Rationale: Sirolimus therapy stabilizes lung function and reduces the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis.Objectives: To determine whether sirolimus has beneficial effects on lung function, cystic areas, and adjacent lung parenchyma; whether these effects are sustained; and whether sirolimus is well tolerated by patients.Methods: Lung function decline over time, lung volume occupied by cysts (cyst score), and lung tissue texture in the vicinity of the cysts were quantified with a computer-aided diagnosis system in 38 patients. Then we compared cyst scores from the last study on sirolimus with studies done on sirolimus therapy. In 12 patients, we evaluated rates of change in lung function and cyst scores off and on sirolimus.Measurements and Main Results: Sirolimus reduced yearly declines in FEV 1 (22.3 6 0.1 vs. 1.0 6 0.3% predicted; P , 0.001) and diffusing capacity of carbon monoxide (22.6 6 0.1 vs. 0.9 6 0.2% predicted; P , 0.001). Cyst scores 1.2 6 0.8 years (30.5 6 11.9%) and 2.5 6 2 years (29.7 6 12.1%) after initiating sirolimus were not significantly different from pretreatment values (28.4 6 12.5%). In 12 patients followed for 5 years, a significant reduction in rates of yearly decline in FEV 1 (21.4 6 0.2 vs. 0.3 6 0.4% predicted; P = 0.025) was observed. Analyses of 104 computed tomography scans showed a nonsignificant (P = 0.23) reduction in yearly rates of change of cyst scores (1.8 6 0.2 vs. 0.3 6 0.3%; P = 0.23) and lung texture features. Despite adverse events, most patients were able to continue sirolimus therapy.Conclusions: Sirolimus therapy slowed down lung function decline and increase in cystic lesions. Most patients were able to tolerate sirolimus therapy.Keywords: sirolimus; lung cystic destruction; LAM Lymphangioleiomyomatosis (LAM) is a multisystem disease affecting almost exclusively women, which is characterized by cystic lung destruction, renal angiomyolipomas, and lymphangioleiomyomas (1-4). Patients with LAM frequently present with dyspnea on exertion; recurrent pneumothoraces; chylous effusions; incidental detection of lung cysts on imaging studies; and, less frequently, bleeding angiomyolipomas (1, 2). The clinical course of LAM is variable but LAM is generally considered to be a chronic disease with a median transplant-free survival time spanning more than a decade (5). LAM lesions are characterized by proliferation of a neoplastic LAM cell, which has features both of smooth muscle and melanocytic cells (4). The histologic features of LAM consist of cysts and LAM cells in the walls of cysts and along blood vessels, lymphatics, and bronchioles, causing airways narrowing, vascular wall thickening, lymphatic disruption, and venous occlusion (4).The inherited form of LAM associated with tuberous sclerosis complex (TSC) is caused by mutations in the TSC1 or TSC2 suppressor genes (6-8). Sporadic LAM has been associated only with mutations of TSC2 (6-8). TSC1 and TSC2 encode, respectively, hamartin and tuberin, two Corres...
What are the clinical features, severity, and rate of progression of lung disease in women with tuberous sclerosis and lymphangioleiomyomatosis (LAM) and how do they differ from patients with sporadic LAM?Data from 94 tuberous sclerosis/LAM and 460 sporadic LAM women were compared. 40 tuberous sclerosis/LAM and 40 sporadic LAM patients were age-and lung function-matched, and changes in volume occupied by cysts (cyst score) and pulmonary function occurring over 6.5 years were evaluated.Tuberous sclerosis/LAM patients had better lung function than sporadic LAM patients, but no difference was observed from sporadic LAM patients in yearly rates of change in forced expiratory volume in 1 s (−1.9±2.7 versus −1.9±1.9% predicted; p=0.302), diffusing capacity of the lung for CO (−2.1±2.8 versus −1.9±2.7% predicted; p=0.282) or cyst scores (+1.0±1.3 versus +1.4±1.7%, p=0.213). However, the proportion of patients with abnormal lung function and higher rates of FEV1 decline was greater in sporadic LAM. Some young tuberous sclerosis/LAM patients (mean age 25.7±3 years) progressed rapidly from minimal to severe lung disease.Tuberous sclerosis/LAM patients may experience abrupt declines in lung function. Consequently, women with tuberous sclerosis found to have lung cysts should undergo periodic functional and radiological testing to follow disease progression and determine need for therapy. @ERSpublicationsWhile the natural history is variable, some women with TSC and LAM may quickly progress to disabling respiratory disease
Purpose: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. Methods: Next-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2 . Extent of disease, onset age, and family history of TSC were determined through retrospective analysis of patient records. Results: The median number of disease findings and age at penetrance differed between mosaic patients with asymmetrically distributed facial angiofibromas (4 findings, 24y, n=7), mosaic patients with bilaterally symmetric facial angiofibromas (8 findings, 10y, n=12), and germline TSC patients (10 findings, 4y, n=29). Cutaneous and internal organ involvement positively correlated in mosaic (R=0.62, p=0.005), but not germline (R=−0.24, p=0.24) TSC. Variant allele fraction (VAF) in the blood (range: 0-19%) positively correlated with the number of major features (R=0.55, p=0.028). Five had a TSC2 variant identified in the skin that was below detection in the blood. One of 12 children from a mosaic parent had TSC. Conclusion: The phenotype of mosaic TSC ranged from mild to indistinguishable from germline disease. Patients with mosaicism and asymmetric facial angiofibromas exhibited fewer findings, later onset, and lower VAF in the blood.
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