The Experts below are selected from a list of 4575 Experts worldwide ranked by ideXlab platform
Joel Moss - One of the best experts on this subject based on the ideXlab platform.
-
Angiotensin-converting enzyme inhibitors may affect pulmonary function in Lymphangioleiomyomatosis
JCI insight, 2019Co-Authors: Wendy K. Steagall, Gustavo Pacheco-rodriguez, Mario Stylianou, Joel MossAbstract:A local renin-angiotensin system exists in the pulmonary nodules of Lymphangioleiomyomatosis patients. Sirolimus, the standard treatment for Lymphangioleiomyomatosis, stabilizes lung function, but all patients do not respond to or tolerate sirolimus. As renin-angiotensin systems may affect tumor growth and metastasis, we questioned if angiotensin-converting enzyme inhibitors affected Lymphangioleiomyomatosis disease progression. Retrospective study of 426 patients was performed, examining angiotensin-converting enzyme levels, pulmonary function data, and angiotensin-converting enzyme inhibitor treatment. Serum angiotensin-converting enzyme levels were elevated in approximately 33% of patients, increased with duration of disease, and were inversely correlated with pulmonary function. Levels decreased significantly over time with sirolimus treatment. Treatment with angiotensin-converting enzyme inhibitors was reported by approximately 15% of patients and was significantly associated with a slower rate of decline in percentage predicted forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) in patients not treated with sirolimus. No significant differences in rates of decline of FEV1 or DLCO were seen in patients treated with both inhibitors and sirolimus versus sirolimus alone. Angiotensin-converting enzyme inhibitors may slow decline of pulmonary function in patients with Lymphangioleiomyomatosis not treated with sirolimus. These inhibitors may be an option or adjunct in the treatment of Lymphangioleiomyomatosis. A clinical trial may be warranted to examine this possibility. NIH.
-
active surveillance of nonfatty renal masses in patients with Lymphangioleiomyomatosis use of ct features and patterns of growth to differentiate angiomyolipoma from renal cancer
American Journal of Roentgenology, 2017Co-Authors: Nilo A Avila, Andrew J Dwyer, Joel MossAbstract:OBJECTIVE. The objective of this study was to report our experience with active surveillance of nonfatty renal masses in a large cohort of patients with Lymphangioleiomyomatosis (LAM), correlate th...
-
sirolimus decreases circulating Lymphangioleiomyomatosis cells in patients with Lymphangioleiomyomatosis
Chest, 2014Co-Authors: Xiong Cai, Mario Stylianou, Thomas N Darling, Gustavo Pachecorodriguez, Mary Haughey, Leigh Samsel, Philip J Mccoy, Joel MossAbstract: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 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.
-
serum vegf d concentration as a biomarker of Lymphangioleiomyomatosis severity and treatment response a prospective analysis of the multicenter international Lymphangioleiomyomatosis efficacy of sirolimus miles trial
The Lancet Respiratory Medicine, 2013Co-Authors: Lisa R. Young, Joel Moss, Yoshikazu Inoue, Jeffrey T. Chapman, Hyeseung Lee, L G Singer, Charlie Strange, Koh Nakata, Alan F Barker, Mark L BrantlyAbstract:Summary Background VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with Lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with Lymphangioleiomyomatosis. Methods In the MILES trial, patients with Lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV 1 ) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. Findings We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99–3·36] vs 0·84 ng/mL [0·52–1·39]; p vs 1·00 ng/mL [0·61–2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV 1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV 1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). Interpretation Serum VEGF-D is a biologically plausible and useful biomarker in Lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk–benefit analysis of sirolimus therapy in patients with Lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. Funding National Institutes of Health, US Department of Defense.
-
Imaging features of Lymphangioleiomyomatosis: diagnostic pitfalls.
AJR. American journal of roentgenology, 2011Co-Authors: Nilo A Avila, Andrew J Dwyer, Joel MossAbstract:The objective of this article is to illustrate CT findings that may be misinterpreted and lead to unnecessary biopsy or surgical procedures in patients with Lymphangioleiomyomatosis. Sequelae of pleurodesis, acutely hemorrhagic renal angiomyolipomas, and lymphatic involvement with Lymphangioleiomyomatosis including enlarged lymph nodes and lymphangioleiomyomas are common benign conditions seen in patients with Lymphangioleiomyomatosis that may be misdiagnosed on CT for malignancy and may prompt unnecessary biopsy and surgery. Ruptured abdominal pelvic lymphangioleiomyomas may be mistaken for appendicitis and other acute abdominal pelvic events.
Simon R. Johnson - One of the best experts on this subject based on the ideXlab platform.
-
effect of doxycycline on proliferation mmp production and adhesion in lam related cells
American Journal of Physiology-lung Cellular and Molecular Physiology, 2010Co-Authors: William Y C Chang, Debbie Clements, Simon R. JohnsonAbstract:Matrix metalloproteinases (MMPs) have been implicated in lung cyst formation in Lymphangioleiomyomatosis (LAM). As doxycycline inhibits MMP activity in vivo, some patients take doxycycline, as one ...
-
Sirolimus therapy in tuberous sclerosis or sporadic Lymphangioleiomyomatosis.
The New England journal of medicine, 2008Co-Authors: D. Mark Davies, Simon R. Johnson, Anne E. Tattersfield, J. Chris Kingswood, J. Cox, Deborah L. Mccartney, Tim Doyle, Frances Elmslie, Anand Saggar, Petrus J De VriesAbstract:To the Editor: Tuberous sclerosis is an autosomal dominant disorder characterized by hamartomatous growths in many organs and caused by inherited mutations of the TSC1 or TSC2 gene. Acquired (somatic) mutations of either gene occur within pathologic cells in patients with sporadic Lymphangioleiomyomatosis. Renal angiomyolipomas occur in both disorders, resulting in substantial morbidity and mortality.1 The proteins TSC1 and TSC2 regulate signaling through the mammalian target of rapamycin (mTOR) pathway to control processes including growth, cell-cycle progression, apoptosis, and autophagy. Constitutive activation of mTOR and its downstream targets occurs in lesions associated with tuberous sclerosis or Lymphangioleiomyomatosis, suggesting that mTOR . . .
-
The TSC‐2 product tuberin is expressed in Lymphangioleiomyomatosis and angiomyolipoma
Histopathology, 2002Co-Authors: Simon R. Johnson, C Clelland, J. Ronan, Anne E. Tattersfield, Alan J. KnoxAbstract:Lymphangioleiomyomatosis is categorized by proliferation of abnormal smooth muscle cells (LAM cells) in the lungs and lymphatics and the presence of angiomyolipomas. Recently mutations in the tuberous sclerosis complex-2 gene (TSC-2) have been described in LAM cells and angiomyolipomas. The TSC-2 protein tuberin is a tumour suppressor and its loss may result in cellular proliferation. We used immunohistochemistry to test the hypothesis that uncontrolled cellular proliferation in Lymphangioleiomyomatosis is the result of reduced tuberin protein expression. Tissue from normal lung, normal kidney, Lymphangioleiomyomatosis and angiomyolipomas was immunostained with three separate anti-tuberin antibodies. Tuberin staining in normal tissues was similar to that previously described. Surprisingly, tuberin was strongly expressed in the LAM cells of all cases of Lymphangioleiomyomatosis and angiomyolipoma at a greater level than in normal smooth muscle cells. The perivascular cells of angiomyolipomas, however, did not stain for tuberin. Our results suggest that a loss of tuberin protein in LAM cells is not the cause of the cellular proliferation seen in Lymphangioleiomyomatosis. Lymphangioleiomyomatosis may result either from the expression of a mutant tuberin with abnormal function, as a result of mutations in functionally related proteins, or from more than one mechanism.
-
Clinical experience of Lymphangioleiomyomatosis in the UK
Thorax, 2000Co-Authors: Simon R. Johnson, A E TattersfieldAbstract:Lymphangioleiomyomatosis is a rare lung disease that affects only women. No controlled trials of management have been performed and, until such data are available, management must be based on clinical experience. This study provides data on the natural history of Lymphangioleiomyomatosis in the UK and compares this with experience from other centres. We tried to identify all cases of Lymphangioleiomyomatosis in the UK over a five year period by contacting all chest physicians. Cases were confirmed by lung biopsy or history and high resolution computed tomographic (CT) scanning. Details of disease and management were obtained from hospital notes. The 50 patients who fitted the diagnostic criteria for Lymphangioleiomyomatosis had a median age at onset of 35 years (range 22-50). Five presented when postmenopausal (four taking hormone replacement therapy). Pneumothorax and dyspnoea were the most common presenting features. Extrapulmonary presentations included renal angiomyolipomas (3) and lymphangiomyomas (2). Only half the patients were assessed for renal angiomyolipoma and six were identified. Thirty patients had had one or more pneumothoraces, of which two thirds recurred if treated conservatively. Chylous effusions occurred in 11 patients, five requiring surgery. Pregnancy was uncommon once the diagnosis was made (n=7), but was associated with an increase in complications. Half the patients were taking a beta agonist and many showed a bronchodilator response in the laboratory. Thirty six patients had received hormone treatment. Our UK five year period prevalence was one per 1.1 million population. Since prophylactic interventions are sometimes indicated for renal angiomyolipoma, these data suggest that screening for angiomyolipoma, ideally by CT scanning, may be underused. Patients need to be aware of the increase in complications associated with pregnancy. Recurrence rate of pneumothorax was high in those not treated surgically. Hormone treatment was used variably and controlled trials are needed to determine their role and the optimum duration and dose.
-
clinical experience of Lymphangioleiomyomatosis in the uk
Thorax, 2000Co-Authors: Simon R. Johnson, A E TattersfieldAbstract:BACKGROUND Lymphangioleiomyomatosis is a rare lung disease that affects only women. No controlled trials of management have been performed and, until such data are available, management must be based on clinical experience. This study provides data on the natural history of Lymphangioleiomyomatosis in the UK and compares this with experience from other centres. METHODS We tried to identify all cases of Lymphangioleiomyomatosis in the UK over a five year period by contacting all chest physicians. Cases were confirmed by lung biopsy or history and high resolution computed tomographic (CT) scanning. Details of disease and management were obtained from hospital notes. RESULTS The 50 patients who fitted the diagnostic criteria for Lymphangioleiomyomatosis had a median age at onset of 35 years (range 22–50). Five presented when postmenopausal (four taking hormone replacement therapy). Pneumothorax and dyspnoea were the most common presenting features. Extrapulmonary presentations included renal angiomyolipomas (3) and lymphangiomyomas (2). Only half the patients were assessed for renal angiomyolipoma and six were identified. Thirty patients had had one or more pneumothoraces, of which two thirds recurred if treated conservatively. Chylous effusions occurred in 11 patients, five requiring surgery. Pregnancy was uncommon once the diagnosis was made (n=7), but was associated with an increase in complications. Half the patients were taking a β agonist and many showed a bronchodilator response in the laboratory. Thirty six patients had received hormone treatment. CONCLUSIONS Our UK five year period prevalence was one per 1.1 million population. Since prophylactic interventions are sometimes indicated for renal angiomyolipoma, these data suggest that screening for angiomyolipoma, ideally by CT scanning, may be underused. Patients need to be aware of the increase in complications associated with pregnancy. Recurrence rate of pneumothorax was high in those not treated surgically. Hormone treatment was used variably and controlled trials are needed to determine their role and the optimum duration and dose.
Lisa R. Young - One of the best experts on this subject based on the ideXlab platform.
-
serum vegf d concentration as a biomarker of Lymphangioleiomyomatosis severity and treatment response a prospective analysis of the multicenter international Lymphangioleiomyomatosis efficacy of sirolimus miles trial
The Lancet Respiratory Medicine, 2013Co-Authors: Lisa R. Young, Joel Moss, Yoshikazu Inoue, Jeffrey T. Chapman, Hyeseung Lee, L G Singer, Charlie Strange, Koh Nakata, Alan F Barker, Mark L BrantlyAbstract:Summary Background VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with Lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with Lymphangioleiomyomatosis. Methods In the MILES trial, patients with Lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV 1 ) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. Findings We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99–3·36] vs 0·84 ng/mL [0·52–1·39]; p vs 1·00 ng/mL [0·61–2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV 1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV 1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). Interpretation Serum VEGF-D is a biologically plausible and useful biomarker in Lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk–benefit analysis of sirolimus therapy in patients with Lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. Funding National Institutes of Health, US Department of Defense.
-
Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis
The New England journal of medicine, 2008Co-Authors: John J. Bissler, Lisa R. Young, Francis X. Mccormack, Jean M. Elwing, Gail Chuck, Jennifer Leonard, Vincent J. Schmithorst, Tal Laor, Alan S. Brody, Judy A. BeanAbstract: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.) 2008 Massachusetts Medical Society
-
diagnostic potential of serum vegf d for Lymphangioleiomyomatosis
The New England Journal of Medicine, 2008Co-Authors: Lisa R. Young, Yoshikazu Inoue, Francis X. MccormackAbstract:To the Editor: Lymphangioleiomyomatosis is a rare, progressive, frequently fatal cystic lung disease that affects women almost exclusively.1,2 It occurs in up to 40% of women with the tuberous scle...
-
Sirolimus Therapy in Tuberous Sclerosis or Sporadic Lymphangioleiomyomatosis
2008Co-Authors: Lisa R. Young, Yoshikazu Inoue, Francis X. MccormackAbstract:Vascular endothelial growth factor (VEGF) is a major angiogenic growth factor produced by malignant cells. VEGF-D, a ligand for the lymphatic growth-factor receptor VEGFR-3/Flt-4, induces formation of lymphatics and promotes the spread of tumor cells to lymph nodes. Seyama et al. reported that levels of VEGF-D, but not VEGF-A or VEGF-C, are elevated in patients with sporadic Lymphangioleiomyomatosis as compared with healthy controls. 5 We conducted a study to determine the diagnostic usefulness of VEGF-D levels in distinguishing Lymphangioleiomyomatosis from other, clinically overlapping disorders. We found that serum VEGF-D levels were elevated by a factor of up to 30 in patients with Lymphangioleiomyomatosis but were normal in patients with lymphangiomatosis, those with pulmonary Langerhans’-cell histiocytosis, and those with emphysema (Fig. 1A). The area under the receiver-operating-characteristic curve was 0.951 for sporadic Lymphangioleiomyomatosis. With a cutoff value for VEGF-D of 574 pg per milliliter, the test sensitivity for sporadic Lymphangioleiomyomatosis was 86%, the specificity was 91%, and the positive likelihood
Francis X. Mccormack - One of the best experts on this subject based on the ideXlab platform.
-
diagnostic potential of serum vegf d for Lymphangioleiomyomatosis
The New England Journal of Medicine, 2008Co-Authors: Lisa R. Young, Yoshikazu Inoue, Francis X. MccormackAbstract:To the Editor: Lymphangioleiomyomatosis is a rare, progressive, frequently fatal cystic lung disease that affects women almost exclusively.1,2 It occurs in up to 40% of women with the tuberous scle...
-
Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis
The New England journal of medicine, 2008Co-Authors: John J. Bissler, Lisa R. Young, Francis X. Mccormack, Jean M. Elwing, Gail Chuck, Jennifer Leonard, Vincent J. Schmithorst, Tal Laor, Alan S. Brody, Judy A. BeanAbstract: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.) 2008 Massachusetts Medical Society
-
Sirolimus Therapy in Tuberous Sclerosis or Sporadic Lymphangioleiomyomatosis
2008Co-Authors: Lisa R. Young, Yoshikazu Inoue, Francis X. MccormackAbstract:Vascular endothelial growth factor (VEGF) is a major angiogenic growth factor produced by malignant cells. VEGF-D, a ligand for the lymphatic growth-factor receptor VEGFR-3/Flt-4, induces formation of lymphatics and promotes the spread of tumor cells to lymph nodes. Seyama et al. reported that levels of VEGF-D, but not VEGF-A or VEGF-C, are elevated in patients with sporadic Lymphangioleiomyomatosis as compared with healthy controls. 5 We conducted a study to determine the diagnostic usefulness of VEGF-D levels in distinguishing Lymphangioleiomyomatosis from other, clinically overlapping disorders. We found that serum VEGF-D levels were elevated by a factor of up to 30 in patients with Lymphangioleiomyomatosis but were normal in patients with lymphangiomatosis, those with pulmonary Langerhans’-cell histiocytosis, and those with emphysema (Fig. 1A). The area under the receiver-operating-characteristic curve was 0.951 for sporadic Lymphangioleiomyomatosis. With a cutoff value for VEGF-D of 574 pg per milliliter, the test sensitivity for sporadic Lymphangioleiomyomatosis was 86%, the specificity was 91%, and the positive likelihood
Anne E. Tattersfield - One of the best experts on this subject based on the ideXlab platform.
-
Sirolimus therapy in tuberous sclerosis or sporadic Lymphangioleiomyomatosis.
The New England journal of medicine, 2008Co-Authors: D. Mark Davies, Simon R. Johnson, Anne E. Tattersfield, J. Chris Kingswood, J. Cox, Deborah L. Mccartney, Tim Doyle, Frances Elmslie, Anand Saggar, Petrus J De VriesAbstract:To the Editor: Tuberous sclerosis is an autosomal dominant disorder characterized by hamartomatous growths in many organs and caused by inherited mutations of the TSC1 or TSC2 gene. Acquired (somatic) mutations of either gene occur within pathologic cells in patients with sporadic Lymphangioleiomyomatosis. Renal angiomyolipomas occur in both disorders, resulting in substantial morbidity and mortality.1 The proteins TSC1 and TSC2 regulate signaling through the mammalian target of rapamycin (mTOR) pathway to control processes including growth, cell-cycle progression, apoptosis, and autophagy. Constitutive activation of mTOR and its downstream targets occurs in lesions associated with tuberous sclerosis or Lymphangioleiomyomatosis, suggesting that mTOR . . .
-
The TSC‐2 product tuberin is expressed in Lymphangioleiomyomatosis and angiomyolipoma
Histopathology, 2002Co-Authors: Simon R. Johnson, C Clelland, J. Ronan, Anne E. Tattersfield, Alan J. KnoxAbstract:Lymphangioleiomyomatosis is categorized by proliferation of abnormal smooth muscle cells (LAM cells) in the lungs and lymphatics and the presence of angiomyolipomas. Recently mutations in the tuberous sclerosis complex-2 gene (TSC-2) have been described in LAM cells and angiomyolipomas. The TSC-2 protein tuberin is a tumour suppressor and its loss may result in cellular proliferation. We used immunohistochemistry to test the hypothesis that uncontrolled cellular proliferation in Lymphangioleiomyomatosis is the result of reduced tuberin protein expression. Tissue from normal lung, normal kidney, Lymphangioleiomyomatosis and angiomyolipomas was immunostained with three separate anti-tuberin antibodies. Tuberin staining in normal tissues was similar to that previously described. Surprisingly, tuberin was strongly expressed in the LAM cells of all cases of Lymphangioleiomyomatosis and angiomyolipoma at a greater level than in normal smooth muscle cells. The perivascular cells of angiomyolipomas, however, did not stain for tuberin. Our results suggest that a loss of tuberin protein in LAM cells is not the cause of the cellular proliferation seen in Lymphangioleiomyomatosis. Lymphangioleiomyomatosis may result either from the expression of a mutant tuberin with abnormal function, as a result of mutations in functionally related proteins, or from more than one mechanism.
-
Decline in lung function in Lymphangioleiomyomatosis: relation to menopause and progesterone treatment.
American journal of respiratory and critical care medicine, 1999Co-Authors: Simon R. Johnson, Anne E. TattersfieldAbstract:The progression of Lymphangioleiomyomatosis, a rare lung disease in women, is thought to be influenced by hormonal factors. We studied the rate of decline in FEV(1) and carbon monoxide transfer factor (TL(CO)) in a national cohort of patients with Lymphangioleiomyomatosis in the United Kingdom and its relation to two factors that might influence the disease, menopausal status and progesterone treatment. We used retrospective data from hospital notes, and of the 50 patients identified 43 had suitable lung function data spanning at least 3 mo. Mean (SD) annual decline in FEV(1) was 118 (142) ml for all patients, and these figures changed little when only data spanning at least 2 and 3 yr were analyzed. There was considerable variation in the rate of decline between subjects, however, and although it tended to be less among postmenopausal women and those receiving progesterone, patient numbers were smaller and the findings were not significant. There was a significant reduction in decline in TL(CO) in premenopausal patients receiving progesterone and in both FEV(1) and TL(CO) after starting progesterone in six patients who had data before and after starting treatment. This study documents the rapid decline in lung function in Lymphangioleiomyomatosis, confirms the wide variation between patients, and provides some support for the suggestion that disease progression may be reduced by progesterone. The data provide a basis for designing prospective studies of treatment for Lymphangioleiomyomatosis.
