Dataset Information

Sirolimus decreases circulating lymphangioleiomyomatosis cells in patients with lymphangioleiomyomatosis.

ABSTRACT:

Background

Lymphangioleiomyomatosis (LAM), sporadic or in women with tuberous sclerosis complex (TSC), is characterized by cystic lung destruction, lymphatic involvement (eg, chylous pleural effusions, lymphangioleiomyomas), and renal angiomyolipomas (AMLs). The multisystem manifestations of LAM appear to result from metastatic dissemination of LAM cells bearing inactivating mutations or having loss of heterozygosity (LOH) of the tumor suppressor genes TSC1 or TSC2, which leads to hyperactivation of the mammalian target of rapamycin. Sirolimus slows the decline of lung function, reduces chylous effusions, and shrinks the size of AMLs. The purpose of this study was to determine the effect of sirolimus on circulating LAM cells.

Methods

Cells from blood were isolated by a density-gradient fractionation system and from urine and chylous effusions by centrifugation. Blood cells were incubated with anti-CD45-fluorescein isothiocyanate (FITC) and anti-CD235a-R-phycoerythrin (PE) antibodies, and urine and chylous effusion cells were incubated with anti-CD44v6-FITC and anti-CD9-R-PE antibodies. Cells were sorted and analyzed for TSC2 LOH.

Results

LAM cells with TSC2 LOH were identified in 100% of blood specimens and 75% of urine samples from patients before therapy. Over a mean duration of 2.2 ± 0.4 years of sirolimus therapy, detection rates of LAM cells were significantly decreased to 25% in blood (P < .001) and 8% in urine (P = .003). Following therapy, a greater loss of circulating LAM cells was seen in postmenopausal patients (P = .025).

Conclusions

Patients receiving sirolimus had a progressive loss of circulating LAM cells that depended on time of treatment and menopausal status.

SUBMITTER: Cai X

PROVIDER: S-EPMC3883264 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

Sirolimus decreases circulating lymphangioleiomyomatosis cells in patients with lymphangioleiomyomatosis.

Cai Xiong X Pacheco-Rodriguez Gustavo G Haughey Mary M Samsel Leigh L Xu Suowen S Wu Hai-Ping HP McCoy J Philip JP Stylianou Mario M Darling Thomas N TN Moss Joel J

Chest 20140101 1

<h4>Background</h4>Lymphangioleiomyomatosis (LAM), sporadic or in women with tuberous sclerosis complex (TSC), is characterized by cystic lung destruction, lymphatic involvement (eg, chylous pleural effusions, lymphangioleiomyomas), and renal angiomyolipomas (AMLs). The multisystem manifestations of LAM appear to result from metastatic dissemination of LAM cells bearing inactivating mutations or having loss of heterozygosity (LOH) of the tumor suppressor genes TSC1 or TSC2, which leads to hypera ...[more]

PMID: 24051985

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Project description:BackgroundLymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM.MethodsWe conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)).ResultsDuring the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.ConclusionsIn patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

Project description:Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Project description:BackgroundLymphangioleiomyomatosis is a rare disease caused by unregulated activation of mammalian target of rapamycin (mTOR) signalling pathway. Sirolimus showed efficacy in a phase 3 trial of patients with lymphangioleiomyomatosis, but the optimal dose remains unclear.MethodsWe investigated the efficacy and safety of low-dose compared with conventional-dose sirolimus. Clinical data of 39 patients with lymphangioleiomyomatosis (mean age, 34.8 years; median treatment period, 29.6 months) who received sirolimus were retrospectively reviewed. Low-dose sirolimus was defined as any dose that maintained mean blood trough levels lower than those maintained with conventional doses (5-15 ng/mL).ResultsFifty-one percent of patients received low-dose therapy. The rate of decline in lung function decreased after treatment in the whole group (forced expiratory volume in 1 s [FEV1], - 0.12 ± 0.47 [before] vs. 0.24 ± 0.48% predicted/month [after], p = 0.027; diffusing capacity for carbon monoxide [DLco], - 0.33 ± 0.61 vs. 0.03 ± 0.26% predicted/month, p = 0.006) compared with before treatment. In the low-dose group, the rate of decline in FEV1 (- 0.08 ± 0.38 [before] vs. 0.19 ± 0.51% predicted/month [after], p = 0.264) and DLco (-0.13 ± 0.62 vs. 0.02 ± 0.28% predicted/month, p = 0.679) showed a numeric trend towards improvement after treatment; however, the conventional-dose group showed significant improvement in FEV1 (- 0.26 ± 0.54 [before] vs. 0.22 ± 0.38 [after] % predicted/month, p = 0.024) and DLco (- 0.55 ± 0.58 vs. 0.04 ± 0.25% predicted/month, p = 0.002) after treatment. Adverse events (AEs) occurred in 89.7% of patients and the most common AEs was hypercholesterolaemia (43.6%), followed by stomatitis (35.9%). The occurrences of AE were similar between the low- and conventional-dose groups (85.0% vs. 94.7%, p = 0.605).ConclusionsLow-dose sirolimus may stabilise lung function decline in lymphangioleiomyomatosis patients, but its efficacy appears to be inferior to that of conventional-dose sirolimus.

Project description:Objectives:We aimed to study sirolimus-related lung parenchymal changes by quantitative analysis of computed tomography (CT) of the lungs in patients with lymphangioleiomyomatosis (LAM). Methods:We studied 20 participants from the Multicenter Lymphangioleiomyomatosis Sirolimus Trial for Safety study, who had undergone both thin-section CT scans and pulmonary function tests at baseline, 12, and 24 months. Quantitative CT parameters such as CT-derived total lung capacity, percentage of low attenuation area (LAA%), lung density histogram, fractal property of low attenuation area, and airway dimensions were analyzed, and correlations were conducted between the longitudinal change in each quantitative CT measurement and changes in pulmonary function were examined. Among 20 participants, pre-trial (n = 8) and post-trial (n = 16) CT data were also analyzed to deduce pathophysiologic implications of the serial changes in CT parameters during trial periods. Results:FEV1 significantly increased from baseline to 24 months (slope 3.71 ± 1.50 ml/month) whereas FVC didn't during sirolimus therapy. Strikingly, LAA%, and skewness and kurtosis of density histogram significantly increased from baseline to 24 months, while mean and mode CT values significantly decreased from baseline to 24 months. Statistically significant positive correlations were found between ?FEV1 and ?skewness (r = 0.465, p = 0.045). Taking the changes in lung density during pre-trial period into consideration, sirolimus decreases the area of -800 to -750 Housefield unit (HU) density and inhibits the decrease of -950 to -800 HU area during treatment, then producing the increased LAA% during the trial and post-trial periods. Given few sirolimus-related changes in airway dimensions, possible changes in lung mechanics may have contributed to increased FEV1. Conclusion:Our study suggests that the lung density histogram parameters, kurtosis, and skewness, may be useful as indicators of the efficacy of sirolimus.

Dataset Information

Sirolimus decreases circulating lymphangioleiomyomatosis cells in patients with lymphangioleiomyomatosis.

Background

Methods

Results

Conclusions

Publications

Sirolimus decreases circulating lymphangioleiomyomatosis cells in patients with lymphangioleiomyomatosis.

Similar Datasets

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