-
Korean Journal of Radiology Sep 2019Lung cysts are commonly seen on computed tomography (CT), and cystic lung diseases show a wide disease spectrum. Thus, correct diagnosis of cystic lung diseases is a... (Review)
Review
Lung cysts are commonly seen on computed tomography (CT), and cystic lung diseases show a wide disease spectrum. Thus, correct diagnosis of cystic lung diseases is a challenge for radiologists. As the first diagnostic step, cysts should be distinguished from cavities, bullae, pneumatocele, emphysema, honeycombing, and cystic bronchiectasis. Second, cysts can be categorized as single/localized versus multiple/diffuse. Solitary/localized cysts include incidental cysts and congenital cystic diseases. Multiple/diffuse cysts can be further categorized according to the presence or absence of associated radiologic findings. Multiple/diffuse cysts without associated findings include lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome. Multiple/diffuse cysts may be associated with ground-glass opacity or small nodules. Multiple/diffuse cysts with nodules include Langerhans cell histiocytosis, cystic metastasis, and amyloidosis. Multiple/diffuse cysts with ground-glass opacity include pneumocystis pneumonia, desquamative interstitial pneumonia, and lymphocytic interstitial pneumonia. This stepwise radiologic diagnostic approach can be helpful in reaching a correct diagnosis for various cystic lung diseases.
Topics: Amyloidosis; Birt-Hogg-Dube Syndrome; Cysts; Diagnosis, Differential; Histiocytosis, Langerhans-Cell; Humans; Lung Diseases; Lymphangioleiomyomatosis; Pneumonia, Pneumocystis; Tomography, X-Ray Computed
PubMed: 31464115
DOI: 10.3348/kjr.2019.0057 -
Radiologia Dec 2022The term cystic lung disease encompasses a heterogeneous group of entities characterised by round lung lesions that correspond to cysts with fine walls, which usually...
The term cystic lung disease encompasses a heterogeneous group of entities characterised by round lung lesions that correspond to cysts with fine walls, which usually contain air. The differential diagnosis of these lesions can be challenging, requiring both clinical and radiological perspectives. Entities such as pulmonary emphysema and cystic bronchiectasis can simulate cystic disease. High-resolution computed tomography (HRCT) is the imaging technique of choice for the evaluation and diagnosis of cystic lung disease, because it confirms the presence of lung disease and establishes the correct diagnosis of the associated complications. In many cases, the diagnosis can be established based on the HRCT findings, thus making histologic confirmation unnecessary. For these reasons, radiologists need to be familiar with the different presentations of these entities. A wide variety of diseases are characterised by the presence of diffuse pulmonary cysts. Among these, the most common are lymphangioleiomyomatosis, which may or may not be associated with tuberous sclerosis, Langerhans cell histiocytosis, and lymphocytic interstitial pneumonia. Other, less common entities include Birt-Hogg-Dubé syndrome, amyloidosis, and light-chain deposit disease. This article describes the characteristics and presentations of some of these entities, emphasizing the details that can help differentiate among them.
Topics: Humans; Lung Diseases, Interstitial; Lung; Lymphangioleiomyomatosis; Histiocytosis, Langerhans-Cell; Cysts
PubMed: 36737165
DOI: 10.1016/j.rxeng.2022.09.005 -
Proceedings of the National Academy of... Feb 2022Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based...
Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography-mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 () mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.
Topics: Animals; Drug Delivery Systems; Female; Gene Transfer Techniques; Genetic Engineering; Liposomes; Lung; Lung Diseases; Lymphangioleiomyomatosis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Protein Corona; RNA, Messenger; RNA, Small Interfering
PubMed: 35173043
DOI: 10.1073/pnas.2116271119 -
American Journal of Respiratory and... Nov 2020Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic...
Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive. Identification and characterization of LAM cells in human lung and uterus using a single-cell approach. Single-cell and single-nuclei RNA sequencing on LAM ( = 4) and control ( = 7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAM cells and secreted biomarkers, predict cellular origins, and define molecular and cellular networks in LAM. A unique cell type termed LAM was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAM cells expressing signature genes included known LAM markers such as , , , and and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic mutations, supporting a potential uterine origin for the LAM cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells. A unique population of LAM cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.
Topics: Adult; Aged; Biomarkers, Tumor; Female; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Middle Aged; Single-Cell Analysis; Transcriptome; United States; Uterine Neoplasms
PubMed: 32603599
DOI: 10.1164/rccm.201912-2445OC -
Immunology and Allergy Clinics of North... May 2023Cysts and cavities in the lung are commonly encountered on chest imaging. It is necessary to distinguish thin-walled lung cysts (≤2 mm) from cavities and characterize... (Review)
Review
Cysts and cavities in the lung are commonly encountered on chest imaging. It is necessary to distinguish thin-walled lung cysts (≤2 mm) from cavities and characterize their distribution as focal or multifocal versus diffuse. Focal cavitary lesions are often caused by inflammatory, infectious, or neoplastic processes in contrast to diffuse cystic lung diseases. An algorithmic approach to diffuse cystic lung disease can help narrow the differential diagnosis, and additional testing such as skin biopsy, serum biomarkers, and genetic testing can be confirmatory. An accurate diagnosis is essential for the management and disease surveillance of extrapulmonary complications.
Topics: Humans; Lymphangioleiomyomatosis; Histiocytosis, Langerhans-Cell; Birt-Hogg-Dube Syndrome; Tomography, X-Ray Computed; Lung Diseases; Lung; Cysts; Diagnosis, Differential
PubMed: 37055093
DOI: 10.1016/j.iac.2023.01.003 -
Archives of Pathology & Laboratory... Dec 2010Lymphangioleiomyomatosis is an uncommon lung disease primarily affecting women of childbearing age. It is characterized by the progressive proliferating and infiltrating...
Lymphangioleiomyomatosis is an uncommon lung disease primarily affecting women of childbearing age. It is characterized by the progressive proliferating and infiltrating smooth musclelike cells (lymphangioleiomyomatosis cells), which lead to the cystic destruction of the lung parenchyma; obstruction of airways, blood vessels, and lymphatics; and loss of pulmonary function. Lymphangioleiomyomatosis cells coexpress smooth muscle markers (such as smooth muscle actin and desmin) and melanocytic markers (such as HMB-45, Melan-A/MART-1, and microphthalmia transcription factor). Dyspnea on exertion and recurrent pneumothorax are the most common clinical features. Somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex (TSC) 1 or TSC2 are closely related to lymphangioleiomyomatosis. The TSC1/TSC2 protein-related signaling pathways are involved in the pathogenesis and may provide novel therapeutic targets for lymphangioleiomyomatosis and diseases associated with TSC1 / TSC2 dysfunction.
Topics: Biomarkers; Diagnosis, Differential; Female; Humans; Lung Diseases; Lymphangioleiomyomatosis; Mutation; Signal Transduction; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins
PubMed: 21128782
DOI: 10.5858/2009-0576-RS.1 -
Chest Jul 2023Lymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mortality...
BACKGROUND
Lymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mortality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined.
RESEARCH QUESTION
Which factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis?
STUDY DESIGN AND METHODS
The progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV, and generalized linear models were used to identify variables affecting FEV decline. A Cox proportional hazards model was used to explore the association between clinical variables and the outcomes of death or lung transplantation in patients with lymphangioleiomyomatosis.
RESULTS
VEGF-D levels and sirolimus treatment were associated with FEV changes and survival prognosis. Compared with patients with VEGF-D of < 800 pg/mL at baseline, patients with VEGF-D of ≥ 800 pg/mL lost FEV faster (SE, -38.86 mL/y; 95% CI, -73.90 to -3.82 mL/y; P = .031). The 8-year cumulative survival rates of patients with VEGF-D of ≥ 2,000 pg/mL and < 2,000 pg/mL were 82.9% and 95.1%, respectively (P = .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV by 65.56 mL/y (95% CI, 29.06-102.06 mL/y) in patients treated with sirolimus compared with those without sirolimus (P < .001). The 8-year risk of death was reduced by 85.1% (hazard ratio, 0.149; 95% CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV of 70% predicted or St. George's Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival.
INTERPRETATION
Serum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis.
TRIAL REGISTRY
ClinicalTrials.gov; No.: NCT03193892; URL: www.
CLINICALTRIALS
gov.
Topics: Humans; Lymphangioleiomyomatosis; Vascular Endothelial Growth Factor D; Sirolimus; Biomarkers; Disease Progression; Lung Neoplasms
PubMed: 36801466
DOI: 10.1016/j.chest.2023.02.026 -
Jornal Brasileiro de Pneumologia :... 2015
Topics: Everolimus; Humans; Immunosuppressive Agents; Lung Transplantation; Lymphangioleiomyomatosis; Rare Diseases; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 26398747
DOI: 10.1590/S1806-37132015000400001 -
American Journal of Physiology. Cell... Feb 2023Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers,... (Review)
Review
Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers, it is metastatic, primarily to the lung. Despite its monogenetic nature, like many cancers, LAM is a heterogeneous disease. The cellular constituents of LAM are very diverse, including mesenchymal, epithelial, endothelial, and immune cells. LAM is characterized by dysregulation of many cell signaling pathways, distinct populations of LAM cells, and a rich microenvironment, in which the immune system appears to play an important role. This review delineates the heterogeneity of LAM and focuses on the metastatic features of LAM, the deregulated signaling mechanisms and the tumor microenvironment. Understanding the tumor-host interaction in LAM may provide insights into the development of new therapeutic strategies, which could be combinatorial or superlative to Sirolimus, the current U.S. Food and Drug Administration-approved treatment.
Topics: Humans; Female; Lymphangioleiomyomatosis; Tumor Suppressor Proteins; Tuberous Sclerosis Complex 2 Protein; Lung; Lung Neoplasms; Tumor Microenvironment
PubMed: 36571446
DOI: 10.1152/ajpcell.00202.2022 -
Chest May 2023A critical need exists to develop remission-inducing therapies for lymphangioleiomyomatosis.
BACKGROUND
A critical need exists to develop remission-inducing therapies for lymphangioleiomyomatosis.
RESEARCH QUESTION
Is the addition of resveratrol safe and more efficacious than sirolimus alone in patients with lymphangioleiomyomatosis?
STUDY DESIGN AND METHODS
We conducted a phase 2, dose-escalating, open-label trial of resveratrol in patients with lymphangioleiomyomatosis receiving a stable regimen of sirolimus. Resveratrol was started at 250 mg/d and escalated every 8 weeks to maximum dose of 1,000 mg/d over 24 weeks. The primary outcome was ≥ 42% decline in serum vascular endothelial growth factor D (VEGF-D) levels on combined therapy compared with baseline VEGF-D levels on sirolimus. Secondary objectives included an assessment of the safety profile and the effect on lung function and health-related quality of life (HRQOL). Longitudinal change in outcome measures was assessed using linear mixed models. Adverse effects were tabulated using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.
RESULTS
Twenty-five patients with lymphangioleiomyomatosis with a median age of 51 years were enrolled. Pulmonary function parameters at study inclusion were: FEV: median absolute, 1.72 L; 64% predicted; FVC: median absolute, 2.99 L; 96% predicted; and diffusing capacity of the lungs for carbon monoxide: median absolute, 14.68 mL/mm Hg/min; 37% predicted. The median serum VEGF-D value at baseline was 617 pg/mL. Patients entered the study with a median sirolimus dose of 2 mg/d with median trough level of 6.3 ng/mL. Despite some GI side effects, the addition of resveratrol was well tolerated. Although the primary outcome was not met, a statistically significant reduction in serum VEGF-D levels and improvement in HRQOL during the study was found.
INTERPRETATION
The addition of resveratrol was safe and well tolerated in patients with lymphangioleiomyomatosis taking sirolimus and was associated with modest improvement in HRQOL. Larger controlled trials of this combination might be warranted to assess definitively the usefulness of resveratrol as an additive therapy in lymphangioleiomyomatosis.
TRIAL REGISTRY
ClinicalTrials.gov; No.: NCT03253913; URL: www.
CLINICALTRIALS
gov.
Topics: Humans; Middle Aged; Sirolimus; Lymphangioleiomyomatosis; Vascular Endothelial Growth Factor D; Resveratrol; Quality of Life; Forced Expiratory Volume
PubMed: 36642366
DOI: 10.1016/j.chest.2023.01.007