mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex.

Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed.

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.

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.

[2 cases of lymphangioleiomyomatosis treated by hormonal manipulation]. / To tilfaelde af lymfangioleiomyomatose behandlet med hormonal manipulation.

The course of disease in two women with bioptically verified lymphangioleiomyomatosis (LAM) is demonstrated. One was oestrogen- and progesterone-receptor negative, but responded promptly to hysterosalpingo-oophorectomy and has had no symptoms later. The other was receptor positive, but in spite of hysterosalpingo-oophorectomy and hormonal manipulation with tamoxifen and medroxyprogesterone, has had a complicated course of the disease with symptoms for ten years. LAM is a hormone dependent disease, but our knowledge is still incomplete. Hormonal manipulation should be tried in receptor positive as well as negative patients. Tamoxifen seems to have deleterious effects on the course of disease.

Pulmonary lymphangiomyomatosis. Follow-up and long-term outcome with antiestrogen therapy; a report of eight cases.

Lymphangiomyomatosis is a rare disease which affects young women of childbearing age. Eight women with pulmonary LAM were treated with antiestrogen therapy and were monitored by blood estrogen measurements along with clinical hypoestrogenic symptoms. Treatment ranged from three to nine years. The response to therapy was evaluated by the clinical course, chest x-ray films, pulmonary function tests and overall long-term outcome. Three patients died of respiratory failure after three, five and nine years of treatment. Of the five patients remaining alive, respiratory function deteriorated in four cases, after a transient period of mild improvement lasting three years in two cases. The last patient appeared stable after three years of follow-up. Time course ranged from 4 to 17 years. However, without a control group, we cannot determine whether or not the apparent improvement of the natural time course was due to the hormonal treatment.

Failure of buserelin-induced medical castration to control pulmonary lymphangiomyomatosis in two patients.

Two women, aged 44 and 29 years, respectively, were admitted to the hospital in early 1987 for recurrent pneumothorax, dyspnea and a diffuse reticulonodular pattern evidenced on the chest x-ray film. Lung biopsy confirmed LAM in both patients. Both were treated sequentially with medroxyprogesterone and a LHRH agonist (buserelin) to achieve reversible medical castration. Neither subjective nor objective improvement was noted after 13 and 5 months, respectively, of buserelin therapy (900 micrograms/day, nasal spray) despite an effective suppression of the pituitary-gonadal axis. Medroxyprogesterone also was ineffective. Buserelin thus failed to control pulmonary LAM in these two patients, in spite of effective medical castration.

Lymphangiomyomatosis: hormonal implications in etiology and therapy.

When a 34-year-old woman had dyspnea and chylothorax 8 months postpartum, lymphangiomyomatosis was diagnosed by open-lung biopsy. Baseline laboratory studies to evaluate infertility had revealed normal hormonal levels. She was subsequently treated with various hormones to aid in conception and in sustaining pregnancy. Her condition has improved with progesterone therapy. This case raises concern about the possible adverse consequences of hormonal manipulation in treating infertility. The need for open-lung biopsy in patients with classic manifestations of LAM is also questioned, especially with the advent of high-resolution CT scanning, the nonspecificity of hormonal receptors with regard to response to therapy, and the possible need for subsequent lung transplantation.

Lymphangioleiomyomatosis--treatment with progesterone.

Lymphangioleiomyomatosis is a rare devastating disease affecting women mostly of child-bearing age. It presents with spontaneous pneumothorax, chylous effusions, hemoptysis and progressive breathlessness. Most patients die from respiratory failure within 10 years. There are no controlled studies on the efficacy of various treatment regimens. We report our experience with progesterone therapy in three patients. Two failed to respond, one died about 11 years after presentation and another after 5 1/2 years. The third patient has survived 11 years after onset of disease.

Response to treatment with an analog of the luteinizing-hormone-releasing hormone in a patient with pulmonary lymphangioleiomyomatosis.

Pulmonary lymphangioleiomyomatosis is a chronic devastating disorder afflicting women of childbearing age, characterized by proliferation of atypical smooth muscle in the lung. Attempts to treat this disease have shown that a number of hormonal manipulations may be helpful but that surgical oophorectomy alone or associated with administration of progesterone is the most effective treatment. This report describes the response to treatment with an analog of luteinizing-hormone-releasing hormone, goserelin, which is able to induce a marked suppression of the secretion of ovarian sex steroid and demonstrates with pulmonary function studies, arterial blood gas determinations, and bronchoalveolar lavage parameters that this patient's disease was responsive to this agent.

[Differential diagnosis of spontaneous pneumothorax--pulmonary lymphangioleiomyomatosis. Clinical aspects, diagnosis and therapy]. / Zur Differentialdiagnose des Spontanpneumothorax--die pulmonale Lymphangioleiomyomatose. Klinik, Diagnostik und Therapie.

As a case report, lymphangioleiomyomatosis is presented--a rare disease that only affects women and up to now with a poor prognosis. It results from a tumorlike proliferation of smooth muscle in the thoracic and retroperitoneal lymphatics. Prominent clinical findings are dyspnea, spontaneous pneumothorax, chylous pleural effusions and chylous ascites. The diagnosis results from typical chest X-rays and is established by open lung biopsy. Treatment should primarily start with medroxyprogesteronacetat (respectively tamoxifen), if necessary with consideration of the hormonal receptors. In an early stage the oophorectomy can be helpful. Surgical intervention is necessary in complications (thoracic drainage, pleurectomy for recurrent pneumothorax, Le Veen-shunt for chylous ascites). If hormonal therapy is not successful, a combined heart and lung transplantation should be attempted in ultima ratio.

[The contribution of computerized tomography to the diagnosis of diffuse pulmonary lymphangiomyomatosis. Apropos of a case]. / Apport de la tomodensitométrie au diagnostic de lymphangiomyomatose pulmonaire diffuse. A propos d'un cas.

The authors report a case of lymphangiomatosis (LAM) proven histologically in a 49 year old female. This case benefitted from very detailed CT-scanning (IDM) with characteristic images obtained from the thorax and bilateral renal tumours suggestive of angiomyolipomas. This association seems to be quasi-pathognomic of the disease. The discovery at CT-scanning of cerebral calcification raises a possible connection of LAM with Bourneville's tuberous sclerosis. This CT-scanning study has several points of interest: the early diagnosis of pulmonary lesions which are under evaluated by standard radiography; a complete inventory of the possible localisations of the disease; it enables a possible diagnosis in very frail patients in whom a lung biopsy would be a risk; an ability to assess further progress as there also exists a good correlation between the extent of the disease assessed by TDM and the disturbance in pulmonary function.

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.