Efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare disease caused by dysregulated activation of the mammalian target of rapamycin (mTOR). Sirolimus, an inhibitor of mTOR, has been reported to decrease the size of angiomyolipomas and stabilize pulmonary function in patients with LAM. However, the optimal dose for the treatment of LAM remains unclear. METHODS: We conducted a retrospective, observational study of 15 patients with LAM who underwent sirolimus therapy for more than 6 months. The efficacy was evaluated by reviewing the patients' clinical courses, pulmonary function and chest radiologic findings before and after the initiation of sirolimus treatment. RESULTS: All patients had blood trough levels of sirolimus lower than 5ng/mL. Sirolimus treatment improved the annual rates of change in FVC and FEV1 in the 9 patients who were free from chylous effusion (FVC, -101.0 vs. +190.0mL/y, p=0.046 and FEV1, -115.4 vs. +127.8mL/y, p=0.015). The remaining 7 patients had chylous effusion at the start of sirolimus treatment; the chylothorax resolved completely within 1-5 months of treatment in 6 of these cases. These results resembled those of previous studies in which blood trough levels of sirolimus ranged from 5 to 15ng/mL. CONCLUSIONS: Low-dose sirolimus (trough level, 5ng/mL or less) performed as well as the higher doses used previously for improving pulmonary function and decreasing chylous effusion in patients with LAM.

Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a disorder that affects women and is characterized by cystic lung destruction, chylous effusions, lymphangioleiomyomas, and angiomyolipomas. It is caused by proliferation of abnormal smooth muscle-like cells. Sirolimus is a mammalian target of rapamycin inhibitor that has been reported to decrease the size of neoplastic growths in animal models of tuberous sclerosis complex and to reduce the size of angiomyolipomas and stabilize lung function in humans. OBJECTIVE: To assess whether sirolimus therapy is associated with improvement in lung function and a decrease in the size of chylous effusions and lymphangioleiomyomas in patients with LAM. DESIGN: Observational study. SETTING: The National Institutes of Health Clinical Center. PATIENTS: 19 patients with rapidly progressing LAM or chylous effusions. INTERVENTION: Treatment with sirolimus. MEASUREMENTS: Lung function and the size of chylous effusions and lymphangioleiomyomas before and during sirolimus therapy. RESULTS: Over a mean of 2.5 years before beginning sirolimus therapy, the mean (±SE) FEV1 decreased by 2.8%±0.8% predicted and diffusing capacity of the lung for carbon monoxide (Dlco) decreased by 4.8%±0.9% predicted per year. In contrast, over a mean of 2.6 years of sirolimus therapy, the mean (±SE) FEV1 increased by 1.8%±0.5% predicted and Dlco increased by 0.8%±0.5% predicted per year (P<0.001). After beginning sirolimus therapy, 12 patients with chylous effusions and 11 patients with lymphangioleiomyomas experienced almost complete resolution of these conditions. In 2 of the 12 patients, sirolimus therapy enabled discontinuation of pleural fluid drainage. LIMITATIONS: This was an observational study. The resolution of effusions may have affected improvements in lung function. CONCLUSION: Sirolimus therapy is associated with improvement or stabilization of lung function and reduction in the size of chylous effusions and lymphangioleiomyomas in patients with LAM. PRIMARY FUNDING SOURCE: Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health.

Signal transducer and activator of transcription 3 is required for abnormal proliferation and survival of TSC2-deficient cells: relevance to pulmonary lymphangioleiomyomatosis.

Tumor suppressor complex TSC1/TSC2 represents a key negative regulator of mammalian target of rapamycin (mTOR)-S6 kinase 1 signaling. Mutational inactivation of TSC1 or TSC2, linked to a rare lung disease, lymphangioleiomyomatosis (LAM), manifests as neoplastic growth of smooth-muscle (SM)-like cells and cystic destruction of the lungs that induces loss of pulmonary function. However, the precise mechanisms of abnormal cell growth in LAM remain uncertain. Here, we demonstrate increased signal transducer and activator of transcription (STAT) 3 expression, phosphorylation, and nuclear localization in SM-like cells in LAM lungs and in TSC2-null xenographic tumors. Treatment of TSC2-null tumors with mTOR inhibitor rapamycin attenuated STAT3 expression and phosphorylation. Increased STAT3 level and activation were also observed in LAM-dissociated (LAMD) cell cultures compared with normal human bronchus fibroblasts (HBFs) from LAM patients. Although interferon (IFN)-gamma inhibited proliferation of HBFs, IFN-gamma treatment had little effect on proliferation of LAMD and TSC2-null cells. Re-expression of TSC2 or treatment with rapamycin inhibited IFN-gamma-induced STAT3 phosphorylation and synergized with IFN-gamma in inhibiting TSC2-null and LAMD cell proliferation. Reduction of STAT3 protein levels or activity using specific small interfering RNA or inhibitory peptide, respectively, decreased proliferation and induced apoptosis in TSC2-null and LAMD cells and sensitized cells to growth-inhibitory and proapoptotic effects of IFN-gamma. Collectively, our data demonstrate that STAT3 activation is required for proliferation and survival of cells with TSC2 dysfunction, that STAT3 impedes growth-inhibitory and proapoptotic effects of IFN-gamma, and that TSC2- and rapamycin-dependent inhibition of STAT3 restores antiproliferative effects of IFN-gamma. Thus, STAT3 may provide a novel therapeutic target for diseases associated with TSC1/TSC2 dysfunction.

[Flutropium bromide was effective in relieving symptoms of lymphangioleiomyomatosis--a case report].

A 32-year-old woman was admitted with persistent dyspnea. Chest roentgenogram showed hyperinflation of the lungs, and diffuse reticular shadows in both lung fields. Chest CT showed diffuse cystic lesions and thickened vasculature. Examinations revealed severe hypoxemia, restrictive and obstructive ventilatory impairments, increased residual volume, and decreased carbon monoxide diffusing capacity. Lymphagioleiomyomatosis was strongly suspected, and a diagnosis confirmed histopathologically by lung biopsies. Inhalation of flutropium bromide was remarkably effective in relieving dyspnea and impaired pulmonary functions. It is suggested that flutropium bromide is beneficial for symptomatic improvement in patients with lymphangioleiomyomatosis.

Linfangioleiomiomatosis pulmonar: reporte de un caso

La linfangioleiomiomatosis es una enfermedad rara con menos de 250 casos reportados en la literatura universal, que ocurre únicamente en mujeres, usualmente en edad reproductiva y que se caracteriza por la proliferación de células de musculo liso en tejido pulmonar y en los vasos linfáticos. Presentamos el caso de una mujer de 29 años, con disnea progresiva, tos con escasa espectoración y neumotórax espontáneo bilateral. El diagnóstico se realizó mediante biopsia pulmonar a cielo abierto, donde se encontró proliferación de haces de músculo liso los cuales se disponían preferentemente alrededor de las estructuras vasculares,bronquiales y septo alveolares. Comentamos los principales hallazgos clínicos, radiológicos e histopatológicos.

[Pulmonary lymphangioleiomyomatosis. A disease which may have a benign progression]. / Linfangioleiomiomatosis pulmonar. Una enfermedad que puede tener un curso benigno.

Pulmonary lymphangioleiomyomatosis (PLLM) is characterized by a benign proliferation of the smooth muscle around lymphatics, venulas and bronchiolus. It is usually fatal within 1 to 9 years. We present a case which remained with scarce symptoms despite receiving no treatment after at least 9 years of evolution of the disease. We highlight the clinical manifestations of the disease and the relevance of pulmonary biopsia with thoracotomy in order to establish the diagnosis.

Pulmonary mechanics in lymphangioleiomyomatosis.

Standard pulmonary function and mechanics studies were done in eight female patients with lymphangioleiomyomatosis diagnosed by open-lung biopsy. Five patients were studied before hormone treatment. The mean age of the patients was 40 +/- 3 (SEM) years. Two of the eight had a smoking history of 10 pack-years or more, but all had quit smoking several years before evaluation. There was a trend toward increased total lung capacity (114 +/- 7% expressed as mean of percentage predicted +/- SEM) and increased residual volume (207 +/- 24%). Of the eight patients seven had expiratory obstruction as evidenced by the reduced forced expiratory volume in 1 s/forced vital capacity ratio [( FEV1/FVC] 61 +/- 6%). Steady-state diffusing capacity for carbon monoxide was reduced in seven of the patients (57 +/- 12%). Pulmonary mechanics studies performed in a body plethysmograph revealed a modest reduction in retractive force both at total lung capacity and at 90% total lung capacity (67 +/- 10 and 59 +/- 9%, respectively). Static compliance tended to be increased (128 +/- 19%). Pulmonary flow resistance was markedly elevated (266 +/- 46%). Maximal flow-static recoll curves revealed that in the seven patients with expiratory obstruction the cause was predominantly airway narrowing rather than loss of lung elastic forces. We conclude that in this group of patients with lymphangioleiomyomatosis there was no evidence for significant restriction. Although there was some decrease in retractive force consistent with emphysema, expiratory flows were reduced predominantly because of airway narrowing or obstruction rather than loss of pulmonary elastic recoil forces.

Lymphangiomyomatosis: CT, chest radiographic, and functional correlations.

Eight patients with the diagnosis of lymphangiomyomatosis were evaluated with computed tomography (CT), chest radiography, and pulmonary function tests to determine the relationship between the extent of disease seen on imaging studies and functional status. Chest radiographic assessment included the subjective determination of disease extent and measurements of lung length and the arc of the right hemidiaphragm. Disease extent on CT scans was scored as a percentage of lung that was abnormal on the basis of visual assessment of the degree of cystic replacement of the lung parenchyma. Significant correlations were observed between CT scores and percentages of predicted forced expiratory volume in 1 second/forced vital capacity (r = -.92, P less than .002) and diffusing capacity of the lungs for carbon monoxide (r = -.80, P less than .017). No significant correlations were observed between subjective chest radiographic scores and pulmonary function tests, although measurements of lung length and percentage of predicted total lung capacity were correlated (r = .76, P less than .045). CT was more accurate than chest radiography in defining the presence and extent of parenchymal cysts and provided for greater morphologic-physiologic correlation. CT, particularly high-resolution CT, may be useful in the diagnosis and longitudinal evaluation of patients with this disease and may be more sensitive than pulmonary function tests in the early stages of lung damage.

Pulmonary lymphangiomyomatosis and tuberous sclerosis: comparison of radiographic and thin-section CT findings.

Chest radiographs, thin-section computed tomographic (CT) scans, and results of pulmonary function tests in nine women with pulmonary lymphangiomyomatosis and two women with pulmonary tuberous sclerosis were retrospectively evaluated. In all patients, CT demonstrated thin-walled cysts less than 20 mm in diameter scattered at random in all parts of the lungs. In eight patients, cysts larger than 20 mm in diameter were also present. Lung tissue between cysts appeared normal in all 11 patients, except one with septal lines and dependent alveolar areas of attenuation. CT showed cysts in three patients whose radiographs were normal, and it demonstrated that many lesions that appeared reticular on plain radiographs were actually cysts. CT findings correlated better with the diffusion capacity of the lungs for carbon monoxide than did the plain radiographic findings. CT was more sensitive and more precise than radiography at showing the presence and morphology of lung abnormalities.

Pulmonary lymphangiomyomatosis: correlation of CT with radiographic and functional findings.

In 14 patients with biopsy-proved lymphangiomyomatosis, disease extent at computed tomography (CT) was correlated with findings at chest radiography and pulmonary-function testing. The CT scans and chest radiographs were read independently by two chest radiologists. Disease extent was assessed on CT scans by using a visual score (0%-100% involvement of the lung parenchyma) and on radiographs by using an adaptation of the International Labour Office classification of the pneumoconioses. There was good concordance between the two observers for CT and radiographic scores (Kendall tau greater than or equal to .86, P less than .01). A significant but relatively low correlation was present between CT findings and radiographic severity of disease (r = .59, P less than .05). Impairment in gas exchange as assessed with the diffusing capacity correlated better with disease extent seen on CT scans (r = .69) than with chest radiographic findings (r = .59). Three patients had evidence of parenchymal disease on the CT scans but not on the radiographs. In one patient CT findings were negative despite a positive finding on chest radiographs. The authors conclude that CT is superior to chest radiography in the assessment of patients with lymphangiomyomatosis.

[3 cases of diffuse lymphangioleiomyomatosis of the lung]. / A propósito de tres casos de linfangioleiomiomatosis pulmonar difusa.

Three new cases of diffuse pulmonary lymphangioleiomyomatosis are presented. Case number 1 is a female patient who presented repeated pneumotorax and dyspnea without evidence by CT scan and gynecological ultrasound of extrathoracic lesions. This patient did not respond to medroxiprogesterone and died 5 years after the initial diagnosis having suffered chronic, severe, global respiratory failure for 4 years. Case number 2 is a female patient who presented dyspnea, chyloptysis and chylothorax, with iliac, paraaortic and mediastinic lymphangioleiomyomas. The last time she was seen, she was still alive after 6 years without treatment. Case number 3 presented lymphangioleiomyomatosis associated to undifferentiated breast carcinoma. The evolution was apparently slow probably because it was diagnosed 14 years after menopause, and died due to a relapse of the neoplasia. All three patients had radiographic images and respiratory functional studies characteristic of this disease and diagnosis was confirmed by biopsy. The literature is reviewed.

Pulmonary lymphangioleiomyomatosis: CT findings.

Lymphangioleiomyomatosis, a rare disease occurring in women of childbearing age, is characterized by proliferation of smooth muscle in pulmonary lymphatic channels and mediastinal and abdominal lymph nodes. Chest radiographs typically reveal interstitial disease with normal lung volume. Pneumothorax and pleural effusions may be present. CT scans in eight patients with biopsy-proved pulmonary lymphangioleiomyomatosis were reviewed. The prominent feature of the disease was multiple thin-walled cysts throughout the lungs, best visualized on scans made with 1.5-mm collimation. Mediastinal and/or retrocrural lymphadenopathy, often not appreciated on the chest radiograph, was present in four of eight patients. CT can suggest a diagnosis of lymphangioleiomyomatosis when diagnosis by clinical presentation and chest radiographs is uncertain.

Elevated pulmonary arterial pressure in pulmonary lymphangiomyomatosis.

Pulmonary lymphangiomyomatosis (LAM) is characterized by proliferation of smooth muscles around lymphatics and bronchovascular bundles, presenting clinical manifestations of obstructive or restrictive lung disease with greatly impaired gas exchange. To date, little attention has been paid in the literature to the pathophysiology of pulmonary hypertension related to this disorder. A case of a 39-year-old woman with the characteristic clinical and histological features of pulmonary LAM is presented. She was found to have moderate pulmonary hypertension. Possible mechanisms for the development of pulmonary hypertension are discussed.

Lymphangiomyomatosis: a respiratory illness with an endocrinologic therapy.

Lymphangiomyomatosis should be considered when unexplained dyspnea, pneumothorax, pleural effusion or infiltrative radiographic changes occurs in a woman of childbearing age. Radiographic and pulmonary function peculiarities help in the diagnosis and evaluation of results of treatment. Diagnosis is dependent on lung biopsy and preferably identification of hormonal receptors. Endocrinological manipulation, in this study with medroxyprogesterone, decreased disability, morbidity and progression of this otherwise fatal illness. Early diagnosis and institution of treatment would appear to provide the best result.

Anaesthetic management for oophorectomy in pulmonary lymphangiomyomatosis.

Pulmonary lymphangiomyomatosis is an idiopathic disease, resulting in severe respiratory impairment. Bilateral oophorectomy has led to objective and subjective amelioration of the pulmonary pathology. In the anaesthetic management of such a patient, careful attention must be paid to pulmonary and systemic haemodynamics, and gas exchange. We describe the successful anaesthetic management of a 34-year-old female, using epidural anaesthesia, and pulmonary artery catheterization. Although the intraoperative and immediate postoperative courses were heralded by marked cardiorespiratory stability, refractory respiratory failure developed, and she died five months after surgery.

Pulmonary lymphangioleiomyomatosis: quantitative analysis of lesions producing airflow limitation.

The lungs of three patients dying of lymphangioleiomyomatosis (LAM), which in two of the patients was associated with tuberous sclerosis, were studied to characterize better the sites of airflow limitation in this condition. Quantitative studies showed that small airways were narrowed and collapsed because of the surrounding emphysema, but few airways contained excess smooth muscle. These findings suggest that the airspace lesions are more important than muscular proliferation in small airways in producing airflow limitation. In the two patients who had LAM with tuberous sclerosis, sex steroid assays were negative. Pleurodesis controlled pleural effusions in all three patients but may have contributed to reductions in lung volume.

A report of two long-surviving cases of pulmonary lymphangioleiomyomatosis and the response to progesterone therapy.

Two cases of pulmonary lymphangioleiomyomatosis, with survival between 12 and 28 years are described. Both were treated with medroxyprogesterone acetate with a slight initial improvement in both lung function and exercise tolerance, and no further deterioration during the period of follow-up of 10-20 months. The results are discussed and other reports of hormonal treatment of this rare condition are reviewed.