Everolimus: A Challenging Drug in the Treatment of Multifocal Inoperable Cardiac Rhabdomyoma

Demir, Hacı Ahmet; Ekici, Filiz; Erdem, Arzu Yazal; Emir, Suna; Tunç, Bahattin

doi:10.1542/peds.2011-3476

Cited by 68 publications

(81 citation statements)

References 20 publications

(33 reference statements)

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“…6,7 The rapidity of regression of the tumor within a month of treatment points to the direct effects of the mTOR inhibitor rather than a natural history of regression in this case. There was a slight rebound increase in size of the left ventricular outflow tract tumor after discontinuation of treatment, which has been reported previously.…”

Section: Discussionmentioning

confidence: 92%

“…Although there are 2 previous reports of everolimus therapy in this setting, the application of sirolimus in the setting of severe neonatal left ventricular outflow tract obstruction with the lesion extending into the region of the right coronary artery has not been previously reported. 6,7 We elected to use sirolimus because it was available in liquid form, unlike everolimus, and as an mTOR inhibitor and antiproliferative agent it has been used in treating hemangiomas in PHACE syndrome. 8 An initial dosage of 0.5 mg once daily was chosen because it was believed to deliver therapeutic levels that would avoid toxicity and was hoped to demonstrate an antiproliferative effect on the rhabdomyoma, as in a previous report on its use in treatment of hemangiomas.…”

Section: Discussionmentioning

confidence: 99%

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Rapid Regression of Left Ventricular Outflow Tract Rhabdomyoma After Sirolimus Therapy

Breathnach¹,

Pears²,

Franklin³

et al. 2014

Pediatrics

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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.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Rapid Regression of Left Ventricular Outflow Tract Rhabdomyoma After Sirolimus Therapy

Breathnach¹,

Pears²,

Franklin³

et al. 2014

Pediatrics

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“…Cardiac rhabdomyomas generally regress in the first six years. Cardiac rhabdomyomas can be treated with medication and rarely surgery, if they lead to hemodynamic impairment (19). In recent years, a significant increase in treatment response has been observed with mTor inhibtor drugs.…”

Section: Discussionmentioning

confidence: 99%

Assessment of tumors in children with tuberous sclerosis: a single centre’s experience

et al. 2017

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Aim: As a result of mutations in TSC1 (9q34) and TSC2 (16p13.3) tumor supressor genes, the mammalian target of the rapamycin (mTor) signaling pathway is overactivated in patients with tuberous sclerosis. Abnormal cell proliferation and differentiation is responsible for the growth several different tumors. The aim of this study was to review tumors in our patients with tuberous sclerosis. Material and Methods: Thirty-six patients with tuberous sclerosis were reviewed retrospectively in terms of age, sex, family history, clinical findings, presence of tumors, and treatments. Results: Our study included 36 patients (18/18:M/F) aged between two days and 17 years with a median age of 6 years. There were hypopigmented spots in 30 patients, seizures in 28 patients, and a family history in 11 patients. Tumors related to tuberous sclerosis were renal angiomyolipomas in 21 patients, cardiac rhabdomyomas in 11, subependymal giant cell astrocytomas in seven, and non renal hamartoma in one patient. Everolimus treatment was used in only two patients because of hemodynamic instability. Conclusions: Tuberous sclerosis is a multisystemic disease characterized by the presence of various benign tumors and neurologic disorders. Renal angiomyolipomas, cardiac rhabdomyomas, and subependymal giant cell astrocytomas are commonly observed in patients with tuberous sclerosis. mTOR inhibitors such as everolimus and sirolimus have been increasingly used in the treatment of these tumors. However, the duration and optimal dose of mTOR inhibitors is still controversial and should be used in selected cases. (Turk Pediatri Ars 2017; 52: 30-4)

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“…6 mTORC1 inhibitors also have been reported to be effective for treatment of topical angiofibromas and cardiac rhabdomyomas in TSC. 7,8 Preclinical studies in TSC mouse models demonstrate that mTORC1 inhibitors effectively prevent seizures.…”

Section: Introductionmentioning

confidence: 99%

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

et al. 2016

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Objective: To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC).Methods: Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a $50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life.Results: Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported $50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months.Conclusions: Improved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC. More than 80% of individuals with tuberous sclerosis complex (TSC) develop epilepsy, usually within the first year of life.1 Epilepsy in an estimated third of these individuals is refractory to conventional anticonvulsant medications, 2 heightening the urgency for development of effective treatments. TSC1 and TSC2, the causative genes for TSC, regulate the protein kinase mammalian target of rapamycin complex 1 (mTORC1). Pharmacologic inhibitors of mTORC1 are now approved to treat multiple clinical aspects of TSC, including subependymal giant cell astrocytomas (SEGA), 3,4 renal angiomyolipomas, 5 and pulmonary lymphangioleiomyomatosis. 6 mTORC1 inhibitors also have been reported to be effective for treatment of topical angiofibromas and cardiac rhabdomyomas in TSC. 7,8 Preclinical studies in TSC mouse models demonstrate that mTORC1 inhibitors effectively prevent seizures.9,10 TSC patients in early (open-label) clinical trials to treat SEGA with everolimus reported reduced frequency of daily seizures and increased rates of seizure freedom, 4,[11][12][13] but seizure benefit could not be demonstrated in more recent (placebo-controlled, randomized) From the Departments of Pediatrics and Neurology

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Everolimus: A Challenging Drug in the Treatment of Multifocal Inoperable Cardiac Rhabdomyoma

Cited by 68 publications

References 20 publications

Rapid Regression of Left Ventricular Outflow Tract Rhabdomyoma After Sirolimus Therapy

Rapid Regression of Left Ventricular Outflow Tract Rhabdomyoma After Sirolimus Therapy

Assessment of tumors in children with tuberous sclerosis: a single centre’s experience

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

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