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Abstract Background Patients with tuberous sclerosis complex (TSC) face an increased risk of maternal health complications and worsening disease manifestations during pregnancy. There are no established consensus guidelines that address the management of pregnancy in patients with TSC and healthcare providers rely on their individual experiences and preferences to derive treatment decisions. We sought to obtain provider opinion of pregnancy related maternal complications in patients with TSC, and the common evaluation and management strategies used to address these issues. Methods We conducted a cross-sectional survey of healthcare providers with diverse areas of expertise related to the multisystem nature of involvement in TSC. Descriptive analyses were used to analyze our three primary variables: (1) provider recognition of maternal risks/complications; (2) provider recommendations before and during pregnancy; and (3) provider/clinic protocols. Results We received responses from 87 providers from 11 countries, with 40.7% (n = 35) seeing > 30 TSC patients yearly. The majority of providers (n = 70, 88.6%) deemed that a patient with TSC needed expert care beyond the standard of care for a typical pregnancy, with over 25% of providers reporting that they have seen lymphangioleiomyomatosis (LAM) exacerbation, seizures, and preterm labor in pregnant patients with TSC. Providers who managed patients treated with mTOR inhibitors (mTORi) also agreed that mTORi use should be stopped prior to pregnancy (n = 45, 68.2%) but there was uncertainty about when to stop the mTORi (one month 28.9%, two months 11.1%, three months 42.2%, and 6–12 months 2.2%). Additionally, there were mixed opinions on restarting mTORi in response to disease progression during pregnancy. When asked about provider or clinic specific protocols, 71.6% (n = 53) of providers stated that they do not have a clear protocol for management decisions for patients with TSC before or during pregnancy. Conclusion Healthcare providers recognize that patients with TSC are at an increased risk for maternal health complications during pregnancy. However, there are wide inter-individual variances in practice, especially pertaining to decisions regarding mTORi use. There is a critical need to better understand the implications of pregnancy for patients with TSC, and to draft consensus recommendations to guide management decisions.

Background: Patients with tuberous sclerosis complex (TSC) face an increased risk of maternal health complications and worsening disease manifestations during pregnancy. There are no established consensus guidelines that address the management of pregnancy in patients with TSC and healthcare providers rely on their individual experiences and preferences to derive treatment decisions. We sought to obtain provider opinion of pregnancy related maternal complications in patients with TSC, and the common evaluation and management strategies used to address these issues. Methods: We conducted a cross-sectional survey of healthcare providers with diverse areas of expertise related to the multisystem nature of involvement in TSC. Descriptive analyses were used to analyze our three primary variables: (1) provider recognition of maternal risks/complications; (2) provider recommendations before and during pregnancy; and (3) provider/clinic protocols. Results: We received responses from 87 providers from 11 countries, with 40.7% (n = 35) seeing > 30 TSC patients yearly. The majority of providers (n = 70, 88.6%) deemed that a patient with TSC needed expert care beyond the standard of care for a typical pregnancy, with over 25% of providers reporting that they have seen lymphangioleiomyomatosis (LAM) exacerbation, seizures, and preterm labor in pregnant patients with TSC. Providers who managed patients treated with mTOR inhibitors (mTORi) also agreed that mTORi use should be stopped prior to pregnancy (n = 45, 68.2%) but there was uncertainty about when to stop the mTORi (one month 28.9%, two months 11.1%, three months 42.2%, and 6–12 months 2.2%). Additionally, there were mixed opinions on restarting mTORi in response to disease progression during pregnancy. When asked about provider or clinic specific protocols, 71.6% (n = 53) of providers stated that they do not have a clear protocol for management decisions for patients with TSC before or during pregnancy. Conclusion: Healthcare providers recognize that patients with TSC are at an increased risk for maternal health complications during pregnancy. However, there are wide inter-individual variances in practice, especially pertaining to decisions regarding mTORi use. There is a critical need to better understand the implications of pregnancy for patients with TSC, and to draft consensus recommendations to guide management decisions. [ABSTRACT FROM AUTHOR]

Abstract Objectives Lymphangioleiomyomatosis (LAM) patients with severe lung disease may be considered for lung transplantation. Clinical, physiologic, and quality of life data are usually employed for referral. The aim of this study was to determine whether computed tomographic measurement of lung volume occupied by cysts (cyst score) complemented clinical and physiologic data in supporting referral for transplantation. Methods Forty-one patients were studied. Pre-referral clinical data, pulmonary function tests, exercise testing, and high-resolution computed tomography (HRCT) scans were obtained. From HRCT, a computer-aided diagnostic program was employed to calculate cyst scores. These data were compared to those of 41 age-matched LAM patients not referred for lung transplantation. Results Cyst score, and % predicted FEV1 and DLCO were respectively, 48.1 ± 9.4%, 36.5 ± 9.1%, and 35.0 ± 10.7%. For the control group, cyst score, FEV1, and DLCO were respectively, 14.8 ± 8.3%, 77.2 ± 20.3%, and 66.7 ± 19.3%. Cyst score values showed a normal distribution. However, the frequency distribution of FEV1 was skewed to the right while the distribution of DLCO was bimodal. Correlations between cyst score and FEV1 and DLCO for the study group were respectively, r = − 0.319 and r = − 0.421. Conclusions LAM patients referred for lung transplantation had nearly 50% of lungs occupied by cysts. Correlations between cyst score and FEV1 or DLCO were weak; as shown previously, DLCO was better related to cyst number while FEV1 had a better association with cyst size. Given its normal distribution, cyst score measurements may assist in evaluation of pre-transplant severity of lung disease before referral for transplantation.

Objectives: Lymphangioleiomyomatosis (LAM) patients with severe lung disease may be considered for lung transplantation. Clinical, physiologic, and quality of life data are usually employed for referral. The aim of this study was to determine whether computed tomographic measurement of lung volume occupied by cysts (cyst score) complemented clinical and physiologic data in supporting referral for transplantation.Methods: Forty-one patients were studied. Pre-referral clinical data, pulmonary function tests, exercise testing, and high-resolution computed tomography (HRCT) scans were obtained. From HRCT, a computer-aided diagnostic program was employed to calculate cyst scores. These data were compared to those of 41 age-matched LAM patients not referred for lung transplantation.Results: Cyst score, and % predicted FEV1 and DLCO were respectively, 48.1 ± 9.4%, 36.5 ± 9.1%, and 35.0 ± 10.7%. For the control group, cyst score, FEV1, and DLCO were respectively, 14.8 ± 8.3%, 77.2 ± 20.3%, and 66.7 ± 19.3%. Cyst score values showed a normal distribution. However, the frequency distribution of FEV1 was skewed to the right while the distribution of DLCO was bimodal. Correlations between cyst score and FEV1 and DLCO for the study group were respectively, r = - 0.319 and r = - 0.421.Conclusions: LAM patients referred for lung transplantation had nearly 50% of lungs occupied by cysts. Correlations between cyst score and FEV1 or DLCO were weak; as shown previously, DLCO was better related to cyst number while FEV1 had a better association with cyst size. Given its normal distribution, cyst score measurements may assist in evaluation of pre-transplant severity of lung disease before referral for transplantation. [ABSTRACT FROM AUTHOR]

Yun Wu,* Hongru Li,* Xiaoli Yu, Ming Lin, Yusheng Chen Department of Respiratory Medicine, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, Fujian 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yusheng ChenDepartment of Respiratory Medicine, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, Fujian 350001, People’s Republic of ChinaEmail cysktz@163.comAbstract: Lymphangioleiomyomatosis (LAM) is a rare disease affecting young women, which occurs sporadically or in patients with tuberous sclerosis complex (TSC). The main manifestations of TSC in the kidney include cysts and angiomyolipoma (AML). Although renal cell carcinoma (RCC) is not a manifestation of TSC, it has a 2– 4% incidence in TSC patients. Furthermore, LAM is rare in patients with RCC. Herein, we present a case of a 40-year-old woman with LAM and RCC in the right kidney. We checked for mutations in the TSC1 and TSC2 genes from both blood and kidney lesions and found a heterozygous mutation of c.1717– 30G> A in intron 16 of TSC2 gene. In TSC patients, the diagnosis of RCC is challenging because the cancer is rare, and it is often difficult to distinguish it from AML with conventional imaging techniques. Therefore, it is recommended that patients with TSC undergo renal imaging follow-ups annually for kidney masses.Keywords: tuberous sclerosis complex, TSC, lymphangioleiomyomatosis, LAM, renal cell carcinoma, RCC, TSC1, TSC2

Objective To quantify the degree of pulmonary cystic damage in CT and compare its correlation with pulmonary function tests（PFTs）and serum levels of vascular endothelial growth factor （VEGF-D），and to study the potential of quantitative CT to assess the degree of lung damage and decide treatment in lymphangioleiomyomatosis（LAM）. Methods Pulmonary cystic areas in CT images were identified by the artificial intelligence software.The volumetric percentage of cystic regions of the total lung volume was calculated to get a cyst score.The association between the 36 times of CT scan and PFTs were analyzed in 21 patients. The correlation of serum VEGF-D levels of 17 patients and their 24 times of CT scan were studied.A ROC curve was calculated to select the threshold at which the cyst scores could predict the lung impairment best. Results Cyst scores correlated significantly with percentage of predicted forced of expiratory volume in one second （FEV1%pred）（r=-0.72，P<0.001） and percentage of predicted diffusion capacity（DLCO/VA%pred）（r=-0.821，P<0.000 1），while its correlation with serum VEGF-D levels（r=-0.143，P=0.506）was not obvious. The Youden index is max（0.667）with a 94.44% sensitivity and a 72.22% specificity when cyst score is 15.80%. Conclusion Pulmonary cyst scores on CT is strongly correlated with FEV1%pred and DLCO/VA% pred. However，the association with serum levels of VEGF-D is not obvious. Cyst score>15.80% might indicate an abnormal lung function and patients are recommended a sirolimus treatment. [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis (LAM) is a rare metastatic cystic lung disease due to a mutation in a TSC tumor suppressor, resulting in hyperactive mTOR growth pathways. Sirolimus (rapamycin), an allosteric mTORC1 inhibitor, is a therapeutic option for women with LAM but it only maintains lung volume during treatment and does not provide benefit for all LAM patients. The two major mTORC1 protein synthesis pathways are via S6K/S6 or 4E-BP/eIF4E activation. We aimed to investigate rapamycin in combination with compounds that target associated growth pathways, with the potential to be additive to rapamycin. In this study we demonstrated that rapamycin, at a clinically tolerable concentration (10 nM), inhibited the phosphorylation of S6, but not the critical eIF4E releasing Thr 37/46 phosphorylation sites of 4E-BP1 in TSC2-deficient LAM-derived cells. We also characterized the abundant protein expression of peIF4E within LAM lesions. A selective MNK1/2 inhibitor eFT508 inhibited the phosphorylation of eIF4E but did not reduce TSC2-null cell growth. In contrast, a PI3K/mTOR inhibitor omipalisib blocked the phosphorylation of Akt and both S6K/S6 and 4E-BP/eIF4E branches, and additively decreased the growth of TSC2-null cells with rapamycin. Omipalisib, or another inhibitor of both major mTORC1 growth pathways and pAkt, might provide therapeutic options for TSC2-deficient cancers including, but not limited to, LAM. [ABSTRACT FROM AUTHOR]

Pulmonary lymphangioleiomyomatosis (LAM) is a rare genetic multisystem disease characterized by the nodular proliferation of smooth muscle-like LAM cells, progressive cystic changes of the lung, lymphatic abnormalities, and renal angiomyolipomas (AMLs). LAM can arise sporadically or in women with the autosomal dominant disorder, tuberous sclerosis complex (TSC), in which hamartomatous tumors of brain, heart, skin, kidney, and lung are found. LAM and TSC are caused by mutations in the TSC1 or TSC2 tumor suppressor genes leading to elevated mechanistic/mammalian target of rapamycin complex activity. Recent data indicate that T cells within LAM nodules and renal AMLs exhibit features of T-cell exhaustion, with coinhibitory receptor programmed cell death protein 1 (PD-1) expression on tumor-infiltrating T cells. Treatment of animal models of TSC and LAM with anti-PD-1 antibodies or with the combination of anti-PD-1 and anti-CTLA4 antibodies has led to remarkable results, suppressing TSC2-null tumor growth and inducing tumor rejection. Here we review our current knowledge about the potential for immunotherapy for the treatment of LAM and TSC and highlight critical unknowns and key next steps. [ABSTRACT FROM AUTHOR]

Background and Objective: Lymphangioleiomyomatosis (LAM) is a rare disease developing mostly on lung and leading to various pulmonary and extra-pulmonary manifestations. Management of this intractable illness has been mostly symptomatic and supplementary until the advent and application of a novel drug, i.e., the mechanistic target of rapamycin (mTOR) inhibitor, and successful disease control using mTOR inhibitors is improving LAM patients. Although mTOR inhibitors are showing remarkable results there are still many rooms for further progress, and partly solved issues on problems seen in LAM still remain. We searched multiple reports and investigational studies regarding LAM, especially the therapeutic achievement won by mTOR inhibitors. This article summarized several characteristics of LAM including pathogenesis, clinical manifestation, laboratory findings, and management. We also attempted to review the latest knowledge and efficacy of mTOR inhibitors and some new drugs., Methods: Online searching of literature was performed. The National Center for Biotechnology Information (NCBI), PubMed, Cochrane Library, Google Scholar, and EMBASE were searched., Key Content and Findings: LAM is a genetic disease with a high predilection toward female subjects. Not only lung but also other organs are involved, hence extrapulmonary symptoms and signs are also noted. Representative objective finding is a progressive deterioration of lung function, sometimes leading to respiratory failure. Supportive and symptomatic care has been the mainstay of therapy with suboptimal result, until a novel drug, the mTOR inhibitor, was developed. Successful deterrence of disease progression was achieved on management with mTOR inhibitors. Several unsolved problems using mTOR inhibitors are a pending issue, such as duration of treatment., Conclusions: LAM has been a rare, stubborn disease to ameliorate in health due to its complex pathogenesis and accompanied by other manifestations. Adopting various tools for relief has been usually suboptimal, but mTOR inhibitors proved to achieve significant improvement in various aspects. Further investigation is needed including refinement of currently available therapeutic applications, development of novel remedies, and so on., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-778/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Objective To determine the expression of vascular endothelial growth factor-D (VEGF-D) in lymphangioleiomyomatosis (LAM) and its differential diagnosis in polycystic lung diseases (PLD).Methods Serum VEGF-D levels were measured by enzyme-linked immunosorbent assay in 50 cases with LAM,34 cases with other polycystic lung disease (OPLD) and 20 cases of healthy volunteers.Results Of the 50 LAM patients,33 cases were diagnosed by pathological examinations,including 23 cases of lung biopsy,5 cases of retroperitoneal neoplasm biopsy and 5 cases of renal angiomyolipoma (AML) biopsy.Of the 50 LAM patients,21 cases associated with chylothorax,2 cases associated with chyloperitoneum,17 cases associated with AML,and 3 cases associated with tuberous sclerosis complex (TSC).Symptoms of the 50 LAM patients started from 19 to 60 years old.Symptoms of 34 OPLD patients started from 30 to 69 years old.The ages of 20 healthy controls were from 24 to 49 years old.Serum VEGF-D levels were significantly greater in LAM patients than in healthy controls ［(3 986.1±361.2) pg/mL vs. (413.4±33.2) pg/mL,P<0.001］.The optimal cutoff point for LAM diagnosis was 692.5 pg/mL with the sensitivity of 98% and the specificity of 100%,respectively.Serum VEGF-D levels were significantly elevated in LAM patients than in OPLD patients ［(3 986.1±361.2) pg/mL vs.(505.7±25.6) pg/mL,P<0.001］.The optimal cutoff point for LAM diagnosis was 901.0 pg/mL with the sensitivity of 94% and the specificity of 100%,respectively.Conclusions Serum VEGF-D levels significantly increased in patients with LAM with a higher sensitivity and specificity.Serum VEGF-D had an important role in the differential diagnosis of LAM and OPLD. [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis (LAM) is a rare metastatic cystic lung disease due to a mutation in a TSC tumor suppressor, resulting in hyperactive mTOR growth pathways. Sirolimus (rapamycin), an allosteric mTORC1 inhibitor, is a therapeutic option for women with LAM but it only maintains lung volume during treatment and does not provide benefit for all LAM patients. The two major mTORC1 protein synthesis pathways are via S6K/S6 or 4E-BP/eIF4E activation. We aimed to investigate rapamycin in combination with compounds that target associated growth pathways, with the potential to be additive to rapamycin. In this study we demonstrated that rapamycin, at a clinically tolerable concentration (10 nM), inhibited the phosphorylation of S6, but not the critical eIF4E releasing Thr 37/46 phosphorylation sites of 4E-BP1 in TSC2-deficient LAM-derived cells. We also characterized the abundant protein expression of peIF4E within LAM lesions. A selective MNK1/2 inhibitor eFT508 inhibited the phosphorylation of eIF4E but did not reduce TSC2-null cell growth. In contrast, a PI3K/mTOR inhibitor omipalisib blocked the phosphorylation of Akt and both S6K/S6 and 4E-BP/eIF4E branches, and additively decreased the growth of TSC2-null cells with rapamycin. Omipalisib, or another inhibitor of both major mTORC1 growth pathways and pAkt, might provide therapeutic options for TSC2-deficient cancers including, but not limited to, LAM.

Background Lymphangioleiomyomatosis (LAM) is a rare disease involving the bronchi, lymphatic vessels, and veins. However, there are few reports about lymphatic vessel abnormalities associated with LAM. Purpose To evaluate computed tomography (CT) lymphangiography findings in cases of LAM, especially lymphatic vessel abnormalities. Material and Methods Twenty-seven patients with LAM underwent direct lymphangiography (DLG), followed by a post-procedural thoracoabdominal CT examination. Results All 27 patients were diagnosed with LAM, including 25 (93%) with chylothorax, eight (30%) with chyloperitoneum, seven (26%) with chylous fluid in the chest and abdomen, and one (4%) with lower-limb lymphedema. The CT lymphangiography showed that 27/27 (100%) patients presented iliac or retroperitoneal lymphatic vessel dilation; 20/27 (74%) presented thoracic duct outlet obstruction; 9/27 (33%) presented pleural lymph leakage; and 13/27 (48%) presented an abnormal distribution of contrast agent in the contralateral lumbar trunk, 3/27 (11%) in the pulmonary field, 1/27 (4%) in the abdominal cavity, and 4/27 (15%) in the pelvic cavity. Five of the 27 patients (19%) had retroperitoneal lymphangioleiomyomas, with contrast agent accumulation in three cases during CT lymphangiography. Two of the 27 (7%) patients had enlarged lymph nodes in the retroperitoneum. All 27 patients (100%) diagnosed with LAM displayed various lung cysts on thoracic high-resolution CT scans. Conclusion CT lymphangiography findings can be used to diagnose most LAM cases accurately. Moreover, these findings also display the various lymphatic vessel abnormalities associated with LAM. [ABSTRACT FROM AUTHOR]

Purpose Lymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial. Methods Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5 to 15 ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses. Results The most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9 months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (<14.5 g/dL) showed significantly higher incidence than those with high Hb (≥14.5 g/dL, P < .01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study. Conclusions Baseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis. [ABSTRACT FROM AUTHOR]

Benign metastasizing leiomyomatosis (BML) is a rare cause of pulmonary lesions found in reproductive age women who have undergone a hysterectomy for uterine leiomyoma. Given the relative rarity of the disease, the management of these lesions varies from surgical (oopherectomy) or medical antiestrogen hormonal therapy to clinical observation and survelliance. The disease generally presents asymptomatically with multiple, well-defined pulmonary nodules discovered incidentally on imaging. We report an atypical presentation of a 46-year-old woman with incidentally found bilateral pulmonary cavitating nodules and cysts, concerning for lymphangioleiomyomatosis (LAM), who was ultimately diagnosed with BML.

The article presents a case study of 61-year old woman who reported discharge of milky white liquid from her vagina. Topics discussed include patient history of chest pain, dyspnea and short term breadth after exercise, patient underwent pleurodesis for chylothorax and vaginal exudate positive for chyle. It highlights that the patient underwent anastomosis of left external iliac vein and lymph vessel.

The article discusses impact of several diseases including Lymphangioleiomyomatosis (LAM) and Gorham-Stout disease (GSD). Topics discussed include proliferation of lymphatic vessels, association of lung diseases with life-threatening complications and mentions the diagnosis of cellular proliferative response.

In just the past 5 years, dramatic changes have occurred in the clinical management of tuberous sclerosis complex ( TSC). Detailed knowledge about the role of the TSC proteins in regulating the activity of the mammalian target of rapamycin complex 1 ( mTORC1) underlies this paradigm-shifting progress. Advances continue to be made in understanding the genetic pathogenesis of the different tumours that occur in TSC, including pivotal discoveries using next-generation sequencing ( NGS). For example, the pathogenesis of angiofibromas is now known to involve UV-induced mutations, and the pathogenesis of multifocal renal cell carcinoma ( RCC) in TSC is now known to result from distinct second-hit mutations. In parallel, the pathological features of TSC-associated tumours, including TSC-associated renal cell carcinoma, continue to be defined, despite the fact that TSC was first described 180 years ago. Here, we review recent discoveries related to the pathological features and genetic pathogenesis of TSC-associated tumours. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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., Results: 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)., Conclusions: 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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-6420/coif). The authors have no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease occurring almost exclusively in premenopausal women and characterized by cystic lung destruction, abdominal tumors (renal angiomyolipomas (AML)), and involvement of the axial lymphatics (adenopathy, lymphangioleiomyomas). Serum vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic factor, has been recently considered as a novel marker for LAM. Herein we report the diagnostic and differential diagnostic value of serum VEGF-D in LAM patients and evaluate the change of serum VEGF-D levels before and after treatment with sirolimus. The study group included 66 patients with LAM (47 definite LAM and 19 probable LAM based on European Respiratory Society guidelines), 14 patients with other polycystic lung diseases, and 20 healthy female controls. Serum VEGF-D levels were quantified by enzymelinked immunoassay (ELISA). Serum VEGFD levels were significantly increased in definite LAM patients compared with healthy controls (3890.3±373.3 pg/ml vs. 413.3±33.2 pg/ml, p<0.05). The optimal cutoff point for LAM diagnosis was 692.5 pg/ml with sensitivity of 97.9% and specificity of 100%. In probable LAM patients, serum VEGF-D levels were all greater than 692.5 pg/ml. Serum VEGF-D levels were significantly increased in definite LAM patients who had chylothorax compared with those without chylothorax (5153.9±598.3 pg/ml vs. 2869.8±372.8 pg/ml, p<0.05). But serum VEGF-D levels in LAM patients with/ without pneumothorax, AML, and lymphangioleiomyomas were not significantly changed. Serum VEGF-D levels in definite LAM patients and patients with other cystic lung diseases were 3890.3±373.3 pg/ml and 412.6±27.5 pg/ml, respectively (p<0.05). We determined an optimal cutoff value of 688.5pg/ml, resulting in sensitivity of 97.9% and specificity of 100%. Following a median of 12-month treatment with sirolimus, serum VEGF-D levels decreased from 3135.0±909.4 pg/ml to 1731.8±621.2 pg/ml and symptoms improved. Our study found that serum VEGF-D levels were significantly higher in LAM patients compared with healthy controls and patients with other polycystic lung diseases and that the levels were further increased when complicated by chylothorax. Serum VEGF-D levels may be useful for diagnosis and differential diagnosis with high specificity and sensitivity as well as for following treatment response with sirolimus. [ABSTRACT FROM AUTHOR]

Abstract: Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine. [Copyright &y& Elsevier]

Abstract: Diffuse cystic lung disease represents a diverse group of uncommon disorders with characteristic appearance on high resolution CT imaging. The combination of imaging appearance with clinical features and genetic testing where appropriate permits a confident and accurate diagnosis in the majority of the diseases without recourse for open lung biopsy. The mechanism of cyst development disease is unclear but in some disorders appears to be related to small airways obstruction. These diseases are incurable, with the exception of Langerhans cell histiocytosis which may spontaneously remit or resolve on smoking cessation. Disease progression is unpredictable; in general older patients have a more benign disease, while young patients may progress rapidly to respiratory failure. An understanding of the complications of cystic lung disease and the appearance of disease progression is essential for the management of these patients. A number of these disorders are associated with malignancy, recognition of the potential tumors permits appropriate imaging surveillance. Due to the widespread use of CT, pulmonary cysts are increasingly discovered incidentally in an asymptomatic individual. The diagnostic challenge is to determine whether these cysts represent an early feature of a progressive disease or have no clinical significance. In the elderly population the cysts are unlikely to represent a progressive disease. In individuals <50 years further evaluation is recommended. [Copyright &y& Elsevier]

Summary: A 37 yr old lady in her 14th week of her second pregnancy presented to chest clinic with breathlessness. Over the preceding month she had gradual onset of exertional breathlessness limiting her activities of daily living. Examination and routine blood tests were unremarkable and she declined a chest radiograph. Her symptoms progressed and she allowed us to perform a chest radiograph, which revealed a large right sided pneumothorax. This was aspirated successfully. During the final few months of her pregnancy she had a further episode of symptomatic ipsalateral pneumothorax, which was treated successfully with aspiration. She delivered a healthy baby via uncomplicated caesarean section under a spinal anaesthetic at term. A chest radiograph taken 2d post-partum showed normal lung fields with no pneumothorax. Unfortunately, 2 weeks later she developed her third ipsalateral pneumothorax and this was treated conservatively pending video-assisted thoracoscopic surgery and pleurodesis, which occurred a few weeks later. At VATS the appearance of her lungs was grossly abnormal and a biopsy was sent for histological analysis. After a HRCT and specialist staining of her lung biopsy the diagnosis of lymphangioleiomyomatosis was established. [Copyright &y& Elsevier]

Tuberous sclerosis (TSC) is a rare, genetically determined disorder / familial tumor syndrome, currently diagnosed using specific clinical criteria proposed by Gomez, including the presence of multiorgan hamartomas. Pulmonary involvement in TSC is well known as pulmonary lymphangioleiomyomatosis (LAM), which has an incidence of 1–2.3% in TSC patients. LAM has immunohistochemical expression of both smooth-muscle actin and a monoclonal antibody specific for human melanoma, HMB-45. It has recently been reported that multifocal micronodular pneumocyte hyperplasia (MMPH) associated with TSC should be considered as a distinct type of lung lesion, whether it occurs with or without LAM. Two predisposing genes have been found in families affected by TSC; approximately half of the families show linkage to TSC1 at 9q34.3, and the other half show linkage to TSC2 at 16p13.3. TSC genes are considered to be tumor suppressor genes, and mutations in them may lead to abnormal differentiation and proliferation of cells. Tuberin, the TSC2 gene product, has recently been found to be expressed in LAM and MMPH. In this article we discuss the histogenesis and genetic abnormalities of neoplastic lesions associated with TSC, and we review the current understanding of the pathogenesis of pulmonary hamartomatous lesions such as LAM and MMPH in TSC. [ABSTRACT FROM AUTHOR]

Benign metastasizing leiomyomatosis (BML) is a rare cause of pulmonary lesions found in reproductive age women who have undergone a hysterectomy for uterine leiomyoma. Given the relative rarity of the disease, the management of these lesions varies from surgical (oopherectomy) or medical antiestrogen hormonal therapy to clinical observation and survelliance. The disease generally presents asymptomatically with multiple, well-defined pulmonary nodules discovered incidentally on imaging. We report an atypical presentation of a 46-year-old woman with incidentally found bilateral pulmonary cavitating nodules and cysts, concerning for lymphangioleiomyomatosis (LAM), who was ultimately diagnosed with BML. [ABSTRACT FROM AUTHOR]

The tuberous sclerosis protein complex (TSC complex) is a key integrator of metabolic signals and cellular stress. In response to nutrient shortage and stresses, the TSC complex inhibits the mechanistic target of rapamycin complex 1 (mTORC1) at the lysosomes. mTORC1 is also inhibited by stress granules (SGs), RNA-protein assemblies that dissociate mTORC1. The mechanisms of lysosome and SG recruitment of mTORC1 are well studied. In contrast, molecular details on lysosomal recruitment of the TSC complex have emerged only recently. The TSC complex subunit 1 (TSC1) binds lysosomes via phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]. The SG assembly factors 1 and 2 (G3BP1/2) have an unexpected lysosomal function in recruiting TSC2 when SGs are absent. In addition, high density lipoprotein binding protein (HDLBP, also named Vigilin) recruits TSC2 to SGs under stress. In this mini-review, we integrate the molecular mechanisms of lysosome and SG recruitment of the TSC complex. We discuss their interplay in the context of cell proliferation and migration in cancer and in the clinical manifestations of tuberous sclerosis complex disease (TSC) and lymphangioleiomyomatosis (LAM)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rehbein, Prentzell, Cadena Sandoval, Heberle, Henske, Opitz and Thedieck.)

Summary: Though pulmonary lymphangioleiomyomatosis (LAM) is a rare disease that affects women in the reproductive years, there have been some reports in postmenopausal women, and even a few reports of pulmonary LAM in postmenopausal women without exogenous estrogen. This is the first report describing progression of pulmonary LAM after menopause. Physicians should be aware that pulmonary LAM could progress after menopause, although the course might run slower than that of LAM in the younger patients. [Copyright &y& Elsevier]

Lymphangioleiomyomatosis (LAM) is characterized by cystic lung disease, abdominal tumor and involvement of the axial lymph nodes. We report a very rare case of LAM with malignant lymphoma. A 51-year-old female had medical history of recurrent pneumothorax and nephrectomy for a left renal angiomyolipoma and was diagnosed with LAM by video-assisted thoracoscopic surgery at the age of 30. She presented with left neck mass. Computed tomography and magnetic response imaging showed multiple enlarged cervical lymph nodes. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed abnormal uptake in the mass. We suspected a malignant tumor or extrapulmonary lesion of LAM, and performed surgical biopsy. Pathologically, diffuse large B-cell lymphoma was diagnosed, but LAM was not detected. After she received six cycles of R–CHOP chemotherapy, FDG-PET turned negative and complete metabolic response was achieved. As LAM is reported to be silent for FDG-PET, unusual uptake of FDG is useful for identifying other neoplasms. For this case, FDG-PET was useful for the differential diagnosis and therapeutic evaluation. [ABSTRACT FROM AUTHOR]

Background: Total pleural covering (TPC) is an innovative surgical procedure in which the entire visceral pleura is wrapped with sheets of oxidized regenerated cellulose (ORC) mesh under video-assisted thoracoscopic surgery. We have previously reported that TPC could successfully prevent pneumothorax recurrence in patients with lymphangioleiomyomatosis (LAM). However, the actual efficacy and preventive effect of TPC on pneumothorax recurrence remains unclear as many LAM patients already had pleural adhesion prior to TPC that was induced by thoracic surgery and/or pleurodesis. The purpose of this study is to evaluate the effects of TPC on pneumothorax recurrence and pulmonary function in LAM patients with no history of thoracic surgeries or pleurodesis., Methods: We retrospectively reviewed medical charts of 52 patients (60 hemithoraces) who underwent TPC at our center, from January 2003 to September 2019, as a first surgical intervention for pneumothorax., Results: Pneumothorax recurrence occurred in 12 patients [14 of 60 hemithoraces (23.3%)] during the observation period [27 months (14.7; 56.4) = median (lower; upper quartiles)]. The probability of recurrence-free hemithorax post TPC was 81.1% at 2.5 years and 64.1% at 5 years. TPC did not produce a significant decrease in either VC %predicted (pred) or FEV 1 /FVC. The pre- vs. post-TPC median (lower; upper quartiles) VC %pred was 85.7% (79.7; 98.0) vs. 87.2% (72.3; 95.6), P=0.535 and the FEV 1 /FVC was 84.6% (75.7; 89.6) vs. 83.0% (71.8; 87.0), P=0.667. Mechanistic/mammalian target of rapamycin (mTOR) inhibitors (mTORI) were subsequently initiated in 19 patients (36.5%) because of the progression of LAM. The postoperative FEV 1% pred was significantly lower in patients who required mTORI than in those who did not [68.1% (57.3; 82.9) vs. 88.7% (84.6; 89.8), P=0.020]; the decline rate in FEV 1% pred/year from pre to post TPC was significantly greater in LAM patients who required mTORI than in those who did not [-9.37% (-4.73; 12.9) vs. -1.94% (1.52; -4.50), P=0.029]. Postoperative complications were found in 25 of 52 hemithoraces (48.1%)., Conclusions: TPC can prevent pneumothorax recurrence without causing ventilatory impairment or severe pleural symphysis in LAM patients. TPC is an effective treatment option for LAM-associated pneumothorax based on its efficacy and safety., Competing Interests: Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (http://dx.doi.org/10.21037/jtd-20-2286). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)