Pediatr Nephrol (2015) 30:173–177 DOI 10.1007/s00467-014-2949-6
BRIEF REPORT
The effects of everolimus on tuberous sclerosis-associated lesions can be dramatic but may be impermanent Joseph M. Miller & Ashley Wachsman & Katherine Haker & Fataneh Majlessipour & Moise Danielpour & Dechu Puliyanda
Received: 5 June 2014 / Revised: 29 July 2014 / Accepted: 20 August 2014 / Published online: 7 September 2014 # IPNA 2014
Abstract Background Tuberous sclerosis complex (TSC) predisposes to the development of benign lesions within multiple organ systems, including the brain, kidneys, heart, lungs, and skin. Disease mortality is due to space-occupying subependymal giant cell astrocytomas and hemorrhage-prone renal angiomyolipomas. The recent use of mTORC1 inhibitors, such as everolimus, has allowed for direct targeting of TSCassociated mass lesions without apparent effect on surrounding tissues. Because of the mechanism of these drugs, there is reason to believe that these effects are not durable and that there may be need for continued long-term maintenance therapy. Case-diagnosis/treatment We present a case of TSCassociated mass lesions that were ill-suited for definitive surgical therapy. The patient was started on everolimus, however due to a complex social situation treatment was discontinued and ultimately resumed many months later. Radiologic studies acquired before and after each period of therapeutic onset/ cessation reveal the dramatic but impermanent effects of mTORC1 inhibition.
J. M. Miller (*) : A. Wachsman : K. Haker Department of Imaging, Cedars Sinai Medical Center, 8700 Beverly Blvd, Suite M-335, Los Angeles, CA 90048, USA e-mail: [email protected] F. Majlessipour Department of Pediatric Hematology and Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA M. Danielpour Department of Pediatric Neurosurgery, Cedars Sinai Medical Center, Los Angeles, CA, USA D. Puliyanda Department of Pediatric Nephrology and Transplant Immunology, Cedars Sinai Medical Center, Los Angeles, CA, USA
Conclusions While everolimus provides a non-invasive way to treat TSC-associated lesions, patients may require lifelong therapy. When termination of therapy is considered, the patient should be made aware of the expectation of potentially dramatic increases in lesion size. If consideration is to be given to definitive surgical therapy, it should be pursued while the patient is still on the medication, or at least soon after treatment is halted. Keywords AML . Angiomyolipoma . SEGA . Subependymal giant astrocytoma . mTORC1 . Tuberous sclerosis
Introduction Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that predisposes to the development of benign lesions within multiple organ systems, including the brain, kidneys, heart, lungs, and skin [1]. Hamartomatous central nervous tubers are the most common cause of disease morbidity, leading to developmental delay, neuropsychiatric derangements, and potentially intractable seizure disorder [2]. Disease mortality is associated with space-occupying subependymal giant cell astrocytomas (SEGAs) and hemorrhage-prone renal angiomyolipomas (AMLs) [3]. For both lesions, worsening outcomes are associated with progressive increases in size [4, 5], necessitating regular surveillance and proactive intervention. Although intervention has traditionally been limited to surgical exploration, in the case of renal AML the development of endovascular techniques has allowed for minimally invasive management. Yet whether the intervention is by resection or embolization, the risk to surrounding healthy tissues is a real and often constraining one. The recent use of
174
Pediatr Nephrol (2015) 30:173–177
Fig. 1 Axial T2 magnetic resonance (MR) images of the brain through the level of the lateral ventricles just above the foramena of Munro. A spaceoccupying subependymal giant cell astrocytoma (SEGA) is visible as a large complex mass within the anterior right lateral ventricle. Multiple small subependymal nodules are seen bilaterally. Images were acquired at baseline (a), after 6 months of everolimus therapy (b; t= 6 months), after extended therapy cessation (c; t=36 months), and after resumption of therapy (d; t= 42 months). Time (t) presented in parenthesis also refer to time (t) presented in Table 1
everolimus has allowed for direct targeting of TSC-associated mass lesions without apparent effect on surrounding tissues. Everolimus is a member of the mTORC1 inhibitor drug class. Since its development, it has been used notably as both an immune suppressant and an anti-neoplastic agent. Its progenitor agent, sirolimus, was initially studied for its antifungal properties under the name rapamycin; it was under this guise that the mTORC (“mammalian target of rapamycin complex”) molecules and their functions were discovered. The complexes (mTORC1 and mTORC2) help to regulate growth and metabolism in ways that are still incompletely understood, but which involve protein and lipid catabolism [6]. The mutations that cause tuberous sclerosis occur in one of two natural suppressors of mTORC1 (hamartin and tuberin) that are activated when the extracellular environment is unfavorable to cell growth. Everolimus provides the missing inhibitory signal which mTORC1 lacks because of impaired hamartin or tuberin activity [7]. Double-blind trials have shown statistically significant decreases in multiorgan lesion volume and improved time-to-progression in TSC patients treated with
daily oral everolimus [8–11]. Due to the mechanism of action of everolimus in inhibiting mTORC1, there is reason to believe that these effects are not permanent. There may therefore be a need for continued long-term maintenance therapy.
Case Institutional Review Board approval was granted and informed consent obtained for this case report. The patient is an 18-year-old male first evaluated for TSC as a neonate, after a prenatal ultrasound demonstrated multiple cardiac masses suspicious for rhabdomyomas. Diagnosis was made after magnetic resonance imaging (MRI) revealed multiple subependymal nodules, and an ophthalmologic exam showed multiple bilateral retinal hamartomas. Although the seizure disorder of our patient responded well to medical therapy, inconsistent administration led to multiple bouts of status epilepticus.
Pediatr Nephrol (2015) 30:173–177
175
Fig. 2 Coronal contrast-enhanced T1 magnetic resonance (MR) image of the abdomen through the right kidney. A dominant angiomyolipoma (AML) is seen as a weakly enhancing exophytic inferior pole mass. Numerous smaller AMLs also present bilaterally. Images acquired at baseline (a), after 6 months of everolimus therapy (b; t= 6 months), after extended therapy cessation (c; t=36 months), and after resumption of therapy (d; t= 42 months). Time (t) presented in parenthesis also refer to time (t) presented in Table 1
Social issues resulted in placement of the patient in foster care at an assisted living facility. The patient was followed with regular MRI of the brain and abdomen for tumor surveillance. A 2.5-cm SEGA was diagnosed at the age of 11 years and found to progressively enlarge over a span of 3 years (Fig. 1a). During this same interval, multiple bilateral renal AMLs were diagnosed and found to be enlarging (Fig. 2a). Additional symptoms included developmental delays, chronic headaches, facial angiofibromas, ash
leaf spots, and shagreen patches. Given his particular risk profile and the location of the lesions, direct surgical and endovascular intervention were deferred, and radiation therapy declined. At the age of 14 years, the decision was made to begin oral everolimus therapy at 5 mg per day, gradually increasing the dose to 7.5 mg per day with the goal of keeping the everolimus level between 3–5 ng/ml [8]. During therapy the patient was monitored for everolimus-associated side effects, such as leucopenia, thrombocytopenia, and
Table 1 Measured diameters of selected lesions over time, with and without everolimus therapy Lesions
Diameter (cm) at baseline (t=0)
Diameter after everolimus therapy (t=6 months)
Diameter after therapy cessation (t=36 months)
Diameter after therapy resumption (t=42 months)
Brain mass
X=4.4 Y=3.7 Z=2.6 X=5.0 Y=2.8 Z=2.7 X=2.5 Y=2.0 Z=1.7
X=3.9 Y=3.0 Z=2.1 X=3.3 Y=2.1 Z=1.7 X=2.2 Y=1.3 Z=1.1
X=5.9 Y=4.5 Z=4.0 X=5.2 Y=5.1 Z=3.6 X=4.2 Y=2.6 Z=3.1
X=4.4 Y=3.0 Z=2.1 X=3.4 Y=2.9 Z=2.2 X=2.5 Y=1.8 Z=2.0
Right renal mass
Left renal mass
t, Time
176
Pediatr Nephrol (2015) 30:173–177
Table 2 Changes in selected lesion volumes over time, with and without everolimus therapy Lesions
Volume (cm3) at baseline (t=0)
Volume after everolimus therapy (t=6 months)
Volume after therapy cessation (t=36 months)
Volume after therapy resumption (t=42 months)
Brain mass
22.2 vs. prior vs. baseline 19.9
12.9 −41.9 % −41.9 % 6.2
55.8 332.0 % 150.9 % 50.2
14.6 −73.9 % −34.5 % 11.4
vs. prior vs. baseline 4.5 vs. prior vs. baseline
−68.8 −68.8 1.7 −63.0 −63.0
710.5 152.5 17.8 978.0 298.6
−77.3 % −42.6 % 4.7 −73.4 % 5.9 %
Right renal mass
Left renal mass
% % % %
hyperlipidemia. Baseline volumes were calculated for dominant brain and renal lesions, treating each lesion as an ellipsoid according to the equation volume=(4/3 × π × a × b × c), with a, b, and c representing the respective three-dimensional radii of the lesion in question. Upon evaluation with MRI 6 months after the baseline study, all of the followed lesions had decreased in size, with the dominant brain lesion decreasing in volume by 42 % (Fig. 1b), the right renal by 69 % (Fig. 2b), and the left renal by 63 %. During this same interval, the patient’s guardians became concerned about apparent increases in aggression and inattention; per their request, everolimus was discontinued. The patient’s aggressive behavior continued, and he was ultimately placed in a group home. He was lost to followup. The patient presented to the emergency department 36 months after the baseline study on account of deteriorating vision and worsening behavioral issues. He had been off everolimus for approximately 2.5 years at this point, and MRI evaluation revealed significant increases in all lesions (Figs. 1c, 2c). During this period the dominant brain lesion had increased in volume by 332 %, the right kidney lesion by 711 %, and the left by 978 %. Significant hydrocephalus and mass effect on the optic chiasm was noted. After discussion with the caregivers regarding the organic source of his behavioral issues, oral everolimus was restarted at 5 mg per day. On the 6-month followup (42 months after baseline), MRI revealed dramatic shrinkage of all masses back to baseline size or below (Figs. 1d; 2d). Diameters and volumes at respective timepoints are listed in Tables 1 and 2.
Discussion In one of the trials that initially demonstrated the effectiveness of the mTORC1 inhibition on the TSC, patients were imaged
% % % %
with MRI during 1 year of sirolimus therapy, followed by an additional year of imaging without the medication [12]. While improvements in pulmonary function persisted 12 months after drug cessation, renal AMLs began to increase in size without continued therapy. Unlike other anti-neoplastic therapies that may stimulate the immune system to kill a tumor, or cause direct cell death by disrupting basic cellular functionality, everolimus therapy is cytostatic as opposed to cytotoxic in many tumors [13]. Although there is evidence of involvement of TSC1 in the innate immune response [14], appropriate mTORC regulation through everolimus likely supports normal autophagy [13]. While some lesions decrease dramatically in size, it is not clear that they will ever ultimately disappear completely. Patients with TSC classically have an error in one of two tumor suppressors involved in cell cycle regulation. These two molecules—hamartin and tuberin—are natural mTORC1 inhibitors that activate whenever needed to prevent harmful cell growth and division. Though everolimus mimics this inhibitory action, causing masses like SEGAs and AMLs to regress, the effect may be impermanent, and may only persist so long as the medication is present to disrupt inappropriate cell division. While everolimus provides a non-invasive way to treat the masses associated with TSC, patients may require lifelong therapy. Although long-term data are lacking, this case highlights the need to maintain drug administration once the decision is made to choose everolimus over surgical resection or embolization. Patients considering terminating therapy should be warned of the expectation of potentially significant increases in lesion size. If consideration is to be given to definitive surgical therapy, it should likely be pursued while the patient is still on the medication, or at the very least soon after treatment is halted.
Pediatr Nephrol (2015) 30:173–177
References 1. Curatolo P, Bombardieri R, Jozwiak S (2008) Tuberous sclerosis. Lancet 372(9639):657–668 2. Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355(13):1345–1356 3. Shepherd CW, Gomez MR, Lie JT, Crowson CS (1991) Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66(8):792– 796 4. Roth J, Roach ES, Bartels U, Jóźwiak S, Koenig MK, Weiner HL, Franz DN, Wang HZ (2013) Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol 49(6):439–444 5. Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K (2002) Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 225(1):78– 82 6. Takei N, Nawa H (2014) mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci 7:28 7. Curatolo P, Moavero R (2012) mTOR inhibitors in tuberous sclerosis complex. Curr Neuropharmacol 10(4):404–415 8. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363(19):1801–1811
177 9. Krueger DA, Care MM, Agricola K, Tudor C, Mays M, Franz DN (2013) Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 80(6):574–580 10. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381(9861):125–132 11. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K (2013) Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebocontrolled trial. Lancet 381(9869):817–824 12. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358(2):140–151 13. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35 14. Pan H, O'Brien TF, Zhang P, Zhong XP (2012) The role of tuberous sclerosis complex 1 in regulating innate immunity. J Immunol 188(8):3658–3666
BRIEF REPORT
The effects of everolimus on tuberous sclerosis-associated lesions can be dramatic but may be impermanent Joseph M. Miller & Ashley Wachsman & Katherine Haker & Fataneh Majlessipour & Moise Danielpour & Dechu Puliyanda
Received: 5 June 2014 / Revised: 29 July 2014 / Accepted: 20 August 2014 / Published online: 7 September 2014 # IPNA 2014
Abstract Background Tuberous sclerosis complex (TSC) predisposes to the development of benign lesions within multiple organ systems, including the brain, kidneys, heart, lungs, and skin. Disease mortality is due to space-occupying subependymal giant cell astrocytomas and hemorrhage-prone renal angiomyolipomas. The recent use of mTORC1 inhibitors, such as everolimus, has allowed for direct targeting of TSCassociated mass lesions without apparent effect on surrounding tissues. Because of the mechanism of these drugs, there is reason to believe that these effects are not durable and that there may be need for continued long-term maintenance therapy. Case-diagnosis/treatment We present a case of TSCassociated mass lesions that were ill-suited for definitive surgical therapy. The patient was started on everolimus, however due to a complex social situation treatment was discontinued and ultimately resumed many months later. Radiologic studies acquired before and after each period of therapeutic onset/ cessation reveal the dramatic but impermanent effects of mTORC1 inhibition.
J. M. Miller (*) : A. Wachsman : K. Haker Department of Imaging, Cedars Sinai Medical Center, 8700 Beverly Blvd, Suite M-335, Los Angeles, CA 90048, USA e-mail: [email protected] F. Majlessipour Department of Pediatric Hematology and Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA M. Danielpour Department of Pediatric Neurosurgery, Cedars Sinai Medical Center, Los Angeles, CA, USA D. Puliyanda Department of Pediatric Nephrology and Transplant Immunology, Cedars Sinai Medical Center, Los Angeles, CA, USA
Conclusions While everolimus provides a non-invasive way to treat TSC-associated lesions, patients may require lifelong therapy. When termination of therapy is considered, the patient should be made aware of the expectation of potentially dramatic increases in lesion size. If consideration is to be given to definitive surgical therapy, it should be pursued while the patient is still on the medication, or at least soon after treatment is halted. Keywords AML . Angiomyolipoma . SEGA . Subependymal giant astrocytoma . mTORC1 . Tuberous sclerosis
Introduction Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that predisposes to the development of benign lesions within multiple organ systems, including the brain, kidneys, heart, lungs, and skin [1]. Hamartomatous central nervous tubers are the most common cause of disease morbidity, leading to developmental delay, neuropsychiatric derangements, and potentially intractable seizure disorder [2]. Disease mortality is associated with space-occupying subependymal giant cell astrocytomas (SEGAs) and hemorrhage-prone renal angiomyolipomas (AMLs) [3]. For both lesions, worsening outcomes are associated with progressive increases in size [4, 5], necessitating regular surveillance and proactive intervention. Although intervention has traditionally been limited to surgical exploration, in the case of renal AML the development of endovascular techniques has allowed for minimally invasive management. Yet whether the intervention is by resection or embolization, the risk to surrounding healthy tissues is a real and often constraining one. The recent use of
174
Pediatr Nephrol (2015) 30:173–177
Fig. 1 Axial T2 magnetic resonance (MR) images of the brain through the level of the lateral ventricles just above the foramena of Munro. A spaceoccupying subependymal giant cell astrocytoma (SEGA) is visible as a large complex mass within the anterior right lateral ventricle. Multiple small subependymal nodules are seen bilaterally. Images were acquired at baseline (a), after 6 months of everolimus therapy (b; t= 6 months), after extended therapy cessation (c; t=36 months), and after resumption of therapy (d; t= 42 months). Time (t) presented in parenthesis also refer to time (t) presented in Table 1
everolimus has allowed for direct targeting of TSC-associated mass lesions without apparent effect on surrounding tissues. Everolimus is a member of the mTORC1 inhibitor drug class. Since its development, it has been used notably as both an immune suppressant and an anti-neoplastic agent. Its progenitor agent, sirolimus, was initially studied for its antifungal properties under the name rapamycin; it was under this guise that the mTORC (“mammalian target of rapamycin complex”) molecules and their functions were discovered. The complexes (mTORC1 and mTORC2) help to regulate growth and metabolism in ways that are still incompletely understood, but which involve protein and lipid catabolism [6]. The mutations that cause tuberous sclerosis occur in one of two natural suppressors of mTORC1 (hamartin and tuberin) that are activated when the extracellular environment is unfavorable to cell growth. Everolimus provides the missing inhibitory signal which mTORC1 lacks because of impaired hamartin or tuberin activity [7]. Double-blind trials have shown statistically significant decreases in multiorgan lesion volume and improved time-to-progression in TSC patients treated with
daily oral everolimus [8–11]. Due to the mechanism of action of everolimus in inhibiting mTORC1, there is reason to believe that these effects are not permanent. There may therefore be a need for continued long-term maintenance therapy.
Case Institutional Review Board approval was granted and informed consent obtained for this case report. The patient is an 18-year-old male first evaluated for TSC as a neonate, after a prenatal ultrasound demonstrated multiple cardiac masses suspicious for rhabdomyomas. Diagnosis was made after magnetic resonance imaging (MRI) revealed multiple subependymal nodules, and an ophthalmologic exam showed multiple bilateral retinal hamartomas. Although the seizure disorder of our patient responded well to medical therapy, inconsistent administration led to multiple bouts of status epilepticus.
Pediatr Nephrol (2015) 30:173–177
175
Fig. 2 Coronal contrast-enhanced T1 magnetic resonance (MR) image of the abdomen through the right kidney. A dominant angiomyolipoma (AML) is seen as a weakly enhancing exophytic inferior pole mass. Numerous smaller AMLs also present bilaterally. Images acquired at baseline (a), after 6 months of everolimus therapy (b; t= 6 months), after extended therapy cessation (c; t=36 months), and after resumption of therapy (d; t= 42 months). Time (t) presented in parenthesis also refer to time (t) presented in Table 1
Social issues resulted in placement of the patient in foster care at an assisted living facility. The patient was followed with regular MRI of the brain and abdomen for tumor surveillance. A 2.5-cm SEGA was diagnosed at the age of 11 years and found to progressively enlarge over a span of 3 years (Fig. 1a). During this same interval, multiple bilateral renal AMLs were diagnosed and found to be enlarging (Fig. 2a). Additional symptoms included developmental delays, chronic headaches, facial angiofibromas, ash
leaf spots, and shagreen patches. Given his particular risk profile and the location of the lesions, direct surgical and endovascular intervention were deferred, and radiation therapy declined. At the age of 14 years, the decision was made to begin oral everolimus therapy at 5 mg per day, gradually increasing the dose to 7.5 mg per day with the goal of keeping the everolimus level between 3–5 ng/ml [8]. During therapy the patient was monitored for everolimus-associated side effects, such as leucopenia, thrombocytopenia, and
Table 1 Measured diameters of selected lesions over time, with and without everolimus therapy Lesions
Diameter (cm) at baseline (t=0)
Diameter after everolimus therapy (t=6 months)
Diameter after therapy cessation (t=36 months)
Diameter after therapy resumption (t=42 months)
Brain mass
X=4.4 Y=3.7 Z=2.6 X=5.0 Y=2.8 Z=2.7 X=2.5 Y=2.0 Z=1.7
X=3.9 Y=3.0 Z=2.1 X=3.3 Y=2.1 Z=1.7 X=2.2 Y=1.3 Z=1.1
X=5.9 Y=4.5 Z=4.0 X=5.2 Y=5.1 Z=3.6 X=4.2 Y=2.6 Z=3.1
X=4.4 Y=3.0 Z=2.1 X=3.4 Y=2.9 Z=2.2 X=2.5 Y=1.8 Z=2.0
Right renal mass
Left renal mass
t, Time
176
Pediatr Nephrol (2015) 30:173–177
Table 2 Changes in selected lesion volumes over time, with and without everolimus therapy Lesions
Volume (cm3) at baseline (t=0)
Volume after everolimus therapy (t=6 months)
Volume after therapy cessation (t=36 months)
Volume after therapy resumption (t=42 months)
Brain mass
22.2 vs. prior vs. baseline 19.9
12.9 −41.9 % −41.9 % 6.2
55.8 332.0 % 150.9 % 50.2
14.6 −73.9 % −34.5 % 11.4
vs. prior vs. baseline 4.5 vs. prior vs. baseline
−68.8 −68.8 1.7 −63.0 −63.0
710.5 152.5 17.8 978.0 298.6
−77.3 % −42.6 % 4.7 −73.4 % 5.9 %
Right renal mass
Left renal mass
% % % %
hyperlipidemia. Baseline volumes were calculated for dominant brain and renal lesions, treating each lesion as an ellipsoid according to the equation volume=(4/3 × π × a × b × c), with a, b, and c representing the respective three-dimensional radii of the lesion in question. Upon evaluation with MRI 6 months after the baseline study, all of the followed lesions had decreased in size, with the dominant brain lesion decreasing in volume by 42 % (Fig. 1b), the right renal by 69 % (Fig. 2b), and the left renal by 63 %. During this same interval, the patient’s guardians became concerned about apparent increases in aggression and inattention; per their request, everolimus was discontinued. The patient’s aggressive behavior continued, and he was ultimately placed in a group home. He was lost to followup. The patient presented to the emergency department 36 months after the baseline study on account of deteriorating vision and worsening behavioral issues. He had been off everolimus for approximately 2.5 years at this point, and MRI evaluation revealed significant increases in all lesions (Figs. 1c, 2c). During this period the dominant brain lesion had increased in volume by 332 %, the right kidney lesion by 711 %, and the left by 978 %. Significant hydrocephalus and mass effect on the optic chiasm was noted. After discussion with the caregivers regarding the organic source of his behavioral issues, oral everolimus was restarted at 5 mg per day. On the 6-month followup (42 months after baseline), MRI revealed dramatic shrinkage of all masses back to baseline size or below (Figs. 1d; 2d). Diameters and volumes at respective timepoints are listed in Tables 1 and 2.
Discussion In one of the trials that initially demonstrated the effectiveness of the mTORC1 inhibition on the TSC, patients were imaged
% % % %
with MRI during 1 year of sirolimus therapy, followed by an additional year of imaging without the medication [12]. While improvements in pulmonary function persisted 12 months after drug cessation, renal AMLs began to increase in size without continued therapy. Unlike other anti-neoplastic therapies that may stimulate the immune system to kill a tumor, or cause direct cell death by disrupting basic cellular functionality, everolimus therapy is cytostatic as opposed to cytotoxic in many tumors [13]. Although there is evidence of involvement of TSC1 in the innate immune response [14], appropriate mTORC regulation through everolimus likely supports normal autophagy [13]. While some lesions decrease dramatically in size, it is not clear that they will ever ultimately disappear completely. Patients with TSC classically have an error in one of two tumor suppressors involved in cell cycle regulation. These two molecules—hamartin and tuberin—are natural mTORC1 inhibitors that activate whenever needed to prevent harmful cell growth and division. Though everolimus mimics this inhibitory action, causing masses like SEGAs and AMLs to regress, the effect may be impermanent, and may only persist so long as the medication is present to disrupt inappropriate cell division. While everolimus provides a non-invasive way to treat the masses associated with TSC, patients may require lifelong therapy. Although long-term data are lacking, this case highlights the need to maintain drug administration once the decision is made to choose everolimus over surgical resection or embolization. Patients considering terminating therapy should be warned of the expectation of potentially significant increases in lesion size. If consideration is to be given to definitive surgical therapy, it should likely be pursued while the patient is still on the medication, or at the very least soon after treatment is halted.
Pediatr Nephrol (2015) 30:173–177
References 1. Curatolo P, Bombardieri R, Jozwiak S (2008) Tuberous sclerosis. Lancet 372(9639):657–668 2. Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355(13):1345–1356 3. Shepherd CW, Gomez MR, Lie JT, Crowson CS (1991) Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66(8):792– 796 4. Roth J, Roach ES, Bartels U, Jóźwiak S, Koenig MK, Weiner HL, Franz DN, Wang HZ (2013) Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol 49(6):439–444 5. Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K (2002) Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 225(1):78– 82 6. Takei N, Nawa H (2014) mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci 7:28 7. Curatolo P, Moavero R (2012) mTOR inhibitors in tuberous sclerosis complex. Curr Neuropharmacol 10(4):404–415 8. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363(19):1801–1811
177 9. Krueger DA, Care MM, Agricola K, Tudor C, Mays M, Franz DN (2013) Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 80(6):574–580 10. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381(9861):125–132 11. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K (2013) Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebocontrolled trial. Lancet 381(9869):817–824 12. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358(2):140–151 13. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35 14. Pan H, O'Brien TF, Zhang P, Zhong XP (2012) The role of tuberous sclerosis complex 1 in regulating innate immunity. J Immunol 188(8):3658–3666
