Lymphangioleiomyomatosis Patients Research Articles

Glycoprotein non-metastatic melanoma protein B promotes tumor growth and is a biomarker for lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including glycoprotein non-metastatic melanoma protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB's unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here, we establish that GPNMB expression is dependent on mTORC1 signaling, and that GPNMB regulates TSC2-null tumor cell invasion in vitro. Further, we demonstrate that GPNMB enhances TSC2-null xenograft tumor growth in vivo, and that ectodomain release is required for this xenograft growth. We also show that GPNMB's ectodomain is released from the cell surface of TSC2-null cells by proteases ADAM10 and 17, and we identify the protease target sequence on GPNMB. Finally, we demonstrate that GPNMB's ectodomain is present at higher levels in LAM patient serum compared to healthy controls and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.

Lymphangioleiomyomatosis and pregnancy: a mini-review.

Lymphangioleiomyomatosis(LAM) is a slow progressive, rare cystic lung disease in women of reproductive age, associated with infiltration of the lung by atypical smooth muscle like cells, leading to the cystic destruction of the lung parenchyma. As LAM exclusively affects women of childbearing age, it can arise or exacerbate during pregnancy. Many patients with LAM are discouraged from pregnancy, although there is not much objective evidence effect on fertility. Patients diagnosed with LAM during pregnancy experience worse outcomes, so the safety of pregnancy is a vexing problem. What was worse, treatment strategies are limited on the effects of LAM on pregnancy outcomes. Pregnancy could be considered in LAM patients. Successful delivery in women with LAM depends on the condition of the LAM, which is in turn dependent on obstetricians and respiratory physicians. In this review, we describe the epidemiology, pathogenesis, diagnosis, clinical features and the treatment strategies of LAM during pregnancy.

Hyperactive mTORC1 in lung mesenchyme induces endothelial cell dysfunction and pulmonary vascular remodeling.

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling. In end-stage LAM lung explants, we identified EC dysfunction characterized by increased EC proliferation and migration, defective angiogenesis, and dysmorphic endothelial tube network formation. To model LAM disease, we used an mTORC1 gain-of-function mouse model with a Tsc2 KO (Tsc2KO) specific to lung mesenchyme (Tbx4LME-Cre Tsc2fl/fl), similar to the mesenchyme-specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from mice exhibited marked transcriptomic changes despite an absence of morphological changes to the distal lung microvasculature. In contrast, 1-year-old Tbx4LME-Cre Tsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. Single-cell RNA-Seq of 1-year-old mouse lung cells identified paracrine ligands originating from Tsc2KO mesenchyme, which can signal through receptors in arterial ECs. These ECs had transcriptionally altered genes including those in pathways associated with blood vessel remodeling. The proposed pathophysiologic mesenchymal ligand-EC receptor crosstalk highlights the importance of an altered mesenchymal cell/EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in patients with LAM and in Tbx4LME-Cre Tsc2fl/fl mice did not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrated dysfunctional EC responses that contributed to pulmonary vascular remodeling.

THU551 Glycoprotein-NMB (GPNMB) Is A Potential Lymphangioleiomyomatosis (LAM) Therapeutic Target And Biomarker

Abstract Disclosure: E. Gibbons: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive, destructive cystic lung disease affecting almost exclusively female-sexed individuals. Mutations in the tuberous sclerosis (TSC1 or TSC2) genes constitutively activate the mTORC1 pathway, promoting hyperproliferation of smooth muscle cells, creating small tumors throughout the lungs. These tumors, through largely unknown mechanisms, result in the formation of large cysts that replace normal alveolar space. Inhibition of mTORC1 with Sirolimus slows but does not stop LAM progression; therefore, there is a need for new LAM treatment options and biomarkers. Due to LAM’s estrogen sensitivity, female specificity, and metastatic nature, we previously proposed LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all the mice generate uterine tumors characteristic of LAM and half develop lung metastases, suggesting that indeed LAM tumors may be derived from the uterus. Using bulk RNASeq analysis of uterine tissue from our mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered increased expression of melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), a known oncogenic protein in other cancers. GPNMB was not only highly expressed in our mouse model; it was also expressed intracellularly and on the cell surface of TSC2-null cell lines and in LAM tumor cells from patient lungs and uteri. Notably, the extracellular domain of GPNMB was released from the surface of TSC2-null cell lines, suggesting that the ectodomain may also be released from TSC2-null cells in LAM patients. Here we show that, GPNMB protein and mRNA expression increased when the cells were serum starved, mimicking conditions of a tumor microenvironment. This increase was dependent on mTORC1 signaling and mRNA transcription. Knocking down GPNMB expression by siRNA had minimal effects on TSC2-null cells pro-tumorigenic functions in vitro aside from decreasing invasion. However, knocking out GPNMB in TSC2-null cells using CRISPR/Cas9 significantly decreased mouse xenograft tumor growth. Additionally, treating mice with a GPNMB antibody drug conjugate abrogated xenograft growth, highlighting GPNMB’s potential as a therapeutic target. Also, GPNMB’s ectodomain was released from the cell surface of TSC2-null cells by the proteases Adam10 and 17. Of note, the ectodomain is implicated in mediating GPNMB’s effects on tumor growth, suggesting that Adam10/17 inhibition may mitigate TSC2-null tumor growth. Importantly, the GPNMB ectodomain is a potential serum biomarker of LAM, as there was a significant increase in GPNMB ectodomain levels in patient serum as compared with healthy controls. Furthermore, serum GPNMB levels decreased in most patients after Sirolimus treatment, implicating GPNMB as a potential marker for responsiveness to treatment. Presentation: Thursday, June 15, 2023

A remote monitoring-enabled home exercise prescription for patients with interstitial lung disease at risk for exercise-induced desaturation

RationaleAlternatives to center-based pulmonary rehabilitation are needed to improve patient access to this important therapy. A critical challenge to overcome is how to maximize safety of unsupervised exercise for at-risk patients. We investigated if a novel remote monitoring-enabled mobile health (mHealth) program is safe, feasible, and effective for patients who experience exercise-induced hemoglobin desaturation. MethodsAn interstitial lung disease (ILD) commonly associated with pronounced exercise desaturation was investigated - the rare, female-predominant ILD lymphangioleiomyomatosis (LAM). Over a 12-week program, hemoglobin saturation (SpO2) was continuously recorded during all home exercise sessions. Intervention effects were assessed with 6-min walk test (6MWT), maximal cardiopulmonary exercise test (CPET), lower extremity computerized dynamometry, pulmonary function tests, and health-related quality of life (QoL) surveys. Safety was assessed by blood biomarkers of systemic inflammation and cardiac wall stress, and incidence of adverse events. ResultsFifteen LAM patients enrolled and 14 completed the intervention, with high adherence to aerobic (87 ± 15%) and strength (87 ± 12%) training components. An innovative characterization of exercise training SpO2 revealed that while mild-to-moderate desaturation was common during home workouts, participants were able to self-adjust exercise intensity and supplemental oxygen levels to maintain recommended exercise parameters. Significant improvements included 6MWT distance (+36 ± 34 m, p = 0.003), CPET time (p = 0.04), muscular endurance (p = 0.008), QoL (p = 0.009 to 0.03), and fatigue (p = 0.001 to 0.03). Patient acceptability and satisfaction indicators were high, blood biomarkers remained stable (p > 0.05), and no study-related adverse events occurred. ConclusionA remote monitoring-enabled home exercise program is a safe, feasible, and effective approach even for patients who experience exercise desaturation.

Estradiol Augments Tumor-Induced Neutrophil Production to Promote Tumor Cell Actions in Lymphangioleiomyomatosis Models.

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease caused by smooth muscle cell-like tumors containing tuberous sclerosis (TSC) gene mutations and found almost exclusively in females. Patient studies suggest LAM progression is estrogen dependent, an observation supported by in vivo mouse models. However, in vitro data using TSC-null cell lines demonstrate modest estradiol (E2) responses, suggesting E2 effects in vivo may involve pathways independent of direct tumor stimulation. We previously reported tumor-dependent neutrophil expansion and promotion of TSC2-null tumor growth in an E2-sensitive LAM mouse model. We therefore hypothesized that E2 stimulates tumor growth in part by promoting neutrophil production. Here we report that E2-enhanced lung colonization of TSC2-null cells is indeed dependent on neutrophils. We demonstrate that E2 induces granulopoiesis via estrogen receptor α in male and female bone marrow cultures. With our novel TSC2-null mouse myometrial cell line, we show that factors released from these cells drive E2-sensitive neutrophil production. Last, we analyzed single-cell RNA sequencing data from LAM patients and demonstrate the presence of tumor-activated neutrophils. Our data suggest a powerful positive feedback loop whereby E2 and tumor factors induce neutrophil expansion, which in turn intensifies tumor growth and production of neutrophil-stimulating factors, resulting in continued TSC2-null tumor growth.

Abstract 1230: The pre-metastatic niche establishment through the induction of the epithelial-to-mesenchymal transition by circulating exosomes in lymphangioleiomyomatosis (LAM): implication of the complement cascade

Abstract Exosomes are a class of extra cellular vesicles (EVs), with a multi vesicular endosomal origin, that are released by all cell types, with sizes ranging from 30-150nm and a lipid bilayer membrane. They have been shown to play key roles in disease progression and have diagnostic and disease monitoring potential. This study aims to characterize exosomes from the serum of patients with Lymphangioleiomyomatosis (LAM), a rare, low-grade, metastasizing neoplasm that occurs predominantly in females. Using Nanoparticle Tracking Analysis (NTA), serum from LAM patients (n=19) have significantly increased numbers of exosomes compared to serum samples from healthy controls (n=20) (8.9x109 vs 13.8x109 particles/ml; p=0.024). Furthermore, particles counts are significantly negatively correlated with the forced expiratory volume (FEV1) (r=-0.4667; p-value=0.0295) in LAM patients. Metalloproteinase activity in exosomes was measured by zymography. Interestingly, these LAM-derived exosomes had significantly higher activity of Pro-MMP-9 (3-fold increase; p-value=0.0278). We analyzed the effects of serum-derived exosomes on cells from an A549 cell line. Increased expression of vimentin, a major marker of EMT, was observed in cells treated with LAM-derived exosomes compared to healthy controls (1.4-fold increase; p=0.0217). Moreover, we showed by a modified Boyden chamber assay that exosomes derived from serum treatment increases the invasive capacity of A549 cells (fold change of 2.2; p-value=0.0004). We interrogated the LAM Single Cell Atlas and identified increased expression of TWIST1, a key transcription factor for EMT. TWIST1 was increased 8-fold in the lung and was uniquely expressed in 'LAM cells', which had metastasized. Furthermore, proteomic analysis revealed high expression of C3 and C5 in LAM-derived exosomes (respectively 1.4- and 2.1-fold change; p=0.0276 and p=0.0034) suggesting the potential regulatory role of the compliment system in the EMT mediated by exosomes These preliminary results highlight the urge to study the specific mechanistic interplay between MMPs and EMT, mediated by exosomes, and whether exosomes are involved in the metastatic spread of LAM cells to the lung and their role in influencing innate and adaptive immune cell response to this invasion. Citation Format: Amina Jouida, Patrick McFadden, Grace Buckley, Evelyn Lynn, O'Callaghan Marissa, Yasuhito Sekimoto, Aurelie Fabre, Michael P. Keane, Cormac McCarthy. The pre-metastatic niche establishment through the induction of the epithelial-to-mesenchymal transition by circulating exosomes in lymphangioleiomyomatosis (LAM): implication of the complement cascade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1230.

Lymphangioleiomyomatosis: circulating levels of FGF23 and pulmonary diffusion.

Lymphangioleiomyomatosis (LAM) is a rare, destructive disease of the lungs with a limited number of determinants of disease activity, which are a critical need for clinical trials. FGF23 has been implicated in several chronic pulmonary diseases. We aimed to determine the association between serum FGF23 levels and pulmonary function in a cohort of patients with LAM. This was a descriptive single-center study in which subjects with LAM and controls with unreported lung disease were recruited. Serum FGF23 levels were measured in all subjects. Clinical data, including pulmonary function testing, were retrospectively obtained from electronic medical records of LAM subjects. Associations between FGF23 levels and clinical features of LAM were explored via nonparametric hypothesis testing. The sample comprised 37 subjects with LAM and 16 controls. FGF23 levels were higher in the LAM group than in the control group. In the LAM group, FGF23 levels above the optimal cutoff point distinguished 33% of the subjects who had nondiagnostic VEGF-D levels. Lower FGF23 levels were associated with impaired DLCO (p = 0.04), particularly for those with isolated diffusion impairment with no other spirometric abnormalities (p = 0.04). Our results suggest that FGF23 is associated with pulmonary diffusion abnormalities in LAM patients and elicit novel mechanisms of LAM pathogenesis. FGF23 alone or in combination with other molecules needs to be validated as a biomarker of LAM activity in future clinical research.

Lymphangioleiomyomatosis: Searching for potential biomarkers.

Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary as well; therefore, defining new biomarkers for LAM is crucial. The aim of this study was to describe the diagnostic accuracy of a variety of biomarkers. We assessed 13 analytes in serum related to extracellular matrix remodeling, lymphatic involvement and angiogenesis in a cohort of patients with LAM, comparing them with patients with other cystic lung diseases (OCLD) and healthy women. A scoring method based on the cut-point of each VEGF-D and metalloproteinase-2 (MMP-2) was used to evaluate the diagnostic performance of the marker combination. A total of 97 subjects were recruited: 59 (61%) LAM patients, 18 (19%) OCLD patients, and 20 (20%) healthy female controls. MMP-2 was the only extracellular matrix remodeling biomarker able to differentiate LAM patients from OCLD and healthy patients. Serum MMP-2 was higher in LAM patients [median 578 (465-832) ng/ml] than in patients with OCLD and healthy controls [medians 360 (314-546) and 427 (365-513) ng/ml, respectively (p < 0.0001)]. The area under ROC curve (AUC) of MMP-2 was 0.785 and that of VEGF-D 0.815 (p = 0.6214). The sensitivity/specificity profiles of each biomarker (54/92% for MMP-2, 59/95% for VEGF-D) yielded a composite score (-6.36 + 0.0059 × VEGF-D + 0.0069 × MMP-2) with higher accuracy than each component alone (AUC 0.88 and sensitivity/specificity 79/87%). Combining MMP-2 and VEGF-D may increase diagnostic accuracy for LAM.

Predicting Individualized Lung Disease Progression in Treatment-Naive Patients With Lymphangioleiomyomatosis

Lung function decline varies significantly in patients with lymphangioleiomyomatosis (LAM), impeding individualized clinical decision-making. Can we aid individualized decision-making in LAM by developing a dynamic prediction model that can estimate the probability of clinically relevant FEV1 decline in patients with LAM before treatment initiation? Patients observed in the US National Heart, Lung, and Blood Institute (NHLBI) Lymphangioleiomyomatosis Registry were included. Using routinely available variables such as age at diagnosis, menopausal status, and baseline lung function (FEV1 and diffusing capacity of the lungs for carbon monoxide [Dlco]), we used novel stochastic modeling and evaluated predictive probabilities for clinically relevant drops in FEV1. We formed predictive probabilities of transplant-free survival by jointly modeling longitudinal FEV1 and lung transplantation or death events. External validation used the UK Lymphangioleiomyomatosis Natural History cohort. Analysis of the NHLBI Lymphangioleiomyomatosis Registry and UK Lymphangioleiomyomatosis Natural History cohorts consisted of 216 and 185 individuals, respectively. We derived a joint model that accurately estimated the risk of future lung function decline and 5-year probabilities of transplant-free survival in patients with LAM not taking sirolimus (area under the receiver operating characteristic curve [AUC], approximately 0.80). The prediction model provided estimates of forecasted FEV1, rate of FEV1 decline, and probabilities for risk of prolonged drops in FEV1 for untreated patients with LAM with a high degree of accuracy (AUC > 0.80) for the derivation cohort as well as the validation cohort. Our tool is freely accessible at: https://anushkapalipana.shinyapps.io/testapp_v2/. Longitudinal modeling of routine clinical data can allow individualized LAM prognostication and assist in decision-making regarding the timing of treatment initiation.

Metabolic signatures of lymphangioleiomyomatosis in biofluids: nuclear magnetic resonance (NMR)-based metabonomics of blood plasma: a case-control study.

Our aim was to analyze and compare the characteristics and differences of blood metabolites between lymphangioleiomyomatosis (LAM) patients and healthy controls, in order to find biomarkers that can be used for the diagnosis and classification of LAM. Between January 2020 to January 2022, 61 eligible LAM patients [51 sporadic LAM (S-LAM) and 10 tuberous sclerosis complex LAM (TSC-LAM)] from the First Affiliated Hospital of Guangzhou Medical University and 30 healthy controls were enrolled. Blood samples were taken for nuclear magnetic resonance (NMR) detection. Data analysis was performed by the umbrella program, and Wilcoxon analysis was used for comparisons between groups. The difference indicators were modeled by logistic regression. Diagnostic accuracy of the best predictive parameters was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC), and the sensitivity and specificity were calculated. The indexes differed between LAM patients and healthy controls, S-LAM patients and healthy controls, and between TSC-LAM patients and healthy controls. There were two different metabolic indexes between S-LAM and TSC-LAM patients. After logistic regression modeling and ROC analysis, methionine (AUC =0.929, sensitivity =73.8%, specificity =100%, cut-off value =0.011 mmol/L) and acetic acid (AUC =0.966, sensitivity =95.1%, specificity =90%, cut-off value =0.006 mmol/L) had the highest diagnostic efficiency in LAM patients, and could be used to distinguish between affected and healthy people. Methionine was significantly associated with pneumothorax (P<0.05), and creatinine was significantly correlated with hysteromyoma (P<0.05). Methionine and acetic acid in the plasma of LAM patients are potential biomarkers. Methionine was also associated with pneumothorax in LAM patients. Also, acetone and creatinine were promising metabolic markers to distinguish S-LAM from TSC-LAM. NMR as a new non-invasive diagnostic method had a good discriminatory power for LAM.

Lung transplantation for lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease, associated with respiratory symptoms of dyspnea and spontaneous pneumothorax, along with various extra-thoracic manifestations. Often a progressive disease, albeit slowly, patients can develop chronic and severe respiratory failure and require supplemental oxygen. Lung transplantation (LTX) can offer improved duration and quality of life for patients with end-stage lung disease due to LAM. There are several unique considerations for LTX in LAM patients, and disease-specific complications of LAM prior to LTX can affect management decisions. Furthermore, there are several possible post-transplant issues specific to LAM. In this review, we discuss evaluation and management, disease-specific complications (both pre- and post-transplant), and outcomes for LAM patients undergoing lung transplantation.

Perioperative management of thoracic surgery in patients with lymphangioleiomyomatosis

BackgroundGeneral surgery for patients with lymphangioleiomyomatosis (LAM) is infrequent, however, general surgeons also occasionally experience it. Only a few reports have described the specific perioperative management appropriate for patients with LAM. Hence, in this case series, we aimed to investigate the surgical outcomes of LAM patients and their characteristics.Case presentationMedical records of 4482 patients who underwent thoracic surgery between 2009 and 2017 at our institution were assessed. Twelve patients were diagnosed with LAM. Details of the postoperative courses and surgical outcomes of LAM patients were retrospectively examined.All LAM patients were female (age 41.3 ± 10.6 years). Surgeries were performed for patients undergoing biopsy (n = 4) and those with pneumothorax (n = 3), lung cancer (n = 2), and other conditions (n = 3). The mortality rate was 0% and the length of hospital stay was 27.4 ± 8.9 days. Ten postoperative complications occurred in six patients (50%): hypoxemia (n = 5), chylothorax (n = 2), and prolonged air leakage (n = 3).ConclusionsThoracic surgery may pose a risk of postoperative complications and long hospitalization for patients with LAM, although it lowers the risk of fatality. Management of perioperative air and chyle leakages and lymphatic stasis in the lungs is important for preventing morbidities.

Sirolimus reduces the risk of pneumothorax recurrence in patients with lymphangioleiomyomatosis: a historical prospective self-controlled study

BackgroundSpontaneous 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.ResultsOf 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).ConclusionSirolimus reduced the risk of pneumothorax recurrence in LAM patients.

Hierarchical cluster analysis based on disease-associated manifestations of patients with lymphangioleiomyomatosis: An analysis of the national database of designated intractable diseases of Japan

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes. Using cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations. Four clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required. Hierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future.

Methylprednisolone in the treatment of lymphangioleiomyomatosis

This case report proposes the use of pulsed methylprednisolone in a patient with lymphangioleiomyomatosis (LAM) who was invasively ventilated. A 38-year-old, East Indian gravida 4, para 1+2, patient with worsening respiratory function with spontaneous pneumothoraxes and hypoxemia was pulsed with methylprednisolone leading to rapid resolution of respiratory failure.The author proposes pulsed methylprednisolone in ventilated LAM patients, which gives another option to patients which resulted in alleviation of hypoxemia and maintaining foetal viability.

Long-term clinical course and progression of lymphangioleiomyomatosis in a single lung transplant referral centre in Korea

We aimed to describe the clinical features of lymphangioleiomyomatosis (LAM) in Korean patients and identify factors associated with progressive disease (PD). Clinical features of 54 patients with definite or probable LAM from 2005 to 2018 were retrospectively analysed. Common features were pneumothorax (66.7%) and abdominal lymphadenopathy (50.0%). Twenty-three (42.6%) patients were initially treated with mechanistic target of rapamycin (mTOR) inhibitors. Lung transplantation (LT) was performed in 13 (24.1%) patients. Grouped based on the annual decline in forced expiratory volume in 1 s (FEV1) from baseline and LT, 36 (66.7%) patients exhibited stable disease (SD). All six deaths (11.1%) occurred in PD. Proportion of SD was higher in those treated initially with mTOR inhibitors than in those under observation (p = 0.043). Univariate analysis revealed sirolimus use, and baseline forced vital capacity, FEV1, and diffusing capacity of the lungs for carbon monoxide are associated with PD. Multivariate analysis showed that only sirolimus use (odds ratio 0.141, 95% confidence interval 0.021–0.949, p = 0.044) reduced PD. Kaplan–Meier analysis estimates overall survival of 92.0% and 74.7% at 5 and 10 years, respectively. A considerable proportion of LAM patients remain clinically stable without treatment. LT is an increasingly viable option for patients with severe lung function decline.

Soluble Immune-Related Proteins as New Candidate Serum Biomarkers for the Diagnosis and Progression of Lymphangioleiomyomatosis.

BackgroundThe goal of this study was to analyze serum from lymphangioleiomyomatosis (LAM) patients and healthy controls to identify novel biomarkers that could shed light on disease diagnosis and pathogenesis.MethodsFrom April 2017 to October 2019, qualified serum samples were obtained to explore differences in 59 immune proteins between 67 LAM patients and 49 healthy controls by the Luminex method.ResultsWe characterized 22 serum immune proteins that were differentially expressed in LAM patients compared with healthy people. Fifty-nine proteins were then classified into eight categories according to their biological function, and the results showed that LAM patients displayed significantly higher levels of growth factors (p = 0.006) and lower levels of costimulatory molecules (p = 0.008). LAG-3 was not only likely to have better predictive value than VEGF-D but also showed a significant difference between patients without elevated VEGF-D and healthy people. IL-18 was positively correlated with lung function and six-minute walk test (6MWT) distance and negatively correlated with St. George’s Respiratory Questionnaire (SGRQ) score and pulmonary artery systolic pressure (PASP), which suggested that IL-18 was related to disease severity. PD-1 was significantly different between patients with pneumothorax and/or chylothorax and those without complications.ConclusionWe performed a large-scale serum immune factor analysis of LAM. Our study provides evidence that LAG-3 may be a novel candidate serum biomarker for the diagnosis of LAM. Future independent validation in prospective studies is warranted.

Reduced risk of recurrent pneumothorax for sirolimus therapy after surgical pleural covering of entire lung in lymphangioleiomyomatosis

BackgroundPatients 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.ResultsOf 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.ConclusionWe 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.

O25‐1: Increased expression of angiotensin‐converting enzyme 2 (ACE2), TMPRSS2 and furin in idiopathic pulmonary fibrosis (IPF) and lymphangioleiomyomatosis (LAM) patients' lung tissue: Implications for COVID ‐19

O25‐1: Increased expression of angiotensin‐converting enzyme 2 (ACE2), TMPRSS2 and furin in idiopathic pulmonary fibrosis (IPF) and lymphangioleiomyomatosis (LAM) patients' lung tissue: Implications for COVID ‐19