The association between computed tomography attenuation value of renal angiomyolipoma associated with tuberous sclerosis complex and response to everolimus.

BACKGROUND: The response to everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC-RAML) varies among individuals. This study aims to identify potential factors associated with the response to everolimus. METHOD: We retrospectively examined data encompassing age, gender, tumor size, computed tomography attenuation value (CT value), CT enhancement, and tumor reduction rate in patients with TSC-RAML undergoing everolimus in two previously registered clinical trials. RESULT: A total of 33 participants (29.33 ± 6.63 years old, 20 females) were included. The correlation analysis conducted separately for tumors located in the left and right kidneys revealed significant negative correlations (P < 0.05) between tumor reduction rate and age, as well as tumor size. While significant positive correlations (P < 0.05) were observed between tumor reduction rate and unenhanced CT value as well as CT enhancement. Nonetheless, based on multiple linear regression analysis, unenhanced CT value emerged as the sole-independent predictor of tumor reduction rate among age, gender, tumor size, unenhanced CT value and CT enhancement for both left (coefficient = 0.00319, P < 0.0001) and right kidneys (coefficient = 0.00315, P = 0.0104). Notable reductions were observed in unenhanced CT value (- 3.81 vs - 24.70HU, P < 0.0001) and CT enhancement (48.16 vs 33.56HU, P < 0.0001) following a 3-month administration of everolimus. The decline in both unenhanced CT value and tumor size predominantly occurred within the initial 3 months, subsequently maintaining a relatively stable level throughout the treatment. CONCLUSION: The unenhanced CT value of TSC-RAML showed an independent correlation with the response to everolimus, suggesting its potential as a predictor of everolimus efficacy in patients with TSC-RAML.

Microscopic Kidney Disease in Tuberous Sclerosis Complex and Treatment With mTOR Inhibition.

Declining kidney function in tuberous sclerosis complex (TSC) is often attributed to large lesions, including angiomyolipomas (AMLs) and cysts, that encroach on the normal parenchyma or that require intervention and loss of parenchyma from surgical debulking or embolization. Consequently, research on inhibitors of the mammalian target of rapamycin (mTOR), a protein complex implicated in TSC pathophysiology for its role in promoting cell growth and proliferation, has largely focused on their ability to reduce AML size. Clinical guidelines distilled from this research limit mTOR inhibition as a first-line treatment to patients with large AMLs. However, chronic kidney disease (CKD) occurs in patients without large AMLs or a history of renal intervention. Alternate mechanisms postulated for CKD in TSC may suggest a role for mTOR inhibition in this population. In this report, we present 2 cases of a microscopic variant of TSC kidney disease causing declining kidney function, as well as anecdotal evidence for the use of mTOR inhibition to improve kidney function in the absence of large AMLs. We highlight the importance of annual kidney function assessment in patients with TSC and suggest a low threshold for kidney biopsy in patients with declining glomerular filtration rate without a clear etiology clinically or radiographically.

Adverse Events of Everolimus in Patients with Tuberous Sclerosis Complex Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma.

Background: Although regarded as a potentially efficient approach to address tuberous sclerosis complex (TSC)-associated complications, the adverse event profile of everolimus has not yet been fully elucidated. The present study aimed to clarify the adverse event spectrum in patients with TSC who are using everolimus for common indications, in comparison to those who do not use everolimus. Materials and Methods: We recruited patients with TSC who were followed up annually at TSC integrated clinics or referred for medical assistance. Medical reviews and laboratory investigations were performed at baseline and annually by clinical physicians. The adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Common adverse events in everolimus users included hypercholesterolemia (55%), gingivostomatitis (50%), proteinuria (50%), and hyperglycemia (40%). Compared with everolimus nonusers, the occurrence of gingivostomatitis and proteinuria was significantly higher in everolimus users (gingivostomatitis, p=0.02; proteinuria, p=0.02). Among the everolimus users, 12 patients had level I CTCAE, and five had level II CTCAE. None of the everolimus users presented with CTCAE level III or higher. Conclusion: Patients with TSC who are everolimus users had a higher tendency to develop gingivostomatitis and proteinuria compared to nonusers. However, no differences were observed in the occurrence of other adverse events between everolimus users and nonusers.

Safety and Effectiveness of Medical Therapy and Surgical Intervention for Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex.

PURPOSE: Our study aimed to evaluate the effect of daily oral dose of everolimus in the treatment of patients with tuberous sclerosis complex (TSC) associated with renal angiomyolipoma (RAML), and the feasibility and safety of surgical treatment approach. METHODS: We retrospectively investigated a total of 13 patients diagnosed of TSC-associated renal angiomyolipoma (TSC-RAML) who were scheduled for everolimus therapy. At 3-9 months after starting everolimus therapy, 4 of the study patients were symptomatic and underwent partial renal resection surgery. Two of these surgeries were performed open nephron sparing surgery (NSS) after TAE (Trans-arterial embolization), while the remaining 2 underwent robot-assisted partial nephrectomy (RAPN). A multi-slice helical CT scan performed among all the patients every 3 months, which was used to measure the volume and the density of the lesion. RESULTS: Follow-up CT images revealed a significant reduction (P < .05) in the RAML volume, at a rate ranging from 11.6 to 42.5%, in response to everolimus therapy (10 mg/day) in TSC-RAML patients. Further, a significant decrease in the mean tumor density (P < .05), as compared to its baseline value, was also observed. Super-selective renal arterial embolization done prior to NSS was effective in reducing the intraoperative bleeding and stabilizing the patient during the NSS procedure: mean warm ischemia time was 29.5 minutes (range 18-40 minutes) and mean intraoperative bleeding volume was 275 mL (range 200-350 mL). Post-surgical (both NSS and RAPN) follow-up showed a favorable perioperative morbidity profile with good renal functional preservation. At the end of 2 years, all patients were well, with no signs of progression or recurrence of the condition, and demonstrated normal renal function. CONCLUSIONS: The results suggested oral everolimus as an effective non-invasive therapy to treat TSC-RAML patients. Post mTOR inhibitor therapy, NSS and RAPN are preferred mode of surgical intervention in symptomatic patients. TAE prior to NSS is beneficial.

Mechanistic Target of Rapamycin (mTOR) Inhibitors.

Mechanistic target of rapamycin (mTOR) inhibitors are macrocyclic lactone antibiotics derived from Streptomyces hygroscopicus that prevent T lymphocyte activation and B cell differentiation. Unlike calcineurin inhibitors (CNIs) that inhibit cytokine production, mTOR inhibitors block the cytokine signal transduction to arrest cells in the G1 to S phase. This class of drugs is commonly used for post-transplantation and cancer management because of its immunosuppressive and antiproliferative properties, respectively. The potential uses of mTOR inhibitors are heavily explored because of their impact on cell growth and proliferation. However, mTOR inhibitors have a broad range of effects that can result in adverse reactions, but side effects can occur with other immunosuppressive agents as well. Thus, the performance of mTOR inhibitors is compared to the outcomes and adverse effects of other immunosuppressive drugs or the combination of other immunosuppressants and mTOR inhibitors. Because mTOR regulates many downstream pathways, mTOR inhibitors can affect these pathways to manage various diseases. Sirolimus (rapamycin) is approved by the Food and Drug Administration (FDA) to treat post-renal transplantation and lymphangioleiomyomatosis (LAM). Everolimus is approved by the FDA to treat postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer in women, progressive neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma (AML) and tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC as well as renal and liver transplantation. Temsirolimus is approved by the FDA to treat advanced RCC. Opportunities to use mTOR inhibitors as therapy for other transplantation, metabolic disease, and cancer management are being researched. mTOR inhibitors are often called proliferation signal inhibitors (PSIs) because of their effects on proliferation pathways.

The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma.

BACKGROUND: Facial angiofibromas may be present since early childhood in individuals with tuberous sclerosis complex (TSC), causing substantial cosmetic disfigurement. Current therapies are partially effective, but they are uncomfortable, produce scarring, and are especially expensive. OBJECTIVE: The aim of the present study was to evaluate the efficacy of oral everolimus for TSC-associated angiofibromas. METHODS: This retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibromas. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus. RESULTS: Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11-44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004). CONCLUSION: Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The current study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC.

Efficacy and safety of low-dose everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex.

BACKGROUND: The aim of this study was to evaluate the safety and efficacy of low-dose everolimus treatment in patients with tuberous sclerosis complex (TSC)-associated angiomyolipoma (AML) with renal dysfunction or low body weight. METHODS: We investigated a total of 50 adult patients underwent everolimus treatment for AML associated with TSC. For patients with renal dysfunction (serum creatinine level ≥ 1.5 mg/dl) or low body weight (body weight < 35 kg), 5 mg of everolimus was administered daily (low-dose group). For patients without renal dysfunction or low body weight, 10 mg of everolimus was administered daily (conventional-dose group). The treatment effects and adverse events were compared between the two groups. RESULTS: There were 20 patients in the low-dose group, and 30 in the conventional-dose group. The average reduction rate of the AML volume in the low-dose group was 52%, whereas it was 60% in the conventional-dose group. No significant differences were found in the average reduction rate between the groups (P = 0.24). The average blood everolimus trough levels were 7.7 ± 3.1 ng/mL in the low-dose group and 12.2 ± 5.7 ng/mL in the conventional-dose group. The level was significantly higher in the conventional-dose group than in the low-dose group (P = 0.004). The incidences of stomatitis and irregular menstruation were significantly lower in the low-dose group than in the conventional-dose group (P = 0.009, P = 0.045, respectively). CONCLUSIONS: The present study demonstrates that low-dose everolimus treatment is safe and effective for TSC-associated AML. This treatment was well tolerated and adverse events were mild in all cases.

Sporadic Angiomyolipomas Growth Kinetics While on Everolimus: Results of a Phase II Trial.

PURPOSE: Everolimus decreases tumor volume of renal angiomyolipomas in patients with tuberous sclerosis. No prospective data are available regarding the effect of everolimus on the growth kinetics in patients with sporadic angiomyolipomas. We sought to determine the safety and efficacy of everolimus in the volumetric reduction of sporadic angiomyolipomas. MATERIALS AND METHODS: This multi-institutional, prospective, phase II trial, enrolled patients with 3 cm or larger sporadic angiomyolipomas who were candidates for surgical resection or percutaneous angioembolization. Patients received 10 mg everolimus daily for 4 planned 28-day cycles. Response was defined as a 25% or greater volumetric reduction of patient angiomyolipoma. Baseline, 4, 6 and 12-month volumetric analyses were performed using magnetic resonance imaging. Everolimus was discontinued in those with less than 25% volumetric reduction after 4 cycles. Those with 25% or greater volumetric reduction received 2 additional cycles. The primary outcomes were the efficacy of everolimus in the volumetric reduction of angiomyolipomas by 25% or more, and the safety and tolerability of everolimus. RESULTS: Overall 20 patients were enrolled at 5 centers. Of these patients 11 (55%) completed 4 cycles and 7 (35%) completed 6 cycles. Efficacy was demonstrated, with 10 of 18 (55.6%) patients exhibiting a 25% or greater reduction in tumor volume at 4 months (median 58.5%) and 10 of 14 (71.4%) patients exhibiting a 25% or greater reduction in tumor volume at 6 months (median 58.2%). Four (20%) patients were withdrawn due to protocol defined toxicities and 8 (40%) self-withdrew from the study due to side effects. CONCLUSIONS: Everolimus was effective in causing volumetric reduction of angiomyolipomas by 25% or greater in most patients but was associated with a high rate of treatment discontinuation.

Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2.

BACKGROUND: A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. METHODS: The long-term effects of EVE on renal function (∼4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5 mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10 mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3 months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88 mL/min/1.73 m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. CONCLUSIONS: The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients.ClinicalTrials.gov identifiers NCT00789828 and NCT00790400.

[The 467th case: proteinuria, periungual fibromas, and facial steatadenomas].

A 22-year-old manpresented as a refractory nephrotic syndrome with edema and proteinuria for more than one year. Physical examination revealed facial steatadenomas and periungual fibromas. Images were characterized by hamartomatous lesions in multiple organs, including the central nervous system, heart, lungs, liver, and kidneys. Gene tests verified TSC2 mutation and confirmed the diagnosis of tuberous sclerosis complex. The APOL1 mutation was positive in this patient, which indicated the possibility of steroid-resistant focal segmental glomerulonephritis. Thus, he was treated with sirolimus. Renal angiomyolipoma was shrunk, but proteinuria was not relieved (24h unine protein>10 g) and eventually led into renal insufficiency. Nondialytic therapy was initiated consequently. Losartan 50 mg/d was used to control proteinuria under the close watch of serum creatinine. A recent phone call on October 2018 failed to reachthe patient. Therefore, the follow-up information was not updated.

[Clinical case of delayed diagnosis of tuberous sclerosis].

A clinical case of successful drug treatment of multiple renal angiomyolipomas in patient with tuberous sclerosis is presented, which suggests potential role of medical treatment of benign kidney tumors.

Urokinase-type plasminogen activator (uPA) is critical for progression of tuberous sclerosis complex 2 (TSC2)-deficient tumors.

Lymphangioleiomyomatosis (LAM) is a fatal lung disease associated with germline or somatic inactivating mutations in tuberous sclerosis complex genes (TSC1 or TSC2). LAM is characterized by neoplastic growth of smooth muscle-α-actin-positive cells that destroy lung parenchyma and by the formation of benign renal neoplasms called angiolipomas. The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin slows progression of these diseases but is not curative and associated with notable toxicity at clinically effective doses, highlighting the need for better understanding LAM's molecular etiology. We report here that LAM lesions and angiomyolipomas overexpress urokinase-type plasminogen activator (uPA). Tsc1-/- and Tsc2-/- mouse embryonic fibroblasts expressed higher uPA levels than their WT counterparts, resulting from the TSC inactivation. Inhibition of uPA expression in Tsc2-null cells reduced the growth and invasiveness and increased susceptibility to apoptosis. However, rapamycin further increased uPA expression in TSC2-null tumor cells and immortalized TSC2-null angiomyolipoma cells, but not in cells with intact TSC. Induction of glucocorticoid receptor signaling or forkhead box (FOXO) 1/3 inhibition abolished the rapamycin-induced uPA expression in TSC-compromised cells. Moreover, rapamycin-enhanced migration of TSC2-null cells was inhibited by the uPA inhibitor UK122, dexamethasone, and a FOXO inhibitor. uPA-knock-out mice developed fewer and smaller TSC2-null lung tumors, and introduction of uPA shRNA in tumor cells or amiloride-induced uPA inhibition reduced tumorigenesis in vivo These findings suggest that interference with the uPA-dependent pathway, when used along with rapamycin, might attenuate LAM progression and potentially other TSC-related disorders.

mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex.

Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed.

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

BACKGROUND: Patients with tuberous sclerosis complex (TSC) often have multiple TSC-associated hamartomas, particularly in the brain and kidney. METHODS: This 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. RESULTS: Overall, 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. CONCLUSIONS: Although 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.

Effect of everolimus treatment for regrown renal angiomyolipoma associated with tuberous sclerosis complex after transcatheter arterial embolization.

BACKGROUND: The aim of this study was to evaluate the effects and the utility of second-line everolimus treatment for regrown renal angiomyolipoma (AML) with tuberous sclerosis complex (TSC) after transcatheter arterial embolization (TAE). METHODS: We investigated a total of 14 patients who underwent second-line everolimus treatment for TSC-AML that regrew after TAE, and assessed their effects and adverse events. Everolimus treatment was performed for AML with a maximum diameter of 4 cm. To determine the reduction ratio of AML, the volume of AML was measured using multislice helical computed tomography. Adverse events were evaluated according to CTCAE v4.0-JCOG. We further compared the treatment effect and adverse events with those in patients receiving first-line everolimus treatment. RESULTS: The AML volume decreased in all patients, with a ≥ 50% volume decrease in 57% (8 of 14) of the cases, and the mean reduction rate was 53%. We observed no significant difference in the mean reduction rate of AML between second-line everolimus treatment for regrown TSC-AML after TAE and first-line everolimus treatment for TSC-AML. The adverse events were mild and consistent with those reported in our previous study. CONCLUSION: Although further studies are needed, everolimus appears to be effective as second-line treatment for TSC-AML that regrew after TAE and a beneficial treatment option for TSC-AML.

Effect of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: an evaluation based on tumor density.

BACKGROUND: The aim of this study was to evaluate the influence of components of angiomyolipoma (AML) on the efficacy of everolimus. METHODS: We investigated a total of 40 patients with tuberous sclerosis complex (TSC) who had AML ≥4 cm in diameter. The components of the AML were determined using abdominal computed tomography (CT) images. The AML density was measured as the mean Hounsfield unit (HU) values of the whole area of the AML on axial CT images. We classified them into two groups, i.e., a lipid group with a predominant lipid component (HU ≤ -50) and a solid group with predominant vascular and muscle components (HU ≥30). For each patient, we measured the AML reduction rate and transition of the mean HU value. RESULTS: The mean reduction rate of AML in the lipid group was 24%, whereas it was 68% in the solid group (P < 0.001). The mean tumor density after 6 months was decreased in both groups. In particular, the density significantly decreased compared to the baseline in the solid group (P < 0.001). The tumor density did not change after 6 months in either group. CONCLUSION: The effect of everolimus on TSC-AML is mainly a reduction of the solid components consisting of angioma and leiomyoma. The tumor density at the start of treatment might be a predictive marker for the response to everolimus in TSC-AML.

Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4-year results from the randomized EXIST-1 and EXIST-2 studies.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. OBJECTIVE: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. MATERIALS AND METHODS: Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. RESULTS: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). CONCLUSION: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

Effects of everolimus on tuberous sclerosis complex-associated renal angiomyolipoma: A preliminary report.

AIM: Tuberous sclerosis complex (TSC) presents with multisystem benign neoplasm induced by dysregulation of the mammalian target of rapamycin pathway. This study aimed to examine the effects of oral everolimus at either 2.5 or 5.0 mg daily on the treatment of TSC-associated renal angiomyolipoma (AML). METHODS: Between July 2012 and August 2015, patients with TSC-associated renal AML were selected for everolimus therapy protocol. An oral everolimus starting dose at 2.5 mg was administered daily, and was gradually increased to 5.0 mg daily. All patients were evaluated using magnetic resonance imaging or computed tomography scanning at baseline, 12, 24, and 36 months after the start of treatment for measuring the changes of renal AML mass volume. RESULTS: Eight patients were finally enrolled for analysis in this study. Everolimus treatment had a statistically significant effect on the renal AML volume reduction during follow-up (P < 0.05). Renal AML mass volume reduction rates were 10.5-45.3% in four patients with everolimus 2.5 mg and 40.7-73.1% in four patients with everolimus 5.0 mg daily; the difference was statistically significant between the two groups (P < 0.05). Longitudinal follow-up for response to everolimus showed volume reduction rates to be around 10.5-73.1% in the initial 6-24 months after everolimus treatment, which remained stable during follow-up up to 36 months. CONCLUSION: The results suggest that an oral everolimus is effective and provides a non-invasive way to treat TSC-associated renal AML, and patients are likely to require maintenance therapy to continue to derive benefit.

Everolimus in pregnancy: Case report and literature review.

There have been few reports on the effects of everolimus on the fetus, but none of six infants with documented everolimus exposure in utero had congenital malformations. A 32-year-old nulliparous woman on everolimus (5.0 mg/day) for renal angiomyolipoma (AML) due to tuberous sclerosis complex (TSC) was found to be pregnant at gestational week (GW) 7-5/7, at which time everolimus was withheld. To control AML in this patient, transarterial embolization was performed in the right and left kidneys at GW 21 and 24, respectively, and everolimus was reinitiated at GW 25. The patient gave birth at GW 37 to a normally formed infant weighing 3057 g, but who had cardiac tumors thought to be rhabdomyomas due to inherited TSC. Thus, although data are still limited, everolimus may be promising with respect to teratogenicity. Everolimus concentration in the maternal and umbilical cord blood at birth was 1.1 ng/mL and 1.0 ng/mL, respectively.

Intermittent everolimus administration for renal angiomyolipoma associated with tuberous sclerosis complex.

OBJECTIVES: To evaluate the effects and utility of intermittent everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex. METHODS: We investigated a total of 26 patients with tuberous sclerosis complex who had angiomyolipoma ≥4 cm in diameter. For each patient, we analyzed the reduction in the size of the angiomyolipoma, the change in size after everolimus withdrawal, the size reduction rate on everolimus readministration and adverse events caused by everolimus. The volume of angiomyolipoma was measured using abdominal computed tomography or magnetic resonance imaging. Adverse events were evaluated according to CTCAE v4.0-JCOG. RESULTS: The average size reduction rate of angiomyolipoma in the initial treatment with everolimus was 67%. Eight patients (31%) did not have enlarged angiomyolipoma after everolimus withdrawal. The other 18 patients (69%) restarted everolimus treatment because of enlargement of the angiomyolipoma. The average size reduction rate of angiomyolipoma in the everolimus retreatment group was 61%, which was equivalent to the rate for the initial treatment. There were fewer adverse events during everolimus retreatment than in the initial treatment. CONCLUSIONS: This is the first report regarding intermittent everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex. This treatment is effective for tumor control and adverse event management. This beneficial treatment option for patients can minimize the drug dosage and the occurrence of adverse events.