Analysis of mTOR pathway expression in lymphatic malformation and related diseases

Hori, Yumiko; Ozeki, Michio; Hirose, Katsutoshi; Matsuoka, Katsuyoshi; Matsui, Takahiro; Kohara, Masaharu; Tahara, Shinichiro; Toyosawa, Satoru; Fukao, Toshiyuki; Morii, Eiichi

doi:10.1111/pin.12913

Cited by 19 publications

(23 citation statements)

References 31 publications

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“…11 Mammalian target of rapamycin (mTOR) is downstream of PI3K/AKT/mTOR pathway and it is proved that mTOR was detected in all lymphatic anomalies but not in normal lymphatics. 12 This evidence supports the therapeutic potential of the mTOR inhibitor sirolimus in LMs. The first report on the successful use of sirolimus as an antiangiogenetic agent was published in 2010.…”

Section: Introductionsupporting

confidence: 68%

Efficacy of Initial Sirolimus Therapy for 27 Patients with Intractable Lymphatic Malformations

et al. 2021

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Objective/Hypothesis: To evaluate the efficacy of initial sirolimus therapy in the treatment of intractable head and neck lymphatic malformations (LMs) in children.Study Design: Prospective open-label study.Methods: In this study, Twenty-seven children diagnosed with LMs were given oral sirolimus as primary treatment over a minimum 6-month trial. The major parameter to evaluate therapeutic outcome was percentage of lesion volume change compared with baseline. Average serum sirolimus concentrations, and adverse side effects, were monitored throughout the study period.Results: Fifteen girls and twelve boys, average age 27 months (16 days-171 months), constitute the study group. Treatment was deemed effective for twenty-three participants, judged as fair in seven, good in nine, and excellent in seven. Two patients had minimal improvement, and two had increased volume to some degree. Effectiveness differed among LMs subtypes with responsiveness of macrocystic LMs exceeding that of microcystic LMs (P < .05). Adverse drug reactions totaled 27 events in ten patients, the majority being mild with upper respiratory infections being most common.Conclusions: Sirolimus as initial therapy is effective in decreasing lesion volume in intractable LMs in head and neck region, especially in macrocystic subtypes. Although most cases cannot be completely cured, side effects are few and tolerable.

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Section: Introductionsupporting

confidence: 68%

Efficacy of Initial Sirolimus Therapy for 27 Patients with Intractable Lymphatic Malformations

et al. 2021

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“…Previous studies demonstrated that p-S6K1 was not detected in non-neoplastic fibrous tissue and adipose tissue [ 16 , 17 ], besides p-S6K1 showed sporadic expression in normal vessels [ 18 , 19 ]. Furthermore, both p-AKT and p-4EBP1 were not detected in non-neoplastic vessels, fibrous tissue and adipose tissue [ 16 , 17 , 19 – 21 ]. Thus, PI3K/AKT/mTOR pathway in mesenchymal malformation of FAVA is activated compared to that in normal tissue.…”

Section: Discussionmentioning

confidence: 99%

Fibro-adipose vascular anomaly (FAVA): three case reports with an emphasis on the mammalian target of rapamycin (mTOR) pathway

et al. 2020

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Background Fibro-adipose vascular anomaly (FAVA) is a new entity of vascular anomalies with somatic and mosaic gain-of-function mutations of the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ). PIK3CA mutation excessively activates mammalian target of rapamycin (mTOR) pathway, which promotes angiogenesis and lymphangiogenesis. Histologically, FAVA is composed of intramuscular fibrous and adipose tissues with venous malformation (VM). Although sirolimus known as a mTOR inhibitor has good response to FAVA, expression pattern of the mTOR pathway was still unclear. Herein, we immunohistochemically investigated three novel FAVA patients with an emphasis on the mTOR pathway (p-S6K1, p-4EBP1 and p-AKT). Case presentation Case 1: A 10-year-old female had complained of pain in the left thigh since she was 6-year-old. Under the clinical diagnosis of VM, she underwent surgical resection for the lesion. Case 2: A 29-year-old female patient had complained of discomfort and mild pain in the left shoulder since she was 18-year-old. After childbirth, she had severe ongoing pain and contracture of the shoulder. Under clinical diagnosis of VM, surgical resection was performed. Case 3: A 53-year-old female had complained of pain and knee restriction after surgical treatment of a knee tumor at the age of 31. Under the clinical diagnosis of atypical lipomatous tumor or high grade liposarcoma, surgical resection was performed. Histologically, all three patients presented with characteristic features of fibrous and adipose tissues with abnormal vessels within the skeletal muscle, leading to diagnosis of FAVA. Although VM has been reported as an important finding in FAVA, immunohistological findings demonstrated that abnormal vessels comprised complex of VM and lymphatic malformation (LM) in all cases. Furthermore, besides vascular malformation, abnormal fibrous and adipose tissues of FAVA expressed mTOR pathway components. Conclusions We presented three new cases of FAVA. Histological and immunohistochemical analyses revealed that VM and LM complex was an important finding in FAVA, and that the mTOR pathway components were expressed in abnormal fibrous tissue, adipose tissue and vascular malformation. These findings suggested that FAVA might be a mesenchymal malformation caused by PI3K/AKT/mTOR pathway.

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“…Therefore, they concluded that lymphangiogenesis is a valuable predictive biomarker for the therapeutic response to sirolimus in children with LM [ 32 ]. Hori et al [ 42 ] analyzed the activation of the mTOR pathway in a subset of lymphatic anomalies in vivo and demonstrated that normal lymphatic vessels expressed neither mTOR nor its phosphorylated form p‐mTOR. In contrast to normal lymphatic vessels, endothelial cells of LM, kaposiform lymphangiomatosis and kaposiform hemangioendothelioma expressed mTOR.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of sirolimus in children with lymphatic malformations of the head and neck

Wiegand

Dietz

Wichmann

2022

Eur Arch Otorhinolaryngol

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Purpose Children with extensive lymphatic malformations of the head and neck often suffer from functional impairment and aesthetic deformity which significantly affect the quality of life and may be life-threatening. Treatment with sirolimus has the potential to improve symptoms and downsize lymphatic malformations. This systematic review summarizes the current information about sirolimus treatment of lymphatic malformations of the head and neck in children, its efficacy and side effects. Methods A systematic search of the literature regarding studies on sirolimus treatment of children with lymphatic malformations of the head and neck was performed in PubMed, Embase, and Google Scholar up to July 2021 with the search terms “lymphatic malformation”, “lymphangioma”, “cystic hygroma”, “low-flow malformation”, “sirolimus”, “rapamycin”, “mTOR inhibitor” and “children”. Results In all, 28 studies including 105 children from newborn to 17 years treated with sirolimus for lymphatic malformations of the head and neck were analyzed. The most frequent initial dose was 0.8 mg/m2 per dose, twice daily at 12-h interval. The target blood level differed between studies, 10–15 ng/mL and 5–15 ng/mL were most often used. More than 91% of the children responded to sirolimus treatment which lasts from 6 months to 4 years. Typical side effects were hyperlipidemia, neutropenia and infections. Methods Sirolimus could be an effective treatment for children with large complicated lymphatic malformations of the head and neck. As not all patients will benefit from treatment, the decision to treat sirolimus should be made by a multidisciplinary team.

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Analysis of mTOR pathway expression in lymphatic malformation and related diseases

Cited by 19 publications

References 31 publications

Efficacy of Initial Sirolimus Therapy for 27 Patients with Intractable Lymphatic Malformations

Efficacy of Initial Sirolimus Therapy for 27 Patients with Intractable Lymphatic Malformations

Fibro-adipose vascular anomaly (FAVA): three case reports with an emphasis on the mammalian target of rapamycin (mTOR) pathway

Efficacy of sirolimus in children with lymphatic malformations of the head and neck

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