Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies

Adams, Denise M.; Trenor, Cameron C.; Hammill, Adrienne M.; Vinks, Alexander A.; Patel, Manish; Chaudry, Gulraiz; Wentzel, Mary Sue; Mobberley‐Schuman, Paula S.; Campbell, Lisa M.; Brookbank, Christine; Gupta, Anita; Chute, Carol; Eile, Jennifer; McKenna, Jesse; Merrow, Arnold C.; Lin, Fang; Hornung, Lindsey; Seid, Michael; Dasgupta, Anasua Roshni; Dickie, Belinda; Elluru, Ravindhra G.; Lucky, Anne W.; Weiss, Brian; Azizkhan, Richard G.

doi:10.1542/peds.2015-3257

Cited by 672 publications

(860 citation statements)

References 31 publications

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“…Rapamycin has shown efficacy in clinical trials of lymphangiomatosis and other lymphatic anomalies (3,4,11,12). Rapamycin has also been used extensively in mice over a wide range of doses (29,30).…”

Section: Dose Response Of Rapamycinmentioning

confidence: 99%

“…Rapamycin and related mTORC1 inhibitors are being used with promising results in the treatment of lymphatic malformations (4,(80)(81)(82), which build on what is known from the treatment of patients with LAM (27,83). Favorable responses provide incentive for learning more about the actions of mTORC1 inhibitors in the treatment of lymphatic anomalies.…”

Section: Attributes and Limitations Of The Ccsp/vegf-c Mouse Model Ofmentioning

confidence: 99%

“…Lymphatic malformations, including generalized lymphatic anomalies, Gorham-Stout disease, Kaposiform lymphangiomatosis, and related lymphatic growths defined by the International Society for the Study of Vascular Anomalies classification (1), are uncommon but serious pathological conditions that present diagnostic and therapeutic challenges (2)(3)(4). Pulmonary lymphangiectasia, in which airway and lung lymphatics are abnormally expanded and leaky (5)(6)(7), is a feature of many widespread lymphatic anomalies.…”

Section: Introductionmentioning

confidence: 99%

“…Discovery of mutations in RAS signaling or PIK3CA in some lymphatic malformations (8)(9)(10) provides insight into potential mechanisms. The mTOR inhibitor rapamycin (sirolimus) has yielded promising results in the treatment of patients with lymphatic malformations (3,4,11,12). However, the absence of experimental models for examining pathophysiology and testing innovative treatments is a limitation.…”

Section: Introductionmentioning

confidence: 99%

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Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Bałuk¹,

Yao²,

Flores³

et al. 2017

JCI Insight

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Section: Dose Response Of Rapamycinmentioning

confidence: 99%

Section: Attributes and Limitations Of The Ccsp/vegf-c Mouse Model Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Bałuk¹,

Yao²,

Flores³

et al. 2017

JCI Insight

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“…Another study showed that Sirolimus is a well-tolerated. The common grade three side effects bone marrow toxicity in 27%, gastrointestinal toxicity in 3% and metabolic toxicity in 3% [74,75].…”

Section: Role Of Mtor Inhibitorsmentioning

confidence: 99%

Clinical Review: Management of Adult Kasabach-Merritt Syndrome Associated with Hemangiomas

Master¹,

Kallam²,

Eo³

et al. 2017

J Blood Disord Transfus

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Kasabach-Merritt syndrome (KMS) consists of a clinical trial of capillary hemangioma, thrombocytopenia and disseminated intravascular coagulation. KMS occurs most commonly in the pediatric population, and its occurrence in adults is rare. Specific guidelines or randomized clinical trials guiding clinical management of KMS in adult patients are lacking. This manuscript provides a comprehensive review of KMS and discusses recent advances in the medical management of KMS. We also propose a systematic therapeutic approach which would serve as a guide in the management of adult patients with KMS caused by hemangiomas.

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Scarring in Patients With PIK3CA-Related Overgrowth Syndromes

et al. 2018

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IMPORTANCEPatients with somatic overgrowth commonly require surgical intervention to preserve function and improve cosmesis. To our knowledge no observation of scarring outcomes in this population has been published to date. OBJECTIVE To observe the frequency of abnormal scarring in patients with somatic overgrowth and sequencing-verified mutations in the PIK3CA gene. DESIGN, SETTING, AND PARTICIPANTSThis retrospective study evaluated scarring outcomes in patients with PIK3CA-related overgrowth. Samples of affected tissue were sequenced between July 2015 and October 2016. Medical records from multiple large academic tertiary care centers were reviewed for surgical history and scar descriptions, and clinical photographs were assessed by 2 surgeons (J.N.J. and D.M.K.) to confirm abnormal scarring. Analysis of medical records and photographs was performed between April 2017 and June 2017 by a multidisciplinary team from dermatology, plastic surgery, orthopedic surgery, radiology, and genetics departments. All patients considered for the study were diagnosed with somatic overgrowth and previously had affected tissue sent for next-generation sequencing. Those with pathogenic PIK3CA variants and 1 or more prior surgical procedures were reviewed. MAIN OUTCOMES AND MEASURES Presence of excessive scarring in patients with PIK3CA overgrowth.RESULTS A total of 57 patients with segmental overgrowth syndromes were sequenced. Of the 57 patients, 25 (44%) had pathogenic or likely pathogenic variants in PIK3CA. Of those with pathogenic PIK3CA variants, 6 (24%) had past surgical procedures, all with preoperative and postoperative photographs. Of 6 patients with PIK3CA-related overgrowth and a history of 1 or more surgical procedure, 4 (67%) developed excessive scarring. The cohort with abnormal scarring comprised 3 females and 1 male, with a median age of 8.5 years. All abnormal scarring occurred in affected overgrowth tissue. Three of the 4 patients developed the excessive scarring after debulking procedures for overgrowth and/or vascular malformations of the upper or lower extremity. CONCLUSIONS AND RELEVANCEExcessive scarring occurred frequently in patients with PIK3CA-related overgrowth syndromes. The risk of abnormal scarring should therefore be discussed preoperatively. Given the activating nature of these PIK3CA variants, we suggest that the excessive scarring may be owing in part to up-regulation of the PI3K-Akt-mTOR pathway. Additional studies are needed to assess scarring outcomes in patients with other types of overgrowth.

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Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies

Abstract: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

Cited by 672 publications

References 31 publications

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Clinical Review: Management of Adult Kasabach-Merritt Syndrome Associated with Hemangiomas

Scarring in Patients With PIK3CA-Related Overgrowth Syndromes

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