|Year : 2018 | Volume
| Issue : 2 | Page : 100-105
Mammalian target of rapamycin inhibitor and transarterial embolization for treatment of tuberous sclerosis complex patients with renal angiomyolipoma
Wei-Chung Hsiao1, Jeng-Dau Tsai2, Shao-Chun Wang3, Sung-Lang Chen3
1 Department of Urology, Chung Shan Medical University Hospital, Taichung, Taiwan
2 Department of Pediatrics, Chung Shan Medical University Hospital; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
3 Department of Urology, Chung Shan Medical University Hospital; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
|Date of Web Publication||30-Apr-2018|
Department of Urology, Chung-Shan Medical University Hospital, #110, Chien-Kuo North Road, Section 1, Taichung 402
Source of Support: None, Conflict of Interest: None
Objective: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease that results in multiorgan hamartomas. Patients with TSC also frequently have renal angiomyolipomas, which are rare but benign renal tumors. However, the main causes of mortality in these patients are angiomyolipoma-related chronic kidney disease and acute tumor hemorrhage. Angiomyolipomas are mostly treated in our hospital using mammalian target of rapamycin (mTOR) inhibitor therapy or transarterial embolization (TAE). This study was undertaken to evaluate and compare the short-term outcomes of a combined therapy of mTOR inhibitor and TAE in patients with TSC-associated angiomyolipoma. Materials and Methods: This was a retrospective observational study based on collected data obtained from chart reviews. The single-center data set covered patients diagnosed, treated, and followed up from September 10, 2008, to March 17, 2016, at a specialist center. Patients with TSC-associated angiomyolipoma treated with monotherapy or combined treatment of mTOR inhibitor and TAE were included in this study. We compared the tumor size with image studies in the baseline and follow-up periods in both groups. Results: In total, 15 patients (3 males and 12 females) were included; 8 patients underwent mTOR inhibitor monotherapy and 7 received the combined mTOR inhibitor and TAE therapy. The mean patient age was 37.7 (17–72) years. The maximal diameters of renal angiomyolipomas ranged from 2 to 20.9 (10.2 ± 5.4) cm for all patients at the time of treatment intervention. During an average follow-up duration of 22 (2–56) months, the mean size of the angiomyolipomas decreased from 9.3 ± 5.6 to 8.5 ± 5.3 cm in the monotherapy group and 11.5 ± 5.4–10.0 ± 5.8 cm in the patients in the combined therapy (P = 0.014). Conclusions: In comparison with m-TOR inhibitor monotherapy, TAE combined with mTOR inhibitor therapy allows management of tumor bleeding with acceptable complications, and it also statistically reduces the tumor size in patients with TSC-associated renal angiomyolipomas.
Keywords: Embolization, rapamycin inhibitor, tuberous sclerosis
|How to cite this article:|
Hsiao WC, Tsai JD, Wang SC, Chen SL. Mammalian target of rapamycin inhibitor and transarterial embolization for treatment of tuberous sclerosis complex patients with renal angiomyolipoma. Urol Sci 2018;29:100-5
|How to cite this URL:|
Hsiao WC, Tsai JD, Wang SC, Chen SL. Mammalian target of rapamycin inhibitor and transarterial embolization for treatment of tuberous sclerosis complex patients with renal angiomyolipoma. Urol Sci [serial online] 2018 [cited 2019 May 19];29:100-5. Available from: http://www.e-urol-sci.com/text.asp?2018/29/2/100/228286
| Introduction|| |
Tuberous sclerosis complex (TSC), also known as Bourneville disease, is an autosomal dominant genetic disease caused by mutations in either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16. The gene product of TSC1 is hamartin and the gene product of TSC2 is tuberin; these combine to form a complex that inhibits the expression of mammalian target of rapamycin (mTOR). Mutation of either the TSC1 or TSC2 gene, therefore, results in overexpression of mTOR and the subsequent development of multiorgan hamartomas., Thus, agents that act as mTOR inhibitors offer an opportunity to inhibit the uncontrolled cell growth associated with TSC-associated tumors.
The estimated prevalence of TSC ranges from 1 in 10,000 to 1 in 30,000 individuals in different studies.,, However, current estimates indicate that more than one-half of patients with TSC mutations are not detected  and that the birth incidence is higher, ranging from 1 in 5000 to 1 in 10,000 individuals. TSC may involve the skin (facial angiofibromas), brain (subependymal giant cell astrocytomas [SEGAs] and epileptogenic tubers), lung (lymphangioleiomyomatosis [LAM]), heart (rhabdomyomas), eye (retinal astrocytic hamartomas), and kidney (cysts or angiomyolipomas) throughout the lifetime of affected individuals. Cortical tubers, which are focal malformations located at the subcortical junction zone, occur in 80%–90% of TSC patients., Subependymal nodules are often located along the lateral ventricle walls and occur in 90% of TSC patients. SEGAs are slow-growing brain tumors that occur in up to 20% of TSC patients. Pulmonary LAMs occur in 40% of premenopausal females , and renal lesions in 60%–80% of patients with TSC.,,
The prevalence of renal lesions in TSC increases with age, eventually affecting up to 80% of patients.,, The most common renal lesions associated with TSC are angiomyolipomas, cysts, and renal cell carcinoma. Renal angiomyolipomas are rare renal tumors that account for <3% of all renal masses, but they are the most common renal presentation in patients with TSC. They are benign mesenchymal tumors composed of abnormal blood vessels, immature smooth muscle spindles, and adipocytes. These tumors can bleed acutely due to the abnormal vasculature that forms aneurysms with a tendency for spontaneous hemorrhage so that these tumors, as well as chronic kidney disease resulting from a progressive loss of normal renal parenchyma, are the main causes of mortality in patients with TSC., These complications also increase the hospital days and costs of healthcare resources for these patients.
Treatment of renal angiomyolipomas associated with TSC, therefore, focuses on preventing acute events, preserving renal parenchyma, and maintaining long-term kidney function. Approximately one-quarter of patients with TSC-associated renal angiomyolipomas undergo interventional procedures. Besides active surveillance, TSC-associated renal angiomyolipomas are mostly managed by selective transarterial embolization (TAE), radical and partial nephrectomy, ablative therapies, including cryoablation and radiofrequency ablation, and mTOR inhibitor therapy. One potent selective inhibitor of mTOR is everolimus, a synthetic derivative of sirolimus, also known as rapamycin, which is thought to act by inhibition of protein translation and impairment of cellular proliferation.
A number of studies have described the treatment of renal angiomyolipomas in patients with TSC; however, research reports are scarce regarding the effects of mTOR inhibitor therapy combined with TAE. The present study was undertaken as a retrospective evaluation and comparison of the short-term outcomes of mTOR inhibitor therapy, applied as monotherapy or combined with TAE, in patients with TSC-associated angiomyolipomas.
| Materials and Methods|| |
The inclusion criterion for this retrospective analysis was a diagnosis of TSC according to the newest diagnostic criteria of the 2012 International TSC Consensus Conference. Patients diagnosed with TSC-associated renal angiomyolipoma were enrolled from September 2008 to March 2016. All the enrolled participants received daily oral sirolimus (1–4 mg) or everolimus (2.5–10 mg). The combined group was treated with mTOR inhibitor and with additional TAE within 1 month of starting the target therapy. The decision to undergo combined therapy was discussed and determined together by the treating physician and the patient. None of the patients underwent any further treatments, such as surgical interventions. TAE was administered by an experienced radiologist. Vascular access was obtained for all the embolization procedures. A vascular sheath (sized 6–7 Fr.) was introduced through the common femoral artery, and its tip was located directly caudally to the origin of the renal arteries. The renal artery was selectively catheterized with the use of a 4–5 Fr. catheter. For superselective embolizations, a 2.2–2.7 Fr. microcatheter was also used. The most commonly used embolization material was a mixture of n-butyl-2-cyanoacrylate (NBCA) glue (Histoacryl ®; B. Braun, Melsungen Germany) and an oil-iodinated contrast medium (Lipiodol ® Ultra-Fluide; Guerbet, USA) at a concentration of 17%–25%. The serum creatinine levels of the patients who underwent TAE were also measured before embolization and monthly during follow-up to monitor renal function.
Data were extracted from electronic medical charts. All sizes of the tumors and responses to therapy were measured by routine computed tomography (CT) or magnetic resonance imaging (MRI) in the largest diameter of the same plane direction (transverse or sagittal). The period from detection of the tumor to the administration of the treatment intervention was defined as the surveillance phase. The end points were set when the patient was lost at follow-up or quit treatment due to adverse effects.
All statistical analyses were conducted in SPSS for Windows (Version 14.0; SPSS Inc., Chicago, IL, USA). The variables were analyzed with the paired t-test and a P < 0.05 was considered statistically significant.
| Results|| |
In total, 16 patients (4 males and 12 females) were included in the study. Eight patients were treated with mTOR inhibitor only (monotherapy group), and 7 underwent the combination of mTOR inhibitor and TAE (combined therapy group) [Table 1]. The one remaining patient was treated with TAE only and was not included in the study samples. No statistically significant differences were detected in the distributions of age, gender, and tumor size of the patients although the patients in the monotherapy group were relatively younger and had smaller sized tumors. The maximal diameters of the renal angiomyolipomas measured during the study period ranged from 2 to 20.9 cm. The mean tumor size of all patients was 9.5 ± 5.5 cm at the time of diagnosis and 10.2 ± 5.4 cm at the time of treatment initiation [Table 2]. The mean durations of surveillance (from diagnosis to the time of treatment) were 31.4 ± 24 months in the monotherapy group and 18 ± 25.6 months in the combined therapy group (P = 0.316) [Table 1]. Obvious and significant tumor enlargements were noted during the surveillance phases when all patients were considered together (P = 0.039); however, only the enlargement occurring in the mTOR inhibitor monotherapy group was statistically significant (P = 0.047). The tumor enlargement in the combined therapy group during this phase was not statistically significant (P = 0.349).
|Table 1: Baseline characteristics of the patients with tuberous sclerosis complex-associated renal angiomyolipoma|
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|Table 2: Size (cm) of tuberous sclerosis complex-associated renal angiomyolipomas on the time of diagnosis, initial treatment, and treatment end point|
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During an average follow-up duration of 22 (2–56) months, the mean size of the angiomyolipomas decreased from 9.3 ± 5.6 cm to 8.5 ± 5.3 cm in the monotherapy group (P = 0.494) and 11.5 ± 5.4 cm to 10.0 ± 5.8 cm in the combined therapy group (P = 0.014). The average interval between initiation of the intervention and the follow-up end point was 16.4 ± 10.1 months in the monotherapy group and 27.1 ± 23 in the combined therapy group (P = 0.285). We also followed up serum creatinine levels in all treated patients. No treatment-related renal function impairment, severe complications, or even death occurred in our study cohort [Table 3].
|Table 3: Serum creatinine levels of the patients with tuberous sclerosis complex-associated renal angiomyolipoma changes from before treatment to last follow-up|
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| Discussion|| |
Angiomyolipomas can arise sporadically or as part of TSC, and they can occur, more rarely, as sporadic LAM, a lung disease found almost exclusively in women. TSC-associated angiomyolipomas are quite common in this hereditary, complex syndrome.,, They are usually multiple and bilateral, and the lesions usually progress over time, with a size increase of 0.088–1.25 cm/year., The growth rate also has a positive association with increasing age. To the best of our knowledge, the largest reported unilateral renal angiomyolipoma measured 39 cm × 29 cm × 9 cm, with a tumor burden of about 7.5 kg, and the largest bilateral lesions measured 29 cm × 27.5 cm × 15.5 cm and 30 cm × 19 cm × 13 cm, with an estimated total weight of more than 8 kg. The mass effect is usually complicated, with a palpable mass, flank pain, hypertension, urinary tract infections, hematuria, life-threatening hemorrhage, and even renal deterioration due to damage to functional renal tissue.
Few prospective randomized trials have compared surveillance and treatment for angiomyolipoma, but continued active surveillance of angiomyolipomas is considered imperative, and routine imaging follow-up is recommended to monitor progression, detect new lesions, screen for malignancy, and manage secondary complications. Younger patients (<20 years) with lower tumor burdens should undergo MRI or ultrasound every 2–5 years,, while older patients should be evaluated by MRI or CT every 1–3 years, depending on tumor size.,,, MRI, when possible, is considered the best imaging modality because of its better resolution of fat-poor lesions and lower radiation exposure compared with CT imaging., Biochemistry analysis, including glomerular filtration rates and quantification of proteinuria, is also recommended at least annually.
The timing of intervention depends on the risk and severity of the symptoms and complications. Patients with a low clinical burden may experience prolonged periods of asymptomatic disease, whereas other patients with larger lesions may need pharmacological or surgical treatment. Our study demonstrated an obvious and significant tumor enlargement during the surveillance phase (from diagnosis to any treatment) when all patients were considered together (P = 0.039), which means that the optimal intervention timing might be delayed in general practice.
Several clinical trials have demonstrated that mTOR inhibitor therapy reduced tumor volumes with an acceptable safety profile.,, mTOR is a kinase that plays a role in regulating protein synthesis, angiogenesis, and cell growth, metabolism, orientation, and migration. Mutations in the TSC1 or TSC2 genes, which encode the proteins hamartin and tuberin, respectively, and form a tumor suppressor complex together, will lead to direct activation of mTOR signaling, in essence, causing increased cell proliferation and growth., Targeted therapy with sirolimus or everolimus for mTOR inhibition has become a feasible medication for treatment of TSC and TSC-associated angiomyolipomas. However, tumor size matters with respect to the patient's morbidity and life quality.
Tumors sized more than 4 cm in diameter are at risk for spontaneous, life-threatening bleeding due to rupture of abnormal vessels, as known as Wunderlich syndrome. The majority of reports that have documented the role of surgical interventions in treating symptomatic angiomyolipoma, such as acute retroperitoneal hemorrhage, now indicate a general trend away from radical surgeries, such as nephron-sparing surgery or total nephrectomy, and toward minimally invasive procedures. TAE, as a minimally invasive procedure, is therefore increasingly used in the treatment of renal angiomyolipoma. In the early 2000s, practitioners began to use embolization on an elective basis in patients with large and growing angiomyolipomas, as a way to prevent hemorrhage and preserve kidney function. This practice was added to the Dutch treatment guidelines in 2006.
A recent systemic review revealed that TAE reduced tumor size by approximately 40%, with low rates of mortality and serious complications. Repeat procedures were sometimes indicated by conditions that included revascularization of the angiomyolipoma on follow-up imaging, unchanged or increasing tumor size, refractory or recurring symptoms, re-presentation of retroperitoneal hemorrhage, failure to devascularize the lesion or control retroperitoneal hemorrhage, failure to identify or cannulate the hemorrhagic vessels, concern about malignancy, and contrast sensitization requiring postponement following corticosteroid therapy. At present, localized therapies such as TAE, percutaneous cryoablation, radiofrequency ablation, or microwave ablation  have become management tools for acute deteriorated events. They also show potential for the prevention of complications in patients with TSC-associated angiomyolipomas when used as selective therapies.
Thus, combined treatment is the management trend in TSC-associated angiomyolipoma. Nevertheless, no studies have yet compared the treatment outcomes of TAE combined with mTOR therapy. A recently published report demonstrated that embolization of the residual tumor would be highly desirable to consolidate the gains made in tumor volume control from mTOR inhibition and thereby prevent rebound growth; however, the addition of TAE to mTOR inhibitor therapy did not provide sustained abrogation of tumor growth. In our patients, we saw a significant angiomyolipoma shrinkage after the combined therapy when compared with the monotherapy. No severe TAE procedure-related complications or even mortality were noted, except for the development of a minor postembolization syndrome (including pain, hematoma, fever, nausea, or vomiting), which was well treated by the primary care physicians. The renal function before and after embolization, measured by serum creatinine levels, indicated no TAE-induced renal insufficiency in the 6 patients who received the combined therapy.
The mean durations of surveillance were 31.4 ± 24 months in the monotherapy group and 18 ± 25.6 months in the combined therapy group [Table 1]. The relatively shorter surveillance period for the combined therapy group might indicate that angiomyolipoma bleeding prompted the physicians and patients to adopt TAE as an adjunctive management as soon as possible. The shorter surveillance time in the combined group could partially explain the lack of conspicuous tumor growth when compared with the longer surveillance period of the mTOR monotherapy group. Furthermore, the longer follow-up duration of combined therapy group (27.1 ± 23 months vs. 16.4 ± 10.1 months), even though not statistically significant (P = 0.285), might also reflect a greater tumor shrinkage in that group.
This study has several limitations. The most important restrictions were its observational single-centered design and the small case number. We also had no TAE monotherapy as a control group. The treatment allocation was not randomized, and the treatment decision was made by the physicians and patients together. However, TSC-associated angiomyolipoma is a rare genetic disease, which precludes the enrollment of a large sample size within a short study period. Larger prospective multicenter and randomized studies may be warranted to confirm the actual superiority of the combined therapy as a treatment for TSC-associated angiomyolipomas.
| Conclusions|| |
TAE combined with mTOR inhibitor therapy plays an important role in the management of tumor bleeding, with acceptable complications, but it can also provide an effective reduction in the tumor size. This combined therapy of TAE and mTOR inhibitor showed a statistically significant reduction in the tumor size progression of TSC-associated renal angiomyolipomas when compared to mTOR monotherapy alone.
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| References|| |
Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N
Engl J Med 2006;355:1345-56.
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008;372:657-68.
O'Donnell A, Faivre S, Burris HA 3rd
, Rea D, Papadimitrakopoulou V, Shand N, et al.
Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008;26:1588-95.
Hallett L, Foster T, Liu Z, Blieden M, Valentim J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: Systematic review. Curr Med Res Opin 2011;27:1571-83.
Levy M, Feingold J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 2000;58:925-43.
Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N
Y Acad Sci 1991;615:125-7.
Baskin HJ Jr. The pathogenesis and imaging of the tuberous sclerosis complex. Pediatr Radiol 2008;38:936-52.
Kopp CM, Muzykewicz DA, Staley BA, Thiele EA, Pulsifer MB. Behavior problems in children with tuberous sclerosis complex and parental stress. Epilepsy Behav 2008;13:505-10.
Crino PB, Mehta R, Vinters HV. Pathogenesis of TSC in the brain. In: Kwiatkowski DJ, Whittemore VH, Thiele EA, editors. Tuberous Sclerosis Complex: Genes, Clinical Features and Therapeutics. Weinheim, Germany: Wiley Blackwell; 2010. p. 159-85.
Franz DN. Non-neurologic manifestations of tuberous sclerosis complex. J Child Neurol 2004;19:690-8.
Johnson SR. Lymphangioleiomyomatosis. Eur Respir J 2006;27:1056-65.
Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA, et al.
Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int 2006;70:1777-82.
O'Callaghan FJ, Noakes MJ, Martyn CN, Osborne JP. An epidemiological study of renal pathology in tuberous sclerosis complex. BJU Int 2004;94:853-7.
Dixon BP, Hulbert JC, Bissler JJ. Tuberous sclerosis complex renal disease. Nephron Exp Nephrol 2011;118:e15-20.
Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES. Renal lesion growth in children with tuberous sclerosis complex. J Urol 1998;160:141-5.
Koo KC, Kim WT, Ham WS, Lee JS, Ju HJ, Choi YD, et al.
Trends of presentation and clinical outcome of treated renal angiomyolipoma. Yonsei Med J 2010;51:728-34.
Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kidney Int 2004;66:924-34.
Eijkemans MJ, van der Wal W, Reijnders LJ, Roes KC, van Waalwijk van Doorn-Khosrovani SB, Pelletier C, et al.
Long-term follow-up assessing renal angiomyolipoma treatment patterns, morbidity, and mortality: An observational study in tuberous sclerosis complex patients in the Netherlands. Am J Kidney Dis 2015;66:638-45.
Vekeman F, Magestro M, Karner P, Duh MS, Nichols T, van Waalwijk van Doorn-Khosrovani SB, et al.
Kidney involvement in tuberous sclerosis complex: The impact on healthcare resource use and costs. J Med Econ 2015;18:1060-70.
Bissler J, Cappell K, Charles H, Song X, Liu Z, Prestifilippo J, et al.
Rates of interventional procedures in patients with tuberous sclerosis complex-related renal angiomyolipoma. Curr Med Res Opin 2015;31:1501-7.
Flum AS, Hamoui N, Said MA, Yang XJ, Casalino DD, McGuire BB, et al.
Update on the diagnosis and management of renal angiomyolipoma. J Urol 2016;195:834-46.
Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 iinternational tuberous sclerosis complex consensus conference. Pediatr Neurol 2013;49:243-54.
Mues AC, Palacios JM, Haramis G, Casazza C, Badani K, Gupta M, et al.
Contemporary experience in the management of angiomyolipoma. J Endourol 2010;24:1883-6.
Seyam RM, Bissada NK, Kattan SA, Mokhtar AA, Aslam M, Fahmy WE, et al.
Changing trends in presentation, diagnosis and management of renal angiomyolipoma: Comparison of sporadic and tuberous sclerosis complex-associated forms. Urology 2008;72:1077-82.
Tsai JD, Wei CC, Chen SM, Lue KH, Sheu JN. Association between the growth rate of renal cysts/angiomyolipomas and age in the patients with tuberous sclerosis complex. Int Urol Nephrol 2014;46:1685-90.
Mistry KA, Sood D, Bhoil R, Chadha V, Ahluwalia AK, Sood S, et al.
Aclassic case of tuberous sclerosis with multisystem involvement including giant bilateral renal angiomyolipomas presenting as massive hematuria. Pol J Radiol 2015;80:435-41.
Kapoor A, Girard L, Lattouf JB, Pei Y, Rendon R, Card P, et al.
Evolving strategies in the treatment of tuberous sclerosis complex-associated angiomyolipomas (TSC-AML). Urology 2016;89:19-26.
Rouvière O, Nivet H, Grenier N, Zini L, Lechevallier E. Guidelines for the management of tuberous sclerosis complex renal disease. Prog Urol 2012;22:367-79.
Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: Recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol 2013;49:255-65.
Lin CY, Chen HY, Ding HJ, Yen KY, Kao CH. FDG PET or PET/CT in evaluation of renal angiomyolipoma. Korean J Radiol 2013;14:337-42.
Radhakrishnan R, Verma S. Clinically relevant imaging in tuberous sclerosis. J Clin Imaging Sci 2011;1:39.
] [Full text]
Halpenny D, Snow A, McNeill G, Torreggiani WC. The radiological diagnosis and treatment of renal angiomyolipoma-current status. Clin Radiol 2010;65:99-108.
Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al.
Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013;381:817-24.
Sasongko TH, Ismail NF, Nik Abdul Malik NM, Zabidi-Hussin ZA. Rapamycin and its analogues (rapalogs) for tuberous sclerosis complex-associated tumors: A systematic review on non-randomized studies using meta-analysis. Orphanet J Rare Dis 2015;10:95.
Tran LH, Zupanc ML. Long-term everolimus treatment in individuals with tuberous sclerosis complex: A Review of the current literature. Pediatr Neurol 2015;53:23-30.
Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K, et al.
Renal angiomyolipoma: Relationships between tumor size, aneurysm formation, and rupture. Radiology 2002;225:78-82.
Murray TE, Doyle F, Lee M. Transarterial embolization of angiomyolipoma: A Systematic review. J Urol 2015;194:635-9.
Krummel T, Garnon J, Lang H, Gangi A, Hannedouche T. Percutaneous cryoablation for tuberous sclerosis-associated renal angiomyolipoma with neoadjuvant mTOR inhibition. BMC Urol 2014;14:77.
Cristescu M, Abel EJ, Wells S, Ziemlewicz TJ, Hedican SP, Lubner MG, et al.
Percutaneous microwave ablation of renal angiomyolipomas. Cardiovasc Intervent Radiol 2016;39:433-40.
Sheth RA, Feldman AS, Paul E, Thiele EA, Walker TG. Angiographic and volumetric effects of mammalian target of rapamycin inhibitors on angiomyolipomas in tuberous sclerosis. World J Radiol 2016;8:308-15.
[Table 1], [Table 2], [Table 3]