Healthcare provider recognition of pregnancy related risks and management considerations in patients with tuberous sclerosis complex.

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.

Spontaneous pneumothoraces during pregnancy in patients with lymphangioleiomyomatosis.

Patients with lymphangioleiomyomatosis (LAM) are prone to developing spontaneous pneumothoraces (SPs). We aimed to characterize the burden of SPs during pregnancy in LAM, using a web-based survey. Among the 50 respondents, 12 (24%) had never been pregnant and 38 (76%) were pregnant at least once, resulting in a total of 80 pregnancies. Respiratory symptoms during pregnancy led to the diagnosis of LAM in 34% of (13/38) patients, with SPs being the presenting manifestation in most of these patients (10/13, 77%). Eleven of the 38 pregnant patients (29%) experienced at least one SP during pregnancy. The majority of the SPs (∼60%) occurred during the second trimester. Our study provides valuable insights regarding the risk, burden, and timing of pregnancy-related SPs in patients with LAM that would be useful for the LAM community.

Probability of sporadic lymphangioleiomyomatosis in women presenting with spontaneous pneumothorax.

BACKGROUND: Sporadic lymphangioleiomyomatosis (S-LAM) is a rare low-grade neoplasm of young women characterized by multiple pulmonary cysts leading to progressive dyspnea and recurrent spontaneous pneumothorax (SP). The diagnosis of S-LAM may be delayed by several years. To reduce this delay, chest computed tomography (CT) screening has been proposed to uncover cystic lung disease in women presenting with SP. However, the probability to discover S-LAM in this population has not been determined precisely. The aim of this study was to calculate the probability of finding S-LAM in women presenting with (a) SP, and (b) apparent primary SP (PSP) as first manifestation of S-LAM. METHODS: Calculations were made by applying the Bayes theorem to published epidemiological data on S-LAM, SP and PSP. Each term of the Bayes equation was determined by meta-analysis, and included: (1) the prevalence of S-LAM in the general female population, (2) the incidence rate of SP and PSP in the general female population, and (3) the incidence rate of SP and apparent PSP in women with S-LAM. RESULTS: The prevalence of S-LAM in the general female population was 3.03 per million (95% confidence interval 2.48, 3.62). The incidence rate of SP in the general female population was 9.54 (8.15, 11.17) per 100,000 person-years (p-y). The incidence rate of SP in women with S-LAM was 0.13 (0.08, 0.20). By combining these data in the Bayes theorem, the probability of finding S-LAM in women presenting with SP was 0.0036 (0.0025, 0.0051). For PSP, the incidence rate in the general female population was 2.70 (1.95, 3.74) per 100,000 p-y. The incidence rate of apparent PSP in women with S-LAM was 0.041 (0.030, 0.055). With the Bayes theorem, the probability of finding S-LAM in women presenting with apparent PSP as first disease manifestation was 0.0030 (0.0020, 0.0046). The number of CT scans to perform in women to find one case of S-LAM was 279 for SP and 331 for PSP. CONCLUSION: The probability of discovering S-LAM at chest CT in women presenting with apparent PSP as first disease manifestation was low (0.3%). Recommending chest CT screening in this population should be reconsidered.

Lymphangioleiomyomatosis: circulating levels of FGF23 and pulmonary diffusion.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Resection of Extrapulmonary Lymphangiomyoma and Post-Operative Management Considerations.

Background: Lymphangiomyomatosis is a rare disease involving the lymph vessels, causing obstruction and cystic formation with an incidence of 3-8 per million women. The disease might be sporadic or inherited. Lymphangiomyomatosis mostly affects the pulmonary system, whereas extrapulmonary Lymphangiomyomatosis may present in various site, occasionally as a localized abdominal mass. The diagnostic process might entail surgical resection to obtain a specimen for pathology that may also help to achieve a long-term control of the disease. Methods: Herein, we present a case of a 45 years old female, who suffered from pulmonary symptoms, and during her workup an abdominal mass was found. The patient underwent exploratory laparotomy with resection of a left retroperitoneal bilobar mass. Results: Histopathological report revealed Lymphangiomyoma. She had a complication of a lymphatic leakage that required a second laparotomy with satisfactory clinical outcome. Conclusions: Surgeons should be aware of the pathological lymphatics and manage post-operative complications by a trial of conservative.

Safety and Efficacy of Combined Resveratrol and Sirolimus in 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: FEV1: 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.

Pulmonary lymphangioleiomyomatosis and renal angiomyolipoma in a patient with systemic lupus erythematosus: A case report.

BACKGROUND: The co-incidence of systemic lupus erythematosus (SLE) and tuberous sclerosis with pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML) is rare. In such patients, the rupture of renal AML may result in fatal circumstances, but this may be preventable. METHODS: A 22-year-old Asian woman with SLE was admitted to our hospital with severe left-flank pain. Imaging studies showed the bilateral rupture of multiple renal AMLs. RESULTS: The patient underwent emergency selective transcatheter embolization (TE) of the left renal artery. After TE and massive hydration, the patient complained of dyspnea and postembolization syndrome with fever. The chest computed tomography (CT) revealed pulmonary LAM, pulmonary edema with bilateral pleural effusions, and pneumonic consolidation. After the emergency procedure, the patient was treated with intravenous administration of antibiotics, diuretics, and nonsteroidal anti-inflammatory drugs for 10 days. The patient recovered favorably and was discharged 20 days after the treatment. She was diagnosed with renal AML and pulmonary LAM along with facial angiofibromas as well as tuberous sclerosis complex (TSC), although she had no TSC1 or TSC2 gene mutations. CONCLUSION: Although rare, SLE may coexist with TSC, along with LAM and AML, with a risk of AML rupture. The activation of the mTOR signaling pathway is shared between SLE and TSC. Thus, in patients with SLE, clinicians should consider imaging studies, such as kidney sonography and chest CT, to screen for possible manifestation of AML and LAM.

Computer grading of lung disease severity in patients with lymphangioleiomyomatosis referred 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.

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

Background: The 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. Methods: From 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. Results: We 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. Conclusion: We 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.

Thrombosed orbital arteriovenous malformation in a patient with lymphangioleiomyomatosis.

A 47 year-old female with lymphangioleiomyomatosis developed right periorbital pain worsened while chewing, six months prior. Neuroimaging demonstrated a heterogenous inferotemporal right orbital mass extending through the inferior orbital fissure into the temporalis fossa, with flow voids. Given the patient's past medical history, the lesion was presumed to be a perivascular epithelioid cell tumor, a manifestation of lymphangioleiomyomatosis. A lateral orbitotomy revealed a well-circumscribed bluish-red lesion with areas of hemorrhage that was resected in total. Histopathology, however, was consistent with a thrombosed orbital arteriovenous malformation likely arising from the zygomaticotemporal neurovascular bundle. Lymphangioleiomyomatosis is a rare progressive disease that causes cystic destruction of the lungs and is frequently associated with extrapulmonary tumor infiltration, typically of the kidney and liver. Lymphangiomyoleiomyomatosis cell pathogenesis includes a pro-angiogenic micro-environment, classically expressing vascular endothelial factor-C and -D, which we postulate may have contributed to the development of the orbital arteriovenous malformation.

Assessment of Lung Structure and Regional Function Using 0.55 T MRI in Patients With Lymphangioleiomyomatosis.

OBJECTIVES: Contemporary lower-field magnetic resonance imaging (MRI) may offer advantages for lung imaging by virtue of the improved field homogeneity. The aim of this study was to evaluate the utility of lower-field MRI for combined morphologic imaging and regional lung function assessment. We evaluate low-field MRI in patients with lymphangioleiomyomatosis (LAM), a rare lung disease associated with parenchymal cysts and respiratory failure. MATERIALS AND METHODS: We performed lung imaging on a prototype low-field (0.55 T) MRI system in 65 patients with LAM. T2-weighted imaging was used for assessment of lung morphology and to derive cyst scores, the percent of lung parenchyma occupied by cysts. Regional lung function was assessed using oxygen-enhanced MRI with breath-held ultrashort echo time imaging and inhaled 100% oxygen as a T1-shortening MR contrast agent. Measurements of percent signal enhancement from oxygen inhalation and percentage of lung with low oxygen enhancement, indicating functional deficits, were correlated with global pulmonary function test measurements taken within 2 days. RESULTS: We were able to image cystic abnormalities using T2-weighted MRI in this patient population and calculate cyst score with strong correlation to computed tomography measurements (R = 0.86, P < 0.0001). Oxygen-enhancement maps demonstrated regional deficits in lung function of patients with LAM. Heterogeneity of oxygen enhancement between cysts was observed within individual patients. The percent low-enhancement regions showed modest, but significant, correlation with FEV1 (R = -0.37, P = 0.007), FEV1/FVC (R = -0.33, P = 0.02), and cyst score (R = 0.40, P = 0.02). The measured arterial blood ΔT1 between normoxia and hyperoxia, used as a surrogate for dissolved oxygen in blood, correlated with DLCO (R = -0.28, P = 0.03). CONCLUSIONS: Using high-performance 0.55 T MRI, we were able to perform simultaneous imaging of pulmonary structure and regional function in patients with LAM.

Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease.

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.

Sleep features in Lymphangioleiomyomatosis and their relationship with disease severity: a pilot study.

Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterized by progressive airflow limitation. We conducted a pilot trial to investigate the incidence of sleep disorders, sleep quality and their relationship with disease severity. We performed pulmonary function tests, blood gas analysis, overnight 12-channels polysomnography and clinical assessments in 15 consecutive LAM patients. For statistics, p values < 0.05 were considered significant. Sleep efficiency (SE) was inversely correlated with RV/TLC (p = 0.035) and positively with daytime SpO2 (p = 0.010) and PaO2 (p = 0.011). Three cases had obstructive sleep apnea (OSA); seven patients (46.7%) showed a REMOSA. AHIREM was correlated with FEV1% (r = 0.75, p = 0.003), TLC% (r = 0.57, p = 0.026), RV% (r = 0.8, p=<0.0001) and RV/TLC (r = 0.77, p = 0.001). No correlations were observed between anxiety/depression and SE, CAP rate, pulmonary function test variables and AHIREM (p > 0.05). four subjects had nocturnal hypoxia (T90 ≥ 1% of TST) showing lower values of DLCO%, daytime SpO2%, PaO2, FEV1% and a higher value of VR/TLC comparing with the subgroup with normal T90 (p < 0.05). This pilot study shows that sleep alterations could be frequent in LAM and associated to disease severity. Nocturnal hypoxemia and SE were related to lung function impairment. A dysregulation of sleep seems to involve exclusively REM phase, while NREM appears to be preserved. This phenomenon might be linked to the pathophysiology of disease: our study, even with the limits of the small sample size, showed that the presence of REMOSA is related to the disease severity, in particular to the degree of airflow limitation and hyperinflation. More studies are needed to assess this topic.