdomyoma were detected by prenatal ultrasonography in 22.1% of patients. The presence of cardiac rhabdomyoma was associated with cardiac arrhythmias in 25.6% (about 13% of all diagnosed patients) in our cohort. The overall prevalence of seizure disorders was 69.8%. The annual incidence rate of TSC is estimated at a minimum of 1:17.785 live births. However correcting for underreporting, the estimated incidence rate of definite or possible TSC is approximately 1:6.760-1:13.520 live births in Germany., Conclusions: This is the first study that assessed prospectively the incidence rate of TSC in children and adolescents using the updated diagnostic criteria of 2012. This prospective surveillance study demonstrates a low age at first diagnosis (median: 6 months), likely due to antenatal detection of cardiac rhabdomyoma. Early diagnosis bears the potential for implementing effective therapies at an earlier stage.

IntroductionIntracardiac rhabdomyomas can cause severe ventricular dysfunction and outflow tract obstruction.Case reportA term newborn infant with antenatal diagnosis of giant left ventricle rhabdomyoma presented with cardiac failure and duct-dependent systemic circulation after birth. She was treated successfully with everolimus, showing decrease in tumour size and improvement in left ventricular ejection fraction.DiscussionTumour regression rate was 0.32 cm2/day and improved to 0.80 cm2/day with the use of everolimus. Herein we report a newborn with inoperable giant left ventricular cardiac rhabdomyoma and significant regression of the tumour. To our knowledge, this is the largest left ventricular rhabdomyoma reported. A review of the literature was undertaken for comparison., Conclusion: Everolimus has proven to be efficacious in size reduction of cardiac rhabdomyomas in cases when surgical resection is not possible.

Cardiac rhabdomyomas are the most common tumours in children and are typically seen in association with the tuberous sclerosis complex. Although benign and often associated with spontaneous regression, in rare circumstances surgical resection is indicated to relieve obstruction or other mass-related effects. Recent clinical trials have demonstrated the benefits of mammalian target of rapamycin inhibitors for the treatment of other tumour sub-types associated with tuberous sclerosis. Here we report rapid regression of several massive cardiac rhadomyomas in two neonates with the use of the mammalian target of rapamycin inhibitor sirolimus.

Background: The combination of vincristine, irinotecan, and temozolomide (VIT) is often used to treat children and adolescents with relapsed rhabdomyosarcoma (RMS); however, the outcome of these patients has not been previously described., Procedures: We sought to determine the response rate (RR) and progression-free survival (PFS) for patients with relapsed RMS treated with VIT by retrospective review of patients treated at five tertiary care hospitals. Prior treatment with irinotecan was permitted., Results: Among 19 patients with a median age of 8 years (range 2-17 years), 12 (63%) were males and 12 (63%) had embryonal histology. Median time to relapse from initial diagnosis was 16 months (range 2.8-45 months). VIT was used as first, second, third, or fourth line of therapy in four (21%), seven (37%), six (32%), and two (10%) patients, respectively. Four patients received VIT as adjuvant therapy following radiation and/or surgery. Therefore, among 15 evaluable patients, the best response to VIT was 0 (complete response, CR), 0 (partial response, PR), 4 (stable disease, SD), and 11 (progressive disease, PD) for an overall clinical benefit rate (CR + PR + SD) of 26.7% (95% CI: 7.8-55.1%). After a median follow-up of 8 months, 2 (10%) patients were alive without disease, 3 (16%) were alive with disease, and 14 (74%) patients died of PD. PFS at 3 months was 23% (95% CI: 5.7-46.7%)., Conclusions: VIT therapy in combination with adequate local control is associated with some disease control in patients with first relapse RMS and may be another reasonable option to offer patients as salvage therapy., (© 2017 Wiley Periodicals, Inc.)

Cardiac rhabdomyoma (CR) is the most common cardiac tumor in newborns. Approximately 75% of cases are associated with tuberous sclerosis complex. Although these tumors usually spontaneously regress after 2 years of age, they can be life-threatening when they obstruct major cardiac inflow or outflow pathways. Everolimus is an inhibitor of the mammalian target of rapamycin, reducing its production of the proteins harmartin and tuberin. Everolimus has demonstrated a remarkable suppression effect in children with tuberous sclerosis complex at doses of 4.7-5.6 mg/M 2 /day and serum trough levels of 5-15 ng/mL. Since 2012, five case reports of neonates with CR have also reported the tumor-regressing effect of everolimus. However, the optimal dosage for neonates is still unknown. Over the past 2 years, we have deliberately used a low dose everolimus regimen (0.3-0.67 mg/M 2 /day) in three neonates with large CRs, in an effort to maintain serum trough levels at 3-7 ng/mL. In all three cases, the tumors regressed smoothly within 2 months. Regarding the drug's side effect of predisposing patients to infection, we observed that adenovirus pneumonia occurred in one case at 3 months of age, and chicken pox occurred in another case at 9 months of age; both recovered smoothly. Our three cases of neonatal CR demonstrate that a low-dose everolimus regimen is an effective treatment for tumor regression.

Tuberous sclerosis complex is associated with benign tumors such as cardiac rhabdomyomas (RHM) caused by the disinhibition of the mammalian target of rapamycin (mTOR) protein. Recent reports on everolimus, an mTOR inhibitor, have shown size reduction of RHM. We compared cases recently treated with everolimus to historic controls whose first echocardiography was within first month of life. The largest dimension of the largest RHM was reported as a percentage compared to the earliest echocardiography study. Treatment of the four cases was started at a median age of 6.5 days (range 2-20) with an initial enteral dose of 0.1 mg daily, aiming at a therapeutic serum trough level of 5-15 ng/mL. Median duration of everolimus treatment was 73 days (range 34-138). Compared to 10 historic controls, everolimus-treated patients had 11.8 times faster RHM size regression rate (slope -0.0285 vs. -0.0024; p < 0.001). The average time to 50% size reduction was 1.13 ± 0.33 month (range 0.66-1.4 months) with everolimus versus 72.9 ± 53.03 months in controls (p = 0.026). Following treatment with everolimus, one case was operated for congenital heart disease, without requirement of RHM resection, two others had the massive left ventricle RHM shrink to non-consequential size. The latter had a disappearance of RHM, but everolimus therapy was maintained to prevent the regrowth of a significant cerebral tumor. Everolimus is efficacious for size reduction of RHM during the neonatal period. With limited safety data, this approach should be used with caution in selective cases.

Objective: To assess the efficacy and safety of mammalian target of rapamycin (mTOR) inhibitor rapamycin in treatment of children with cardiac rhabdomyoma, associated with tuberous sclerosis complex (TSC)., Method: The clinical data of children with cardiac rhabdomyomas, who had received a diagnosis of TSC previously, were collected between September 2011 and November 2015 from Pediatric Department of the People's Liberation Army General Hospital.Patients in line with the inclusion criteria received long-term treatment with sirolimus.The starting doses of sirolimus was 1 mg/ (m(2)·d), and the plasma concentration was maintained at 5-10 μg/L.The size and number of cardiac rhabdomyomas were analyzed after treatment with rapamycin, and the efficacy and safety were assessed. The Wilcoxon test was used to analyze data., Result: All the 51 children met the inclusion and exclusion criteria, including 30 males and 21 females.The median age for rapamycin treatment was 15.0 months (7.0-35.0 months). Tumors disappeared in 26 (51%) children, decreased by more than 50%(including 50%) in 15 (29%) children, decreased by less than 50% in 5 (12%) children, and had no change or progressed in 4 (8%) children.The number of tumors decreased by 77(72%). The median maximum diameter of tumor was 8.7 (5.9-11.3) mm before treatment, 0.0 (0.0-4.0) mm after treatment, and the median decrease of tumor size were 6.7 (3.9-10.0) mm (Z=-8.817, P<0.01). The median disappearance time was 3.26 (2.92-5.37) months.Among different age groups, after treatment by rapamycin, the rate of tumor's disappearance was 50% (12/24) in 0-1 years group.Tumors disappeared in 10 of 16 patients in >1-3 years group and in 4 of 11 patients in >3 years group.The rate of tumor's disappearance was the highest after 3 months of treatment as compared with 6 and 12 months of treatment.Ten children had adverse event that was related to rapamycin.Canker sore was reported in one child and dyslipidemia was reported in 9 children., Conclusion: Rapamycin is efficacious and well tolerate in treatment of cardiac rhabdomyomas associate with TSC, and lead to a reduction in tumor size and number, in addition, significantly shorten the duration of cardiac rhabdomyoma.

We report a case of a newborn, affected by tuberous sclerosis complex, with a prenatally diagnosed giant cardiac rhabdomyoma associated with a large renal angiomyolipoma presenting as a duct-depending lesion not treatable by surgery. After receiving everolimus, a mammalian target of rapamycin inhibitor, we observed a rapid, significant, and durable reduction of both lesions without remarkable side effects.

Cardiac rhabdomyoma is the most common primary cardiac tumour during childhood and is usually associated with tuberous sclerosis complex (TSC). These tumours are generally considered benign, and spontaneous regression occurs commonly. However, when the tumours cause significant symptoms, the current standard treatment is surgical resection. Everolimus is an mammalian target of rapamycin (mTOR) complex 1 inhibitor that has been successfully used to treat subependymal giant cell astrocytomas and renal angiomyolipomas associated with TSC. A few case reports have described the effectiveness of everolimus therapy in treating cardiac rhabdomyomas as well. We report a case of a newborn who had near complete resolution of multiple rhabdomyomas within a month of receiving everolimus therapy for non-cardiac masses. To the best of our knowledge, this is the fastest resolution of cardiac rhabdomyomas associated with everolimus therapy to date. Everolimus may be a promising alternative for high-risk surgical candidates with haemodynamically significant cardiac rhabdomyomas., (2015 BMJ Publishing Group Ltd.)

The presented case reports on successful treatment with everolimus in a neonate with left ventricular giant rhabdomyoma. The authors used a different dosage regime compared to literature and documented rapid tumor regression by 3D echocardiography., (© 2015, Wiley Periodicals, Inc.)

Rhabdomyoma is the most common cardiac tumour in children often associated with tuberous sclerosis. Arrhythmia caused by cardiac rhabdomyomas may be the initial sign of tuberous sclerosis. Rhabdomyomas unresponsive to other treatments could be successfully managed with everolimus, which has demonstrated benefit in tuberous sclerosis. We report a case of rhabdomyoma causing severe arrhythmia in a newborn managed successfully with everolimus.

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by abnormal cell proliferation and tumor growth in a number of organ systems, primarily the brain, kidneys, eyes and heart. Clinical symptoms vary according to the location of the tumor. The most common disorders are seizures, neurodevelopmental disorders, renal failure and arrhythmias. TSC was found to be influenced by inhibitors of the protein kinase mammalian target of rapamycin (mTOR), which regulates abnormal cellular proliferation. mTOR inhibitors have been studied effectively in patients with subependymal giant-cell astrocytomas and renal angiolipomas in the context of TSC. We describe a prenatally diagnosed case of giant rhabdomyoma, due to right ventricular outflow tract obstruction, which presented as a duct-dependent lesion. Postnatal treatment with the mTOR inhibitor everolimus initiated significant regression of the cardiac tumor. This finding suggests that mTOR inhibitor therapy is an option for giant rhabdomyomas that develop in the neonatal period., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Tuberous sclerosis complex is characterized by the growth of benign tumors in multiple organs, caused by the disinhibition of the mammalian target of rapamycin (mTOR) protein. mTOR inhibitors, such as everolimus, are used in patients with tuberous sclerosis complex, mainly to reduce the size of renal angiomyolipomas and subependymal giant cell astrocytomas. There are minimal data available regarding its use during the neonatal period., Methods: We report clinical and pharmacological data of three neonates treated with the mTOR inhibitor everolimus (two hemodynamically significant cardiac rhabdomyomas and one voluminous subependymal giant cell astrocytoma)., Results: Beneficial clinical responses were observed in all three patients and the medication was generally well-tolerated. Optimal dose was 0.1 mg orally once daily and was confirmed with therapeutic drug monitoring., Conclusion: Everolimus is a promising pharmacological approach to treat clinically significant inoperable cardiac rhabdomyomas or subependymal giant cell astrocytoma associated with tuberous sclerosis complex during the neonatal period., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: Cardiac rhabdomyoma is the most common primary cardiac tumor, is considered to be a hamartoma of developing cardiac myocytes. Cardiac rhabdomyoma is associated with tuberous sclerosis complex (TSC) in 50-86% of cases. Mutations in TSC-1/TSC-2 genes result in increased mammalian target of rapamycin (mTOR) pathway activation responsible for the hamartomatous lesions of tuberous sclerosis complex. Therapy with mTOR inhibitors is currently under investigation as a treatment option for tumors associated with TSC. In this report we present a case with multiple symptomatic rhabdomyomas associated with tuberous sclerosis complex, deemed to be ineligible for surgical removal, treated with everolimus (mTOR inhibitor)., Conclusion: As we observed in our patient, in cases with inoperable symptomatic rhabdomyomas associated with TSC, everolimus, an mTOR inhibitor, may be the treatment of choice, which should be confirmed with additional studies., (© The Author [2014]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Rhabdomyoma (RHM) is a benign cardiac tumour usually associated with tuberous sclerosis complex (TSC). Most RHMs are asymptomatic and regress spontaneously during the first years of life. Haemodynamically significant RHMs are classically treated with surgical excision. We present a case of a premature infant, born to a mother having TSC, with a prenatal diagnosis of pulmonary valve atresia and a large ventricular septal defect. Multiple cardiac RHMs were also present, including a large tumour affecting the right ventricular filling. Owing to the prematurity and low birth weight, the infant was inoperable. In this report, we describe our approach to pharmacologically reduce the RHM size using oral everolimus in preparation for a two-ventricle surgical repair of the structural cardiac defect. We also specifically describe the dose of everolimus that was used in this case to achieve therapeutic serum levels, which was seven times lower than the conventional dose applicable for older infants., (2014 BMJ Publishing Group Ltd.)

The neonatal presentation of cardiac rhabdomyomas varies in severity from severe outflow tract obstruction to minimal cardiac dysfunction. The natural history for these lesions is spontaneous regression in the majority of cases. We describe a newborn boy with severe left ventricular outflow tract obstruction secondary to a large rhabdomyoma. The tumor infiltrated the paraaortic area and extended around the origin of the right coronary artery, making surgical resection challenging. Oral sirolimus therapy resulted in a rapid regression of the tumor and alleviation of outflow tract obstruction within 1 month of treatment. This is the first report of sirolimus therapy in alleviating critical left ventricular outflow tract obstruction in this condition., (Copyright © 2014 by the American Academy of Pediatrics.)

Primary cardiac tumors are rare in childhood. The most common of these are rhabdomyomas. Considering that rhabdomyomas often show spontaneous regression, close follow-up may be sufficient in hemodynamically stable cases. However, hemodynamically significant cardiac rhabdomyomas confer a risk of morbidity and mortality. Herein, we report a newborn infant with multifocal cardiac rhabdomyomas treated with everolimus. The optimal dose of the drug was 0.25 mg 2 times per day, 2 days per week. Patients with inoperable cardiac rhabdomyomas and with symptoms may be candidates for everolimus treatment.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder that can affect every organ of the body, most commonly the brain, kidneys, heart, and lungs. The TSC mutation results in abnormal cellular proliferation and differentiation, which are responsible for hamartomatous lesions that affect the brain, kidney, heart, and lungs. mTOR (mammalian target of rapamycin) is a protein kinase that regulates the abnormal cellular proliferation and differentiation. Consequently, mTOR inhibitors are being studied to treat the subependymal giant-cell astrocytomas and renal angiomyolipomas that are commonly seen with TSC. We describe here the case of a patient with significant regression of a cardiac rhabdomyoma after receiving everolimus, an mTOR inhibitor. This finding suggests a possible novel therapy for patients with clinically significant cardiac rhabdomyomas.

Tuberous sclerosis complex (TSC) is an inherited disorder characterized by hamartomas in different body organs, mainly in the brain, skin, kidney, liver, lung, and heart. The clinical manifestations of TSC are the result of a mutation of one of two tumor suppressor genes, TSC1 and TSC2. Cutaneous findings in TSC should be regarded as cutaneous signs of a pivotal systemic disease. The authors elucidate the variety of neoplasms seen in TSC patients, along with their clinical significance, and suggest suitable evaluation and management strategies., (© 2011 The International Society of Dermatology.)

A case of cutaneous rhabdomyomatous mesenchymal hamartoma in a 6-year-old Afro-Caribbean girl is reported with review of the literature. The lesions were fine, located on the central face and became inapparent after six months. Spontaneous regression of these lesions has not been previously reported. Although rare, continued reporting will facilitate the elucidation of the clinical features and natural history of these lesions and the relationship to disordered embryogenesis.