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.

Spectrum of germline and somatic mitochondrial DNA variants in Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is caused by loss of function variants in either and is characterized by broad phenotypic heterogeneity Currently, there is limited knowledge regarding the role of the mitochondrial genome (mtDNA) in TSC pathogenesis. In this study, we aimed to determine the prevalence and spectrum of germline and somatic mtDNA variants in TSC and identify potential disease modifiers. Analysis of mtDNA amplicon massively parallel sequencing (aMPS) data, off-target mtDNA from whole-exome sequencing (WES), and/or qPCR, revealed mtDNA alterations in 270 diverse tissues (139 TSC-associated tumors and 131 normal tissue samples) from 199 patients and six healthy individuals.

Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells.

Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either or Cytokine profiling of TSC2-deficient LAM patient-derived cells revealed striking up-regulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed up-regulation of IL-6 transcription and secretion compared to wild-type cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced oxygen consumption and extracellular acidification.

Alterations in Polyamine Metabolism in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex 2-Deficient Cells.

Background: Lymphangioleiomyomatosis (LAM), a destructive lung disease that affects primarily women, is caused by loss-of-function mutations in TSC1 or TSC2, leading to hyperactivation of mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Rapamycin (sirolimus) treatment suppresses mTORC1 but also induces autophagy, which promotes the survival of TSC2-deficient cells. Based on the hypothesis that simultaneous inhibition of mTORC1 and autophagy would limit the availability of critical nutrients and inhibit LAM cells, we conducted a phase 1 clinical trial of sirolimus and hydroxychloroquine for LAM.

Serum endostatin levels are associated with diffusion capacity and with tuberous sclerosis- associated lymphangioleiomyomatosis.

Endostatin is a naturally occurring collagen fragment with anti-angiogenic properties. We investigated the association between serum endostatin levels and DLCO in a cohort of patients with lymphangioleiomyomatosis (LAM). Associations of endostatin levels to clinical features of LAM were explored using logistic regression models.

Circulating Biomarkers From the Phase 1 Trial of Sirolimus and Autophagy Inhibition for Patients With Lymphangioleiomyomatosis.

Background: We have previously conducted the Sirolimus and Autophagy Inhibition in LAM (SAIL) trial, a phase 1 dose-escalation study of the combination of sirolimus and hydroxychloroquine in patients with lymphangioleiomyomatosis (LAM). The goal of the present study was to analyze sera from the SAIL trial to identify novel biomarkers that could shed light into disease pathogenesis and response to therapy.

Methods: We used the DiscoveryMAP platform from Rules Based Medicine to simultaneously measure 279 analytes in sera collected at each visit from subjects enrolled in the SAIL trial.

Characterization of lymphangioleiomyomatosis patients with discordance between spirometric and diffusion measurements of pulmonary function.

A subset of lymphangioleiomyomatosis (LAM) patients present with normal FEV1 and FVC but with reduced DLCO. Patients with an isolated reduction in DLCO in other diseases appear to be at higher risk for pulmonary hypertension and worse survival but this has not been previously described in LAM patients. To characterize the prevalence and clinical progression of LAM patients who present with discordantly low DLCO.

Blood transfusion indications in neurosurgical patients: A systematic review.

Neurosurgical procedures can be complicated by significant blood losses that have the potential to decrease tissue perfusion to critical brain tissue. Red blood cell transfusion is used in a variety of capacities both inside, and outside, of the operating room to prevent untoward neurologic damage. However, evidence-based guidelines concerning thresholds and indications for transfusion in neurosurgery remain limited.

Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis: Results of a Phase I Clinical Trial.

Background: Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function.