Warren Grant Magnuson Clinical Center

Bethesda, MD, United States

Warren Grant Magnuson Clinical Center

Bethesda, MD, United States

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Papadakis G.Z.,Warren Grant Magnuson Clinical Center
Clinical nuclear medicine | Year: 2015

Talc pleurodesis (TP) is a technique, widely employed in the management of patients with persistent pleural effusions or pneumothoraces not amenable to other treatment options. It is well documented that talc deposits produce areas of highly increased F-FDG uptake, because of talc-induced inflammation. We present a case of a patient with history of TP who was evaluated with both F-FDG and Ga-DOTA-TATE. The hypermetabolic area seen on F-FDG-PET-CT in the region of talc placement showed no uptake by Ga-DOTA-TATE, suggesting the potential role of Ga-DOTA-TATE-PET-CT in elucidating F-FDG-postitive lesions in patients with history of both neuroendocrine malignancy and TP.


Papadakis G.Z.,Warren Grant Magnuson Clinical Center | Millo C.,Warren Grant Magnuson Clinical Center | Sadowski S.M.,Warren Grant Magnuson Clinical Center | Karantanas A.H.,Warren Grant Magnuson Clinical Center | And 2 more authors.
Clinical nuclear medicine | Year: 2017

Fibrous dysplasia of the bone is a developmental benign skeletal disorder characterized by replacement of normal bone and normal bone marrow with abnormal fibro-osseous tissue. We report on a case of a biopsy-proven fibrous dysplasia lesion in the left temporal bone, with intensely increased activity (SUVmax, 56.7) on Ga-DOTATATE PET/CT. The presented data indicate cell surface overexpression of somatostatin receptors by fibrous dysplastic cells and highlight the need of cautious management of Ga-DOTATATE-avid bone lesions, which could mimic malignancy especially in patients with history of neuroendocrine tumors.


Papadakis G.Z.,Warren Grant Magnuson Clinical Center | Millo C.,Warren Grant Magnuson Clinical Center | Karantanas A.H.,Warren Grant Magnuson Clinical Center | Bagci U.,Warren Grant Magnuson Clinical Center | Patronas N.J.,Warren Grant Magnuson Clinical Center
Clinical nuclear medicine | Year: 2017

Prolonged exposure to cortisol is one of the major causes of avascular bone necrosis (AVN). We report on a case of a woman with Cushing syndrome attributed to ectopic adrenocorticotropic hormone-secreting tumor who was evaluated with whole-body PET/CT study using Ga-DOTATATE. The scan showed increased activity by both femoral heads, corresponding to the margins of bilateral AVN seen on MRI. The presented data suggests AVN-induced reactive inflammatory alterations adjacent to the necrotic segment of the bone, which can be effectively targeted using radiolabeled somatostatin (SST) analogs.


Musil Z.,Institute of Biology and Medical Genetics | Duskova J.,Charles University | Burton D.,Warren Grant Magnuson Clinical Center | Merino M.J.,U.S. National Institutes of Health | And 2 more authors.
European Journal of Clinical Investigation | Year: 2011

Background Pheochromocytomas are tumours arising from chromaffin tissue located in the adrenal medulla associated with typical symptoms and signs which may occasionally develop metastases, which are defined as the presence of tumour cells at sites where these cells are not found. This retrospective analysis was focused on clinical, genetic and histopathologic characteristics of primary metastatic versus primary benign pheochromocytomas. Materials and methods We identified 41 subjects with metastatic pheochromocytoma and 108 subjects with apparently benign pheochromocytoma. We assessed dimension and biochemical profile of the primary tumour, age at presentation and time to develop metastases. Results Subjects with metastatic pheochromocytoma presented at a significantly younger age (41·4±14·7 vs. 50·2±13·7years; P<0·001) with larger primary tumours (8·38±3·27 vs. 6·18±2·75cm; P<0·001) and secreted more frequently norepinephrine (95·1% vs. 83·3%; P=0·046) compared to subjects with apparently benign pheochromocytomas. No significant differences were found in the incidence of genetic mutations in both groups of subjects (25·7% in the metastatic group and 14·7% in the benign group; P=0·13). From available histopathologic markers of potential malignancy, only necrosis occurred more frequently in subjects with metastatic pheochromocytoma (27·6% vs. 0%; P<0·001). The median time to develop metastases was 3·6years with the longest interval 24years. Conclusions In conclusion, regardless of a genetic background, the size of a primary pheochromocytoma and age of its first presentation are two independent risk factors associated with the development of metastatic disease. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation. No claim to original US government works.


Hsu A.P.,National Institute of Allergy and Infectious Diseases | Dowdell K.C.,National Institute of Allergy and Infectious Diseases | Davis J.,National Institute of Allergy and Infectious Diseases | Niemela J.E.,Warren Grant Magnuson Clinical Center | And 4 more authors.
Genetics in Medicine | Year: 2012

Purpose: Autoimmune lymphoproliferative syndrome is a disorder of lymphocyte apoptosis. Although FAS molecules bearing mutations in the signal-transducing intracellular death domain exhibit dominant-negative interference with FAS-mediated apoptosis, mechanisms for pathology of non-death domain FAS mutations causing autoimmune lymphoproliferative syndrome are poorly defined. Methods: RNA stability, protein expression, ligand binding, and ability to transmit apoptosis signals by anti-FAS antibody or FAS ligand were determined for a cohort of 39 patients with non-death domain autoimmune lymphoproliferative syndrome. Correlations between mutation type and disease penetrance were established in mutation-positive family members. Results: Frameshifts or transcriptional stop mutations before exon 7 resulted in messenger RNA haploinsufficiency, whereas an amino-terminal signal sequence mutation and certain intracellular truncations prevented cell surface localization of FAS. All resulted in decreased FAS localization, inability to bind FAS ligand, and reduced FAS ligand-induced apoptosis. Extracellular missense mutations and in-frame deletions expressed defective FAS protein, failed to bind FAS ligand, and exhibited dominant-negative interference with FAS-mediated apoptosis. Mutation-positive relatives with haploinsufficient or extracellular mutations had lower penetrance of autoimmune lymphoproliferative syndrome clinical phenotypes than did relatives with death domain mutations. Conclusion: We have defined molecular mechanisms by which non-death domain FAS mutations result in reduced lymphocyte apoptosis, established a hierarchy of genotype-phenotype correlation among mutation-positive relatives of patients with autoimmune lymphoproliferative syndrome, and demonstrated that FAS haploinsufficiency can lead to autoimmune lymphoproliferative syndrome. © 2012 American College of Medical Genetics.


Niemela J.E.,Warren Grant Magnuson Clinical Center | Lu L.,Warren Grant Magnuson Clinical Center | Fleisher T.A.,Warren Grant Magnuson Clinical Center | Davis J.,National Institute of Allergy and Infectious Diseases | And 8 more authors.
Blood | Year: 2011

Somatic gain-of-function mutations in members of the RAS subfamily of small guanosine triphosphatases are found in > 30% of all human cancers. We recently described a syndrome of chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity associated with a mutation in NRAS affecting hematopoietic cells, and initially we classified the disease as a variant of the autoimmune lymphoproliferative syndrome. Here, we demonstrate that somatic mutations in the related KRAS gene can also be associated with a nonmalignant syndrome of autoimmunity and breakdown of leukocyte homeostasis. The activating KRAS mutation impaired cytokine withdrawal-induced T-cell apoptosis through the suppression of the proapoptotic protein BCL-2 interacting mediator of cell death and facilitated proliferation through p27kip1 down-regulation. These defects could be corrected in vitro by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 or phosphatidyl inositol-3 kinase inhibition.We suggest the use of the term RAS-associated autoimmune leukoproliferative disease to differentiate this disorder from autoimmune lymphoproliferative syndrome.


Martiniova L.,U.S. National Institutes of Health | Martiniova L.,Slovak Academy of Sciences | Perera S.M.,U.S. National Institutes of Health | Brouwers F.M.,U.S. National Institutes of Health | And 11 more authors.
Endocrine-Related Cancer | Year: 2011

[131I]meta-iodobenzylguanidine ([131I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [123I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [ 3H]norepinephrine, [123I]MIBG, and [18F] fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [ 3H] norepinephrine, [123I]MIBG, and [18F] fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [ 18F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1±3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9±0.6%; P<0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [123I]MIBG was significantly increased in liver metastases 9.5±1.1% compared to 3.19±0.4% in untreated control liver metastases (P<0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [131I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma. © 2011 Society for Endocrinology.


Sato K.,U.S. National Cancer Institute | Watanabe R.,U.S. National Cancer Institute | Hanaoka H.,U.S. National Cancer Institute | Harada T.,U.S. National Cancer Institute | And 5 more authors.
Molecular Oncology | Year: 2014

Photoimmunotherapy (PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. Herein we compare two commonly available anti-EGFR monoclonal antibodies, cetuximab and panitumumab, for their effectiveness as PIT agents in EGFR positive tumor models. A photosensitizer, IR-700, conjugated to either cetuximab (cet-IR700) or panitumumab (pan-IR700), was evaluated using EGFR-expressing A431 and MDAMB468-luc cells in 2D- and 3D-culture. PIT was conducted with irradiation of NIR light after exposure of the sample or animal to each conjugate. Invivo PIT was performed with fractionated exposure of NIR light after injection of each agent into A431 xenografts or a MDAMB468-luc orthotopic tumor bearing model.Cet-IR700 and pan-IR700 bound with equal affinity to the cells in 2D-culture and penetrated equally into the 3D-spheroid, resulting in identical PIT cytotoxic effects invitro. In contrast, invivo anti-tumor effects of PIT with cet-IR700 were inferior to that of pan-IR700. Assessment of the biodistribution showed lower accumulation into the tumors and more rapid hepatic catabolism of cet-IR700 compared to pan-IR700. Although cet-IR700 and pan-IR700 showed identical invitro characteristics, pan-IR700 showed better therapeutic tumor responses than cet-IR700 in invivo mice models due to the prolonged retention of the conjugate in the circulation, suggesting that retention in the circulation is advantageous for tumor responses to PIT. These results suggest that the choice of monoclonal antibody in photosensitizer conjugates may influence the effectiveness of PIT. © 2014 .


Papadakis G.Z.,Warren Grant Magnuson Clinical Center | Millo C.,U.S. National Institutes of Health | Bagci U.,University of Central Florida | Sadowski S.M.,U.S. National Cancer Institute | Stratakis C.A.,U.S. National Institutes of Health
Clinical Nuclear Medicine | Year: 2016

Schmorl node (SN) is the herniation of the nucleus pulposus through the cartilaginous and bony endplate into the adjacent vertebral body. It is documented that SNs produce areas of moderately increased 18F-FDG uptake.We present a case of a patient with history of neuroendocrine tumor, who underwent 68Ga DOTATATE PET/CT for follow-up, showing increased focal vertebral uptake suggestive of bone metastasis. CT revealed typical findings of an SN. The presented case indicates that SNs should be considered when encountering focally increased skeletal uptake in 68Ga DOTATATE PET/CT studies, which can mimic metastasis in patients with history of neuroendocrine tumors. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


PubMed | Leidos Inc., Warren Grant Magnuson Clinical Center and U.S. National Cancer Institute
Type: Comparative Study | Journal: Molecular oncology | Year: 2014

Photoimmunotherapy (PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. Herein we compare two commonly available anti-EGFR monoclonal antibodies, cetuximab and panitumumab, for their effectiveness as PIT agents in EGFR positive tumor models. A photosensitizer, IR-700, conjugated to either cetuximab (cet-IR700) or panitumumab (pan-IR700), was evaluated using EGFR-expressing A431 and MDAMB468-luc cells in 2D- and 3D-culture. PIT was conducted with irradiation of NIR light after exposure of the sample or animal to each conjugate. Invivo PIT was performed with fractionated exposure of NIR light after injection of each agent into A431 xenografts or a MDAMB468-luc orthotopic tumor bearing model. Cet-IR700 and pan-IR700 bound with equal affinity to the cells in 2D-culture and penetrated equally into the 3D-spheroid, resulting in identical PIT cytotoxic effects invitro. In contrast, invivo anti-tumor effects of PIT with cet-IR700 were inferior to that of pan-IR700. Assessment of the biodistribution showed lower accumulation into the tumors and more rapid hepatic catabolism of cet-IR700 compared to pan-IR700. Although cet-IR700 and pan-IR700 showed identical invitro characteristics, pan-IR700 showed better therapeutic tumor responses than cet-IR700 in invivo mice models due to the prolonged retention of the conjugate in the circulation, suggesting that retention in the circulation is advantageous for tumor responses to PIT. These results suggest that the choice of monoclonal antibody in photosensitizer conjugates may influence the effectiveness of PIT.

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