Maintenance therapy with everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis (the EMINENTS study).

OBJECTIVE: One of the therapeutic options for patients with tuberous sclerosis (TCS) and subependymal giant cell astrocytoma (SEGA) is everolimus treatment once daily, every day, to attain trough concentrations of 5-15 ng/ml (standard treatment). The aim of this study was to evaluate the efficacy and safety of a reduced dose of everolimus (three times a week with a daily dose as in standard treatment-maintenance therapy) in a group of patients who were previously treated with standard dose for at least 12 months. MATERIALS AND METHODS: Ten patients (six males, four females; median age 14.23 years) with TSC-related SEGA who met inclusion criteria were included into a single-arm, prospective trial. All the patients were followed over at least 12 months (median 12 and range 12-24 months). Tumor volumes from day 0, 90, 180, and 360 were evaluated by an experienced radiologist and an objective computer-based method and compared. Adverse events (AEs) noted during maintenance therapy were compared to the AEs observed during standard everolimus therapy. RESULTS: The differences in SEGA volume between subsequent time points (day 0, 90, 120, and 360) were not statistically significant. No clinical symptoms of tumor regrowth were observed. AEs were significantly less severe and less frequent during maintenance compared with standard therapy. CONCLUSIONS: Maintenance therapy with reduced-dose everolimus is an effective therapeutic option for patients with TSC and SEGA after the completion of standard therapy and may moderate the rates of adverse effects.

What are the true volumes of SEGA tumors? Reliability of planimetric and popular semi-automated image segmentation methods.

OBJECTIVE: To evaluate the reliability of the standard planimetric methodology of volumetric analysis and three different open-source semi-automated approaches of brain tumor segmentation. MATERIALS AND METHODS: The volumes of subependymal giant cell astrocytomas (SEGA) examined by 30 MRI studies of 10 patients from a previous everolimus-related trial (EMINENTS study) were estimated using four methods: planimetric method (modified MacDonald ellipsoid method), ITK-Snap (pixel clustering, geodesic active contours, region competition methods), 3D Slicer (level-set thresholding), and NIRFast (k-means clustering, Markov random fields). The methods were compared, and a trial simulation was performed to determine how the choice of approach could influence the final decision about progression or response. RESULTS: Intraclass correlation coefficient was high (0.95; 95% CI 0.91-0.98). The planimetric method always overestimated the size of the tumor, while virtually no mean difference was found between ITK-Snap and 3D Slicer (P = 0.99). NIRFast underestimated the volume and presented a proportional bias. During the trial simulation, a moderate level of agreement between all the methods (kappa 0.57-0.71, P < 0.002) was noted. CONCLUSION: Semi-automated segmentation can ease oncological follow-up but the moderate level of agreement between segmentation methods suggests that the reference standard volumetric method for SEGA tumors should be revised and chosen carefully, as the selection of volumetry tool may influence the conclusion about tumor progression or response.

Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening.

The aim of this study was to evaluate the most common adverse events (AEs) linked to everolimus therapy, a mammalian target of rapamycin (mTOR) inhibitor, in children and adolescents with tuberous sclerosis complex (TSC) hospitalized in one medical center. The study group included 18 patients with a diagnosis of subependymal giant cell astrocytoma or renal angiomyolipoma related to TSC. The median duration of therapy was 15 months. All clinical symptoms and laboratory abnormalities including complete blood count, fasting lipid profile, glucose level, and liver and kidney function tests were analyzed as potential AEs. The most common AEs of everolimus therapy were laboratory abnormalities (100% of patients) and infection complications (83 episodes in 15 patients). Infectious episodes of pharyngitis (67%), diarrhea (44%), stomatitis (39%), and bronchitis (39%) were the most common infections. They were mostly mild or moderate in severity (grade 1-2). In two cases, life-threatening conditions related to mTOR inhibitor treatment were encountered. The first was classified as grade 4 pleuropneumonia and Streptococcus pneumoniae sepsis, whereas the second was classified as death related to AE (grade 5) Escherichia coli sepsis. The most common laboratory abnormalities were hypercholesterolemia (13/18 patients - 72%) and hypertriglyceridemia (12/18 patients - 66%). Neutropenia (12/18 patents - 66%) and anemia (8/18 patients - 44%) were the most common hematologic toxicities. Everolimus treatment in TSC patients may lead to life-threatening outcomes, including sepsis and death. Long-lasting effects of everolimus treatment in the context of high incidences of different laboratory abnormalities found in TSC patients are another subject that should be researched further.

Factors affecting response to everolimus therapy for subependymal giant cell astrocytomas associated with tuberous sclerosis.

BACKGROUND: The aim of the study was to investigate factors affecting response to everolimus, a mammalian-target-of-rapamycin (mTOR) inhibitor, of subependymal giant cell astrocytomas (SEGA) in patients with tuberous sclerosis complex (TSC). METHODS: The study group consisted of 15 children with a diagnosis of TSC-related SEGA. Median therapy duration was 13 months. Age, sex, previous neurosurgical or mTOR inhibitor treatment, everolimus blood concentration and anticonvulsant therapy were analyzed as potential factors affecting reduction of SEGA tumor volume. RESULTS: Significant reductions in SEGA volumes were noted at 3 and 6 months (median tumor volume 0.97 cm(3) and 0.70 cm(3) , respectively, versus 2.70 cm(3) at baseline, P = 0.001). Responses were observed in 11/15 (73.3%) and 10/12 (83.3%) patients at 3 and 6 months, respectively. The most rapid reduction of SEGA volume (58.6%) was found during the initial 3 months of treatment. There was no statistical difference in the extent of SEGA volume reduction between patients with everolimus trough levels <5 ng/ml and ≥5 ng/ml. Patients treated with ≤1 anticonvulsant had greater tumor reduction after 6 months of treatment. CONCLUSIONS: Everolimus is an effective and safe treatment option for TSC-related SEGA. Drug dose titration according to blood concentration did not appear to be crucial to achieve clinical efficacy; however, concomitant anticonvulsant therapy may affect response to mTOR inhibitors.

Physical workload and glycemia changes during football matches in adolescents with type 1 diabetes can be comparable.

AIMS: To analyze physical performance and diabetes-related outcomes in adolescents with type 1 diabetes (T1DM) during two semi-competitive football matches utilising precise physical activity monitoring. METHODS: The study was conducted during an annual summer camp for adolescents with T1DM. After physical examination and glycated hemoglobin measurement, 16 adolescent players completed Cooper's 12-min running test and, in the following days, took part in two football matches while wearing heart rate (HR) monitors coupled with global positioning system (GPS) tracking. RESULTS: Both matches were comparable in terms of covered distances, number of sprints, achieved velocities and heart rate responses. During both games, capillary blood lactate increased significantly (Match 1: 1.75 ± 0.16-6.13 ± 1.73 mmol/l; Match 2: 1.77 ± 0.18-3.91 ± 0.63 mmol/l, p = 0.004). No significant differences in blood glucose were observed between the matches (p = 0.83) or over each match (p = 0.78). Clinically significant hypoglycemia (< 54 mg/dl) occurred in two children during the first match. None of the players experienced severe hypoglycemia. Despite similar workloads, players consumed significantly less carbohydrates during Match 2 [median difference: - 20 g (25-75%: - 40 to 0), p = 0.006]. CONCLUSIONS: HR monitoring and GPS-based tracking can effectively parameterize physical activity during a football match. In T1DM patients, exercise workload and glycemic changes during similar matches are comparable, which provides an opportunity to develop individual recommendations for players with T1DM.

Everolimus treatment among patients with tuberous sclerosis affects serum lipid profile.

BACKGROUND: The purpose of the study was to evaluate lipid homeostasis before and after treatment of everolimus, the mammalian target of the rapamycin (mTOR) inhibitor, among patients with tuberous sclerosis complex (TSC). METHODS: The study group consisted of 15 patients with a diagnosis of subependymal giant cell astrocytoma (SEGA) related to TSC. The following lipid parameters were determined: total serum cholesterol (TCh), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), total serum triglyceride (TG) concentration at baseline, then after three and 12 months of observation. The values were compared with those of age-matched healthy controls. RESULTS: In the study group TCh, LDL and HDL levels at baseline were significantly higher than in the control group. TCh and LDL levels were positively correlated with baseline SDS-BMI in TSC patients. Everolimus treatment resulted in significant increases of TCh (from 192.04±40.51mg/dl to 210.74±51.12mg/dl and to 216.69±45.43mg/dl; p=0.0273) and LDL (from 113.21±38.72mg/dl to 133.88±50.71mg/dl and to 141.58±40.67mg/dl; p=0.0006) after three and 12 months respectively. The differences between the TCh and LDL levels at baseline and after 12 months of therapy were negatively correlated with baseline SDS-BMI. The observed increase of BMI after 12 months was correlated with increases in TCh and LDL levels. CONCLUSIONS: Patients with TSC have disrupted lipid homeostasis before and during treatment with everolimus, which might be partially connected to the mTOR-dependent nutritional status of the patients. There is a need to develop strategies for children with TSC treated with everolimus, who experience hyperlipidemia.

Abnormal serum microRNA profiles in tuberous sclerosis are normalized during treatment with everolimus: possible clinical implications.

BACKGROUND: Tuberous sclerosis (TSC) is a monogenic disease resulting from defects of the TSC1 or TSC2 genes, which encode the proteins forming hamartin-tuberin tumor suppressor complex, the mammalian target of rapamycin complex (mTOR). The mTOR pathway is constitutively activated in response to tuberin or hamartin defects. The mTOR pathway is also regulated by a multitude of epigenetic mechanisms, one of which is regulation by microRNA (miRNA) inhibition. This leads us to hypothesize that organ-level abnormalities of miRNA expression patterns are widespread in TSC. The aim of the study was to evaluate the serum profiles of miRNAs in patients with TSC and subependymal giant cell astrocytoma (SEGA) treated with mTOR inhibitor (everolimus). METHODS: Serum microRNA profiling was performed in 10 TSC-patients before and three months after everolimus treatment, as well as in 10 sex- and age-matched healthy controls. MicroRNAs were profiled using qPCR panels (Exiqon). RESULTS: Of 752 tested miRNAs, 11 showed statistically significant dysregulation in patients with TSC in comparison to controls. The following miRNAs were downregulated in TSC: miR-142-3p, miR-199a-5p, miR-142-5p and miR-136-5p; while miR-130a-3p, miR-378a-3p, miR-130b-3p, miR-192-5p, miR-25-3p, miR-215-5p and miR-222-3p were upregulated in TSC in comparison to the control group. After three months of everolimus treatment, mean dose 5.1 (2.6-9.7) mg/m2, seven miRNAs reached expression levels similar to healthy controls, with miR-142-3p and miR-136 showed significant increase over baseline levels in TSC patients. Moreover, miR-222-3p normalization due to treatment differed between patients with mutation in TSC1 and TSC2 gene. CONCLUSIONS: Activation of the mTOR pathway in TSC patients alters serum miRNA levels, which may be partially reversed by an mTOR inhibitor. This indicates the involvement of miRNA dysregulation in the pathogenesis of TSC, linking miRNA profiles with treatment efficiency.