641353 TAU0010.1177/1756287216641353Therapeutic Advances in UrologyJJ Bissler and JC Kingswood
`
`research-article2016
`
`Review
`
`Ther Adv Urol
`
` 1 –12
`
`DOI: 10.1177/
`1756287216641353
`
`© The Author(s), 2016.
`Reprints and permissions:
`http://www.sagepub.co.uk/
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`Correspondence to:
`John J. Bissler, MD
`FedEx Chair of Excellence,
`Director, Tuberous
`Sclerosis Center of
`Excellence, Director,
`Division of Nephrology
`at St. Jude Children’s
`Research Hospital and
`LeBonheur Children’s
`Hospital, University of
`Tennessee Health Science
`Center, Professor of
`Pediatrics, 51 North
`Dunlap Street, Memphis,
`TN 38103, USA
`jbissler@uthsc.edu
`John C. Kingswood, MD
`Royal Sussex County
`Hospital, Brighton, UK
`
`Optimal treatment of tuberous
`sclerosis complex associated renal
`angiomyolipomata: a systematic review
`
`John J. Bissler and John C. Kingswood
`
`Abstract: Renal angiomyolipomata associated with tuberous sclerosis complex are often
`bilateral, multiple and progressive. They cause significant morbidity and mortality in older
`children and adults. Surveillance and pre-emptive treatment reduce this risk. Recent research
`suggests treatment with mammalian target of rapamycin inhibitors is better at preventing
`bleeding, recurrence, and preserving renal function than percutaneous embolization.
`
`Keywords: angiomyolipoma, therapy, tuberous sclerosis complex
`
`Introduction
`Tuberous sclerosis complex (TSC) is a multisys-
`tem disorder that affects about 1 in 10,000 indi-
`viduals worldwide [EMA, 2010]. It is caused by
`mutations in one of two genes, TSC1 and TSC2,
`causing a very variable spectrum of problems
`including: epilepsy; intellectual disability; autistic
`spectrum disorder and other neuropsychiatric
`problems; skin, heart, lung and kidney lesion
`[Curatolo et al. 2008].
`
`review is to critically assess the published and pre-
`sented data on treatment pertaining to TSC-
`related angiomyolipomata. This aspect of patient
`care is particularly important following the dis-
`covery that dysregulation of the mammalian tar-
`get of rapamycin (mTOR) is fundamental to the
`pathogenesis of TSC [Tee et  al. 2003], and
`because mTOR inhibitors have been proposed as
`an alternative to surgery or merely supportive
`treatment.
`
`Renal involvement is a major cause of morbidity
`and mortality in TSC [Shepherd et  al. 1991]
`(Table 1). The severity of the conditions caused
`by this genetic disease means that TSC not only
`affects 1:10,000 individuals, but also has a pro-
`found effect on 1:10,000 families. The renal dis-
`ease prevalence is such that 80% of patients have
`renal angiomyolipomata, leading to life-threaten-
`ing bleeding in 25%, and can be associated with
`renal failure. Most patients’ angiomyolipomata
`are multiple, bilateral and progressive [Bissler
`and Kingswood, 2004]. In contrast, sporadic
`renal angiomyolipomata are twice as common but
`usually occur in an older age group, and are sin-
`gle, small and rarely progress to cause significant
`morbidity [Bissler and Kingswood, 2004].
`
`Methodology
`
`Literature search strategy
`The literature search included three topics:
`everolimus, sirolimus and surgery/embolization.
`Three separate searches from 2000 to 2014 were
`performed, using Ovid, with the following search
`criteria.
`
` • AML or Angiomyolipoma plus TSC and
`treatment plus Surgery or Embolization.
` • AML or Angiomyolipoma plus TSC and
`treatment plus Sirolimus.
` • AML or Angiomyolipoma plus TSC and
`treatment plus Everolimus.
`
`Medical care of a TSC patient is often splintered
`between multiple subspecialists; not uncom-
`monly the practitioners also have very limited
`experience with the disease. The purpose of this
`
`All titles and abstracts were inspected. Duplicates
`within each search were removed, as were dupli-
`cates between searches. Publications on topics
`that did not include renal disease (e.g. topics such
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`Table 1. TSC renal disease features.
`
` • Angiomyolipomata approximately 80% and
`most common cause of death in adults with
`TSC1,2
` • Risk of bleeding 25–50%3,4
` • LAM ~30–80% of women1,2
` • Kidney cancer ~1–3%
` • Polycystic kidney 5%
` • Needing dialysis ~1%
` • Reduced kidney function 40% (Adults)5
`• High blood pressure 27% (Adults)5
`–
` 1. Franz et al. (2010) Neuropediatrics 41:
`199–208.
` 2. Dixon et al. (2011) Nephron Exp Nephrol 118:
`e15–e20.
`– 3. Kessle et al. (1998) Eur Urol 33: 572–575.
`– 4. Mouded et al. (1978) J Urol 119: 684–688.
`– 5. Kingswood et al. CPRD Eur Assoc Urol 201.
`
`–
`
`LAM, lymphangioleiomyomatosis.
`
`as epilepsy, subependymal giant cell astrocytoma
`(SEGA), pulmonary lymphangioleiomyomatosis
`(LAM), neuropsychiatric problems, molecular
`mechanisms in animal models and studies in car-
`cinoma) were removed. Papers that were reviews
`without any original data were excluded, but their
`references were inspected to find any possible
`missing references. Original papers, conference
`abstracts and case reports have been included in
`this review. Abstracts that have been superseded
`by more detailed later publications were removed
`(Figures 1–3).
`
`The initial search found 204 publications. There
`were 38 duplicates and 11 reviews. Of the rest,
`only 58 were about treatment or natural history of
`TSC renal disease or angiomyolipomata. Of these
`14 were papers, 19 abstracts and 25 case series.
`
`These results were combined with relevant results
`from the previous systematic literature search car-
`ried out in 2012 in preparation for writing the new
`international guidelines for the surveillance and
`management of TSC [Krueger et al. 2013a]. That
`review used the PUBMED and SCOPUS data-
`bases to find all papers published between 1997
`and March 2012 which included the terms ‘tuber-
`ous sclerosis’ and ‘diagnosis or therapy’ +/−
`‘humans’. The search returned 2692 references; of
`which 604 included information on renal disease
`in TSC. These 604 references were reviewed again
`to find any papers relevant to this search that had
`not already been included. There were 14 of these.
`
`Figure 1. Search 1: surgery/embolization and
`relevant natural history.
`Of these 26 relevant publications; 10 were papers, 9
`abstracts and seven single case reports.
`
`Figure 2. Search 2: sirolimus treatment.
`Of these 7 relevant publications; 2 were papers, 1 abstract
`and 4 single case reports.
`
`Figure 3. Search 3: everolimus treatment.
`Of these 11 relevant publications; 2 were papers, 9
`abstracts, there were no single case reports.
`
`Natural history of TSC associated renal
`angiomyolipomata
`Data from TOSCA (a worldwide database study,
`now including 2226 subjects) is consistent with
`the adverse role of renal disease in the health of
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`Figure 4. Prevalence of CKD in the overall TSC population by age compared with the general UK population.
`Data from December 1998 to November 2003 as reported by Stevens et al. [2007] and from Kingswood et al. [2014b].
`CKD, chronic kidney disease; TSC, tuberous sclerosis complex.
`
`Table 2. Distribution of potential predictors of bleeding in patients with AML who had or not had bleeding.
`From Nikolskaya et al. [2014].
`
`Parameters
`
`Number of patients
`Age (years)
`GFR initial level
`GFR final level
`
`Bleeding
`
`56
`34 (5.9–66.4)
`77.5 (31–124)
`51.6 (10–89)
`
`No bleeding
`
`112
`23.2 (1.7–56.6)
`84.9 (45–109)
`55.8 (13–89)
`
`p value
`
`NA
`0.0001
`0.45
`0.65
`
`Cross-sectional analysis of renal function and possible role of haemorrhage. Follow-up duration of for both groups varied
`widely but was similar. Haemorrhage alone did not impact loss of renal function.
`AML, angiomyolipoma; GFR, glomerular filtration rate; NA, not applicable.
`
`a patient with TSC. Analysis of the first 508
`patients revealed 53% had been diagnosed with
`renal angiomyolipomata [Kingswood et  al.
`2014c], despite the young median age of 16
`years. The relatively low prevalence of haemor-
`rhage (4.8%), pain (3.7%), impaired renal func-
`tion (3%) and hypertension (4.4%), is probably
`explained by the high incidence of pre-emptive
`treatment of angiomyolipomata (28%), in addi-
`tion to the young age of the subjects [Kingswood
`et  al. 2014c]. Significant and life-threatening
`renal complications are common in TSC patients
`with angiomyolipomata [Cappell et al. 2014].
`
`In addition to the risks from haemorrhage, prema-
`ture impairment of glomerular filtration rate (GFR)
`has been reported in up to 40% of subjects
`[Kingswood et  al. 2014a]. Figure 4 shows that
`these 40% (with GFR <60 ml/min) effectively have
`
`a level of renal function that would be expected if
`they were 30 years older [Kingswood et al. 2014a].
`
`study by Nikolskaya and colleagues
`The
`[Nikolskaya et al. 2014] showed that renal impair-
`ment occurs in the absence of overt bleeding from
`angiomyolipomata or intervention (Table 2). This
`underscores the need to use methods that preserve
`kidney function when treating angiomyolipomata
`pre-emptively, to prevent bleeding.
`
`Angiomyolipomata progressively enlarge from
`early childhood onwards (Figure 5) with an
`apparent growth spurt in teenage/early adulthood
`(Figure 6). In older adults about 33% stop grow-
`ing [Cox et al. 2012]. Data from Cox and col-
`leagues [Cox et al. 2012] suggest that it is
`angiomyolipomata that are still enlarging (and
`>30 mm) that are most at risk of haemorrhage;
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`Figure 5. The largest angiomyolipoma in individual patients versus age from Cox et al. [2012].
`
`Figure 6. Growth velocity of angiomyolipomata versus age from Cox et al. [2012].
`
`and the number needed to treat (NNT) to pre-
`vent one bleed is low (see Table 3).
`
`Embolization
`Prior to the availability of mTOR inhibitors, sur-
`gery or percutaneous embolization were the only
`options available for pre-emptive treatment of angi-
`omyolipomata [Nelson and Sanda, 2002]. Surgery
`
`was considered second choice in TSC associated
`angiomyolipomata because of the technical diffi-
`culties caused by their multifocal bilateral nature
`[Sooriakumaran et al. 2010].
`
`The main problem with embolization is the
`trade-off between completely occluding the angi-
`omyolipoma blood supply, with the risk of infarct-
`ing normal surrounding renal tissue, versus a more
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`Table 3. Risk of AML bleeding stratified by growth/no
`growth. From Cox et al. [2012].
`
`Table 4. Case series of treatment of renal
`angiomyolipomata by embolization.
`
`9.5 Year Follow Up (n = 54)
` • Growth 34 (63%)
` • bleed 11 (20%)/3 (6%) commenced mTOR
`inhibitor
` • no bleed 20 (37%)
` • No growth 20 (37%)
` • bleed 2 (4%)
` • no bleed 18 (33%)
`χ2 = 6.7, p < 0.01
` • NNT: for patients with growing AMLs, the
`NNT to prevent one bleed is 3.2
`
`AML, angiomyolipoma; mTOR, mammalian target of
`rapamycin; NNT, number needed to treat.
`
`conservative approach which minimises collateral
`damage but increases the risk of recurrence. In
`addition, embolization of a single lesion does not
`prevent other lesions from progressing. There are
`also the risks of short-term complications (post-
`embolization syndrome, acute renal failure and
`infection) [Sooriakumaran et al. 2010].
`
`There have not been any controlled trials of
`embolization, nor any trials to compare treatment
`modalities (surgery, embolization & mTOR
`inhibitor treatment). There have been a number
`of small case series of embolization that contain
`enough detail to draw some tentative conclusions.
`These are listed in Table 4. Of the 125–132
`embolizations reported in TSC patients, 32 (24–
`26%) had a recurrence. However, these were
`short-term findings and, as the paper by Kothary
`and colleagues [Kothary et al. 2005] pointed out,
`the mean time to recurrence of critical problems
`from angiomyolipomata post embolization was
`78 months, which was longer than most of the
`follow up periods reported in the case series. One
`recent paper reviewed the long-term outcome
`(median 15.8 years) in 351 TSC patients from a
`single clinic, 244 of who had angiomyolipomata
`that were systematically pre-emptively treated
`with embolization [Eijkemans et  al. 2015]. This
`confirmed that the outcome was suboptimal and
`patients in that clinic are now treated with mTOR
`inhibitor as a first line instead.
`
`Lee et al. [1998]
`Kessler et al. [1998]
`Mourikis et al. [1999]
`Lazarov et al. [2002]
`Hashimoto et al. [2003]
`Ewalt et al. [2005]
`Kothary et al. [2005]
`Williams et al. [2006]
`Seyam et al. [2008]
`
`Ramon et al. [2009]
`Bishay et al. [2010]
`Chick et al. [2010]
`Leong et al. [2010]
`El-Assmy et al. [2011]
`Koo et al. [2010]
`Vallejo et al. [2008]
`Haber et al. [2005]
`Lee et al. [2009]
`
`longer-term; and that premature loss of kidney
`function is a long-term risk in TSC renal disease
`and can be exacerbated by embolization, the 96
`expert TSC physicians who drew up the new
`international guidelines felt that an mTOR inhibi-
`tor should be first choice for pre-emptive treat-
`ment of angiomyolipomata, and embolization
`should be reserved for angiomyolipomata that are
`acutely bleeding [Krueger et al. 2013a].
`
`The wisdom of this pharmacological strategy is
`supported by
`the
`findings
`reported by
`Zonnenberg and colleagues [Zonnenberg et al.
`2014]. This investigation supervised care of a
`group of 351 adults in a TSC specialist clinic in
`Utrecht, over an average follow-up period of
`15.8 years, undertaking a policy of active pre-
`emptive embolization. A total of 144 patients
`had one or more embolizations for angiomyoli-
`pomata greater than 3.5 cm. The median age at
`end of the follow-up period was 39.8 years. Of
`the 29 deaths, nine (31%) were due to renal
`complications, making it the most common
`cause of death in this group. The overall mortal-
`ity was significantly higher than the Dutch gen-
`eral population. Although embolization managed
`individual large angiomyolipomata as a strategy
`to improve mortality, it did not prevent the pro-
`gression renal disease [Zonnenberg et al. 2014].
`In addition, Zonnenberg and colleagues have
`previously reported that a significant number of
`these patients with a high angiomyolipoma bur-
`den needed dialysis or transplantation [van der
`Wal et al. 2012].
`
`Given that, in at least 40% of patients, TSC asso-
`ciated angiomyolipomata are: multiple, bilateral,
`show an aggressive growth pattern in a majority of
`patients; that the recurrence rate post-emboliza-
`tion is at least 24% but probably higher over the
`
`Sirolimus
`The initial studies of the efficacy of mTOR inhibi-
`tors in animal models and in humans with TSC
`were carried out using sirolimus (see the refer-
`ences cited below). In TSC renal disease, there
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`Figure 7. Longer-term efficacy of everolimus in Exist-2, from Bissler et al. [2014a].
`
`were only three protocol specified phase II studies
`in humans: using the patients as their own con-
`trols [Bissler et al. 2008; Davies et al. 2011; Dabora
`et al. 2011]. There has also been a single phase III
`(placebo-controlled) study in pulmonary LAM,
`which is arguably a renal disease because the angi-
`omyolipoma or LAM cells may metastasize from
`renal lesion to the lung [Henske, 2003]. However,
`the MILES study did not consider renal out-
`comes, although sirolimus was highly efficacious
`in halting deterioration in lung disease in both
`an open-label trial [Bissler et al. 2008] and a pla-
`cebo-controlled trial [McCormack et al. 2011].
`
`The renal studies all showed that sirolimus was
`very effective at not only preventing angiomyolipo-
`mata from enlarging, but also significantly reduc-
`ing their size, while the medication was taken
`continuously. When discontinued after 12 months
`[Bissler et al. 2008; Dabora et al. 2011] the angio-
`myolipomata started to enlarge again, demonstrat-
`ing that the mTORC1 inhibitors need to be
`continued. No studies of stopping treatment after
`a few years’ therapy have yet been undertaken.
`
`Everolimus
`The phase II studies of sirolimus for TSC renal dis-
`ease led to a landmark phase III study: Exist-2.
`Publication of the initial results [Bissler et al. 2013]
`
`showed good efficacy and acceptable side effects
`(minor side effects being frequent but tolerable, and
`serious side effects rare); which led to the licensing
`of everolimus for the treatment of angiomyolipo-
`mata in adults in the USA and Europe [EMA,
`2012]. Previously, everolimus had gained a provi-
`sional license for the treatment of SEGA in TSC:
`which was confirmed following the publication of
`the Exist-1 study [Franz et al. 2012]. Subsequently,
`everolimus has been adopted into widespread use,
`worldwide, in clinical practice for these two indica-
`tions [Nicholson and Wood, 2014; Narayanan et al.
`2013]: as recommended in the international clinical
`guidelines [Krueger et al. 2013a].
`
`Analysis of the continuing Exist-2 study has shown
`that efficacy increases over time (see Figure 7)
`[Bissler et  al. 2014a]. In contrast, adverse events
`have diminished dramatically over time (see Table
`5) [Bissler et  al. 2014a, 2014b; Kingswood et  al.
`2013]. This may be due in part to increasing toler-
`ance of normal cells to everolimus (as opposed to
`the TSC null cells which remain exquisitely sensi-
`tive), and partly due to the dosing strategy of lower-
`ing the dose in those who had recurrent or persistent
`side effects [Bissler et al. 2013].
`
`The dose or plasma level of everolimus did not
`correlate with the incidence of side effects
`[Kingswood et al. 2014c]. Nor did they correlate
`
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`Table 5. Incidence of side effects over time in Exist-2 from Bissler et al. [2014a].
`
`EXIST-2 adverse events by preferred term and year of emergence occurring in >10% of patients: 2.45-year
`update
`
`Everolimus
`
`Adverse event, n (%)
`
`⩽12 months
`
`13–24 months
`
`25–36 months
`
`37–48 months
`
`(n = 112)
`
`(n = 101)
`
`Stomatitis
`Nasopharyngitis
`Acne
`Headache
`Hypercholesterolaemia
`Aphthous stomatitis
`Fatigue
`Cough
`Diarrhoea
`Nausea
`Mouth ulceration
`Urinary tract infection
`Vomiting
`Hypertension
`Oedema peripheral
`Amenorrhoea
`Leukopenia
`Back pain
`Blood lactate dehydrogenase
`increased
`Hypophosphataemia
`
`46 (41.1)
`36 (32.1)
`28 (25.0)
`26 (23.2)
`25 (22.3)
`21 (18.8)
`19 (17.0)
`18 (16.1)
`17 (15.2)
`17 (15.2)
`17 (15.2)
`16 (14.3)
`15 (13.4)
`14 (12.5)
`12 (10.7)
`12 (10.7)
`12 (10.7)
`12 (10.7)
`12 (10.7)
`
`11 (9.8)
`
`9 (8.9)
`19 (18.8)
`8 (7.9)
`11 (10.9)
`9 (8.9)
`14 (13.9)
`2 (2.0)
`4 (4.0)
`6 (5.9)
`5 (5.0)
`3 (3.0)
`14 (13.9)
`7 (6.9)
`3 (3.0)
`8 (7.9)
`7 (6.9)
`6 (5.9)
`5 (5.0)
`2 (2.0)
`
`5 (5.0)
`
`(n = 77)
`
`2 (2.6)
`14 (18.2)
`3 (3.9)
`3 (3.9)
`6 (7.8)
`6 (7.8)
`2 (2.6)
`4(5.2)
`3 (3.9)
`0 (0.0)
`2 (2.6)
`6 (7.8)
`1 (1.3)
`3 (3.9)
`4 (5.2)
`3 (3.9)
`0 (0.0)
`2 (2.6)
`1 (1.3)
`
`4 (5.2)
`
`(n = 18)
`
`0 (0.0)
`5 (27.8)
`0 (0.0)
`0 (0.0)
`3 (16.7)
`1 (5.6)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`2 (11.1)
`0 (0.0)
`1 (5.6)
`1 (5.6)
`1 (5.6)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`1 (5.6)
`0 (0.0)
`
`2 (11.1)
`
`with efficacy, except for one significant relation-
`ship between the concentration at 2 h post-dose
`(Cmin) and the percentage decrease in total vol-
`ume of renal angiomyolipomata in the early
`phase of the study [Zonnenberg et al. 2012], such
`that for every doubling of Cmin there was a 10%
`extra decrease in angiomyolipoma total volume.
`This implies that for TSC renal disease the doses
`used (and plasma levels achieved) in most
`patients were higher than needed, and the main
`effect of the higher doses was to shrink angiomy-
`olipomata slightly more rapidly.
`
`The MILES and Malinowska studies found a
`relationship between vascular endothelial growth
`factor D (VEGF-D), a vascular promoting cytokine,
`and treatment with sirolimus [McCormack et al.
`2011; Malinowska et  al. 2013]. Exist-2 tested
`the relationship between a number of potential
`biomarkers, angiomyolipoma mass and treat-
`ment. This confirmed a highly significant
`
`in
`correlation between percentage change
`VEGF-D and decrease in angiomyolipoma mass
`on mTORC1 inhibitor treatment, with a weaker
`correlation between VEGF-D change and
`increase in angiomyolipoma mass on placebo
`(see Figure 8) [Bissler et  al. 2013]. There was
`also a significant correlation between angiomy-
`olipoma size at baseline, and both VEGF-D and
`collagen IV plasma levels [Bissler et  al. 2013;
`Budde et al. 2013]. The changes in these bio-
`markers may be useful in future clinical practice
`in order to measure response, and also may help
`to explain the protection from haemorrhage that
`treatment with mTOR inhibitors confers. No
`patient in Exist-2 has had a renal haemorrhage
`after commencing on everolimus; the study is
`now completing its fifth year.
`
`Another finding from the longer-term data in
`Exist-2 was that the mean GFR did not signifi-
`cantly change (see Figure 9) [Bissler et  al.
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`Figure 8. The relationship between the vascular growth promoting cytokine VEGF-D and change in
`angiomyolipoma mass in the Exist-2 study from Bissler et al. [2013].
`VEGF-D, vascular endothelial growth factor D.
`
`Figure 9. The effect of everolimus on renal function in Exist-2 from Bissler et al. [2014c].
`
`2014c]. Some individuals (most of whom started
`the trial with a GFR <30 ml/min) did have dete-
`rioration in renal function; but in most GFR
`remained stable or improved [Bissler et  al.
`
`2014c]. This is a very encouraging finding in a
`group of individuals who would otherwise have
`been at high risk of developing chronic kidney
`disease.
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`JJ Bissler and JC Kingswood
`
`Figure 10. The effect of everolimus on angiomyolipomata in a paediatric population from Kingswood et al. [2014c].
`
`Although Exist-1 was primarily designed to
`test the efficacy and safety of treating SEGA in
`children with TSC [Franz et  al. 2012], the
`exploratory endpoint of the effect of everoli-
`mus on angiomyolipomata greater than 1 cm
`was also analysed. In the 44 subjects (median
`age 12.5 years) with at least one angiomyoli-
`poma greater than one centimetre, 80% on
`everolimus and 0% of those on placebo had a
`decrease in total volume of target angiomyoli-
`pomata of >50%. In addition, a decrease of
`more than 30% was found in all of the patients
`taking everolimus, and in only 17% of those on
`placebo [Kingswood et  al. 2014b]; also see
`Figure 10. This clearly shows that everolimus
`is highly effective in preventing angiomyoli-
`poma progression in children with TSC. The
`side-effect profile of the patients in Exist-1 has
`also been relatively mild and tolerable [Franz
`et al. 2014].
`
`One initial concern when designing studies with
`mTORC1 inhibitors was that the mTOR path-
`way is of such fundamental significance in cellular
`metabolism that an mTORC1 inhibitor might
`cause a deterioration in other aspects of TSC. In
`fact, the opposite has been demonstrated. The
`MILES study showed Sirolimus was highly
`
`efficacious for pulmonary LAM, as did one of the
`phase II angiomyolipoma studies [McCormack
`et  al. 2011; Bissler et  al. 2008]. In addition, an
`ongoing study has shown similar findings for
`treatment with everolimus [Goldberg et al. 2014].
`Exist-2 also examined the effect of everolimus on
`skin rash as a secondary endpoint; the rash
`showed a significant improvement, varying from
`moderate to marked on everolimus, but not on
`placebo [Bissler et al. 2013].
`
`Seizures are the major cause of morbidity and
`mortality in TSC. Work in animal models and
`case studies suggested mTORC1
`inhibitors
`might have a beneficial effect. This was proven in
`a phase II study of the effect of everolimus in
`resistant seizures, for which it proved highly effi-
`cacious [Krueger et al. 2013b]. The utility of this
`and the risk/benefit ratio is currently being
`explored in an Exist-3 study [ClinicalTrials.gov
`identifier: NCT01713946].
`
`Finally, case reports of improvements in neurocog-
`nition and autistic spectrum disorder, as well as
`work in animal models, has led to ongoing studies
`to assess the magnitude of the effect of everolimus
`on these two complications of TSC in the TRON
`study in the UK [ClinicalTrials.gov identifier:
`
`http://tau.sagepub.com
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`Therapeutic Advances in Urology
`
`NCT01954693], the RAPIT study in Holland
`[ClinicalTrials.gov
`identifier: NCT01730209],
`and a further study in the USA [ClinicalTrials.gov
`identifier: NCT01289912].
`
`Conclusion
`The aggressive nature of renal angiomyolipomata
`in patients with TSC and their natural history jus-
`tifies the recommendation of the international
`guidelines [Krueger et al. 2013a] proposing pre-
`emptive treatment with an mTOR inhibitor as
`first choice of therapy. All the evidence suggests
`that this will not only prevent the high morbidity
`and mortality due to renal complications, but
`may also confer other significant benefits in TSC.
`
`Funding
`This research received no specific grant from any
`funding agency in the public, commercial, or not-
`for-profit sectors.
`
`Conflict of interest statement
`The authors declare no conflicts of interest in
`preparing this article.
`
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