scholarly journals Low-Dose Everolimus Maintenance Therapy for Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex

2021 ◽  
Vol 8 ◽  
Author(s):  
Cong Luo ◽  
Wen-Rui Ye ◽  
Xiong-Bin Zu ◽  
Min-Feng Chen ◽  
Lin Qi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Maintenance Therapy ◽  
Tuberous Sclerosis ◽  
Induction Therapy ◽  
Tuberous Sclerosis Complex ◽  
Low Dose ◽  
Standard Dose ◽  
Gene Mutations ◽  
Renal Angiomyolipoma ◽  
Significance Level

Objective: To assess the safety and efficacy of low-dose everolimus maintenance therapy for tuberous sclerosis complex-related renal angiomyolipoma (TSC-RAML) patients that had previously undergone standard-dose treatment for a minimum of 6 months.Materials and Methods: In total, 24 patients with a definitive TSC diagnosis were enrolled from April 2018 – April 2019 at Xiangya Hospital, Central South University. All patients underwent low-dose everolimus maintenance therapy following standard-dose everolimus induction therapy for a minimum of 6 months. Patients additionally underwent TSC1/TSC2 genetic testing, And they were followed-up at 3, 6, 12, 18, and 24 months. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were used to monitor patient RAML responses, while adverse events (AEs) were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). P < 0.05 was the significance level for all analyses, which were performed using SPSS 19.0.Results: TSC1/TSC2 gene mutations were present in all 24 patients, all of whom achieved a significant reduction in TSC-RAML volume within the initial 6-month induction therapy period, and exhibited volume stabilization during the low-dose maintenance therapy treatment period without any instances of TSC-RAML regrowth. Adverse events (AEs) were significantly less severe and less frequent over the course of maintenance therapy relative to standard therapy.Conclusions: Low-dose everolimus maintenance therapy represents an effective approach to achieving TSC-RAML control following a minimum of 6 months of full-dose induction therapy, and may be associated with decreases in everolimus-related AE frequency and severity.

scholarly journals Mutational analysis of renal angiomyolipoma associated with tuberous sclerosis complex and the outcome of short-term everolimus therapy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jianxin Ni ◽  
Fengqi Yan ◽  
Weijun Qin ◽  
Lei Yu ◽  
Geng Zhang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Adverse Events ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Gene Mutations ◽  
Chinese Patients ◽  
Term Therapy ◽  
Renal Angiomyolipoma ◽  
Efficacy And Safety ◽  
Short Term

Abstract To identify clinical characteristics and mutation spectra in Chinese patients with renal angiomyolipoma (AML) associated with the tuberous sclerosis complex (TSC, TSC-AML), examined the efficacy and safety of short-term everolimus therapy (12 weeks). We analyzed the frequency distribution of each TSC-related clinical feature and investigated gene mutations by genetic testing. Some subjects received everolimus for 12 weeks at a dose of 10 mg/day, and the efficacy and safety of short-term everolimus therapy were examined. Finally, 82 TSC-AML patients were enrolled for analysis in this study. Of the 47 patients who underwent genetic testing, 22 patients (46.81%) had at least one detectable mutation in the TSC1 or TSC2 gene: 7 were TSC1 gene mutations, 13 were TSC2 gene mutations, and 2 were found in both TSC1 and TSC2. Everolimus treatment had a statistically significant effect on the renal AML volume reduction during follow-up (P < 0.05), and the mean reduction rate of volume for all cases was 56.47 ± 23.32% over 12 weeks. However, 7 patients (7/25; 28.00%) experienced an increase in renal AML tumor volume within 12 weeks after discontinuation of the everolimus treatment. Although most patients (27/30, 90.00%) experienced some adverse events during the treatment period, all such events were mild, and no patients discontinued or needed dose reduction because of adverse events. Overall, in this study, the mutation rate of TSC-AML patients is much lower than other reports. Short-term everolimus treatment for TSC-AML is effective and safe, but the stability is much lower than long-term therapy.

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

2020 ◽  
Author(s):  
Takashi Hatano ◽  
Katsuhisa Endo ◽  
Mayumi Tamari
Keyword(s):  
Body Weight ◽  
Adverse Events ◽  
Renal Dysfunction ◽  
Tuberous Sclerosis Complex ◽  
Dose Group ◽  
Low Dose ◽  
Reduction Rate ◽  
Renal Angiomyolipoma ◽  
Efficacy And Safety ◽  
Conventional Dose

Abstract Background: Tuberous sclerosis complex (TSC) is a rare disease, with an autosomal dominant mode of inheritance, that results in systemic hamartoma. Renal angiomyolipoma (AML) is observed in 50-80% of TSC patients. Everolimus is recommended as an initial treatment for TSC-associated AML; however, few studies have investigated the efficacy and safety of low-dose everolimus therapy. In the present study, we evaluated the safety and efficacy of low-dose everolimus treatment in patients with TSC-associated AML with renal dysfunction or low body weight.Methods: From January 2014 through December 2018, 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 (graded according to the Common Terminology Criteria for Adverse Events v5.0–JCOG) 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. Based on our results, low-dose everolimus can be considered a treatment option for patients with TSC-associated AML, especially for those who have renal dysfunction or low body weight.

Continuous low-dose everolimus shrinkage tuberous sclerosis complex-associated renal angiomyolipoma: a 48-month follow-up study

2018 ◽  
Vol 67 (3) ◽  
pp. 686-690 ◽  
Author(s):  
Chang-Ching Wei ◽  
Jeng-Daw Tsai ◽  
Ji-Nan Sheu ◽  
Sung-Lang Chen ◽  
Teng-Fu Tsao ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Low Dose ◽  
Benign Neoplasm ◽  
Volume Reduction ◽  
Response To Treatment ◽  
Renal Angiomyolipoma ◽  
Group I ◽  
Group Ii

Tuberous sclerosis complex (TSC) is a rare disease that causes multisystem benign neoplasm, induced by dysregulation of the mammalian target of the rapamycin pathway (mTOR). This study aimed to examine the effects of continuous low-dose everolimus, a potent and selective inhibitor of mTOR, on the treatment of TSC-associated renal angiomyolipoma (AML). Between July 2013 and August 2017, 11 patients with TSC-AML were enrolled for an everolimus therapy protocol. An oral everolimus dose starting at 2.5 mg daily was gradually increased to 5.0 mg daily. All patients were evaluated using MRI or CT scanning at baseline, 12, 24, 36 and 48 months after the start of treatment for measuring changes of renal AML mass volume. Everolimus therapy resulted in significant shrinkage of TSC-AML volume after 48 months follow-up. Serum levels of everolimus were subdivided into group I (<8 ng/mL, n=6) and group II (>8 ng/mL, n=5). The volume reduction rates were 10.6%–65.2% in group I and 42.5%–70.6% in group II. To evaluate the response to treatment, three of six (50%) were responders in group I, and all the patients in group II (5/5, 100%) were responders. The differences in AML volume reduction between the groups were statistically significant at 12 months (p=0.011), 24 months (p=0006), 36 months (p=0.014) and 48 months (p=0.05). These results suggest that continuous low-dose everolimus therapy (2.5–5 mg daily) might be effective in shrinking TSC-AML volume and minimizes adverse effects and subsequent reducing medical costs.

scholarly journals High-throughput screening of circRNAs reveals novel mechanisms of tuberous sclerosis complex-related renal angiomyolipoma

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Yang Zhao ◽  
Hao Guo ◽  
Wenda Wang ◽  
Guoyang Zheng ◽  
Zhan Wang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Regulatory Network ◽  
High Throughput Screening ◽  
Kidney Tissue ◽  
Cell Types ◽  
The Body ◽  
Differentially Expressed ◽  
Renal Angiomyolipoma

Abstract Objective Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by lesions throughout the body. Our previous study showed the abnormal up-regulation of miRNAs plays an important part in the pathogenesis of TSC-related renal angiomyolipoma (TSC-RAML). circRNAs were known as important regulators of miRNA, but little is known about the circRNAs in TSC-RAMLs. Methods Microarray chips and RNA sequencing were used to identify the circRNAs and mRNAs that were differently expressed between the TSC-RAML and normal kidney tissue. A competitive endogenous RNA (ceRNA) regulatory network was constructed to reveal the regulation of miRNAs and mRNAs by the circRNAs. The biological functions of circRNA and mRNA were analyzed by pathway analysis. Microenvironmental cell types were estimated with the MCP-counter package. Results We identified 491 differentially expressed circRNAs (DECs) and 212 differentially expressed genes (DEGs), and 6 DECs were further confirmed by q-PCR. A ceRNA regulatory network which included 6 DECs, 5 miRNAs, and 63 mRNAs was established. Lipid biosynthetic process was significantly up-regulated in TSC-RAML, and the humoral immune response and the leukocyte chemotaxis pathway were found to be down-regulated. Fibroblasts are enriched in TSC-RAML, and the up-regulation of circRNA_000799 and circRNA_025332 may be significantly correlated to the infiltration of the fibroblasts. Conclusion circRNAs may regulate the lipid metabolism of TSC-RAML by regulation of the miRNAs. Fibroblasts are enriched in TSC-RAMLs, and the population of fibroblast may be related to the alteration of circRNAs of TSC-RAML. Lipid metabolism in fibroblasts is a potential treatment target for TSC-RAML.

scholarly journals RARE-25. RETINAL ASTROCYTOMA mTOR INHIBITOR THERAPY IN TUBEROUS SCLEROSIS MOSAICISM

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii447-iii447
Author(s):  
Naomi Evans ◽  
Katherine Paton ◽  
Harinder Kaur Gill ◽  
Juliette Hukin
Keyword(s):  
Optic Nerve ◽  
Retinal Detachment ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mtor Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Neovascular Glaucoma ◽  
Renal Angiomyolipoma ◽  
Gradual Reduction ◽  
Health Canada

Abstract INTRODUCTION Everolimus is an inhibitor of mTORC1 (mammalian target of rapamycin complex 1), it is Health Canada and FDA approved for SEGA and renal angiomyolipoma in the setting of tuberous sclerosis complex (TSC). There is little data available in regards to this treatment of TSC associated retinal astrocytoma (RA). Although the behaviour of RA is often indolent or slowly progressive, aggressive behaviour with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients. Definite TSC diagnosis is established when either two major features or one major and two minor features are present. Probable TSC diagnosis is established when one major plus one minor feature is present. METHODS We report a child with probable TSC mosaicism, with negative serum NGS for TSC but RA and retinal achromic patch on the left. A left retinal peripapillary astrocytoma around optic nerve and very close to fovea was noted. There was concern that if it grew or there were to be any leakage it would cause visual impairment. This lead to therapy with everolimus 4.5 mg/m2/d aiming for level between 5 and 10 mcg/L. RESULTS This boy has had a gradual reduction of the RA over the last 29 months, with healthy retina in the region no longer occupied by the lesion and preserved vision. He has tolerated therapy well with occasional mouth ulcers. CONCLUSION mTORC1 inhibition is effective therapy to preserve vision in the setting of retinal astrocytoma and tuberous sclerosis mosaicism.

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