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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.


Lodish M.B.,Eunice Kennedy Shriver National Institute of Child Health and Human Development | Lodish M.B.,U.S. National Institutes of Health | Hsiao H.-P.,Eunice Kennedy Shriver National Institute of Child Health and Human Development | Hsiao H.-P.,Kaohsiung Municipal HsiaoKang Hospital | And 8 more authors.
Journal of Pediatrics | Year: 2010

Objective: To evaluate bone mineral density (BMD) in children with Cushing disease before and after transphenoidal surgery (TSS). Study design: Hologic dual-energy x-ray absorptiometry (DXA) scans of 35 children with Cushing disease were analyzed retrospectively. Sixteen of the 35 patients had follow-up DXA scans performed 13 to 18 months after TSS. BMD and bone mineral apparent density (BMAD) for lumbar spine (LS) L1 to L4 and femoral neck (FN) were calculated. Results: Preoperatively, 38% and 23% of patients had osteopenia of the LS and FN, respectively. Both BMD and BMAD Z-scores of the LS were worse than those for the FN (-1.60 ± 1.37 versus -1.04 ± 1.19, P = .003), and (-1.90 ± 1.49 versus -0.06 ± 1.90, P < .001); postoperative improvement in BMD and BMAD were more pronounced in LS than in the FN (0.84 ± 0.88 versus 0.15 ± 0.62, P<.001; and 0.73 ± 1.13 versus -0.26 ± 1.21, P = .015). Pubertal stage, cortisol levels, and length of disease had no effect on BMD. Conclusions: In children with Cushing disease, vertebral BMD was more severely affected than femoral BMD and this effect was independent of degree or duration of hypercortisolism. BMD for the LS improved significantly after TSS; osteopenia in this group may be reversible.


PubMed | Warren Grant Magnuson Clinical Center
Type: Case Reports | Journal: 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 p27(kip1) 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.

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