Measuring the impact of community-based interventions on type 2 diabetes control during the COVID-19 pandemic in Cape Town - A mixed methods study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic exposed the risks of poorly controlled noncommunicable diseases, especially in persons with diabetes. The pandemic outbreak in Cape Town, South Africa, required a rapid reorganisation of primary care services. Community-based measures were activated to ensure continuity of care by implementing home delivery of medication by community health workers. After five months of de-escalated chronic care, observations at an urban primary care facility suggested that noncommunicable disease patients had not overtly decompensated despite suspending regular in-facility services. This study attempted to understand what impact de-escalation of regular care and escalation of community-based interventions had on type 2 diabetes patients at this primary care facility. METHODS: A mixed methods study design was used, consisting of data captured prospectively from diabetic patients who returned to the facility for routine care post-lockdown, as well as qualitative interviews to ascertain patients' experiences of the home delivery service. RESULTS: The data set included 331 (72%) patients in the home delivery group and 130 (28%) in the non-home delivery group. Regression analysis demonstrated a statistically significant relationship between home delivery and improved diabetic control (p  0.01), although this may be because of confounding factors. The mean glycaemic control was suboptimal both at baseline and post-lockdown in both groups. Interviews with 83 study patients confirmed the acceptability of the home delivery intervention. CONCLUSION: The rapid reorganisation of primary care services illustrates the versatility of a functional community-oriented primary care service, although not fully developed yet, to adapt to emerging community healthcare needs in the pandemic era.

Krüppel-like Factor 4 Supports the Expansion of Leukemia Stem Cells in MLL-AF9-driven Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow with 5-year overall survival of less than 10% in patients over the age of 65. Limited progress has been made in the patient outcome because of the inability to selectively eradicate the leukemic stem cells (LSC) driving the refractory and relapsed disease. Herein, we investigated the role of the reprogramming factor KLF4 in AML because of its critical role in the self-renewal and stemness of embryonic and cancer stem cells. Using a conditional Cre-lox Klf4 deletion system and the MLL-AF9 retroviral mouse model, we demonstrated that loss-of-KLF4 does not significantly affect the induction of leukemia but markedly decreased the frequency of LSCs evaluated in limiting-dose transplantation studies. Loss of KLF4 in leukemic granulocyte-macrophage progenitors (L-GMP), a population enriched for AML LSCs, showed lessened clonogenicity and percentage in the G2/M phase of the cell cycle. RNAseq analysis of purified L-GMPs revealed decreased expression of stemness genes and MLL-target genes and upregulation of the RNA sensing helicase DDX58. However, silencing of DDX58 in KLF4 knockout leukemia indicated that DDX58 is not mediating this phenotype. CRISPR/Cas9 deletion of KLF4 in MOLM13 cell line and AML patient-derived xenograft cells showed impaired expansion in vitro and in vivo associated with a defective G2/M checkpoint. Collectively, our data suggest a mechanism in which KLF4 promotes leukemia progression by establishing a gene expression profile in AML LSCs supporting cell division and stemness.

Corrigendum: Community-based screening and testing for Coronavirus in Cape Town, South Africa: Short report.

No abstract available.

Prenatal Sirolimus Treatment for Rhabdomyomas in Tuberous Sclerosis.

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/m2/day, preferably 3-3.5 mg/m2/day to achieve a target trough level of 10-12 ng/mL.

Telemedicine in the Western Cape Department of Health during the first peak of the COVID-19 pandemic: Leveraging data to save lives by activating a telemedicine response.

The pandemic caused by coronavirus disease 2019 (COVID-19) has put health systems across the globe under strain. There has been much suffering and loss, but a silver lining is emerging - a growing list of deeply contextualised, resource-light and patient-centric innovations that are showing the promise of reshaping health care delivery as we know it. Some of these innovations were lying latent in the system, waiting for the 'dots to be joined'. The Western Cape was the first province in South Africa to experience a COVID-19 wave from May 2020 to July 2020, with 60-70 deaths being reported daily. To bend the mortality curve during this crisis was not easy but was made possible using a rudimentary telehealth system. This project represents an exemplar of innovation, built out of necessity to save lives and may well become a staple component of the health service in a post-crisis era.

Frequency, Progression, and Current Management: Report of 16 New Cases of Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex and Comparison With Previous Reports.

Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC. Methods: This retrospective chart review was performed by a query of the TS Alliance's Natural History Database and the Cincinnati Children's Hospital TSC Database for patients with nonfunctional PNET. Clinical data from these two groups was summarized for patients identified to have a nonfunctional PNET and compared to previously reported cases with TSC and nonfunctional PNETs. Results: Our calculated frequency of nonfunctional PNETs is 0.65%. We identified 16 individuals, nine males and seven females, with a median age of 18.0 years (interquartile range: -15.5 to 25.5). Just over half (56.3%, n = 9) of the patients provided results from genetic testing. Six had pathogenic variants in TSC2 whereas three had pathogenic variants in TSC1. The average age at PNET diagnosis was 15.0 years (range: 3-46 years). Almost all individuals were diagnosed with a PNET during routine TSC surveillance, 56.3% (n = 9) by MRI, 12.5% (n = 2) by CT, 25% (n = 4) by ultrasound, and 6.2% (n = 1) through a surgical procedure. Follow up after diagnosis involved 68.8% (n = 11) having serial imaging and nine of the sixteen individuals proceeding with surgical removal of the PNET. Eight individuals had a history of using systemic mTOR inhibitors. Tumor growth rate was slightly less in individuals taking an mTOR inhibitor (-0.8 mm/yr, IQR: -2.3 to 2.2) than those without (1.6 mm/yr; IQR: -0.99 to 5.01, p > 0.05). Conclusions: Nonfunctional PNETs occurred at younger ages in our TSC cohort and more commonly compared to ages and prevalence reported for the general population. PNETs in patients on systemic mTOR inhibitors had lower rates of growth. The outcome of this study provides preliminary evidence supporting the use of mTOR inhibitor therapy in conjunction with serial imaging as medical management for nonfunctional PNETs as an alternative option to invasive surgical removal.

Community-based screening and testing for Coronavirus in Cape Town, South Africa: Short report.

Corona Virus Infectious Disease 2019 (COVID-19) was first reported in Cape Town in March 2020 and the transmission was soon observed in local communities. Cape Town has many vulnerable communities because of poverty, overcrowding and comorbidities, although it has a relatively small elderly population. Amongst the unique and early responses to the pandemic in South Africa has been the strategy of community screening and testing (CST). This process has been drawn from health department's prior adoption of a community-orientated primary care (COPC) approach, which relies on teams of community health workers working in delineated communities to prevent disease and provide early interventions for those at higher risk. The COPC principles were applied in the CST programme, which involved collaboration between facility and community-based teams, linking public health and primary care approaches, careful mapping of cases in highly vulnerable communities, targeted screening around cases, testing of those that screened positive, health education and linkage to primary care. The overall aim was to slow down transmission through early identification and isolation of diagnosed cases. Key challenges involved the designing of a screening tool with appropriate sensitivity and specificity as well as the logistics of staffing, transport, consumables, data collection and capture, security, ablutions and personal protective equipment. Key opportunities included synergies between CST and evolving commitment to COPC in the health system. Key threats were the deteriorating security situation in the most vulnerable communities because of loss of income, food insecurity and CST distrust as well as increasing turn-around-times for test results.

Pharmacological treatment strategies for subependymal giant cell astrocytoma (SEGA).

INTRODUCTION: Subependymal ependymal giant cell astrocytomas (SEGAs) occur almost exclusively in the setting of tuberous sclerosis (TSC). They are low-grade gliomas which typically produce clinical symptoms through either mass effect or hydrocephalus. As do other manifestations of tuberous sclerosis, these lesions result from mutations in either the TSC1 or the TSC2 gene. These mutations cause hyperactivation of the mechanistic target of rapamycin (mTOR). In view of their tendency to grow slowly, clinical symptoms usually only occur when the tumors reach a considerable size. Therapy can involve surgical resection, cerebrospinal fluid diversion, or medical therapy with an mTOR inhibitor. AREAS COVERED: Herein, the authors discuss the diagnosis, symptoms, and practical management of SEGAs as well as providing their expert opinion. EXPERT OPINION: mTOR inhibitors have largely replaced surgery as the primary modality for the management of SEGAs. Surgical treatment is largely limited to tumors that present with acute hydrocephalus and increased intracranial pressure. Patients with TSC should undergo periodic screening with CT or preferably MRI scans of the brain from childhood to approximately age 25 to identify SEGAs which require treatment. In addition to avoiding potential morbidity associated with surgical resection, mTOR inhibitors have the potential to improve the clinical status of tuberous sclerosis patients generally.

A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC).

OBJECTIVE: This review will summarize current knowledge on the burden of illness (BOI) in tuberous sclerosis complex (TSC), a multisystem genetic disorder manifesting with hamartomas throughout the body, including mainly the kidneys, brain, skin, eyes, heart, and lungs. METHODS: We performed a systematic analysis of the available literature on BOI in TSC according to the PRISMA guidelines. All studies irrespective of participant age that reported on individual and societal measures of disease burden (e.g. health care resource use, costs, quality of life) were included. RESULTS: We identified 33 studies reporting BOI in TSC patients. Most studies (21) reported health care resource use, while 14 studies reported quality of life and 10 studies mentioned costs associated with TSC. Only eight research papers reported caregiver BOI. Substantial BOI occurs from most manifestations of the disorder, particularly from pharmacoresistant epilepsy, neuropsychiatric, renal and skin manifestations. While less frequent, pulmonary complications also lead to a high individual BOI. The range for the mean annual direct costs varied widely between 424 and 98,008 International Dollar purchasing power parities (PPP-$). Brain surgery, end-stage renal disease with dialysis, and pulmonary complications all incur particularly high costs. There is a dearth of information regarding indirect costs in TSC. Mortality overall is increased compared to general population; and most TSC related deaths occur as a result of complications from seizures as well as renal complications. Long term studies report mortality between 4.8 and 8.3% for a follow-up of 8 to 17.4 years. CONCLUSIONS: TSC patients and their caregivers have a high burden of illness, and TSC patients incur high costs in health care systems. At the same time, the provision of inadequate treatment that does not adhere to published guidelines is common and centralized TSC care is received by no more than half of individuals who need it, especially adults. Further studies focusing on the cost effectiveness and BOI outcomes of coordinated TSC care as well as of new treatment options such as mTOR inhibitors are necessary.

Cannabidiol Elevates Mechanistic Target of Rapamycin Inhibitor Levels in Patients With Tuberous Sclerosis Complex.

BACKGROUND: The mechanistic target of rapamycin inhibitors everolimus and sirolimus have activity against multiple manifestations of tuberous sclerosis complex and are approved to treat astrocytomas, angiomyolipomas, lymphangioleiomyomatosis, and epilepsy. Cannabidiol is a novel antiepileptic medication. There is lack of information regarding drug-drug interactions between mechanistic target of rapamycin inhibitors and cannabidiol in clinical practice. METHODS: We reviewed patients with tuberous sclerosis complex who were treated with a mechanistic target of rapamycin inhibitor (everolimus, sirolimus) and cannabidiol. Clinical information, mechanistic target of rapamycin inhibitor and cannabidiol dosing, concomitant antiepileptic drugs, as well as laboratory and adverse events were reviewed before and after initiation of cannabidiol. RESULTS: A total of 25 patients were treated with cannabidiol and a mechanistic target of rapamycin inhibitor (18 everolimus, seven sirolimus). All mechanistic target of rapamycin inhibitor levels were drawn as troughs. Levels were significantly higher in 76% patients after cannabidiol treatment (P = 0.0003). Median change from baseline was +9.8 ng/mL for everolimus and +5.1 ng/mL for sirolimus. Adverse events occurred in 40%, with diarrhea being the most frequent adverse event occurring in three patients. No severe adverse events occurred during the treatment period. CONCLUSIONS: Cannabidiol resulted in increased serum levels of everolimus and/or sirolimus. Some patients experienced doubling or tripling of their mechanistic target of rapamycin inhibitor trough following the addition of cannabidiol. In some cases, this resulted in clinical toxicity, as well as laboratory abnormalities. Awareness of this interaction can lead clinicians to evaluate serum levels and other safety laboratory studies more closely, and thereby avoid potentially significant adverse effects. In patients known to be prone to mechanistic target of rapamycin inhibitor toxicity, preemptive reduction in dose may be warranted upon initiation of cannabidiol.

Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures.

Introduction: Tuberous sclerosis complex (TSC) is a rare genetic disorder resulting in benign tumors in various organs. It is caused by mutations in TSC1 or TSC2 genes causing hyperactivation of the mammalian target of rapamycin (mTOR) pathway. The majority of patients with TSC develop epilepsy, and approximately two-thirds become refractory to antiepileptic drugs (AEDs). Recently, the mTOR inhibitor everolimus was approved as adjunctive therapy for TSC-associated partial seizures. Areas covered: This article covers different characteristics of everolimus, including major clinical trials leading to its approval in TSC-associated partial seizures, safety concerns, drug pharmacokinetics/pharmacodynamics, and an overview of potential competitors and other agents used to treat TSC-associated seizures. Expert opinion: Unlike many other therapies for treating TSC-associated seizures, everolimus addresses the underlying pathophysiology of TSC, and since it has also been shown to improve other TSC manifestations such as subependymal giant cell astrocytomas and renal angiomyolipomas, everolimus provides a potential multisystemic therapy for TSC. An important avenue for future research is exploring the possible use of everolimus as a preventative treatment for seizures as there is the potential to prevent negative developmental outcomes associated with TSC.

Longitudinal Effects of Everolimus on White Matter Diffusion in Tuberous Sclerosis Complex.

OBJECTIVE: We studied the longitudinal effects of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), on callosal white matter diffusion tensor imaging (DTI) in patients with tuberous sclerosis complex (TSC). METHODS: Serial imaging data spanning nine years were used from the open label, Phase I/II trial (NCT00411619) and open-ended extension phase of everolimus for the treatment of subependymal giant cell astrocytoma associated with TSC. From 28 patients treated with everolimus and 25 untreated control patients, 481 MRI scans were available. Rigorous quality control resulted in omission of all scans with diffusion weighted imaging data in less than 15 directions or more than eight artifacted volumes, and all postsurgical scans. We applied a linear mixed-effects model to the remaining 125 scans (17 treated, 24 controls) for longitudinal analysis of each DTI metric of manually drawn callosal regions of interest. RESULTS: On a population level, mTOR inhibition was associated with a decrease in mean diffusivity. In addition, in treated patients only, a decrease of radial diffusivity was observed; in untreated patients only, an increase of axial diffusivity was seen. In patients below age 10, effect-sizes were consistently greater, and longer treatment was associated with greater rate of diffusion change. There was no correlation between DTI metrics and reduction of subependymal giant cell astrocytoma volume, or everolimus serum levels. CONCLUSIONS: Effects from mTOR overactivity on white matter microstructural integrity in TSC were modified through pharmacologic inhibition of mTOR. These changes sustained over time, were greater with longer treatment and in younger patients during a time of rapid white matter maturation.

mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex.

Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed.

Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience.

OBJECTIVE: To evaluate the safety of mTOR inhibitors (sirolimus or everolimus) in infants and very young children with tuberous sclerosis complex (TSC) under two years of age. METHODS: Study design was retrospective to capture medical record data from 52 international TSC Centres who initiated treatment with sirolimus or everolimus in TSC children before the age of two years. Data collection included demographic and clinical information including reason(s) for initiating treatment with mTOR inhibitors, treatment duration, dosing, and corresponding serum trough levels, response to treatment, and adverse events (AE). RESULTS: 19 of 52 (37%) TSC Centres reported treatment of at least one child with TSC under the age of two years with everolimus or sirolimus. Treatment-related data were provided for 45 patients meeting inclusion criteria. Everolimus was utilised 87% of the time, compared to 24% for sirolimus (5 subjects, 11%, were treated separately with both). Refractory epilepsy (45%) was the most common primary reason for initiating treatment and treatment was initiated on average at 11.6 ± 7.6 months of age. At least one AE, suspected or definitely treatment-related, occurred in 35 of 45 (78%) treated subjects. Most AEs were mild (Grade 1) or moderate (Grade 2) in severity and most commonly related to infections. Severe AE (Grade 3) was reported in 7 subjects (20%) and no life-threatening AE (Grade 4) or death/disability (Grade 5) was reported. Treatment was discontinued due to an AE in 9 of 45 (20%). CONCLUSIONS: Everolimus, and to a lesser extent sirolimus, are increasingly being used to treat TSC infants and very young children for multiple TSC-associated clinical indications. While AEs were common, most were not severe and did not prevent continued treatment in the majority of this younger population.

Calcification in cerebral parenchyma affects pharmacoresistant epilepsy in tuberous sclerosis.

PURPOSE: Tuberous sclerosis (TSC) is an autosomal dominant inherited disease caused by mutations in the TSC1 or TSC2 gene and results in the over-activation of the mammalian target of the rapamycin (mTOR) signaling pathway. Rapamycin, an mTOR inhibitor, is clinically used to treat hamartomatous lesionsas in TSC and its effect on controlling epilepsy is also reported in many studies. This study aims to evaluate the risk factors of pharmacoresistant epilepsy in patients with TSC receiving long-term rapamycin treatment. METHOD: A total of 108 patients with TSC taking rapamycin for over 1 year were enrolled in this study. Factors that might influence seizure control were statistically analyzed by multiple factor analysis. A subgroup analysis was also conducted to access the relationship between calcified epileptic foci and pharmacoresistant epilepsy. (Clinical trial registration number: ChiCTR-OOB-15006535(2015-05-29)). RESULTS: Seizure was controlled in 53 patients but was not managed in 55 patients considered to be drug resistant. Logistic regression analysis showed that calcification in the cerebral parenchyma was a risk factor of pharmacoresistant epilepsy [P = 0.006, odds ratio (OR) = 4.831 (1.577, 14.795)]. Fifteen of 17 patients with calcified epileptic foci suffered from pharmacoresistant epilepsy (88.2%). Seizures in patients with calcified epileptic foci were probably pharmacoresistant (P = 0.010). CONCLUSION: Calcification in epileptic foci strongly indicates pharmacoresistant epilepsy in patients with TSC even when treated with appropriate anti-epilepsy drugs (AEDs) and rapamycin. Calcification can be used to evaluate pharmacoresistant epilepsy in patients with TSC.

Long-term treatment of epilepsy with everolimus in tuberous sclerosis.

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. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with TSC with medically refractory epilepsy everolimus improves seizure control.

Profile of everolimus in the treatment of tuberous sclerosis complex: an evidence-based review of its place in therapy.

Tuberous sclerosis complex (TSC) is a relatively rare genetic disorder, affecting one in 6,000 births. Mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, which have been previously used to prevent solid organ transplant rejection, augment anticancer treatment regimens, and prevent neovascularization of artificial cardiac stents, are now approved for treating TSC-related manifestations, such as subependymal giant cell astrocytomas and renal angiomyolipomas. The use of everolimus in treating subependymal giant cell astrocytomas is supported by long-term Phase II and III clinical trials. Seizures are a common feature in TSC, occurring in up to 96% of patients. While mTOR inhibitors currently do not have regulatory approval in treating this manifestation, small clinical studies have demonstrated beneficial outcomes with everolimus. Further evidence from a forthcoming Phase III clinical study may provide additional support for the use of everolimus for this indication. Also, there are no approved treatments for TSC-associated neuropsychiatric disorders, which include intellectual disability, behavioral difficulties, and autism spectrum disorder, but preclinical data and small studies have suggested that some neuropsychiatric symptoms may be improved through mTOR inhibition therapy. More evidence is needed, particularly regarding safety in young infants. This review focuses on the current evidence supporting the use of everolimus in neurologic and neuropsychiatric manifestations of TSC, and the place of everolimus in therapy.

Safety of Everolimus in Patients Younger than 3 Years of Age: Results from EXIST-1, a Randomized, Controlled Clinical Trial.

OBJECTIVES: To assess the long-term safety of everolimus in young children with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA). STUDY DESIGN: EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (EXIST-1) was a multicenter, randomized, double-blind phase 3 study with an open-label extension evaluating the efficacy and tolerability of everolimus in patients with TSC-associated SEGA. Everolimus was initiated at 4.5 mg/m(2)/day and titrated to blood trough levels of 5-15 ng/mL. Post hoc analysis of safety data (adverse events [AEs]) was performed in a subgroup of patients aged <3 years at everolimus initiation. RESULTS: Eighteen patients (median age 1.82 years) were included; 16 were still receiving everolimus at the analysis cut-off date of January 11, 2013. Median everolimus exposure was 31.1 months (range, 11.5-39 months). One patient discontinued treatment because of AEs (ie, Acinetobacter bacteremia, increased blood alkaline phosphatase, and viral infection). AEs were reported in all patients, but events were mostly grade 1/2 in severity; 12 patients (66.7%) experienced grade 3 events, and 2 patients (11.1%) reported grade 4 events. The most common AEs were stomatitis, cough, pharyngitis, and pyrexia; no new safety issues were identified in this population. Serious AEs were reported in 50% of patients; these were suspected to be medication related in 4 patients (22.2%). CONCLUSIONS: Everolimus appears to be a safe therapeutic option for patients aged <3 years with TSC-associated SEGA. The small sample size in this subpopulation limits interpretation of the results; additional studies in the pediatric population are needed and are underway. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00789828.