Angiomyolipoma Volume Research Articles

Serum lactate dehydrogenase concentration after transcatheter renal artery embolization correlates with reduction in renal angiomyolipoma volume.

The extent of renal angiomyolipoma (AML) volume reduction after renal transcatheter arterial embolization (TAE) varies between patients, with no predictive measure available. To determine whether the serum lactate dehydrogenase (LDH) concentration shortly after TAE correlates with the extent of tumor shrinkage. In a cohort of 36 patients undergoing prophylactic renal TAE for unruptured renal AML, we retrospectively acquired data from patient medical records, including serum LDH before and within 7 days after TAE and the tumor volume before and 12-36 months after TAE. The relationship between the serum level of LDH and reduction in tumor volume was evaluated using Spearman correlation analysis. The median LDH concentration was significantly higher after TAE than before (909.0 U/L vs. 186.5 U/L). This early post-TAE serum LDH level and LDH index (post-TAE LDH / pre-TAE LDH) correlated significantly and positively with the absolute decrease in tumor volume (both P < 0.0001). We observed no significant correlation between the relative tumor volume reduction and serum LDH level or LDH index. Serum LDH elevation occurs shortly after TAE and correlates with the extent of absolute decrease in AML volume at 12-36 months after TAE. Further large-scale studies are warranted to confirm the predictive role of post-TAE serum LDH level and LDH index in tumor shrinkage in patients with unruptured renal AML.

Everolimus versus sirolimus for angiomyolipoma associated with tuberous sclerosis complex: a multi-institutional retrospective study in China

PurposeTo evaluate the efficacy and safety of everolimus and sirolimus in patients with tuberous sclerosis complex-associated angiomyolipomas (TSC-AML).Materials and methods We performed a multi-institutional retrospective study of TSC-AML patients treated with oral everolimus 10 mg or sirolimus 2 mg per day for at least 3 months. Angiomyolipoma volume was estimated using orthogonal measurements by MRI or CT. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events. All analyses were performed using SPSS 19.0 software.ResultsResponse rates were high in both groups. With the prolonged medication durations, the therapeutic efficacy of both agents became more significant. The TSC-AML volume reduction after 6 and 12 months was more pronounced in patients with everolimus than those with sirolimus. More than half of the patients treated with everolimus had ≥ 50% reduction, and approximately 80% of them had ≥ 30% reduction, which was higher than that in patients treated with sirolimus. Regarding safety, there was no significant difference in the incidence of AEs between the two groups.ConclusionsBoth everolimus and sirolimus are excellent therapeutic options for TSC-AML. However, everolimus has a better therapeutic efficacy than sirolimus, particularly in reducing TSC-AML volume. Everolimus is therefore recommended as the first choice of therapy for TSC-AML.

Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial

BackgroundTuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder characterized by the development of numerous benign tumors. Renal angiomyolipoma (RAML) occur in up to 80% of TSC patients, which is a leading cause of TSC-related death in adult patients. The aim of the study was to evaluate the efficacy and safety profiles of everolimus in Chinese patients of TSC associated with RAML(TSC-RAML).MethodsIn this 2-years, nonrandomized, open-label trial, 18 patients of TSC-RAML, with at least one RAML 3 cm or larger in its longest diameter, were enrolled to assess the efficacy and safety of everolimus therapy in Chinese patients. Everolimus was administered for the first 12 months only. The primary endpoint was a reduction of 50% or more relative in RAML volume to the baseline in the absence of new RAML ≥1 cm and no RAML-related bleeding of grade ≥ 2. The secondary endpoints included: safety, lung function and skin lesions response rate. Serial computed tomography of RAML, magnetic resonance imaging of brain lesions and pulmonary-function tests were performed. Adverse events were investigated using CTCAE v4.0. All analyses used a significance level of 0.05 and were generated in SPSS19.0 software.ResultsThe proportion of patients who achieved ≥50% reduction from baseline in the sum of volumes of target lesions increased from 52.94% at 3 months, to 58.82% and 66.67% at months 6 and 12, respectively. During the period of everolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 s (FEV1) increased by 276 ± 78 ml (P < 0.001), the forced vital capacity (FVC) increased by 433 ± 170 ml (P < 0.001), and the residual volume decreased by 408 ± 243 ml (P = 0.009), as compared with baseline values. The angiomyolipoma volume and the lung function approached, but did not completely return to, the baseline values. The skin lesions response rate was 37.5% after 12 months of therapy falling to 21.4% at 12 months after stopping everolimus. The most common adverse events were mucositis oral, irregular menstruation, abdominal pain, hypertriglyceridemia and headache. The most common grade 3 adverse events were irregular menstruation and mucositis oral. In addition, one patient died from RAML spontaneous haemorrhage during treatment with everolimus, even with reduction in RAML volume of 60.68% at 3 months. A second death was due to epithelioid RAML progression, with metastasis to multiple retroperitoneal lymph node, who died from severe infection one month after surgery.ConclusionsAngiomyolipomas regressed somewhat during everolimus therapy but tended to increase in volume after the therapy was stopped. Everolimus was well tolerated and showed promising activity in Chinese patients with TSC-RAML, however, we should alert the life-threatening hemorrhage of large RAML in the early period and the lymph node metastasis of epithelioid RAML.Trial registrationChiCTR-OPC-14005488. Registered November 17, 2014.

The effect of everolimus on renal angiomyolipoma in pediatric patients with tuberous sclerosis being treated for subependymal giant cell astrocytoma

BackgroundPatients with tuberous sclerosis complex (TSC) often have multiple TSC-associated hamartomas, particularly in the brain and kidney.MethodsThis was a post hoc analysis of pediatric patients being treated for subependymal giant cell astrocytomas (SEGAs) during the phase 3, randomized, double-blind, placebo-controlled EXIST-1 trial. Patients were initially randomly assigned to receive everolimus 4.5 mg/m2/day (target blood trough 5–15 mg/dl) or placebo and could continue in an open-label extension phase. Angiomyolipoma response rates were analyzed in patients aged <18 years with ≥1 target angiomyolipoma lesion at baseline. Response was defined as the proportion of patients with a ≥50% reduction in the sum volume of target renal angiomyolipomata from baseline, in the absence of new target angiomyolipomata, a >20% increase in kidney volume from nadir, and angiomyolipoma-related bleeding ≥ grade 2. Tolerability was also assessed.ResultsOverall, this analysis included 33 patients. Renal angiomyolipoma response was achieved by 75.8% of patients (95% confidence interval, 57.7–88.9%), with sustained mean reductions in renal angiomyolipoma volume over nearly 4 years of treatment. In addition, most (≥80%) achieved clinically relevant reductions in angiomyolipoma volume (≥50%), beginning at week 24 and continuing for the remainder of the study. Everolimus was generally well tolerated in this subgroup, with most adverse events being grade 1 or 2 in severity.ConclusionsAlthough everolimus is currently not indicated for this use, this analysis from EXIST-1 demonstrates its long-term efficacy and safety for the treatment of renal angiomyolipoma in pediatric patients undergoing treatment for TSC-associated SEGA.

Outcomes of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: A single institution experience in Japan.

To evaluate the efficacy and toxicity profiles of everolimus in Japanese patients with renal angiomyolipoma associated with tuberous sclerosis complex. Patients with a 4-cm or larger angiomyolipoma meeting the diagnostic criteria of tuberous sclerosis complex were selected as participants of our investigation. In each case, we assessed tuberous sclerosis complex-associated symptoms, the treatment effect and adverse events. The treatment effect was evaluated by measuring the tumor volume reduction rate using abdominal computed tomography or magneitc resonance imaging. Adverse events were investigated using CTCAE v4.0-JCOG. The dose of everolimus was set at 10 mg once a day for adults. For childhood angiomyolipoma, everolimus administration was initiated at a dose of 5 mg once a day. Blood everolimus level was measured, and the dose was adjusted to maintain this within a range of 5-15 ng/mL. The angiomyolipoma volume decreased in 46 of 47 cases, and the mean reduction rate for all cases was 60% in 12 months. The angiomyolipoma volume markedly decreased in the first 3 months, and the size leveled off after 6 months. The main adverse events related to everolimus treatment were stomatitis (91%) and irregular menstruation (65%). Grade 3 or severer adverse events were noted in three cases (6%). All patients developed some adverse events in the first 6 months. The incidence markedly decreased to 40-50% after 13 months. The tumor volume-reducing effect of everolimus in a Japanese population was equivalent to or higher than that in Western populations. A wide variety of everolimus treatment-related adverse events can be observed, but most cases are very mild. Special attention should be given to stomatitis, irregular menstruation and interstitial lung disease as adverse events.

Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial.

Mammalian target of rapamycin (mTOR) inhibitors are recommended as first-line treatment of renal angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sporadic LAM), but follow-up is limited. Longer term efficacy and tolerability data from a Phase 3, double-blind, placebo-controlled trial are presented. Following favorable results from the primary analysis (data cutoff 30 June 2011) of the EXIST-2 trial, patients still receiving study treatment were allowed to enter an open-label extension. Everolimus was initiated at 10 mg once daily and titrated based on tolerability. The primary outcome was angiomyolipoma response rate (≥ 50% reduction from baseline in target lesion volumes). Safety was a secondary endpoint. As of the cutoff date (1 May 2013), 112 patients had received everolimus, and the response rate in 107 patients with angiomyolipoma (median duration of medication exposure of 28.9 months) was 54%. The proportion of patients achieving angiomyolipoma reductions of ≥ 30% and ≥ 50% increased over time, reaching 81.6% (62/76) and 64.5% (49/76), respectively, by Week 96. No everolimus-treated patients experienced renal bleeding. The long-term safety profile was consistent with previous reports; adverse events (AEs) were mostly Grade 1/2, and there were no new safety issues. The frequency of emerging AEs and severe AEs lessened over time. Longer term everolimus treatment appeared safe and effective in patients with TSC- or sporadic LAM-associated renal angiomyolipoma not requiring surgical intervention. Continued reduction in angiomyolipoma volume was demonstrated, and there was no angiomyolipoma-related bleeding; AEs were predictable and generally manageable. clinicaltrialsgov identifier: NCT00790400 (http://clinicaltrials.gov/ct2/show/NCT00790400).

PD35-10 EVEROLIMUS FOR RENAL ANGIOMYOLIPOMA ASSOCIATED WITH TUBEROUS SCLEROSIS COMPLEX: EFFICACY AND SAFETY AFTER 3.5 YEARS OF TREATMENT IN THE EXIST-2 STUDY

You have accessJournal of UrologyKidney Cancer: Advanced I1 Apr 2015PD35-10 EVEROLIMUS FOR RENAL ANGIOMYOLIPOMA ASSOCIATED WITH TUBEROUS SCLEROSIS COMPLEX: EFFICACY AND SAFETY AFTER 3.5 YEARS OF TREATMENT IN THE EXIST-2 STUDY John Bissler, J. Kingswood, Elzbieta Radzikowska, Bernard Zonnenberg, Michael Frost, Elena Belousova, Matthias Sauter, Norio Nonomura, Susanne Brakemeier, Petrus de Vries, Noah Berkowitz, Severine Peyrard, and Klemens Budde John BisslerJohn Bissler More articles by this author , J. KingswoodJ. Kingswood More articles by this author , Elzbieta RadzikowskaElzbieta Radzikowska More articles by this author , Bernard ZonnenbergBernard Zonnenberg More articles by this author , Michael FrostMichael Frost More articles by this author , Elena BelousovaElena Belousova More articles by this author , Matthias SauterMatthias Sauter More articles by this author , Norio NonomuraNorio Nonomura More articles by this author , Susanne BrakemeierSusanne Brakemeier More articles by this author , Petrus de VriesPetrus de Vries More articles by this author , Noah BerkowitzNoah Berkowitz More articles by this author , Severine PeyrardSeverine Peyrard More articles by this author , and Klemens BuddeKlemens Budde More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2233AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES EXIST-2 (NCT00790400), a randomized, double-blind, phase 3 trial, assessed everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, for the treatment of renal angiomyolipoma associated with either tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM). Here we present longer-term safety and efficacy data for everolimus that include the open-label extension phase (cutoff date, April 1, 2014). METHODS 118 patients who had renal angiomyolipoma associated with TSC (n=113) or sLAM (n=5) were randomly assigned 2:1 to receive 10 mg/day everolimus (n=79) or placebo (n=39). Angiomyolipoma response rate, the primary endpoint, was defined as the proportion of patients with confirmed ≥50% reduction in sum of volumes of all target angiomyolipoma relative to baseline in the absence of an increase in kidney volume (>20% from nadir), no new angiomyolipoma lesions, and no angiomyolipoma-related bleeding of ≥ grade 2. Adverse events (AEs) were monitored at each visit. RESULTS At the initial cutoff (June 30, 2011), everolimus was superior to placebo for angiomyolipoma response rate (42% vs 0%, P<0.0001). Following these positive results, all patients still in the study were offered open-label everolimus in the extension phase. As of April 1, 2014, 112 patients (median age, 32 years [range 18-62]) received ≥1 dose of everolimus. Median duration of exposure was 39.8 months (range, 0.5-57.3). Angiomyolipoma response rate was 56.3% (95% confidence interval [CI], 46.6%-65.6%). At week 96 (n=98), 80.6% and 63.3% of patients had reductions ≥30% and ≥50%, respectively, in angiomyolipoma volume. Progression-free rate at 48 months was 78.3% (95% CI, 63.6%-87.6%). AEs were similar to previous reports and remained mostly grade 1 or 2. AEs most commonly reported in ≥20% of patients were nasopharyngitis (44.6%), stomatitis (42.9%), hypercholesterolemia (35.7%), acne and headache (31.3% each), urinary tract infection (30.4%), aphthous stomatitis (25.9%), diarrhea (24.1%), hypertension (23.2%), cough (21.4%), and nausea (20.5%). Incidence of emerging AEs decreased over the study period. The most frequent grade 3 AEs (≥3%) were blood phosphorus decreased (4.5%) and amenorrhea (5.6%, n=4 out of 71 females aged 10-55). The only grade 4 event occurring in ≥2 patients was blood uric acid increased (2.7%). CONCLUSIONS A sustained reduction in angiomyolipoma volume was seen with continued everolimus treatment. No new safety concerns were noted. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e763 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Bissler More articles by this author J. Kingswood More articles by this author Elzbieta Radzikowska More articles by this author Bernard Zonnenberg More articles by this author Michael Frost More articles by this author Elena Belousova More articles by this author Matthias Sauter More articles by this author Norio Nonomura More articles by this author Susanne Brakemeier More articles by this author Petrus de Vries More articles by this author Noah Berkowitz More articles by this author Severine Peyrard More articles by this author Klemens Budde More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD17-01 EVEROLIMUS FOR RENAL ANGIOMYOLIPOMA ASSOCIATED WITH TUBEROUS SCLEROSIS COMPLEX: EXIST-2 LONG-TERM EFFICACY AND SAFETY

You have accessJournal of UrologyKidney Cancer: Localized II1 Apr 2014PD17-01 EVEROLIMUS FOR RENAL ANGIOMYOLIPOMA ASSOCIATED WITH TUBEROUS SCLEROSIS COMPLEX: EXIST-2 LONG-TERM EFFICACY AND SAFETY John Bissler, J. Christopher Kingswood, Elzbieta Radzikowska, Bernard A. Zonnenberg, Michael Frost, Matthias Sauter, Norio Nonomura, Susanne Brakemeier, Petrus J. de Vries, Scott Segal, Oezlem Anak, Severine Peyard, and Klemens Budde John BisslerJohn Bissler More articles by this author , J. Christopher KingswoodJ. Christopher Kingswood More articles by this author , Elzbieta RadzikowskaElzbieta Radzikowska More articles by this author , Bernard A. ZonnenbergBernard A. Zonnenberg More articles by this author , Michael FrostMichael Frost More articles by this author , Matthias SauterMatthias Sauter More articles by this author , Norio NonomuraNorio Nonomura More articles by this author , Susanne BrakemeierSusanne Brakemeier More articles by this author , Petrus J. de VriesPetrus J. de Vries More articles by this author , Scott SegalScott Segal More articles by this author , Oezlem AnakOezlem Anak More articles by this author , Severine PeyardSeverine Peyard More articles by this author , and Klemens BuddeKlemens Budde More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1508AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives To assess the long-term efficacy and safety of everolimus, an oral mTOR inhibitor, for the treatment of renal angiomyolipoma associated with either tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). Methods EXIST-2 (NCT00790400), a randomized, double-blind, phase 3 trial, assessed the efficacy and safety of everolimus for the treatment of renal angiomyolipoma associated with either TSC or sporadic LAM. A total of 118 patients (median age, 31 years [range, 18-61]) who had renal angiomyolipoma associated with TSC (n=113) or sporadic LAM (n=5) were randomly assigned (2:1) to 10 mg/day everolimus (n=79) or placebo (n=39). Angiomyolipoma response rate (primary end point) was defined as the proportion of patients with confirmed ≥50% reduction in the sum of volumes of all target angiomyolipoma relative to baseline in the absence of kidney increase (>20% from nadir), no new angiomyolipoma lesions, and no angiomyolipoma-related bleeding of ≥ grade 2. Adverse events (AEs) were monitored at every visit. Results Everolimus was superior to placebo for the primary end point, renal angiomyolipoma response rate (42% vs 0%; P<0.0001; original data cutoff, 6/30/2011). Following positive results for the original cutoff, placebo patients were offered open-label everolimus in the study extension phase. As of 5/1/2013, 112 patients received ≥1 dose of everolimus, and the median duration of exposure was 29 months (range, 0.5-46). The angiomyolipoma response rate was 54% (95% confidence interval, 44-63). AEs were similar to those at the original cutoff and continued to be grade 1 or 2. The most frequent grade 3 AEs were blood phosphorus decreased (4%) and amenorrhea (3%). Individual grade 4 AEs occurred in <2% of patients; they were blood uric acid increase (n=2), convulsion, hydrocephalus, hypertensive crisis, neutropenia, pancreatic carcinoma, and rhabdomyolysis (n=1 each). The most common AEs reported in ≥20% of patients were nasopharyngitis and stomatitis (43% each), headache, acne and hypercholesterolemia (30% each), urinary tract infection (28%), aphthous stomatitis (26%), and cough (21%). Hemorrhages were seen in 34 patients (30%), with the most frequently (≥5%) reported AEs being epistaxis (10%), menorrhagia (8%), and vaginal hemorrhage unrelated to normal menstruation (7%). Of note, there were no renal hemorrhages in patients taking everolimus. Conclusions Everolimus continued to reduce angiomyolipoma volume with no new safety concerns. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e540 Advertisement Copyright & Permissions© 2014MetricsAuthor Information John Bissler More articles by this author J. Christopher Kingswood More articles by this author Elzbieta Radzikowska More articles by this author Bernard A. Zonnenberg More articles by this author Michael Frost More articles by this author Matthias Sauter More articles by this author Norio Nonomura More articles by this author Susanne Brakemeier More articles by this author Petrus J. de Vries More articles by this author Scott Segal More articles by this author Oezlem Anak More articles by this author Severine Peyard More articles by this author Klemens Budde More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Everolimus for renal angiomyolipoma in tuberous sclerosis

In The Lancet, John Bissler and colleagues1 report the first randomised, double-blind, placebo-controlled, phase 3 trial of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis, and angiomyolipoma. Their findings suggest a clear advantage for everolimus over placebo in reducing angiomyolipoma volume with an acceptable safety profile in patients with tuberous sclerosis.

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial

Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata. In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400. 118 patients (median age 31·0 years; IQR 18·0–61·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31–53%]) for everolimus and 0% (0 of 39 [0–9%]) for placebo (response rate difference 42% [24–58%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]). Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. Novartis Pharmaceuticals.

Nephron-sparing resection of angiomyolipoma after sirolimus pretreatment in patients with tuberous sclerosis

Renal angiomyolipoma in patients with tuberous sclerosis can cause life-threatening bleeding. Embolization or resection is recommended, but either intervention may result in substantial loss of renal function. Recently, regression of angiomyolipoma size has also been achieved with mTOR inhibitor therapy, but recurrent lesion growth after treatment cessation has to be expected. This is the first report on a multimodal therapeutic approach facilitating a nephron-sparing, definitive resection. Three patients with renal angiomyolipoma not amenable to nephron-sparing surgery were treated with sirolimus aiming trough levels of 4-8ng/ml. Treatment was well tolerated. mTOR inhibitor treatment resulted in a regression of angiomyolipoma volume by 38-95%. Thereafter, nephron-sparing angiomyolipoma resection conserved normal renal function. Neoadjuvant use of mTOR inhibitor pretreatment may represent a novel approach facilitating nephron-sparing resection.

Mechanism of Activation of AMPK and Upregulation of OGG1 by Rapamycin in Cancer Cells

Mechanism of Activation of AMPK and Upregulation of OGG1 by Rapamycin in Cancer Cells

Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling. We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed. Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections. Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Embolization of Renal Angiomyolipomata in Patients With Tuberous Sclerosis Complex

Renal angiomyolipomata can reduce renal reserve and lead to renal insufficiency and failure. Angiomyolipomata often have abnormal vasculature, with aneurysms that can hemorrhage. Treatment of angiomyolipomata greater than 4 cm in diameter is suggested to decrease the risk for hemorrhage. Nephron-sparing procedures are critical in patients because of their limited renal reserve. Embolization has been used to treat these tumors, but there are limited studies examining efficacy. Our study examines the efficacy of selective embolization in decreasing tumor burden, preventing hemorrhage, and preserving renal function. We conducted a retrospective study of 16 patients with 20 angiomyolipomata on 18 kidneys who underwent 18 transcatheter transarterial embolization procedures. Aneurysm number and size were documented and tumor volumes were measured before and after embolization. Preprocedure and follow-up renal function also were measured. Changes in angiomyolipoma volume and kidney function were assessed for significance by using paired t-test. Before embolization, 7 angiomyolipomata had more than 5 aneurysms, 9 had 1 to 5 aneurysms, and 4 had no aneurysms, but showed tortuous dysmorphic arteries. Mean aneurysm size was 5 mm. In patients available for follow-up, 15 of 16 tumors had decreased in volume (mean decrease, 56.1%; P = 0.001). At an average of 40 months' follow-up, there have been no subsequent hemorrhages. Patients' decline in renal function was not significantly different from that expected because of the natural course of the disease. Selective embolization decreases tumor size, prevents hemorrhage, and preserves kidney function in patients with tuberous sclerosis with renal angiomyolipomata.