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Rapamycin causes regression of astrocytomas in tuberous sclerosis complex.

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Rapamycin Causes Regression of
Astrocytomas in Tuberous Sclerosis Complex
David Neal Franz, MD,1,2 Jennifer Leonard, MSN, FNP,1,2 Cynthia Tudor, MSN, PNP,1,2 Gail Chuck, BS,1,2
Marguerite Care, MD,1,3 Gopalan Sethuraman, PhD,4 Argirios Dinopoulos, MD,1,2 George Thomas, PhD,5
and Kerry R. Crone, MD1,6
Objective: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in
multiple organs. Five to 15% of affected individuals display subependymal giant cell astrocytomas, which can lead to
substantial neurological and postoperative morbidity due to the production of hydrocephalus, mass effect, and their
typical location adjacent to the foramen of Monro. We sought to see whether therapy with oral rapamycin could affect
growth or induce regression in astrocytomas associated with TSC. Methods: Five subjects with clinically definite TSC and
either subependymal giant cell astrocytomas (n ⴝ 4) or a pilocytic astrocytoma (n ⴝ 1) were treated with oral rapamycin
at standard immunosuppressive doses (serum levels 5–15ng/ml) from 2.5 to 20 months. All lesions demonstrated growth
on serial neuroimaging studies. Magnetic resonance imaging scans were performed before and at regular intervals following initiation of therapy. Results: All lesions exhibited regression and, in one case, necrosis. Interruption of therapy
resulted in regrowth of subependymal giant cell astrocytomas in one patient. Resumption of therapy resulted in further
regression. Treatment was well tolerated. Interpretation: Oral rapamycin therapy can induce regression of astrocytomas
associated with TSC and may offer an alternative to operative therapy of these lesions.
Ann Neurol 2006;59:490 – 498
Tuberous sclerosis complex (TSC) is an autosomal
dominant genetic disorder with a birth incidence of approximately 1 in 6,000. Affected individuals develop
hamartomatous growths in multiple organs of the body
that occur throughout their life span. Low-grade neoplastic lesions of the central nervous system (CNS),
usually in the form of subependymal giant cell astrocytomas (SEGAs), are reported in 5 to 15% of such
individuals. These lesions exhibit insidious slow
growth, often remaining clinically asymptomatic until
causing obstructive hydrocephalus. This has led to recommendations for periodic neuroimaging of persons
with TSC, with resection of SEGAs that exhibit serial
growth, cause hydrocephalus, or produce any clinical
symptomatology.1–3 SEGAs are low-grade astrocytomas
(World Health Organization [WHO] grade 1), which
do not typically respond to radiation therapy or chemotherapy. Less commonly, more aggressive CNS tumors may occur, in the retina or in other locations.4 – 6
Finally, given the genetic basis of tuberous sclerosis,
there is a risk for inducing second malignancies
through utilization of standard chemotherapeutic
agents or radiation therapy.7
The function of the tuberous sclerosis gene products,
hamartin and tuberin, has become increasingly evident
over the past several years. Together, they form a tumor suppressor complex, which through the GTPaseactivating function of tuberin drives the small GTPase,
termed Ras homolog enhanced in brain (Rheb), into
the inactive guanosine diphosphate–bound state. Rheb
in the guanosine triphosphate–bound active state is a
positive effector of the mammalian target of rapamycin
(mTOR). mTOR is an evolutionarily conserved protein kinase, which is expressed from fungi to humans.
Results over the past 10 years have shown that mTOR
serves as a major effector of cell growth as opposed to
cell proliferation. Mutations in either hamartin or tuberin drive Rheb into the guanosine triphosphate–
bound state, which results in constitutive mTOR signaling. mTOR appears to mediate many of its effects
on cell growth through the phosphorylation of the ribosomal protein S6 kinases (S6Ks) and the repressors
From the Departments of 1Pediatrics, 2Neurology, and 3Radiology,
Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH; 4Neuroscience Platform, Eli Lilly & Company, Indianapolis, IN; and Departments of
5
Genome Science and 6Neurosurgery, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine,
Cincinnati, OH.
Published online Feb 1, 2006, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20784
Address correspondence to Dr Franz, Department of Neurology,
Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, ML 2015, Cincinnati, OH 45229-3039.
E-mail: david.franz@cchmc.org
Received Oct 9, 2005, and in revised form Nov 14. Accepted for
publication Nov 21, 2005.
490
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
of protein synthesis initiation factor eIF4E, the 4EBPs.
The S6Ks act to increase cell growth and protein synthesis, whereas the 4EBPs serve to inhibit these processes. mTOR interacts with the S6Ks and 4EBPs
through an associated protein, Raptor. When mTOR is
constitutively activated through mutations in either
hamartin or tuberin, this results in the hamartomatous
lesions of tuberous sclerosis in the brain, kidney, heart,
lung, and other organs of the body (Fig 1).8,9 Recent
studies have also shown that to function under homeostatic conditions, the mTOR pathway requires both a
growth factor/hormone and a nutrient input (see Fig
1). Interestingly, recent studies have shown that mTOR
signaling is also constitutive in neurofibromatosisassociated tumors, and that these effects are also mediated by the de-repression of hamartin/tuberin tumor
suppressor complex.10 Moreover, it is becoming clear
that excessive mTOR signaling is likely to contribute
to other forms of nonsyndromic, sporadic human neoplastic diseases, such as breast, prostate, and gastrointestinal cancers.11–16 Indeed, lack of expression of
hamartin or tuberin was recently suggested to predict
poorer outcome and a more aggressive course in human breast cancers.17,18
Rapamycin (sirolimus [Rapamune]) is a commercially available immunosuppressant, that forms an inhibitory complex with the immunophilin FKBP12,
which then binds to and inhibits the ability of mTOR
to phosphorylate downstream substrates, such as the
S6Ks and 4EBPs. It is marketed as an immunosuppressant, because of its propensity to inhibit T-cell proliferation, and has been approved for use in this therapeutic setting in the United States since 2001. Two
derivatives of rapamycin, RAD001 (everolimus [Certican]) and a prodrug for rapamycin, CCI-779 or temsirolimus, are in clinical development in a number of
therapeutic indications, including oncology.19,20 They
act in a similar fashion to rapamycin, although their
pharmacokinetics, bioavailability, and side effect profiles may differ. In oncology trials, common side effects
include aphthous oral ulcers, hyperlipidemia, thrombocytopenia, acneiform rash, immunosuppression, and
impaired wound healing.21 Animal studies have demonstrated the ability of rapamycin to inhibit the aber-
Fig 1. Schematic of mammalian target of rapamycin (mTOR) pathway: TSC1 protein, hamartin; TSC2 protein, tuberin; Rheb,
Ras homolog enhanced in brain; PTEN, phosphatase and tensin homolog deleted on chromosome 10, 4E-BP1, eukaryotic initiation
factor binding protein 1; Raptor, regulatory associated protein of mTor; PKD1, phosphoinositide-dependent protein kinase; IRS,
insulin regulated substrate; LST, lethal with sec-thirteen. S6 kinases (S6Ks) are upregulated and 4E-BP1s are downregulated in
tuberous sclerosis complex (TSC)–deficient cells as a result of overactivation of mTor.
Franz et al: Rapamycin Therapy in TSC
491
rant growth of TSC-deficient cells in vitro and to induce apoptosis of renal tumors in animal models of
TSC.22 Clinical trials of rapamycin for renal angiomyolipomas associated with tuberous sclerosis are nearing completion at our institution and elsewhere. Rapamycin is believed to cross the blood–brain barrier to a
limited but unknown extent. These observations plus
the morbidity associated with SEGAs led us to consider
rapamycin as an alternative therapy for CNS neoplastic
disease associated with TSC.
Subjects and Methods
Approval of the Cincinnati Children’s Hospital Medical
Center institutional review board for off-label treatment of
patients with TSC and SEGAs in lieu of standard operative
therapy was obtained. Patients with tuberous sclerosis and
neoplastic disease were identified from the population of our
Tuberous Sclerosis Clinic. Families were advised of the potential side effects and risks of rapamycin therapy, as well as
those of standard operative therapy. Informed consent for
off-label therapy with rapamycin was obtained. Laboratory
studies consisting of complete blood count/differential, serum electrolytes, hepatic enzymes, fasting lipids, and rapamycin levels were monitored at baseline, after 2 weeks of therapy, 2 weeks after dosage changes, and a minimum of every
3 months once a stable dosage was achieved.
Rapamycin therapy was initiated at 1.5mg/m2/day
rounded up to the next highest milligram as a single oral
dose. Baseline and follow-up laboratory studies were obtained with a goal of obtaining 24-hour trough rapamycin
levels of between 10 and 15ng/ml. Patients unable to tolerate
levels in this range had their doses held or reduced with the
goal of achieving trough serum levels of between 5 and
10ng/ml. The generally accepted therapeutic immunosuppressive trough serum level for rapamycin is 5 to 15ng/ml.
Magnetic resonance imaging (MRI) scans including measurements and MRI spectroscopy of the lesions were performed
at baseline and at periodic intervals thereafter. For the purposes of this report, all lesion measurements and volume determinations were performed by the same neuroradiologist
(M.C.). Volumes were obtained with a Vitrea 2 workstation
based on volume of interest tracings of 1mm coronal reformatted images from either postcontrast sagittal SPGR (1.5tesla GE [GE Medical Systems, Milwaukee, WI] or Siemens
MRI [Siemens Medical Systems, South Iselin, NJ]) or T1
MPRAGE (3-tesla Siemens MRI [Siemens Medical Systems])
volume acquisition. Because of technical considerations (ie,
studies performed at outside institutions, among other considerations), volume determinations were not possible on all
occasions.
Results
Case 1
The first case is a 21-year-old woman who presented
for a routine follow-up visit. She has a 10bp deletion
in exon 39 of the TSC2 gene. Her mother, who also
had TSC, died of complications from surgical resection
of a SEGA. She recently developed nonspecific headaches without clinical signs of increased intracranial
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pressure. A routine follow-up MRI scan demonstrated
new enhancing masses in the region of the right foramen of Monro measuring 13.2 ⫻ 10.7mm (volume,
1.6cc) and on the left measuring 6.6 ⫻ 10.3mm (volume, 1cc) in diameter, as well as mild ventriculomegaly. The patient was placed on rapamycin therapy.
Follow-up MRI approximately 2.5 months later demonstrated reduction in size of the lesion dimensions to
10.2 ⫻ 6.6mm (right volume, 0.87cc) and 8.2 ⫻
7.8mm (left volume, 0.48cc). A further follow-up scan
approximately 5 months after the initiation of rapamycin demonstrated a lesion size of 10.3 ⫻ 6.0mm
(right) and 6.0 ⫻ 6.9mm (left). Volumetric analysis
was not possible on this study. At this point the patient
had symptoms of aphthous ulcers and an acneiform
rash, known side effects of rapamycin, at a daily dose
of 6mg with a maximum trough serum level of 7.7ng/
ml. Her headaches resolved shortly after starting rapamycin therapy and she wished to stop taking the medication. She was taken off the drug and had a
follow-up MRI 4 months later. On this scan her lesions were noted to have increased in size, now measuring 14.2 ⫻ 11.2mm (right volume, 1.5cc) and
6.0 ⫻ 10.9mm (left volume, 0.69cc). She was placed
back on rapamycin therapy at her previous dosage and
received follow-up imaging 4 months later. Despite being prescribed a similar dosage to that she had received
previously, there was no recurrence of aphthous ulcers
or skin rash. Some modest elevation of cholesterol resolved spontaneously. Follow-up imaging 4 months
after resuming rapamycin therapy once again demonstrated regression in her SEGA with lesion measurements of 10.8 ⫻ 6.6mm (right) and 4.2 ⫻ 8.6mm
(left). The patient continues to take rapamycin at this
time with her latest follow-up imaging demonstrating a
lesion size of 4.3 ⫻ 9.5mm (right volume, 0.61cc) and
5.6 ⫻ 7.3mm (left volume, 0.25cc) 20 months after
starting therapy. Previously noted side effects have not
recurred (Fig 2).
Case 2
The second case is a 15-year-old girl with a history of
previous giant cell astrocytoma resection at 9 months
old. She has a point mutation (G ⬎ A) in intron 35 of
the TSC2 gene. Resection at that time was complicated
by significant intraoperative hemorrhage, requiring cerebrospinal fluid diversion after surgery. Mild generalized cerebral volume loss was noted on remote postoperative imaging, as well as stigmata of TSC. The
patient has partial and complex partial epilepsy, which
is well controlled with lamotrigine and phenobarbital.
Serial MRI scans demonstrated growth of a giant cell
astrocytoma contralateral to her original lesion. No increase in ventricular size was noted, but the patient developed progressive headache and abnormal nystagmoid ocular movements. Rapamycin was instituted at
Fig 2. Case 1. Coronal T1 contrast-enhanced magnetic resonance imaging. (A) Baseline. (B) After 2.5 months of rapamycin therapy. (C) Recurrence after total of 8 months on rapamycin therapy, then 4 months without drug. (D) Long-term follow-up: continued regression 20 months after starting rapamycin therapy, 8 months after therapy resumed.
2mg daily and titrated to 7mg daily to achieve a trough
level of 10.9ng/ml. This relatively high dose was likely
required due to induction of rapamycin metabolism by
intercurrent phenobarbital therapy. The patient’s headaches resolved and abnormal ocular movements improved on the concurrent initiation of rapamycin.
Follow-up MRI performed after 5 months of rapamycin therapy demonstrated reduction of lesion size from
23 ⫻ 20mm (volume, 6cc) to 18 ⫻ 13mm (volume,
2.4cc) (Fig 3). No clinical side effects were noted consequent to rapamycin therapy, with the exception of
elevation of serum cholesterol. Patient has remained
seizure free while receiving rapamycin therapy.
Case 3
The third case is a 3-year-old girl with a history of
tuberous sclerosis, partial epilepsy, and infantile
spasms. TSC genotyping has not been performed. Sei-
Franz et al: Rapamycin Therapy in TSC
493
Fig 3. Case 2. Reduction in size of subependymal giant cell astrocytoma after 5 months of rapamycin therapy. (Left) Pretreatment;
lesion volume is 6cc. (Right) After treatment; lesion volume is 2.4cc. Axial T1 contrast-enhanced magnetic resonance imaging.
zures were well controlled with topiramate and Vigabatrin. On routine MRI scanning she was noted to
have a hypothalamic mass. This mass was followed expectantly and exhibited progressive increase in size over
approximately 16 months. It ultimately reached dimensions of 66 ⫻ 50 ⫻ 43mm (craniocaudal ⫻ anteroposterior ⫻ transverse). At this point it extended superiorly from the hypothalamic region obstructing the
foramen of Monro with subsequent development of
hydrocephalus. Volumetric analysis was not available
for this patient. Ventriculoperitoneal shunt was placed
and endoscopic biopsy performed. Pathology demonstrated a low-grade pilocytic astrocytoma. The patient
was prescribed rapamycin therapy and titrated to 4mg
daily to achieve a maximum trough serum level of
10.2ng/ml. On follow-up MRI scanning 5 weeks after
initiation of rapamycin, there was persistent but improved ventriculomegaly and minimal increase in the
lesion size, but development of central necrosis.
Follow-up MRI 3.5 months after initiation of rapamycin therapy demonstrated resolution of residual ventriculomegaly, a decrease in lesion size to 65 ⫻ 47 ⫻
44mm, as well as more extensive necrotic changes, confirmed by MR spectroscopy. Follow-up imaging after 6
months of rapamycin therapy showed further reduction
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in lesion size to 58 ⫻ 42 ⫻ 38mm (Fig 4). Side effects
consisted of transient hypercholesterolemia, as well as
irritability and fussiness, which subsided with a short
course of oral codeine. The latter symptoms likely reflected initial persistence of obstructive hydrocephalus.
Consequent to initiation of rapamycin, the patient was
noted to be more verbal and interactive with improved
progress in speech and rehabilitative therapies. The patient has remained seizure free throughout despite taper
and discontinuation of Vigabatrin as rapamycin was instituted.
Case 4
The fourth case is a 5.5-year-old boy with tuberous
sclerosis. TSC genotyping has not been performed. His
seizures were well controlled with divalproex sodium
(Depakote) 250mg bid. He has significant sleep and
behavioral problems for which he is treated with
clonidine 0.1mg qhs, quetiapine 100mg tid, and amitriptyline 10mg qhs. The patient developed episodes of
headache and change in mental status, and a computed
tomography scan ordered by his local physician showed
increase in size of previously noted SEGA. This was
confirmed on subsequent MRI. The lesion was measured at 10.2 ⫻ 12.7mm (volume, 1.1cc). Rapamycin
Fig 4. Case 3. (A) Hypothalamic lesion, baseline (57 ⫻ 58 ⫻ 44mm). (B) After 5 weeks of rapamycin therapy, s/p ventricular
drainage with development of central necrosis (66 ⫻ 50 ⫻ 43mm). (C) After 3.5 months (65 ⫻ 47 ⫻ 44mm). (D) After 6
months (58 ⫻ 42 ⫻ 38mm). Sagittal T1 contrast-enhanced magnetic resonance imaging.
2mg daily was added to his regimen. Dosage was progressively increased to 5mg daily to produce maximum
trough serum level of 9.6ng/ml. No alterations in serum lipids were noted, nor were there any clinical side
effects. The patient’s seizures remained well controlled
throughout. There was no appreciable change in his
premorbid behavioral or sleep difficulties. Follow-up
MRI scanning 3 months after initiation of rapamycin
demonstrated reduction in lesion size to 7.3 ⫻ 9.9mm
(volume, 0.41cc) (Fig 5).
Case 5
The fifth case is a 14.5-year-old boy with a history of
tuberous sclerosis. He had infantile spasms and seizures
as a young child but is now seizure free without anticonvulsants for 8 years. He has a point mutation in
exon 29 of the TSC2 gene with thymidine replacing
cytosine at position 3491. The patient has a baseline
mild degree of cognitive impairment. This is a familial
case of TSC. His uncle died of complications of a giant
cell astrocytoma resection. Although no clinical symp-
Franz et al: Rapamycin Therapy in TSC
495
Fig 5. Case 4. Reduction in size of giant cell astrocytoma following 3 months rapamycin therapy (white arrows). (Left) Baseline
10.2 ⫻ 12.7mm (volume, 1.1cc). (Right) Posttreatment 7.3 ⫻ 9.9mm (volume 0.41cc). Coronal T1 contrast-enhanced magnetic
resonance imaging.
toms were noted, progressive growth of an SEGA with
both cystic and soft components was noted on three
consecutive MRI scans over a 9-month period. The patient was prescribed rapamycin 3mg daily, which was
titrated sequentially to 6mg daily. He developed some
mild difficulty with an acneiform rash about the lower
extremities, some oral aphthous ulcers, and transient
increase in serum cholesterol. These symptoms did not
cause the patient significant distress. They resolved despite progressive escalation in dosage. Maximum
trough rapamycin level achieved was 10.4ng/ml. Prior
to rapamycin therapy, MRI scan demonstrated lesion
size to be 13.7 ⫻ 23.4mm (volume, 3.6cc). Following
2.5 months of rapamycin therapy, reduction in lesion
size to 8.1 ⫻ 13.7mm (volume, 1.7cc) was noted. Both
the cystic and solid components of the tumor decreased in size (Fig 6).
Discussion
This is the first report in the literature of successful
medical therapy for neoplastic disease of the CNS associated with TSC. Effectiveness was noted at serum
concentrations typically used in transplantation medicine. This is consistent with the known action of rapa-
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mycin on mTOR by causing either a reduction in cell
size or apoptosis. There may be additional mechanisms
of action, such as reduction of vascular endothelial
growth factor levels or induction of intratumoral
thrombosis.23 It is possible that reduction in cell volume, as in Cases 1 and 2, or induction of apoptosis or
intratumoral thrombosis (Case 3) may be the predominant effects of rapamycin therapy in particular tumors.
These findings are preliminary and do not by themselves prove the efficacy of mTOR inhibition for the
treatment of tuberous sclerosis–associated astrocytomas.
However, the recurrence of the SEGAs in Case 1 on
discontinuation of treatment, followed by their further
regression when it was reinstituted, coupled with our
additional cases provides compelling circumstantial evidence. Spontaneous regression of pilocytic astrocytomas and optic gliomas has been reported, sometimes
after biopsy or partial resection. The majority of these
cases are individuals with neurofibromatosis; it has not
been reported in SEGAs, TSC, or hypothalamic lesions
of the size described here. Regression in these cases typically has occurred over a longer time and has not been
preceded by intralesional necrosis, as in Case 3.24,25
Given the ability of mTOR inhibition to induce apo-
Fig 6. Case 5. Reduction in cystic (black arrows) and solid (white arrows) components of a giant cell astrocytoma following 2.5
months rapamycin therapy. (Left) Baseline 13.7 ⫻ 23.4mm (volume, 3.4cc). (Right) Posttreatment 8.1 ⫻ 13.7mm (volume,
1.7cc). Coronal T1 contrast-enhanced magnetic resonance imaging.
ptosis,26,27 as well as its activation in neurofibromatosis-1–associated tumors,10 it is conceivable that modulation of this pathway may play a role in cases of
spontaneous astrocytoma regression. The lack of reported spontaneous regression or subsequent stabilization in SEGAs has led to the recommendation that resection be considered once growth is demonstrated on
serial imaging, as discussed earlier.1–3 Disregarding
Case 3 (pilocytic astrocytoma), based on the Bernoulli
distribution principle and assuming a spontaneous regression rate for SEGAs of 25%, the probability that
the observed result would occur by chance in four separate cases would be (0.25)4 ⫽ 0.0039. Even assuming
a spontaneous regression rate of 50%, the probability
that this result happened by chance alone would still
only be (0.5)4 ⫽ 0.0625. Although an exact incidence
of spontaneous regression in SEGAs cannot be stated,
it is not greater than 25%, if it occurs at all. We do
not think the changes reported would have occurred in
the absence of rapamycin, or by random chance.
The extent to which rapamycin penetrates the CNS
is unknown. Furthermore, its use in TSC patients can
be hampered by that they often receive concomitant
antiepileptic medications that induce its metabolism
(eg, carbamazepine, phenytoin). A recent open-label
trial of the rapamycin prodrug CCI-779 (temsirolimus)
in glioblastoma multiforme demonstrated improved
time to relapse, even in those patients receiving
enzyme-inducing antiepileptic drugs. Importantly, response was predicted by the extent of S6K activation
within the tumors, suggesting a mechanism identical to
that known to be operative in patients with TSC.28 –30
Although multiple signaling pathways may drive glioblastoma proliferation, only overactivation of mTOR
pathway should be operative in patients with TSC and
SEGAs or other types of CNS neoplastic disease.
Rapamycin is generally a well-tolerated medication.
Common, typically self-limited side effects include
aphthous ulcers, acneiform rash, diarrhea, and arthralgias, as well as potentially dramatic elevation of serum
cholesterol and lipoproteins. The latter may subside
over time but can require management with dietary
modification or drug therapy. More serious but infrequent side effects such as interstitial pneumonitis, opportunistic infections, impaired wound healing, and
lymphoproliferative disease have been reported in the
transplant population. These risks would likely be lessened to some extent by the fact that TSC patients
would presumably not receive multiple concurrent immunosuppressive agents such as azathioprine, cyclosporine, or steroids. Rapamycin is, in fact, believed to
have less risk for lymphoproliferative, neurological, and
Franz et al: Rapamycin Therapy in TSC
497
renal complications than other types of immunosuppressive agents. Traditional chemotherapy and radiation is traditionally ineffective for low-grade gliomatous
lesions such as those that occur in these patients. Furthermore, the use of traditional chemotherapeutic
agents in a genetic disorder such as TSC has the theoretical disadvantage of leading to additional “second
hits” in an unaffected allele, which could produce an
increased risk for subsequent malignancies both within
the CNS and in other organs of the body. Adequate
duration of therapy must also be established, given the
relapse seen in this series. Rapamycin resistance has
been reported in animal models of TSC and may occur
in humans as well.31 There may also be a role for use
of combination therapies, such as rapamycin and
␥-interferon.32 These results, although encouraging, require confirmation and further elucidation by subsequent prospective trials.
The authors wish to acknowledge the invaluable assistance and
thoughtful criticism of Dr. Francis X. McCormack, Mrs. Melody
Gulleman, and Ms. Mary Franz in the preparation of this manuscript.
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complex, rapamycin, regression, causes, tuberous, sclerosis, astrocytoma
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