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Discov Oncol
Discov Oncol
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Springer US New York

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10.1007/s12672-024-01329-x
Research
The impact of everolimus on hematologic parameters in patients with renal angiomyolipoma associated with tuberous sclerosis complex
Qiu Dongxu 12
Wang Wenda 1
Zhao Yang 1
Wang Zhan 1
Wang Xu 1
Liao Zhangcheng zc.liao2020@gmail.com

34
Zhang Yushi beijingzhangyushi@126.com

1
1 grid.506261.6 0000 0001 0706 7839 Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Beijing, 100730 People’s Republic of China
2 https://ror.org/03rmrcq20 grid.17091.3e 0000 0001 2288 9830 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 Canada
3 grid.452223.0 0000 0004 1757 7615 Department of Urology, Xiangya Hospital, Central South University, Changsha, China 410008
4 grid.452223.0 0000 0004 1757 7615 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China 410008
12 9 2024
12 9 2024
12 2024
15 43823 5 2024
9 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Everolimus is an effective treatment for renal angiomyolipoma associated with TSC (TSC-RAML). However, its impact on hematologic parameters in TSC-RAML patients remains unclear.

Methods

Hematologic data were collected from TSC-RAML patients undergoing everolimus treatment in two registered clinical trials. Dynamic changes in hematologic parameters during treatment were analyzed. Additionally, we also explored variations in hematologic impact based on gender and age within the patient population.

Result

A total of 55 patients from the two clinical trials are included in this analysis. Hemoglobin, white blood cells (WBC), lymphocytes, neutrophils, and platelet showed significant decreases during everolimus treatment (P < 0.05). However, the decline in hemoglobin, WBC, and neutrophils attenuated by the 12th month (P ≥ 0.05). Aspartate transaminase (AST), Alanine transferase (ALT), total cholesterol (TC), and triglyceride (TG) increased significantly during everolimus treatment (P < 0.05), and these increases persisted throughout the year-long treatment. Hemoglobin decreased significantly more in male patients (− 15 vs − 6, P = 0.010), and AST showed a more significant increase in males (7.0 vs 3.0, P = 0.041). Platelet counts decreased significantly more in younger patients (≤ 30 years old) compared to older patients (− 50 vs − 14, P = 0.020).

Conclusion

Everolimus administration in TSC-RAML patients may increase hematologic risks, with male and younger patients potentially exhibiting greater susceptibility to these effects.

Keywords

Everolimus
Tuberous sclerosis complex associated (TSC)
Renal angiomyolipoma (RAML)
Hematologic parameters
National High-Level Hospital Clinical Research Funding2022-PUMCH-B-010 National High Level Hospital Clinical Research Funding2022-PUMCH-A-151 Postdoctoral Fellowship Program of CPSFGZC20230301 GZC20230301 Zhang Yushi issue-copyright-statement© Springer Science+Business Media, LLC 2024
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pmcIntroduction

Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by multiple organ lesions resulting from mutations in either TSC1 or TSC2 genes. The protein products of these genes negatively regulate the mammalian target of rapamycin (mTOR) signaling pathway [1, 2]. TSC-related renal lesion is prevalent among TSC patients, with up to 80% exhibiting renal abnormality, among which angiomyolipoma is the most common, affecting 56% of boys and 66% of girls [3]. Renal disease also is reported as a leading cause of mortality in these TSC patient [4]. Renal angiomyolipoma associated with TSC (TSC-RAML) predominantly affects younger individuals and is characterized by larger, faster-growing, multiple, and bilateral lesions, posing a higher risk of renal rupture and hemorrhage compared to sporadic renal angiomyolipoma (S-RAML) [5–7]. Treatment options were historically limited until the emergence of everolimus as a promising therapy in recent years [8]. Several clinical studies have demonstrated the efficacy of everolimus, an mTOR inhibitors, in reducing TSC-RAML volume, preventing tumor rupture and bleeding, and preserving renal function. Discontinuation of everolimus results in tumor rebound, necessitating its continuous administration to suppress tumor growth [9–11]. However, the use of everolimus is associated with significant side effects that can diminish a patient's quality of life, necessitating dose adjustments or treatment discontinuation [12]. Studies indicate that everolimus administration in TSC-RAML patients may increase hematologic risks, but understanding of its specific impact on hematologic parameters remains limited [10, 11].

In this study, we aim to elucidate the dynamic changes in hematologic parameters during one year of everolimus treatment among TSC-RAML patients. Furthermore, we investigate how these changes vary based on gender and age within the patient population. We anticipate that our research will provide valuable insights and guidance for optimizing everolimus management in TSC-RAML patients, thereby minimizing potential risks associated with treatment.

Materials and methods

Study design

Our research team conducted two previous clinical trials aimed at evaluating the effects of everolimus on TSC-RAML in the Chinese population. One trial, referred to as clinical trial 1, was a 2-year, nonrandomized, open-label trial, phase 2 study (ChiCTR-OPC-14005488, registered on the Chinese Clinical Trial Registry, https://www.chictr.org) [10]. The other trial, referred to as clinical trial 2, was a 1-year open-label, single-arm, multi-center Phase IV study (NCT03525834, registered on ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT03525834) [11]. Retrospectively, we analyzed the prospectively collected hematologic data from TSC-RAML patients undergoing everolimus treatment in these two clinical trials to investigate the potential impact of everolimus on hematologic parameters.

Patients and clinical data

The patients enrolled in both trials were diagnosed with definite TSC based on the consensus criteria published in 2013 [13]. All participants were Chinese adults aged 18 years or older. The two published studies provided comprehensive details regarding the inclusion and exclusion criteria [10, 11]. Initially, patients received an oral dose of 10 mg of everolimus per day, which was subsequently adjusted based on safety considerations during treatment.

Blood samples for hematological evaluation, including blood cell counts and biochemical analyses, were collected from patients between 8:00 and 10:00 a.m. at baseline, and at the 3rd, 6th, and 12th months of treatment. If potential factors, such as active infection or inflammation, were suspected to cause significant fluctuations in hematologic parameters, the patients would undergo re-evaluation in a timely manner.

The protocols of both studies were reviewed and approved by the respective local independent ethics committees at each center. The studies were conducted in compliance with the guidelines of Good Clinical Practice (GCP) and the ethical principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all patients before their enrollment.

Statistical methods

Numerical variables were presented as the mean ± standard deviation (SD) if they followed a normal distribution, or as the median (first quartile–third quartile) if they exhibited a non-normal distribution. Categorical variables were reported as frequencies and percentages.

Paired t-tests were conducted to analyze the differences in hematologic parameter values between the baseline and the treatment periods (3rd, 6th, or 12th month) for normally distributed data, while the Wilcoxon test was employed for non-normally distributed data. Additionally, the differences in value changes of hematological parameters among populations with varying genders or ages at the time point that showed the greatest increase or decrease (3rd, 6th, or 12th month), as determined from the analysis, were assessed using appropriate statistical tests. Specifically, unpaired t-tests were used for normally distributed data with equal SD, Welch’s t-test was employed for normally distributed data without equal SD, and the Mann–Whitney test was applied for non-normally distributed data. The analysis of categorical data was performed using the Chi-Squared test. Statistical analyses were conducted using GraphPad Prism 9.0 for Windows (GraphPad Software, Inc.). A significance level of P < 0.05 was adopted to determine statistical significance.

Result

A total of 55 patients were included in this analysis, comprising 15 patients from clinical trial 1 (out of the initially enrolled 18 patients, 3 patients discontinued the study within the first year) and 40 patients from clinical trial 2. The demographic and clinical characteristics of the patients are presented in Table 1. The mean age of the patients was 31, with 30 patients being above 30 years old. Of the patients, 36 were male, while 4 female patients presented with lymphangioleiomyomatosis (LAM). Four patients were diagnosed with subependymal giant cell astrocytoma (SEGA), and all 55 patients exhibited skin lesions. Table 1 Demographics and baseline characteristics

Characteristics	Clinical trial 1	Clinical trial 2	Total	
Number of patients	15	40	55	
Age in years, median (range)	30 (20–46)	33 (18–60)	31 (18–60)	
 ≦ 30y	8 (53.3%)	17 (42.5%)	25 (45.5%)	
 > 30y	7 (46.7%)	23 (57.5%)	30 (54.5%)	
Sex	
 Female	11 (73.3%)	26 (65.0%)	37 (67.3%)	
 Male	4 (26.6%)	14 (35.0%)	18 (32.7%)	
Race (n, %)	
 Asian	15 (100%)	40 (100%)	55 (100%)	
 Presence of SEGA	0 (0%)	3 (7.5%)	3 (5.5%)	
 Diagnosis of LAM	5 (40.0%)	13 (32.5%)	18 (32.7%)	
 Skin lesion (≥ 1)	15 (100%)	40 (100%)	55 (100%)	
SEGA subependymal giant cell astrocytoma, LAM lymphangioleiomyomatosis

Significant reductions were observed in hemoglobin, white blood cells (WBC), lymphocytes, neutrophils, and platelets during everolimus treatment (P < 0.05). However, the decreases in hemoglobin, WBC, and neutrophils attenuated in the 12th month (P > 0.05) (Fig. 1A, B, E, F). Importantly, lymphocytes exhibited a persistent and significant decrease throughout the entire year of treatment (Fig. 1C). Conversely, monocytes showed a consistent increasing trend, although this change was not statistically significant (Fig. 1D).Fig. 1 Changes in hematologic parameters in TSC-RAML patients during everolimus treatment

Aspartate transaminase (AST), alanine transferase (ALT), and total cholesterol (TC) exhibited a sharp and significant increase during the initial 3 months of treatment (P < 0.05), and these levels remained significantly elevated thereafter (Fig. 1G, H, K). Triglyceride levels showed a significant increase starting from the 3rd month and continued to rise throughout the treatment period, despite a subsequent decrease after peaking in the 6th month (Fig. 1L). Although creatinine and glucose levels displayed a general increasing trend over the one-year treatment period, these changes were not statistically significant (Fig. 1I, J).

The differences in the changes in hematologic parameters between female and male patients are presented in Table 2. The age difference between females and males was not statistically significant (31 vs 33, P = 0.620). Male patients exhibited a significantly greater decrease in hemoglobin compared to female patients (− 15 vs − 6, P = 0.010). The increase in AST was significantly higher in male patients compared to female patients (7.0 vs 3.0, P = 0.041), and a similar trend was observed for ALT, indicating a higher increase in male patients. Furthermore, female patients exhibited a higher increase in creatine, glucose, total cholesterol (TC), and triglycerides, although these differences were not statistically significant. The gender distribution between younger and older patients were not statistically significant (female/male: 18/7 vs 18/12, P = 0.351). However, Table 3 demonstrates that the decrease in platelet count (− 50 vs − 14, P = 0.020) was significantly greater in younger patients (≦30 years old) compared to older patients (> 30 years old). Table 2 Differences in hematologic parameter changes between females and males

Parameter	Female (n = 29)	Male (n = 16)	P	
Hemoglobin (g/L)	− 6 (− 12, − 4)	− 15 (− 20, − 5)	0.010	
WBC (× 109/L)	− 0.64 ± 0.93	− 0.62 ± 1.98	0.965	
Lymphocyte (× 109/L)	− 0.20 ± 0.41	− 0.20 ± 0.70	0.998	
Monocyte (× 109/L)	0.052 ± 0.136	− 0.001 ± 0.143	0.191	
Neutrophil (× 109/L)	− 0.38 (− 0.84, 0.12)	− 0.43 (− 2.06, 1.27)	0.614	
Platelet (× 109/L)	− 32 ± 59	− 30 ± 51	0.899	
AST (U/L)	3.0 (0.3, 7.0)	7.0 (3.0, 16.0)	0.041	
ALT (U/L)	4.5 (0.3, 8.8)	13.0 (− 1.0, 30.0)	0.132	
Creatine (μmol/L)	3.0 (− 2.0, 7.3)	1.5 (− 6.8, 5.0)	0.388	
Glucose (nmol/L)	0.13 (− 0.20, 0.58)	− 0.06 (− 0.40, 0.30)	0.150	
TC (nmol/L)	1.47 ± 1.03	1.02 ± 1.01	0.151	
Triglyceride (nmol/L)	1.07 (0.52, 1.73)	0.75 (− 0.07, 1.16)	0.084	
WBC white blood cell, TC Total cholesterol

Table 3 Differences in hematologic parameter changes between the younger and older

Parameters	Younger (≦ 30 y, n = 25)	Elder (> 30 y, n = 30)	P	
Hemoglobin (g/L)	− 6 ± 11	− 11 ± 16	0.265	
WBC (× 109/L)	− 0.39 ± 1.13	− 0.85 ± 1.49	0.223	
Lymphocyte (× 109/L)	− 0.15 (− 0.60, 0.09)	− 0.19 (− 0.44, 0.12)	0.703	
Monocyte (× 109/L)	0.019 ± 0.117	0.039 ± 0.144	0.608	
Neutrophil (× 109/L)	− 0.46 ± 1.27	− 0.60 ± 1.73	0.366	
Platelet (× 109/L)	− 50 ± 54	− 14 ± 54	0.020	
AST (U/L)	4.0 (0, 8.0)	4.0 (1, 12.5)	0.407	
ALT (U/L)	7.0 (2.5, 20)	3.5 (− 3.0, 10.0)	0.095	
Creatine (μmol/L)	2.32 ± 7.02	5.63 ± 16.80	0.355	
Glucose (nmol/L)	0.07 ± 0.41	0.20 ± 0.67	0.420	
TC (nmol/L)	1.35 ± 0.90	1.32 ± 1.16	0.913	
Triglyceride (nmol/L)	0.94 (0.42, 1.49)	0.84 (0.42, 1.60)	0.933	
WBC white blood cell, TC Total cholesterol

Discussion

The TSC1-TSC2 complex, composed of hamartin and tuberin encoded by the TSC1 and TSC2 genes, respectively, is a crucial inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1). Mutations in either TSC1 or TSC2 can lead to the functional loss of the TSC1-TSC2 complex, resulting in unregulated and constitutive activation of mTORC1. This dysregulation causes uncontrolled protein synthesis, cellular growth, proliferation, and angiogenesis [14]. Everolimus, an mTOR inhibitor, has shown efficacy in reducing tumor size, preventing tumor rupture and bleeding, and preserving renal function, making it the recommended first-line therapy for TSC patients [9–11]. However, the potential risks associated with its treatment cannot be overlooked. Our study specifically examined the potential hematologic impact and risks of everolimus in patients with TSC-RAML.

Many hematologic parameters were significantly impacted by everolimus throughout the treatment period, with most blood cells, except for monocytes, as well as hemoglobin showing significant decreases. A published study on the effectiveness and safety of everolimus treatment in TSC patients also demonstrated that anemia and leukopenia were the most frequent laboratory abnormalities during the entire treatment period [12]. In our study, hemoglobin, WBC, neutrophil, and platelet exhibited significant decreases followed by rebound increases, which may be attributed to the homeostatic regulation of blood cells to maintain parameter fluctuations around a certain level [15]. Hemoglobin and lymphocyte exhibited significant decreases in a shorter duration (≤ 3 months) compared to WBC, neutrophils, and platelets, suggesting that hemoglobin and lymphocytes were more susceptible to the effects of everolimus. This vulnerability may be due to the dynamic turnover of these cell types. Notably, red blood cells and lymphocytes have longer lifespans than neutrophils and platelets [16–19], indicating lower turnover activity in red blood cells and lymphocytes, and thus resulting in significant decreases within a shorter timeframe under the influence of everolimus. The decrease may be associated with inhibition on the cell cycle and subsequent proliferation of normal cells when everolimus suppresses tumor progression. Additionally, mTOR inhibitors block the interleukin-2 receptor and CD28-dependent signaling pathways, which could further contribute to the observed myelosuppression and inhibition of blood cell proliferation [20]. Everolimus also is used as an immune system suppressor in transplantation recipients, inhibiting the ability of white blood cells (WBC) to reject the transplanted organ [21]. The significant decrease in WBC, lymphocyte, and neutrophil levels, indicating immune suppression and toxicity of everolimus, may weaken the anti-infection capacity of TSC-RAML patients undergoing everolimus treatment. It is important to note that lymphocyte levels consistently decrease during the treatment and may further decline with continued therapy. Hematological toxicity and bone marrow suppression are common side effects of mTOR inhibitor treatment. Thrombocytopenia and neutropenia rarely lead to clinically significant bleeding or infection, and thus usually do not require platelet transfusions or growth factor support. However, in cases of grade 3 toxicity, it is necessary to interrupt the treatment and reduce the dose when resuming. Additionally, everolimus should be discontinued immediately if any life-threatening toxicity occurs [22].

Everolimus undergoes extensive metabolism primarily through the cytochrome P450 system (CYP3A4) and P-glycoprotein in the liver [23]. Liver injury may result from the direct effects of everolimus or intermediate toxicity generated during its metabolism. Both ALT and AST, key markers of liver function in clinical practice, showed a significant increase after 3 months and remained elevated throughout the treatment period. Therefore, careful monitoring of liver function is essential in TSC-RAML patients during treatment, especially when everolimus is co-administered with inhibitors or inducers of cytochrome P450 drug-metabolizing enzymes, as potential drug interactions may occur. Many studies have also documented hyperlipidemia as another common adverse effect of everolimus [10, 12]. Lipid levels, including total cholesterol (TC) and triglycerides (TG), also exhibited significant increases in the short term, specifically within less than 3 months in our study. Research has shown that everolimus can significantly elevate serum lipid levels by reducing lipoprotein lipase activity [24]. On the other hand, the metabolism of apolipoprotein B (apoB) is mediated through the mTOR signaling pathway, and the catabolism of apoB-containing lipoproteins is diminished by mTOR inhibitors [25]. Both cholesterol and triglycerides are apoB-containing particles, and the increased levels of apoB lipoproteins may contribute to elevated lipid levels [26]. We recommend drug intervention for severe hyperlipidemia or grade 3 liver injury. However, elevated lipid levels, particularly in TSC-RAML patients with comorbidities such as hyperlipidemia, hyperglycemia, and hypertension, may significantly increase the risk of cardiovascular and cerebrovascular diseases [22].

Limited studies have investigated hematologic response differences among TSC-RAML patients of different genders and age groups to everolimus treatment. Our analysis revealed that male patients experienced a greater decrease in hemoglobin levels and a greater increase in AST levels due to everolimus treatment. Estrogen has the potential to stimulate hematopoiesis in females and enhance the proliferation of hematopoietic stem cells (HSCs) and various blood cell types, including erythrocytes [27]. The higher renewal capacity of erythrocytes in females may help mitigate the side effects on hemoglobin levels. Although females are generally considered to be at higher risk for drug-induced liver injury [28], gender disparities in drug-induced liver injury vary depending on the specific drugs, with a higher frequency of reported drug-induced liver events in males for certain medications [29]. Our findings indicated that male patients exhibited higher elevations in alanine aminotransferase (ALT) levels, suggesting a potentially greater risk of drug-induced liver injury associated with everolimus in males.

Our results also revealed a greater decrease in platelet levels among younger patients. The tortuous aneurysmal vessels within the angiomyolipoma, which are more susceptible to rupture and bleeding compared to normal vessels, constitute a high-risk factor for tumor hemorrhage [30]. Tumor rupture and hemorrhage pose a significant life-threatening risk for TSC-RAML patients. The decrease in platelet count may further enhance the risk of hemorrhage due to the potential platelet-related coagulation dysfunction. Everolimus is an immune inhibitor that can potentially result in immune system dysfunction. Besides inhibiting platelet proliferation, it remains uncertain whether the decrease in platelets is related to drug-induced immune thrombocytopenia, as everolimus may lead to possible immune dysfunction. Furthermore, significant differences exist in the immune systems of younger and older individuals, which may contribute to the varying platelet decreases observed between younger and older patients. Additional research is necessary to further elucidate this potential relationship.

There are several limitations in our study: (1) The sample size was relatively small due to the rarity of TSC-RAML. (2) The generalizability of our findings might be limited because all patients included were Asians. (3) Hematologic parameters can be affected by various factors, such as active infection or inflammation. These factors might have influenced the accuracy of our results, although measures were taken to minimize potential influences as much as possible.

Conclusion

Hemoglobin, WBC, neutrophil, platelet and lymphocytes underwent a significant decrease during everolimus treatment in TSC-RAML patients, whereas AST, ALT, TC, and TG demonstrated significant increases. Male patients exhibited higher vulnerability to everolimus-induced decreases in hemoglobin and platelet counts, while younger patients showed greater susceptibility to everolimus-induced platelet reduction.

Acknowledgements

We want to particularly acknowledge patients for their collaboration. Thank China Scholarship Council (CSC) for funding Dongxu Qiu's studies in University of British Columbia, Canada.

Author contributions

Study concept and design: ZCL and YSZ. Acquisition of data: ZCL DXQ, YZ, ZW. Analysis and interpretation of data: WDW, ZCL, DXQ, YZ. Drafting of the manuscript: ZCL. Statistical analysis: ZCL, ZW, XW. Critical revision of the manuscript for important intellectual content: YSZ. Administrative, technical, or material support: YSZ, WDW.

Funding

This study was supported by National High-Level Hospital Clinical Research Funding (2022-PUMCH-B-010), National High Level Hospital Clinical Research Funding (2022-PUMCH-A-151), and Postdoctoral Fellowship Program of CPSF (Grant Number: GZC20230301).

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was done in accordance with the Declaration of Helsinki and local regulations and was approved by the ethics committee of Peking Union Medical College Hospital, the ethics committee of Chinese PLA General Hospital, the ethics committee of Cancer Hospital Afliated to Fudan University, the ethics committee of West China Hospital, the ethics committee of Tongji Hospital.

Patient consent statement

Informed written consent was obtained from all participants included.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Henske EP Tuberous sclerosis complex Nat Rev Dis Primers 2016 2 16035 10.1038/nrdp.2016.35 27226234
Henske EP, et al. Tuberous sclerosis complex. Nat Rev Dis Primers. 2016;2:16035.27226234 10.1038/nrdp.2016.35
2. Volpi A Tuberous sclerosis complex: new insights into clinical and therapeutic approach J Nephrol 2019 32 3 355 363 10.1007/s40620-018-0547-6 30406604
Volpi A, et al. Tuberous sclerosis complex: new insights into clinical and therapeutic approach. J Nephrol. 2019;32(3):355–63.30406604 10.1007/s40620-018-0547-6
3. Franz DN Bissler JJ McCormack FX Tuberous sclerosis complex: neurological, renal and pulmonary manifestations Neuropediatrics 2010 41 5 199 208 10.1055/s-0030-1269906 21210335
Franz DN, Bissler JJ, McCormack FX. Tuberous sclerosis complex: neurological, renal and pulmonary manifestations. Neuropediatrics. 2010;41(5):199–208.21210335 10.1055/s-0030-1269906
4. Amin S Causes of mortality in individuals with tuberous sclerosis complex Dev Med Child Neurol 2017 59 6 612 617 10.1111/dmcn.13352 27935023
Amin S, et al. Causes of mortality in individuals with tuberous sclerosis complex. Dev Med Child Neurol. 2017;59(6):612–7.27935023 10.1111/dmcn.13352
5. Seyam RM Changing trends in presentation, diagnosis and management of renal angiomyolipoma: comparison of sporadic and tuberous sclerosis complex-associated forms Urology 2008 72 5 1077 1082 10.1016/j.urology.2008.07.049 18805573
Seyam RM, et al. Changing trends in presentation, diagnosis and management of renal angiomyolipoma: comparison of sporadic and tuberous sclerosis complex-associated forms. Urology. 2008;72(5):1077–82.18805573 10.1016/j.urology.2008.07.049
6. Sooriakumaran P Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated BJU Int 2010 105 1 101 106 10.1111/j.1464-410X.2009.08649.x 19493268
Sooriakumaran P, et al. Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated. BJU Int. 2010;105(1):101–6.19493268 10.1111/j.1464-410X.2009.08649.x
7. Fernández-Pello S Management of sporadic renal angiomyolipomas: a systematic review of available evidence to guide recommendations from the european association of urology renal cell carcinoma guidelines panel Eur Urol Oncol 2020 3 1 57 72 10.1016/j.euo.2019.04.005 31171501
Fernández-Pello S, et al. Management of sporadic renal angiomyolipomas: a systematic review of available evidence to guide recommendations from the european association of urology renal cell carcinoma guidelines panel. Eur Urol Oncol. 2020;3(1):57–72.31171501 10.1016/j.euo.2019.04.005
8. Budde K Gaedeke J Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition Am J Kidney Dis 2012 59 2 276 283 10.1053/j.ajkd.2011.10.013 22130643
Budde K, Gaedeke J. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. Am J Kidney Dis. 2012;59(2):276–83.22130643 10.1053/j.ajkd.2011.10.013
9. Bissler JJ Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial Lancet 2013 381 9869 817 824 10.1016/S0140-6736(12)61767-X 23312829
Bissler JJ, 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(9869):817–24.23312829 10.1016/S0140-6736(12)61767-X
10. Cai Y Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial Orphanet J Rare Dis 2018 13 1 43 10.1186/s13023-018-0781-y 29587809
Cai Y, et al. Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial. Orphanet J Rare Dis. 2018;13(1):43.29587809 10.1186/s13023-018-0781-y
11. Wang W A multi-centric study assessing safety and efficacy of everolimus in adult chinese patients with tuberous sclerosis complex associated renal angiomyolipomas Front Oncol 2022 12 871723 10.3389/fonc.2022.871723 35860575
Wang W, et al. A multi-centric study assessing safety and efficacy of everolimus in adult chinese patients with tuberous sclerosis complex associated renal angiomyolipomas. Front Oncol. 2022;12: 871723.35860575 10.3389/fonc.2022.871723
12. Cockerell I Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice Orphanet J Rare Dis 2023 18 1 377 10.1186/s13023-023-02982-1 38042867
Cockerell I, et al. Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Orphanet J Rare Dis. 2023;18(1):377.38042867 10.1186/s13023-023-02982-1
13. Krueger DA Northrup H Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference Pediatr Neurol 2013 49 4 255 265 10.1016/j.pediatrneurol.2013.08.002 24053983
Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):255–65.24053983 10.1016/j.pediatrneurol.2013.08.002
14. Laplante M Sabatini DM mTOR signaling in growth control and disease Cell 2012 149 2 274 293 10.1016/j.cell.2012.03.017 22500797
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.22500797 10.1016/j.cell.2012.03.017
15. Scheiermann C Frenette PS Hidalgo A Regulation of leucocyte homeostasis in the circulation Cardiovasc Res 2015 107 3 340 351 10.1093/cvr/cvv099 25750191
Scheiermann C, Frenette PS, Hidalgo A. Regulation of leucocyte homeostasis in the circulation. Cardiovasc Res. 2015;107(3):340–51.25750191 10.1093/cvr/cvv099
16. Arias CF Arias CF How do red blood cells know when to die? R Soc Open Sci 2017 4 4 160850 10.1098/rsos.160850 28484605
Arias CF, Arias CF. How do red blood cells know when to die? R Soc Open Sci. 2017;4(4): 160850.28484605 10.1098/rsos.160850
17. Tough DF Sprent J Lifespan of lymphocytes Immunol Res 1995 14 1 1 12 10.1007/BF02918494 7561338
Tough DF, Sprent J. Lifespan of lymphocytes. Immunol Res. 1995;14(1):1–12.7561338 10.1007/BF02918494
18. Pillay J In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days Blood 2010 116 4 625 627 10.1182/blood-2010-01-259028 20410504
Pillay J, et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood. 2010;116(4):625–7.20410504 10.1182/blood-2010-01-259028
19. Lebois M Josefsson EC Regulation of platelet lifespan by apoptosis Platelets 2016 27 6 497 504 10.3109/09537104.2016.1161739 27100842
Lebois M, Josefsson EC. Regulation of platelet lifespan by apoptosis. Platelets. 2016;27(6):497–504.27100842 10.3109/09537104.2016.1161739
20. Sofroniadou S Goldsmith D Mammalian target of rapamycin (mTOR) inhibitors: potential uses and a review of haematological adverse effects Drug Saf 2011 34 2 97 115 10.2165/11585040-000000000-00000 21247219
Sofroniadou S, Goldsmith D. Mammalian target of rapamycin (mTOR) inhibitors: potential uses and a review of haematological adverse effects. Drug Saf. 2011;34(2):97–115.21247219 10.2165/11585040-000000000-00000
21. Tedesco-Silva H An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients Transplant Rev (Orlando) 2022 36 1 100655 10.1016/j.trre.2021.100655 34696930
Tedesco-Silva H, et al. An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients. Transplant Rev (Orlando). 2022;36(1): 100655.34696930 10.1016/j.trre.2021.100655
22. Davies M Saxena A Kingswood JC Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide Orphanet J Rare Dis 2017 12 1 35 10.1186/s13023-017-0581-9 28202028
Davies M, Saxena A, Kingswood JC. Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide. Orphanet J Rare Dis. 2017;12(1):35.28202028 10.1186/s13023-017-0581-9
23. Kirchner GI Meier-Wiedenbach I Manns MP Clinical pharmacokinetics of everolimus Clin Pharmacokinet 2004 43 83 95 10.2165/00003088-200443020-00002 14748618
Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet. 2004;43:83–95.14748618 10.2165/00003088-200443020-00002
24. Luo C Perfect match: mTOR inhibitors and tuberous sclerosis complex Orphanet J Rare Dis 2022 17 1 106 10.1186/s13023-022-02266-0 35246210
Luo C, et al. Perfect match: mTOR inhibitors and tuberous sclerosis complex. Orphanet J Rare Dis. 2022;17(1):106.35246210 10.1186/s13023-022-02266-0
25. Sidiropoulos KG Insulin inhibition of apolipoprotein B mRNA translation is mediated via the PI-3 kinase/mTOR signaling cascade but does not involve internal ribosomal entry site (IRES) initiation Arch Biochem Biophys 2007 465 2 380 388 10.1016/j.abb.2007.06.029 17698027
Sidiropoulos KG, et al. Insulin inhibition of apolipoprotein B mRNA translation is mediated via the PI-3 kinase/mTOR signaling cascade but does not involve internal ribosomal entry site (IRES) initiation. Arch Biochem Biophys. 2007;465(2):380–8.17698027 10.1016/j.abb.2007.06.029
26. Hoogeveen RC Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients Transplantation 2001 72 7 1244 1250 10.1097/00007890-200110150-00011 11602850
Hoogeveen RC, et al. Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Transplantation. 2001;72(7):1244–50.11602850 10.1097/00007890-200110150-00011
27. Kumar RS Goyal N Estrogens as regulator of hematopoietic stem cell, immune cells and bone biology Life Sci 2021 269 119091 10.1016/j.lfs.2021.119091 33476629
Kumar RS, Goyal N. Estrogens as regulator of hematopoietic stem cell, immune cells and bone biology. Life Sci. 2021;269: 119091.33476629 10.1016/j.lfs.2021.119091
28. Floreani A Sex disparity and drug-induced liver injury Dig Liver Dis 2023 55 1 21 28 10.1016/j.dld.2022.06.025 35843842
Floreani A, et al. Sex disparity and drug-induced liver injury. Dig Liver Dis. 2023;55(1):21–8.35843842 10.1016/j.dld.2022.06.025
29. George N Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury Regul Toxicol Pharmacol 2018 94 101 107 10.1016/j.yrtph.2018.01.018 29407200
George N, et al. Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury. Regul Toxicol Pharmacol. 2018;94:101–7.29407200 10.1016/j.yrtph.2018.01.018
30. Rimon U Large renal angiomyolipomas: digital subtraction angiographic grading and presentation with bleeding Clin Radiol 2006 61 6 520 526 10.1016/j.crad.2006.02.003 16713423
Rimon U, et al. Large renal angiomyolipomas: digital subtraction angiographic grading and presentation with bleeding. Clin Radiol. 2006;61(6):520–6.16713423 10.1016/j.crad.2006.02.003
