The Experts below are selected from a list of 171 Experts worldwide ranked by ideXlab platform
Erik A Eklund - One of the best experts on this subject based on the ideXlab platform.
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pulmonary and pleural Lymphatic endothelial cells from pediatric but not adult patients with gorham stout disease and generalized Lymphatic Anomaly show a high proliferation rate
Orphanet Journal of Rare Diseases, 2016Co-Authors: Michiko Mori, Michael Dictor, Nicholas Brodszki, Juan Carlos Lopezgutierrez, Maria Jose Beato, Jonas S Erjefalt, Erik A EklundAbstract:Gorham-Stout disease (OMIM 123880) and generalized Lymphatic Anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized Lymphatic Anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. These malformations of the Lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
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Pulmonary and pleural Lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized Lymphatic Anomaly, show a high proliferation rate
Orphanet Journal of Rare Diseases, 2016Co-Authors: Michiko Mori, Michael Dictor, Nicholas Brodszki, Maria Jose Beato, Jonas S Erjefalt, Juan Carlos López-gutiérrez, Erik A EklundAbstract:Background Gorham-Stout disease (OMIM 123880) and generalized Lymphatic Anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Methods Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized Lymphatic Anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). Results We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. Conclusions These malformations of the Lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
Denise M Adams - One of the best experts on this subject based on the ideXlab platform.
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kaposiform lymphangiomatosis effectively treated with mek inhibition
Embo Molecular Medicine, 2020Co-Authors: Jessica B Foster, Michael E March, Denise M Adams, Sarah E Sheppard, Hakon Hakonarson, Yoav DoriAbstract:Kaposiform lymphangiomatosis (KLA) is a rare Lymphatic Anomaly primarily affecting the mediastinum with high mortality rate. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the Casitas B lineage lymphoma (CBL) gene. She was treated with MEK inhibition with complete resolution of symptoms, near-complete resolution of Lymphatic fluid burden, and remodeling of her Lymphatic system. While patients with KLA have been reported to harbor mutations in NRAS, here we report for the first time a causative mutation in the CBL gene in a patient with KLA, successfully treated with Ras pathway inhibition.
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signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis
Pediatric Blood & Cancer, 2019Co-Authors: Elisa Boscolo, Adrienne M Hammill, Denise M Adams, Patricia A Pastura, Kathryn Glaser, Jillian Goines, Peter DickieAbstract:Background Kaposiform lymphangiomatosis (KLA) is a rare Lymphatic Anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of "kaposiform" spindled cells accompanying malformed Lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies. Procedure Cells were obtained from the lungs of one patient isolated at autopsy and the spleen of two patients removed in surgery due to disease complications. A protein kinase array was performed on the KLA cell lysates and normal Lymphatic endothelial cells. Results Higher activation of key signaling pathways in the KLA cells, including PRAS40, AKT1/2/3, and ERK-1/2, was identified by protein kinase array and confirmed by Western blot analysis. This indicated a role for highly activated PI3K-AKT and MAPK-ERK-1/2 signaling pathways in KLA cells. Cell proliferation studies assessed PI3K inhibitors (LY294002; BYL719), AKT inhibitor ARQ092, mTOR inhibitor rapamycin, and MAPK inhibitor U0126. These studies demonstrated that PI3K-AKT-mTOR and MAPK signaling are important mediators of KLA cell proliferation. BYL719 and rapamycin were more effective at inhibiting KLA cell proliferation than U0126. Conclusions Our studies using cells from KLA patient lesions demonstrate that these cells are highly proliferative and the PI3K-AKT-mTOR and MAPK pathways are promising therapeutic targets. Development and clinical trials of PI3K, AKT, and MAPK inhibitors for cancer treatment and the data in this study lend support for early clinical trials assessing the efficacy of these inhibitors in KLA patients.
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efficacy of systemic sirolimus in the treatment of generalized Lymphatic Anomaly and gorham stout disease
Pediatric Blood & Cancer, 2019Co-Authors: Kiersten W Ricci, Adrienne M Hammill, Paula S Mobberleyschuman, Stephen C Nelson, Julie Blatt, Julia Glade L Bender, Catherine Mccuaig, Anna Synakiewicz, Ilona J Frieden, Denise M AdamsAbstract:Background Generalized Lymphatic Anomaly (GLA) and Gorham-Stout disease (GSD) are rare complicated Lymphatic malformations that occur in multiple body sites and are associated with significant morbidity and mortality. Treatment options have been limited, and conventional medical therapies have been generally ineffective. Emerging data suggest a role for sirolimus as a treatment option for complex Lymphatic anomalies. Procedure Disease response was evaluated by radiologic imaging, quality of life (QOL), and clinical status assessments in children and young adults with GLA and GSD from a multicenter systematic retrospective review of patients treated with oral sirolimus and the prospective phase 2 clinical trial assessing the efficacy and safety of sirolimus in complicated vascular anomalies (NCT00975819). Sirolimus dosing regimens and toxicities were also assessed. Results Eighteen children and young adults with GLA (n = 13) or GSD (n = 5) received oral sirolimus. Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%). No patients with bone involvement had progression of bone disease, and the majority had symptom or functional improvement on sirolimus. Improvement of pleural and pericardial effusion(s) occurred in 72% and 50% of affected patients; no effusions worsened on treatment. Conclusions Sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA and GSD. Functional impairment and/or QOL improved in the majority of individuals with GLA and GSD with sirolimus treatment.
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angiopoietins as serum biomarkers for Lymphatic anomalies
Angiogenesis, 2017Co-Authors: Timothy Le D Cras, Paula S Mobberleyschuman, Mary Broering, Cameron C Trenor, Denise M AdamsAbstract:Vascular anomalies can cause significant morbidity and mortality. Advances in diagnosis will be improved if noninvasive biomarkers can be identified, as obtaining a tissue biopsy can worsen the disease and precipitate complications. The goal of this study was to identify biomarkers for vascular Anomaly patients to aid diagnosis and potentially give insights into pathogenesis. Blood was collected at baseline and then 6 and 12 months after treatment with the mTOR inhibitor sirolimus. Patients groups included generalized Lymphatic Anomaly (GLA), kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE) with or without the Kasabach–Merritt phenomenon (KMP) coagulopathy. Serum was obtained from healthy controls selected to match the age and sex of the patients (21 days–28.5 years; 42% males; 58% females). Angiogenic and lymphangiogenic factors (VEGF-A, C, D, Ang-1 and Ang-2) were measured in serum using ELISA. In Lymphatic Anomaly patients, baseline levels of VEGF-A and VEGF-D were not different compared to controls. Angiopoietin-2 (Ang-2) levels were near controls levels in GLA patients but 10-fold greater in KLA patients and 14-fold greater in KHE patients when the KMP coagulopathy was present but not when it was absent. VEGF-C and angiopoietin-1 (Ang-1) levels were lower in KHE patients with KMP. Our analyses suggest that Ang-2 and Ang-1 can be used as biomarkers to help identify KLA and KHE patients with KMP coagulopathy with high sensitivity and specificity. After 12 months of sirolimus treatment, Ang-2 levels were lower in KLA and KHE with KMP patients compared to baseline levels and with most patients showing a clinical response. Hence, serum Ang-2 and Ang-1 levels may help in the diagnosis of patients with Lymphatic anomalies and are concordant to sirolimus response.
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kaposiform lymphangiomatosis a newly characterized vascular Anomaly presenting with hemoptysis in an adult woman
Annals of the American Thoracic Society, 2013Co-Authors: Fadi Safi, Denise M Adams, Anita Gupta, Vasuki Anandan, Francis X Mccormack, Ragheb AssalyAbstract:Disorders of the pulmonary Lymphatic system include macro- and microcystic Lymphatic malformations, primary or secondary lymphangiectasias, generalized Lymphatic anomalies, diffuse pulmonary lymphangiomatosis, and combinations of Lymphatic and other tissue anomalies, including lymphangioleiomyomatosis (LAM). We report a case of a patient with a newly defined entity classified as kaposiform lymphangiomatosis (KLA). This 50-year-old nonsmoking Hispanic woman presented with a 20-year history of cough, hemoptysis, chyloptysis, and pleuritic chest pain. Laboratory evaluation demonstrated a low normal platelet count, elevated d-Dimer, low normal fibrinogen, and elevated fibrin split products. Chest computerized tomography imaging showed enlarged hypodense lymph nodes in the mediastinum and hila, and peribronchovascular thickening, without evidence of cystic parenchymal lesions. Magnetic resonance imaging of the chest showed cystic mediastinal lymph nodes with heterogeneously increased T2 and decreased T1 signal intensity. Fiberoptic bronchoscopy revealed hyperemic mucosa with granular appearance suggestive of a submucosal infiltrative process. Pathological specimens revealed dilated, malformed Lymphatic channels within the pleura, pulmonary septa, and bronchovascular bundles, and foci of periLymphatic and intraLymphatic spindle cells which reacted with the Prospero homeobox protein 1 (PROX-1) immunostain. The morphology and immunohistochemistry results were consistent with a diagnosis of KLA. This newly recognized clinical-pathological entity among intrathoracic Lymphatic anomalies is distinguished from generalized Lymphatic Anomaly and diffuse pulmonary lymphangiomatosis in part by characteristic hematological abnormalities and hemorrhagic complications, including hemoptysis, as experienced by our patient.
Michiko Mori - One of the best experts on this subject based on the ideXlab platform.
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pulmonary and pleural Lymphatic endothelial cells from pediatric but not adult patients with gorham stout disease and generalized Lymphatic Anomaly show a high proliferation rate
Orphanet Journal of Rare Diseases, 2016Co-Authors: Michiko Mori, Michael Dictor, Nicholas Brodszki, Juan Carlos Lopezgutierrez, Maria Jose Beato, Jonas S Erjefalt, Erik A EklundAbstract:Gorham-Stout disease (OMIM 123880) and generalized Lymphatic Anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized Lymphatic Anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. These malformations of the Lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
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Pulmonary and pleural Lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized Lymphatic Anomaly, show a high proliferation rate
Orphanet Journal of Rare Diseases, 2016Co-Authors: Michiko Mori, Michael Dictor, Nicholas Brodszki, Maria Jose Beato, Jonas S Erjefalt, Juan Carlos López-gutiérrez, Erik A EklundAbstract:Background Gorham-Stout disease (OMIM 123880) and generalized Lymphatic Anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Methods Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized Lymphatic Anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). Results We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. Conclusions These malformations of the Lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
Nicholas Brodszki - One of the best experts on this subject based on the ideXlab platform.
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pulmonary and pleural Lymphatic endothelial cells from pediatric but not adult patients with gorham stout disease and generalized Lymphatic Anomaly show a high proliferation rate
Orphanet Journal of Rare Diseases, 2016Co-Authors: Michiko Mori, Michael Dictor, Nicholas Brodszki, Juan Carlos Lopezgutierrez, Maria Jose Beato, Jonas S Erjefalt, Erik A EklundAbstract:Gorham-Stout disease (OMIM 123880) and generalized Lymphatic Anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized Lymphatic Anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. These malformations of the Lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
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Pulmonary and pleural Lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized Lymphatic Anomaly, show a high proliferation rate
Orphanet Journal of Rare Diseases, 2016Co-Authors: Michiko Mori, Michael Dictor, Nicholas Brodszki, Maria Jose Beato, Jonas S Erjefalt, Juan Carlos López-gutiérrez, Erik A EklundAbstract:Background Gorham-Stout disease (OMIM 123880) and generalized Lymphatic Anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Methods Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized Lymphatic Anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). Results We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. Conclusions These malformations of the Lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
Maria Jose Beato - One of the best experts on this subject based on the ideXlab platform.
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pulmonary and pleural Lymphatic endothelial cells from pediatric but not adult patients with gorham stout disease and generalized Lymphatic Anomaly show a high proliferation rate
Orphanet Journal of Rare Diseases, 2016Co-Authors: Michiko Mori, Michael Dictor, Nicholas Brodszki, Juan Carlos Lopezgutierrez, Maria Jose Beato, Jonas S Erjefalt, Erik A EklundAbstract:Gorham-Stout disease (OMIM 123880) and generalized Lymphatic Anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized Lymphatic Anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. These malformations of the Lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
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Pulmonary and pleural Lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized Lymphatic Anomaly, show a high proliferation rate
Orphanet Journal of Rare Diseases, 2016Co-Authors: Michiko Mori, Michael Dictor, Nicholas Brodszki, Maria Jose Beato, Jonas S Erjefalt, Juan Carlos López-gutiérrez, Erik A EklundAbstract:Background Gorham-Stout disease (OMIM 123880) and generalized Lymphatic Anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Methods Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized Lymphatic Anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). Results We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. Conclusions These malformations of the Lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
