sirolimus and Pneumothorax

Tuberous sclerosis complex has manifestations in many organ systems, including brain, heart, kidney, skin, and lung. The primary manifestations in the lung are lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). LAM affects almost exclusively women, and causes cystic lung destruction, pneumothorax, and chylous pleural effusions. LAM can lead to dyspnea, oxygen dependence, and respiratory failure, with more rapid disease progression during the premenopausal years. In contrast, MMPH affects men and women equally, causing small nodular pulmonary deposits of type II pneumocytes that rarely progress to symptomatic disease. Here, we review the clinical features and pathogenesis of LAM and MMPH.

Topics: Animals; Female; Humans; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Mice; Multiple Pulmonary Nodules; Pneumothorax; Prognosis; Sirolimus; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein

Lymphangioleiomyomatosis is a rare multisystem disease predominantly affecting women that can occur sporadically or in association with tuberous sclerosis. Lung cysts progressively replace the lung parenchyma, which leads to dyspnea, recurrent pneumothorax, and in some cases respiratory failure. Patients may also have lymphatic disease in the thorax, abdomen, and pelvis, and renal angiomyolipomas. Treatment includes supportive care, bronchodilators, and for those with progressive disease, mammalian target of rapamycin (mTOR) inhibitors.

Topics: Angiomyolipoma; Antibiotics, Antineoplastic; Bronchodilator Agents; Everolimus; Humans; Kidney Neoplasms; Lung Neoplasms; Lymphangioleiomyomatosis; Pleurodesis; Pneumothorax; Sirolimus; Tomography, X-Ray Computed; Tuberous Sclerosis; Ultrasonography

Lymphangioleiomyomatosis (LAM) is a rare, cystic lung disease that is associated with mutations in tuberous sclerosis genes, renal angiomyolipomas, lymphatic spread, and remarkable female gender restriction. The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid collections. Lung function declines at approximately twofold to threefold times the rate of healthy subjects, based on an annual drop in FEV1 of 75 to 120 mL in reported series. The diagnosis of pulmonary LAM can be made on high-resolution CT (HRCT) scan with reasonable certainty by expert radiologists, but generally requires a lung biopsy in cases in which tuberous sclerosis complex, angiomyolipomata, or chylous effusions are absent. The currently available treatment strategies are based on the antagonism of estrogen action, and are empiric and unproven. A trial of bronchodilators is warranted in patients with reversible airflow obstruction seen on pulmonary function testing. Pleurodesis should be performed with the initial pneumothorax, because the rate of recurrence is high. Angiomyolipomas that exceed 4 cm in size are more likely to bleed and should be evaluated for embolization. Air travel is well-tolerated by most patients with LAM. Lung transplantation is an important option for LAM patients, and can be safely performed by experienced surgeons despite prior unilateral or bilateral pleurodesis in most patients. Women with unexplained recurrent pneumothorax, tuberous sclerosis, or a diagnosis of primary spontaneous pneumothorax or emphysema in the setting of limited or absent tobacco use should undergo HRCT scan screening for LAM. Multicenter clinical trials based on several well-defined molecular targets are currently underway in the United States and Europe.

Topics: Aerospace Medicine; Diagnosis, Differential; Humans; Immunosuppressive Agents; Lung Transplantation; Lymphangioleiomyomatosis; Pneumothorax; Prevalence; Protein Kinases; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Travel

Topics: Female; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Pneumothorax; Sirolimus

Spontaneous pneumothorax has a high incidence and high rate of recurrence in patients with lymphangioleiomyomatosis (LAM). The risk factors for pneumothorax and the effects of sirolimus on pneumothorax in patients with LAM are unknown. In our study, multivariate logistic regression was applied to a cross-sectional cohort to investigate factors associated with pneumothorax in LAM patients. Kaplan-Meier analysis was applied in the historical prospective self-controlled study to determine whether sirolimus reduces the risk of pneumothorax recurrence in patients with LAM.. Of the 399 patients registered with LAM-CHINA at our center between May 10, 2017 and August 31, 2020, 142 had a history of pneumothorax at registration. High CT grade and age at presentation ≤ 35 years were associated with a higher risk of pneumothorax in patients with LAM. Postmenopausal status was correlated with a lower risk of pneumothorax. In the historical prospective self-controlled study, the 5-year probability of pneumothorax recurrence was 80% lower in the sirolimus group than in the control group (hazard ratio for pneumothorax recurrence, 0.20; 95% CI, 0.14 to 0.30, P < 0.001 by log-rank test).. Sirolimus reduced the risk of pneumothorax recurrence in LAM patients.

Topics: Cross-Sectional Studies; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Pneumothorax; Prospective Studies; Sirolimus

Patients with lymphangioleiomyomatosis (LAM) frequently experience pneumothorax. Although sirolimus is the standard therapy for LAM, its effect on pneumothorax is controversial. Recently, total pleural covering (TPC) and modified TPC (mTPC) were introduced as surgical treatment options for pneumothorax for patients with LAM. However, the effect of sirolimus on the recurrence of pneumothorax in patients who underwent the treatments is still uncertain. We hypothesized that some clinical factors including sirolimus treatment could predict postoperative recurrence of pneumothorax. In order to clarify this hypothesis, we retrospectively analyzed the clinical data from 18 consecutive patients with LAM who underwent 24 surgical pleural covering of entire lung (SPC) as 17 TPC and 7 mTPC against pneumothoraces from surgical database between January 2005 and January 2019, and we determined the predictors of postoperative recurrence.. Of the 24 surgeries of SPC, 14 surgeries (58.3%) had a history of two or more ipsilateral pneumothoraces, and 11 surgeries (45.8%) had a history of ipsilateral pleural procedures before SPC. Sixteen surgeries (66.6%) in 12 patients received treatment of sirolimus after SPC (sirolimus group). With a median follow-up time of 69.0 months after SPC, four surgeries (16.6%) in three patients had a postoperative recurrence, and the 5-year recurrence-free survival (RFS) after SPC was 82.9%. In patients with postoperative recurrence, serum level of vascular endothelial growth factors D was significantly higher than that in those with non-recurrence (3260.5 vs. 892.7 pg/mL, p = 0.02), and the rate of sirolimus treatment in the recurrence group was significantly lower than that in the no-recurrence group (0 vs. 80%, p = 0.006). The log-rank test showed that the RFS of the sirolimus group (sirolimus use after SPC) was significantly better than that of the non-sirolimus group (p = 0.001), and no significant difference was observed for other factors.. We first reported sirolimus might effectively suppress the recurrence of pneumothoraces in LAM patients who received SPC. Sirolimus induction after SPC (TPC or mTPC) might be a feasible option for frequent pneumothorax in LAM.

Topics: Humans; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Neoplasm Recurrence, Local; Pneumothorax; Retrospective Studies; Sirolimus

Topics: Chest Pain; Cough; Diagnosis, Differential; Dyspnea; Female; Humans; Lung; Lung Diseases, Fungal; Lung Neoplasms; Lymphangioleiomyomatosis; Magnetic Resonance Imaging; Pneumonia, Bacterial; Pneumothorax; Radiography, Thoracic; Risk Factors; Shock; Sirolimus; Thoracostomy; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Young Adult

Pneumothorax is one of the most common symptoms in patients with lymphangioleiomyomatosis (LAM). However, current management strategies for patients with LAM who present with recurrent pneumothorax remain inadequate. Here, we describe the successful prevention of recurrent pneumothorax by sirolimus treatment in five women with LAM. Before sirolimus treatment, all patients had received supplemental oxygen support, repeated chest tube drainage, or surgeries for management of the recurrent pneumothorax. Sirolimus treatment was initiated when the pneumothorax was completely resolved, and no patient developed pneumothorax during treatment. Moreover, they exhibited a significantly improved subjective quality of life, increased exercise capacity, and mild adverse effects such as mucositis, irregular menstruation, and delayed wound healing. On discontinuation of sirolimus or in the event that the plasma sirolimus level was markedly low, pneumothorax tended to relapse. The findings from these cases provide valuable insights that will aid in the improvement of treatment strategies for patients with LAM and recurrent pneumothorax.

Topics: Adult; Female; Humans; Lymphangioleiomyomatosis; Pneumothorax; Quality of Life; Sirolimus; Young Adult

Lymphangioleiomyomatosis (LAM) either sporadic or a part of tuberous sclerosis complex is rare in paediatric age group. Here, we report a case of LAM with tuberous sclerosis in an infant. She was referred to our institute at the age of 4 months as a case of recurrent bilateral pneumothorax requiring intercostal tube drainage. Detailed history revealed that patient was symptomatic since 1 month of age in the form of seizures. She had respiratory symptoms for last 15 days. General physical examination revealed whitish macular patches. Brain imaging was suggestive of cortical tubers and subependymal nodules. The echocardiography showed right atrial rhabdomyoma. Chest CT revealed multiple cysts suggesting LAM. On the basis of above findings, a diagnosis of tuberous sclerosis complex with LAM was made. The infant was started on sirolimus and there was significant clinical and radiological improvement over a period of 2 and half years without any side effects.

Topics: Antibiotics, Antineoplastic; Diagnosis, Differential; Female; Humans; Infant; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Pneumothorax; Recurrence; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome; Tuberous Sclerosis

We report a successful pregnancy in a patient with longstanding LAM on treatment with sirolimus. During temporary discontinuation fo sirolimus in early pregnancy, lung function declined but recovered after resumption of sirolimus. Pregnancy was complicated by a persistent pneumothorax which was treated surgically postnatally. The child has had a normal development despite exposure to low dose sirolimus intermittently during early embryonal and mid-fetal life.

Topics: Adult; Antibiotics, Antineoplastic; Drug Administration Schedule; Female; Humans; Live Birth; Lung; Lymphangioleiomyomatosis; Pneumothorax; Pregnancy; Pregnancy Complications, Neoplastic; Radiography; Sirolimus

Spontaneous pyopneumothorax is a very rare occurrence, even in cancer treated patients. Here we present two consecutive cases of spontaneous pyopneumothorax that occurred early after initiation of mTOR inhibitors for the treatment of renal cell carcinoma with subpleural pulmonary metastasis. In these two cases, necrosis and excavation of lung metastasis were observed, suggesting their involvement in the pathogenic mechanism of pyopneumothorax. This report extends the available experience of the pulmonary side effects of these novel targeted therapies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Calcitonin; Carcinoma, Renal Cell; Combined Modality Therapy; Disease Susceptibility; Everolimus; Fatal Outcome; Female; Humans; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Necrosis; Neoplasm Proteins; Nephrectomy; Niacinamide; Phenylurea Compounds; Pneumonia, Bacterial; Pneumothorax; Protein Precursors; Pyridines; Pyrroles; Rupture, Spontaneous; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases