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1.
Surgery ; 161(1): 176-187, 2017 01.
Article in English | MEDLINE | ID: mdl-27866718

ABSTRACT

BACKGROUND: Limited data are available on the analysis of somatic mutations in metastatic lymph nodes in adult and pediatric patients with papillary thyroid carcinomas. METHODS: A total of 92, microdissected, formalin-fixed, paraffin-embedded tissue specimens from 39 patients were analyzed for the presence of somatic mutations utilizing the ThyGenX next-generation sequencing test. RESULTS: Somatic mutations were detected in 67% of papillary thyroid carcinoma specimens. The majority of patients with synchronous and all 6 patients with radioactive iodine-resistant (metachronous) metastatic lymph nodes contained BRAF mutations. Four patients had mutations detected in their metastatic lymph nodes that were not detected in their primary tumors. For the most part, BRAF mutations were seen in adults, and RAS mutations were seen in children. CONCLUSION: Findings of different mutations in metastatic lymph nodes compared with the primary papillary thyroid carcinomas are probably the result of tumor heterogeneity. The presence of the BRAF mutation in metastatic lymph nodes might be responsible for the recurrence of papillary thyroid carcinomas and resistance to radioactive iodine therapy. The good prognosis observed in papillary thyroid carcinomas found in pediatric and young adult patients might be explained by the predominance of RAS rather than BRAF mutations.


Subject(s)
Carcinoma/genetics , DNA Mutational Analysis , Lymph Nodes/pathology , Neoplasm Recurrence, Local/genetics , Proto-Oncogene Proteins B-raf/genetics , Thyroid Neoplasms/genetics , Adult , Age Factors , Aged , Biopsy, Needle , Carcinoma/pathology , Carcinoma, Papillary , Child , Female , Humans , Immunohistochemistry , Lymphatic Metastasis/genetics , Male , Middle Aged , Mutation , Neoplasm Recurrence, Local/pathology , Prognosis , Risk Assessment , Sampling Studies , Sex Factors , Thyroid Cancer, Papillary , Thyroid Neoplasms/pathology , Thyroidectomy/methods , Young Adult
2.
World J Oncol ; 7(5-6): 104-108, 2016 Dec.
Article in English | MEDLINE | ID: mdl-28983374

ABSTRACT

BACKGROUND: Multiple endocrine neoplasia (MEN) type 2 is an autosomal dominant cancer syndrome associated with the development of thyroid cancer and tumors or hyperplasia in other endocrine organs. It is caused by mutations in the RET gene and can be phenotypically classified into MEN types 2A and 2B. MEN2B is often sporadic resulting from a spontaneous mutation, M981T. A positive paternal germline selection has been reported for this mutation. METHODS: We analyzed the V804M mutation in the RET gene which also affects the intracellular domain of the protein but results in a different phenotype, MEN2A. We compared the observed and expected frequencies of the V804M mutation and the paternal and maternal germline transmission frequency of V804M mutation in three previously reported multigenerational families. RESULTS: Our analysis indicates that the observed frequency of the V804M mutation is significantly greater than the expected frequency suggesting positive germline selection (P < 0.001). Furthermore, comparative analysis of observed versus expected transmission frequencies from affected parents shows a higher maternal germline transmission frequency (P = 0.001). CONCLUSIONS: Our results suggest that in the RET gene, positive germline selection may extend to mutations other than M918T and, furthermore, at least for the V804M mutation in these families, there is evidence for maternal germline selection.

3.
Endocr Pract ; 19(6): e163-7, 2013.
Article in English | MEDLINE | ID: mdl-24014011

ABSTRACT

OBJECTIVE: To describe a unique case of a metastatic thymic carcinoma to the hyperplastic parathyroid gland and to present a challenging management dilemma. METHODS: Our patient is 60-year-old, intellectually disabled man with history of the multiple endocrine neoplasia type 1 (MEN1) syndrome, a surgery in 1985 for hypercalcemia with removal of one parathyroid gland, surgery in 2007 with findings of extensively necrotic well differentiated neuroendocrine carcinoma (carcinoid tumor) of the thymus. In 2012, he presented with persistent hypercalcemia (calcium level 11.7 mg/dL [range, 8.6-10.2]), and a parathyroid hormone (PTH) level of 225 pg/mL (range, 15-65 pg/mL). He underwent a repeat neck exploration with removal of 2 small inferior and a large left superior 4.5 × 2.5 × 1.5 cm parathyroid glands, all of which showed hyperplasia on intraoperative frozen section. A small portion of the superior gland was reimplanted into the patient's forearm. Final pathology showed the presence of a focus of neuroendocrine tumor within the left superior parathyroid gland with immunostain identical to the thymic carcinoma. His postoperative PTH level was 14 pg/mL and calcium 8.5 mg/dL. A positron emission tomography-computed tomography (PET-CT) and octreotide scans revealed an extensive metastatic disease within the lung, mediastinum, and bones. RESULTS: We decided to leave a portion of the reimplanted parathyroid gland with possible metastatic thymic carcinoid in his forearm because of the presence a widespread metastatic disease and his intellectual disability that would result in noncompliance with calcium replacement in case of permanent hypocalcemia. CONCLUSION: Metastatic thymic carcinoma to the parathyroid gland has never been reported in the literature. We have described the first case and presented a challenging management dilemma.


Subject(s)
Forearm/pathology , Multiple Endocrine Neoplasia Type 1/pathology , Neoplasm Transplantation , Parathyroid Neoplasms/secondary , Thymoma/pathology , Thymus Neoplasms/pathology , Humans , Immunohistochemistry , Intellectual Disability , Male , Middle Aged , Neck/surgery , Necrosis , Parathyroid Hormone/metabolism , Parathyroid Neoplasms/surgery , Pedigree , Positron-Emission Tomography , Tomography, X-Ray Computed
5.
Surgery ; 148(6): 1274-80; discussion 1280-1, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21134561

ABSTRACT

BACKGROUND: Single nucleotide polymorphisms (SNPs) may function as modifiers of the RET proto-oncogene, resulting in the expression of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC). We present 2 non-related Italian-American families (Family 1, n = 107; Family 2, n = 31) with the RET V804M mutation. We have correlated the presence of specific SNPs and the rare RET V804M mutation to MTC, C-cell hyperplasia (CCH), and PTC. METHODS: Sequencing was performed on exons 10, 11, and 13-16 of the RET proto-oncogene. The presence of MTC, CCH, and PTC were correlated to specific SNPs. RESULTS: In both families, 3 SNPs in exon 11 (G691S), exon 13 (L769L), and exon 15 (S904S) were detected in 100% of patients with overt MTC. The SNP L769L was present in all patients including patients with PTC, MTC, and CCH. CONCLUSION: SNP analysis revealed a similar pattern between the 2 families. SNPs in exon 11 (G691S) and exon 15 (S904S) appear to influence the development of MTC. A SNP in exon 13 (L769L) may serve as a modifier in the development of simultaneous MTC and PTC, as well as presentation of MTC, in patients with the RET V804M mutation.


Subject(s)
Polymorphism, Single Nucleotide , Proto-Oncogene Proteins c-ret/genetics , Adolescent , Adult , Aged , Carcinoma , Carcinoma, Neuroendocrine , Carcinoma, Papillary , Child , Child, Preschool , Exons/genetics , Family , Female , Gene Rearrangement/genetics , Humans , Hyperparathyroidism, Primary/genetics , Male , Middle Aged , Mutation , Pedigree , Proto-Oncogene Mas , Retrospective Studies , Thyroid Cancer, Papillary , Thyroid Neoplasms/genetics
7.
Surgery ; 146(6): 998-1005, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19958926

ABSTRACT

BACKGROUND: The rearranged during transfection (RET) V804M proto-oncogene mutation is rare and associated with medullary thyroid carcinoma (MTC). We present 40 members from a total cohort of 107 family members with this mutation. METHODS: Family members were tested for RET mutations, calcitonin levels, and screened for pheochromocytoma and primary hyperparathyroidism (PHPT). Thyroidectomies were performed on 15 members. Surgery and pathology reports were obtained and reviewed. A pedigree was constructed. RESULTS: A high penetrance was found for MTC and simultaneous papillary thyroid carcinoma (PTC; 40%). The incidence of PHPT was low (13%). There were no findings of pheochromocytoma. The course in the first family generation was indolent, with late onset of MTC. The second generation experienced earlier disease development; onset occurred earliest in the third generation. The second generation experienced a higher incidence of PTC than the first. CONCLUSION: This is the largest family with this mutation reported to date. However, it does not fit the classic familial MTC or MEN 2A cancer syndrome. Considering that PTC is not an incidental finding, but the result of an inherited RET V804 M mutation, we propose to identify this phenotypic expression as a unique syndrome consistent with manifestations of MTC, PHPT, and PTC.


Subject(s)
Carcinoma, Medullary/genetics , Carcinoma, Papillary/genetics , Hyperparathyroidism, Primary/genetics , Multiple Endocrine Neoplasia/genetics , Point Mutation , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/genetics , Adrenal Gland Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Amino Acid Substitution , Anticipation, Genetic , Female , Humans , Italy , Male , Middle Aged , Multiple Endocrine Neoplasia/classification , Pedigree , Penetrance , Pheochromocytoma/genetics , Proto-Oncogene Mas , Proto-Oncogenes , Retrospective Studies , Syndrome
9.
Surgery ; 137(5): 545-51, 2005 May.
Article in English | MEDLINE | ID: mdl-15855927

ABSTRACT

BACKGROUND: The objective of these studies is to determine the effects of macrophage ablation on the course of acute viral pancreatitis. Macrophages secrete proinflammatory cytokines triggering local pancreatic and systemic inflammation in the acute phase of virus-induced pancreatitis. We hypothesized that ablation of macrophages should attenuate the host inflammatory response in a mouse model of adenovirus-induced pancreatitis. METHODS: Liposome-encapsulated dichloromethylene-diphosphonate, a macrophage-depleting agent, was used before direct pancreatic injection of a recombinant adenovirus expressing a marker gene in C57Bl/6 and IL-6 knockout (KO) mice. RESULTS: C57Bl/6 mice depleted of macrophages had diminished pancreatic inflammation in the first 24 hours after vector administration. IL-6 KO mice depleted of macrophages had more severe inflammation than similarly treated C57Bl/6 mice. C57Bl/6 mice depleted of macrophages, and IL-6 KO mice had prolonged transgene expression and diminished cytotoxic T lymphocyte responses to adenoviral vector. Mortality was highest in IL-6 KO mice depleted of macrophages. Depletion of macrophages also prevented detectable serum IL-6, IL-10, or IL-12 levels in C57Bl/6 mice. CONCLUSIONS: The data suggest that macrophages play a role in the acute inflammatory response to viral vector-induced pancreatitis and that IL-6 may be protective. Understanding of the mechanisms that initiate the host immune cascade will allow more effective use of adenoviral vector-based pancreatic gene delivery.


Subject(s)
Diphosphonates/therapeutic use , Macrophages/drug effects , Methane/therapeutic use , Pancreatitis/drug therapy , Pancreatitis/virology , Acute Disease , Adenoviridae , Animals , Diphosphonates/pharmacology , Disease Models, Animal , Female , Genetic Vectors , Methane/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Pancreatitis/pathology
10.
Pancreas ; 30(2): 122-9, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15714134

ABSTRACT

OBJECTIVES: The role of innate immunity in the development of acute viral pancreatitis is not well understood. The aim of the study was to characterize the role of the innate immune system, especially macrophages, natural killer (NK), and NK T (NKT) cells, in the generation of immune responses to intrapancreatic delivery of recombinant adenoviral vector. METHODS: Adenoviral vectors expressing beta-galactosidase or green fluorescent protein genes with viral capsid conjugated covalently with carbocyanine dye were directly injected into the pancreas of C57Bl/6 mice. RESULTS: Fluorescent microscopy of the pancreas showed that 30 minutes after vector administration, adenoviral particles localized to cell membranes, internalized, and localized to the nucleus by 4 hours, and transgene expression began at 24 hours. Immunohistochemical staining showed macrophages entering the pancreas shortly after vector administration, with maximal infiltration at day 4, and then disappearing as antigen-expressing cells were eliminated. Intrapancreatic macrophages appeared to deliver viral capsid proteins to the spleen. Flow cytometry showed that NK and NKT cells migrate to the pancreas and persist. Serum cytokines IL-6, IL-10, and IL-12 were all elevated. CONCLUSION: Macrophages and NK and NKT cells play a major role in the development of acute adenovirus-mediated pancreatitis.


Subject(s)
Adenoviridae Infections/immunology , Adenoviridae/genetics , Pancreatitis/immunology , Pancreatitis/virology , Acute Disease , Adenoviridae/immunology , Adenoviridae Infections/complications , Animals , Capsid , Female , Genes, Reporter , Genetic Vectors , Green Fluorescent Proteins/genetics , Interleukin-10/blood , Interleukin-12/blood , Interleukin-6/blood , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/virology , Mice , Mice, Inbred C57BL , Spleen/immunology , Spleen/virology , beta-Galactosidase/genetics
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