Endocrinology and Metabolism

Original Articles

Clinical Significance of Routine Measurement of Serum Calcitonin in Korean Patients with Thyroid Nodules as a Screening test of Sporadic Thyroid Medullary Carcinoma.: Young Kee Shong, Cheol Soo Choi, Hye Young Park, Bo Youn Cho; J Korean Endocr Soc. 1996;11(1):11-17. Published online November 7, 2019

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Abstract PDF: Background
: It is not easy to diagnose sporadic medullary thyroid carcinoma(MTC) before surgery and this might lead the patient reoperation and/or lowered chance of definite cure. Methods : The prevalence of sporadic MTC in Korean was studied in patients with thyroid nodules. A prospective study of 1048 consecutive patients with thyroid nodules was performed. In all patients, measurements of basal serum calcitonin, thyroid hormones, TSH, anti-thyroglobulin antibody and anti-thyroperoxidase antibody were undertaken along with technetium-99m thyroid scintigraphy and fine needle aspiration cytology. In patients with elevated basal calcitonin levels, calcium stimulated calcitonin level was determined. Results: Two patient had markedly elevated calcitonin levels(over 3,200 pg/mL and 1,763 pg/ mL) and another one slightly elevated calcitoni#n(71.9 pg/mL). Fine needle aspiration cytology was suggestive of MTC in one and nodular hyperplasia in the other two. They underwent surgery and histological examination revealed MTC in those two with markedly elevated calcitonin levels. The patient with slightly elevated calcitonin, who was on the maintenance hemodialysis due to chronic renal failure, had nodular hyperplasia. Conclusion: MTC was found in 0.19% of patients with thyroid nodules, which was not different with the previously reported prevalence in Europe. Routine measurements of serum calcitonin might be of value to detect sporadic MTC; however, the cost-effectiveness of routine measurement of serum calcitonin is not clear, considering the relatively low prevalence of MTC in Koreans.

Endocrine Research
Selective Mitochondrial Uptake of MKT-077 Can Suppress Medullary Thyroid Carcinoma Cell Survival In Vitro and In Vivo: Dmytro Starenki, Jong-In Park; Endocrinol Metab. 2015;30(4):593-603. Published online December 31, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.4.593

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Background

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the rearranged during transfection (RET) proto-oncogene. Not all patients with progressive MTC respond to current therapy inhibiting RET, demanding additional therapeutic strategies. We recently demonstrated that disrupting mitochondrial metabolism using a mitochondria-targeted agent or by depleting a mitochondrial chaperone effectively suppressed human MTC cells in culture and in mouse xenografts by inducing apoptosis and RET downregulation. These observations led us to hypothesize that mitochondria are potential therapeutic targets for MTC. This study further tests this hypothesis using1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-oxothiazolidin-2-ylidenemethyl] pyridinium chloride (MKT-077), a water-soluble rhodocyanine dye analogue, which can selectively accumulate in mitochondria.

Methods

The effects of MKT-077 on cell proliferation, survival, expression of RET and tumor protein 53 (TP53), and mitochondrial activity were determined in the human MTC lines in culture and in mouse xenografts.

Results

MKT-077 induced cell cycle arrest in TT and MZ-CRC-1. Intriguingly, MKT-077 also induced RET downregulation and strong cell death responses in TT cells, but not in MZ-CRC-1 cells. This discrepancy was mainly due to the difference between the capacities of these cell lines to retain MKT-077 in mitochondria. The cytotoxicity of MKT-077 in TT cells was mainly attributed to oxidative stress while being independent of TP53. MKT-077 also effectively suppressed tumor growth of TT xenografts.

Conclusion

MKT-077 can suppress cell survival of certain MTC subtypes by accumulating in mitochondria and interfering with mitochondrial activity although it can also suppress cell proliferation via other mechanisms. These results consistently support the hypothesis that mitochondrial targeting has therapeutic potential for MTC.

Citations

Citations to this article as recorded by

Immunoexpression of HSPA9 and CUL2 in prostatic tissue and adenocarcinoma
Carlos Gustavo Hirth, Gislane Rocha Vasconcelos, Maria do Perpétuo Socorro Saldanha da Cunha, Carlos Heli Bezerra Leite, Conceição Aparecida Dornelas
Annals of Diagnostic Pathology.2022; 56: 151843. CrossRef
Analogs of the Heat Shock Protein 70 Inhibitor MKT-077 Suppress Medullary Thyroid Carcinoma Cells
Seung-Keun Hong, Dmytro Starenki, Oleta T. Johnson, Jason E. Gestwicki, Jong-In Park
International Journal of Molecular Sciences.2022; 23(3): 1063. CrossRef
Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation
Mikhail V. Dubinin, Alena A. Semenova, Darya A. Nedopekina, Eldar V. Davletshin, Anna Yu. Spivak, Konstantin N. Belosludtsev
Membranes.2021; 11(5): 352. CrossRef
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Elena Mariotto, Giampietro Viola, Carlo Zanon, Sanja Aveic
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Emerging insights into mitochondria-specific targeting and drug delivering strategies: Recent milestones and therapeutic implications
Sugapriya Dhanasekaran, Divya Venugopal, Noura Al-Dayan, Vijaya Ravinayagam, Arif Ahmed Mohammed
Saudi Journal of Biological Sciences.2020; 27(12): 3581. CrossRef
Growth Inhibitory Signaling of the Raf/MEK/ERK Pathway
Pui-Kei Wu, Andrew Becker, Jong-In Park
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Heat Shock Proteins (HSPs): A Novel Target for Cancer Metastasis Prevention
Vinayak Narayanankutty , Arunaksharan Narayanankutty, Anusree Nair
Current Drug Targets.2019; 20(7): 727. CrossRef
Токсичність МАРК у карциномах щитоподібної залози. Механізми пригнічення сигнального каскаду (огляд літератури та власних даних)
B. B. Guda, V. V. Pushkarev, O. I. Kovzun, V. P. Pushkarev, M. D. Tronko
Шпитальна хірургія. Журнал імені Л. Я. Ковальчука.2019; (3): 84. CrossRef
Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells
Dmytro Starenki, Nadiya Sosonkina, Seung-Keun Hong, Ricardo V. Lloyd, Jong-In Park
International Journal of Molecular Sciences.2019; 20(9): 2069. CrossRef
Mitochondrial autophagosomes as a mechanism of drug resistance in breast carcinoma
Ayman N. Abunimer, Heba Mohammed, Katherine L. Cook, David R. Soto-Pantoja, Maria Mercedes Campos, Mones S. Abu-Asab
Ultrastructural Pathology.2018; 42(2): 170. CrossRef
Genotoxic Responses of Mitochondrial Oxygen Consumption Rate and Mitochondrial Semiquinone Radicals in Tumor Cells
Kumiko Yamamoto, Hironobu Yasui, Tomoki Bo, Tohru Yamamori, Wakako Hiraoka, Toshihide Yamasaki, Ken-ichi Yamada, Osamu Inanami
Applied Magnetic Resonance.2018; 49(8): 837. CrossRef
Suppression of B-RafV600E melanoma cell survival by targeting mitochondria using triphenyl-phosphonium-conjugated nitroxide or ubiquinone
Seung-Keun Hong, Dmytro Starenki, Pui-Kei Wu, Jong-In Park
Cancer Biology & Therapy.2017; 18(2): 106. CrossRef
Mitochondria chaperone GRP75 moonlighting as a cell cycle controller to derail endocytosis provides an opportunity for nanomicrosphere intracellular delivery
Zhihui Gao, Xiuran Niu, Qing Zhang, Hang Chen, Aiai Gao, Shanshan Qi, Rong Xiang, Mattias Belting, Sihe Zhang
Oncotarget.2017; 8(35): 58536. CrossRef
Targeted Therapy for Medullary Thyroid Cancer: A Review
S. R. Priya, Chandra Shekhar Dravid, Raghunadharao Digumarti, Mitali Dandekar
Frontiers in Oncology.2017;[Epub] CrossRef
Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells
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Cancer Biology & Therapy.2017; 18(7): 473. CrossRef

Case Reports

Thyroid
Medullary Thyroid Carcinoma with Ectopic Adrenocorticotropic Hormone Syndrome: Hong Seok Choi, Min Joo Kim, Chae Ho Moon, Jong Ho Yoon, Ha Ra Ku, Geon Wook Kang, Im Il Na, Seung-Sook Lee, Byung-Chul Lee, Young Joo Park, Hong Il Kim, Yun Hyi Ku; Endocrinol Metab. 2014;29(1):96-100. Published online March 14, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.1.96

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Ectopic adrenocorticotropic hormone (ACTH) syndrome is caused most frequently by a bronchial carcinoid tumor or by small cell lung cancer. Medullary thyroid carcinoma (MTC) is a rare etiology of ectopic ACTH syndrome. We describe a case of Cushing syndrome due to ectopic ACTH production from MTC in a 48-year-old male. He was diagnosed with MTC 14 years ago and underwent total thyroidectomy, cervical lymph node dissection and a series of metastasectomies. MTC was confirmed by the pathological examination of the thyroid and metastatic mediastinal lymph node tissues. Two years after his last surgery, he developed Cushingoid features, such as moon face and central obesity, accompanied by uncontrolled hypertension and new-onset diabetes. The laboratory results were compatible with ectopic ACTH syndrome. A bilateral adrenalectomy improved the clinical and laboratory findings that were associated with Cushing syndrome. This is the first confirmed case of ectopic ACTH syndrome caused by MTC in Korea.

Citations

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Medullary Thyroid Cancer with Ectopic Cushing's Syndrome: A Case Report and Systematic Review of Detailed Cases from the Literature
Andrea Corsello, Vittoria Ramunno, Pietro Locantore, Giovanni Pacini, Esther Diana Rossi, Francesco Torino, Alfredo Pontecorvi, Carmela De Crea, Rosa Maria Paragliola, Marco Raffaelli, Salvatore Maria Corsello
Thyroid.2022; 32(11): 1281. CrossRef
Mucosal Neuroma Cues for Endocrine Emergency Treatment
Gyu Gang Choi, Hwan Jin Lee, Hyo Jin Han, Young Beom Jeong, Heung Bum Lee, Ji Hyun Park
Endocrinology and Metabolism.2021; 36(6): 1312. CrossRef
Articles in 'Endocrinology and Metabolism' in 2014
Won-Young Lee
Endocrinology and Metabolism.2015; 30(1): 47. CrossRef
Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome
Fabián Pitoia, Fernanda Bueno, Angélica Schmidt, Sabrina Lucas, Graciela Cross
Archives of Endocrinology and Metabolism.2015; 59(4): 343. CrossRef

A Case of Sporadic Medullary Thyroid Cancer with RET G691S Polymorphism.: Min Kyu Kang, Jung Min Lee, Ji Hyun Kim, Min Young Lee, Ji Hyun Kim, Sung Dae Moon, Je Ho Han, Sang Ah Chang; J Korean Endocr Soc. 2009;24(4):293-297. Published online December 1, 2009; DOI: https://doi.org/10.3803/jkes.2009.24.4.293

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Abstract PDF: Sporadic medullary thyroid carcinoma (MTC) is the most common form of MTC and somatic RET proto-oncogene mutations account for approximately 25% of the patients with sporadic MTC. However, other pathogeneses of sporadic MTC are still unclear. Not only RET mutation, but also polymorphisms of RET may have an association with sporadic MTC. We herein describe the association of MTC and RET proto-oncogene polymorphism. A 51-year-old man was diagnosed with MTC, which was incidentally found on a thyroid sonogram. The patient underwent total thyroidectomy and genetic mutational analysis of the RET gene. Genetic testing detected a polymorphism in codon 691 (G691S) on exon 11 of the RET proto-oncogene. His son and daughter had the same polymorphism. We report on this case along with a review of the related literature on RET gene polymorphism of sporadic MTC.

Original Article

Search for Materials that Influence Human Medullary Thyroid Carcinoma Cell Proliferation.: Hyun Won Shin, Hye Won Jang, Keun Sook Kim, Ji In Lee, Ji Young Park, Sun Wook Kim, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim, Jae Hoon Chung; J Korean Endocr Soc. 2009;24(2):93-99. Published online June 1, 2009; DOI: https://doi.org/10.3803/jkes.2009.24.2.93

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Abstract PDF

BACKGROUND
Surgical excision is the only effective treatment of medullary thyroid carcinoma (MTC) and there is no certain treatment for recurrence or distant metastasis. Materials that influence MTC cell proliferation were recently reported. Presently, we evaluated the influence of dexamethasone, somatostatin, progesterone, estradiol-17-beta, forskolin and gastrin on MTC cell proliferation and calcitonin secretion. METHODS: Genomic DNA was extracted and sequenced from untreated thyroid TT cells and cells treated with 10-5~10-10 M dexamethasone, somatostatin, progesterone, estradiol-17-beta, forskolin or gastrin, and cultured for 1~6 days. Cell proliferation was assessed using a BrdU assay at days 1, 2, 3, and 6. Calcitonin in the culture medium from dexamethasone-treated TT cells was measured at days 1~3. RESULTS: Replacement of cysteine with tryptophan at codon 634 of exon 11 was evident in treated TT cells. There was no significant difference in cell proliferation at days 1~3 in cells treated with somatostatin, progesterone, estradiol-17-beta, gastrin and forskolin, while proliferation was inhibited in dexamethasone-treated cells in a concentration-dependent manner from 10-5~10-8 M with no inhibition evident at 10-10 M. Calcitonin levels in 10-5~10-8 M dexamethasone-treated cells were decreased. CONCLUSION: Dexamethasone is a potentially useful compound to suppress MTC cell proliferation. Further studies are necessary to explore this potential further prior to clinical use.

Citations

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Identification of Growth Regulatory Factors in Medullary Thyroid Carcinoma Cell Line
Young Suk Jo, Minho Shong
Journal of Korean Endocrine Society.2009; 24(2): 84. CrossRef

Case Report

A Case of Familial Medullary Thyroid Carcinoma with a E768D Mutation in RET Proto-Oncogene.: Yeon Kyeong Kim, Jin Woo Kim, Sang Mi Ahn, Kyoung Eun Song, Sun Hye Jung, Dae Jung Kim, Yoon Sok Chung, Kwan Woo Lee, Chul Ho Kim, Ji Hee Hong, Seon Yong Jeong, Hyon Ju Kim; J Korean Endocr Soc. 2005;20(4):375-380. Published online August 1, 2005; DOI: https://doi.org/10.3803/jkes.2005.20.4.375

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Abstract PDF

A medullary thyroid carcinoma, a neoplasm of parafollicular C cell origin, occurs as a sporadic or hereditary disease. A hereditary medullary thyroid carcinoma is an autosomal dominantly inherited disease, which is composed of multiple endocrine neoplasia 2A and 2B, with a familial medullary thyroid carcinoma. Germline mutations of the RET gene are the underlying cause of the majority of hereditary medullary carcinomas. Here, the case of a 42 years-old man with a familial medullary thyroid carcinoma, confirmed by the detection of a RET proto-oncogene mutation at exon 13 on codon 768 from a GAG(Glu) to a GAT(Asp), is described. The patient underwent a total thyroidectomy and modified radical neck dissection. His sister was found to have the same mutant gene.

Citations

Citations to this article as recorded by

A Case of Medullary Thyroid Carcinoma with de novo V804M RET Germline Mutation
Young Sik Choi, Hye Jung Kwon, Bu Kyung Kim, Su Kyoung Kwon, Yo Han Park, Jeong Hoon Kim, Sang Bong Jung, Chang Hoon Lee, Seong Keun Lee, Shinya Uchino
Journal of Korean Medical Science.2013; 28(1): 156. CrossRef
A Family of Multiple Endocrine Neoplasia Type 2A with a C634R Mutation and a G691S Polymorphism in RET Proto-oncogene
Seoung Wook Yun, Won Sang Yoo, Koo Hyun Hong, Bae Hwan Kim, Min Ho Kang, Young Kwang Choo, Hee Yoon Park, Do Hee Kim, Hyun-Kyung Chung, Myung-Chul Chang, Mi Seon Kwon, Hee Jin Kim
Journal of Korean Endocrine Society.2007; 22(6): 453. CrossRef

Original Articles

A Case of Multiple Endocrine Neoplasia 2A with Germ Line Mutation of RET Gene.: Hee Young Kim, Ji Yeon Lee, Sung Bum Kim, Kye Won Lee, Ji A Seo, Jeong Heon Oh, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Dong Seop Choi, Nan Hee Kim; J Korean Endocr Soc. 2003;18(5):481-488. Published online October 1, 2003

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Abstract PDF: Multiple endocrine neoplasia 2A (MEN 2A) is an autosomal dominantly inherited disease, composed of medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. The activation of germ-line mutations in the RET proto-oncogene are responsible for MEN 2. The analysis of the RET mutations has replaced the measurement of the calcitonin level in the diagnosis of the MEN carrier state. Specific RET codon mutations correlate with the MEN 2 syndromic variant, the age at onset of the medullary thyroid carcinoma (MTC) and the aggressiveness of the MTC. Herein, our experience of a 47-year-old woman, who had a bilateral pheochromocytoma and MTC, and MEN 2A confirmed by the detection of an RET proto-oncogene mutation at axon 10 on codon 618, is reported. Her sister was found to have the same mutant gene. After a total thyroidectomy and bilateral adrenalectomy, the calcitonin and catecholamine levels were normalized, and the patient discharged without problems. This case is reported, with a review of the literature.

Analysis of Ret Proto-oncogene Mutation in Korean Patients with Medullary Thyroid Carcinomas.: Hyung Hoon Kim, Hyun Jin Kim, Yun Jae Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim, Chang Seok Ki, Jong Won Kim, Jae Hoon Chung; J Korean Endocr Soc. 2003;18(4):360-370. Published online August 1, 2003

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Abstract PDF: BACKGROUND
Medullary thyroid carcinomas (MTC) have been reported as hereditary in about 25 ~30% of cases. The identification of germline mutation in RET proto-oncogene is important in the diagnosis of hereditary MTC, and occurs in three forms: MEN 2A, MEN 2B and familial MTC (FMTC). To evaluate the prevalence of the relationship of RET proto-oncogene mutation and genotype-phenotype was studied in Korean patients with MTC. METHODS: Genomic DNA was obtained from 29 patients, with MTC, who underwent a total thyroidectomy, between 1997 and 2003, at the Samsung Medical Center. There were 7 male and 22 female patients, with an average age of 39, ranging from 20 to 60 years. Exon 10, 11, 13, 14 and 16 of the RET proto-oncogene were amplified, with specific primers, using PCR. A sequencing analysis was performed on the PCR product using an automatic sequencing analyzer. RESULTS: Nine of the 29 patients (31%) were identified as having RET mutations. The average age of these 9 patients was 33 years, ranging from 20 to 51, with a female to male ratio of 2. Five patients had MEN 2A and one had FMTC, with the other 3 thought to have non-hereditary (sporadic) MTC. The 4 patients with MEN 2A had RET mutations on codon 634 of exon 11 (2 patients, C634R; 2 patients, C634Y) and the other patient on codon 618 of exon 10 (C618R). One patient with FMTC had a mutation on codon 634 (C634W). Three patients with sporadic MTC had RET mutations on codon 634 (2 patients, C634Y; 1 patient, C634S). However, no genotype- phenotype relationship could be found, due to the limited number of patients. CONCLUSION: Thirty-one percent (9/29) of the patients with MTC had RET proto-oncogene mutations. Three-quarters (9/12) of the Korean patients with MEN 2A, including another 7 patients reported in 3 papers in Korea, had RET mutations on codon 634 of exon 11 (4 patients, C634R; 4 patients, C634Y; 1 patient, C634W), but a quarter (3/12) had mutations on codon 618 of exon 10 (2 patients, C618R; 1 patient, C618S). Although no relations could be found between the genotypes and phenotypes, extensive prospective studies will be required to verify this.

Case Reports

A Case of Multiple Endocrine Neoplasia Type 2B associated with a M918T Mutation in RET Proto-Oncogene.: Tae Yong Kim, Jae Kyung Hwang, Min Kyong Moon, Young Joo Park, Do Joon Park, Seong Yeon Kim, Hong Kyu Lee, Yo Kyu Yoon, Bo Youn Cho; J Korean Endocr Soc. 2003;18(1):85-93. Published online February 1, 2003

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Abstract PDF: A multiple endocrine neoplasia type 2B(MEN2B) is the most distinct and aggressive form of the MEN type 2 variants. We report a case of a 24-years-old woman with MEN2B. The patient had previously undergone a Duhamel's operation due to a megacolon at 6 years old, minor surgery to remove small tumors on the lip at 8 years old, and a bilateral osteotomy of the femur, due to coxa valga, at 15 years old. She underwent a total thyroidectomy and neck dissection, due to a growing thyroid nodule, despite thyroxine treatment, at 19 years old. The pathology revealed a medullary thyroid carcinoma. There was no history of MEN 2B in her family. She had prominent lips, multiple oral mucosal masses, and marfanoid habitus. During the subsequent follow-up, a positron emission tomogram was taken due to a persistently high level of serum calcitonin, despite repeated neck dissections, which revealed a mass in the right adrenal gland. Adrenomedullary function tests showed high levels of urinary catecholamine metabolites, and a genetic analysis of the peripheral leukocyte showed a codon 918 mutation (Met918Thr) at exon 16 of the RET proto-oncogene. The patient underwent a right adrenalectomy and the pathology revealed a pheoch-romocytoma.

A Case of Papillary Thyroid Carcinoma Combined with Multiple Endocrine Neoplasia Type 2A.: Ja kyung Kim, Hae Won Chung, Hye Sun Seo, Dae Jung Kim, Sang Su Chung, Young Duk Song, Kuk Hwan Kwon, Yoon Mi Jin, Mi Kyung Lee, Sung Kil Lim, Il Jin Kim, Hio Chung Kang, Jae Hyun Park, Jae Gahb Park; J Korean Endocr Soc. 2002;17(5):730-738. Published online October 1, 2002

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Abstract PDF: Multiple endocrine neoplasia (MEN) type 2A is a syndrome of medullary thyroid carcinomas, pheochromocytomas and parathyroid hyperplasia. The simultaneous occurrence of medullary, and papillary, thyroid carcinomas is rare because they are derived from, apparently, different germ layers, the former from the neuroectoderm and the latter from the endoderm. We report a case of a papillary thyroid carcinoma, combined with a medullary thyroid carcinoma, in a patient with MEN type 2A. Molecular genetic studies for screening a RET proto-oncogene mutation revealed a point mutation in codon 631 on chromosome 10, which is reported as highly uncommon in MEN type 2A.

Original Articles

Early Detection of Medullary Thyroid Cancer by Screening of the RET Proto-oncogene Germ Line Point Mutation in Family Members Affected with Hereditary Medullary Thyroid Cancer .: Sun Wook Kim, Tae Yong Kim, Young Joo Park, Won Bae Kim, Chan Soo Shin, Do Joon Park, Kyoung Soo Park, Seong Yeon Kim, Bo Youn Cho, Hong Kyu Lee; J Korean Endocr Soc. 2001;16(1):54-64. Published online February 1, 2001

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Abstract PDF: BACKGROUND
Conventional biochemical screening for family members with hereditary medullary thyroid cancer (MTC) is associated with problems of sensitivity and, specificity and it frequently detects gene carriers only after disease progression. Molecular genetic screening tests that detect germ-line point mutations of the RET proto-oncogene has changed our approach to hereditary MTC. In this study we screened members of a large Korean family that had a history of hereditary MTC by a molecular genetic method and propose a therapeutic approach in managing the disorder. METHODS: Using DNA acquired from peripheral blood leukocytes of the index patient, we performed PCR and direct sequencing of exon 10 of the RET proto-oncogene. PCR-RFLP using an Mbo II restriction enzyme was performed on family members who were at risk of MTC according to the family pedigree. Basal serum calcitonin level was determined in family members who had a point mutation of the RET proto-oncogene and a pentagastrin stimulation test was performed in 3 members. RESULTS: Genetic analysis in the index case revealed a mutation in exon 10, codon 618 of the RET proto-oncogene (TGC to AGC). Out of 28 members who were at risk of MTC, 24 members participated in the screening test. 9 members tested positive for a mutation in the same chromosomal location as the index patient by PCR-RFLP. Basal serum calcitonins were above 100 pg/mL in 2 members. 3 members who had a RET point muatation but a normal basal serum calcitonin level participated in the pentagastrin stimulation test and the results were negative in all members. We found a small medullary thyroid carcinoma that had a diameter of 0.2 cm in a 16 years old boy according to a negative pentagastrin stimulation test and who had received a prophylactic total thyroidectomy. He had no evidence of a lymph node metastasis. CONCLUSION: We detected a germ-line mutation of the RET proto-oncogene in codon 618 of Exon 10 by a molecular genetic method in a family with a hereditary MTC and found 9 members that had a negative history of MTC but had a RET point mutation. There was a very small MTC found in a 16 years old boy who had a normal pentagastrin stimulation test result. Therefore, It is recommended that a prophylactic total thyroidectomy be performed as well as in members that have a mutation of the RET proto-oncogene because MTC can metastasize early in its disease course.'

Routine Measurement of Serum Calcitonin Concentration is Useful in Early Detection of Medullary Thyroid Carcinoma Among Patients with Nodular Thyroid Disease.: Jong Ryeal Hahm, Jae Hoon Chung, Eun Young Oh, In Kyung Chung, Tae Young Yang, Dong Jun Kim, Byung Ju Kim, Sung Hoon Kim, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; J Korean Endocr Soc. 2000;15(1):70-84. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Serum calcitonin is a sensitive and specific marker for diagnosis of medullary thyroid carcinoma (MTC) and its determination leads to accurate preoperative diagnosis and gives chances of definite cure. However, since many non-MTC diseases are also associated with calcitonin elevation, its significance in patients with mild or moderately elevated basal serum calcitonin levels is not clear. Furthermore, the normal value of calcitonin using immunoradiometric assay (IRMA) kit has not so far been definitely ascertained. This study is aimed at assessing the clinical significance of routine measurement of serum basal calcitonin concentration in nodular thyroid disease patients and evaluating the pentagastrin stimulation test in case of mild or moderate elevation of basal calcitonin level. We also measured serum calcitonin value in 408 normal individuals. METHODS: The basal serum calcitonin concentrations using a commercial IRMA kit (Medgenix CT-U.S.-IRMA) were measured in 818 patients with nodular thyroid disease (average age 45 years with a range from 13 to 82 years; 125 males and 693 females) who visited thyroid clinics in Samsung Medical Center between June 1997 and December 1998. Serum concentrations of T3, T4, TSH and thyroid autoantibodies were measured and ultrasonography of thyroid and thyroid scan using 131I or 99mTc-pertechnetate were performed in all patients. We also studied 408 healthy subjects without any thyroid disease (average age 48 years with a range from 20 to 86 years; 224 females). RESULTS: The calcitonin value in normal subjects was found to range from 0 to 13 pg/mL, and it was shown that men had higher calcitonin level than women (p< 0.05). The rate of serum calcitonin elevation (> 10pg/mL) in nodular thyroid disease was 1.71% (14/818), and the incidence of MTC was 0.73% (6/818) in this study. MTC was found in all patients with basal serum calcitonin levels more than 100 pg/mL. Pentagastrin stimulation test was also required to diagnose MTC in patients with basal serum calcitonin levels between 30 and 100pg/mL. The calcitonin concentration stimulated by pentagastrin increased more than 400pg/mL or more than 3.8 times of basal concentration. It was possible to diagnose MTC with fine needle aspiration and cytology in only one case out of six patients with MTC. CONCLUSION: Fine needle aspiration and cytology in diagnosing MTC was not sensitive and not devoid of false positive results. We confirmed that serum calcitonin measurement was very useful means for the preoperative diagnosis of unsuspected MTC. Pentagastrin stimulation test may be a reliable means of evaluation in nodular thyroid disease patients with mild or moderate elevation of basal calcitonin level. We recommend routine measurement of serum calcitonin concentration in patients with nodular thyroid disease.

Small Medullary Thyroid Cancer Dectected by Genetic Mutation Screening in Men IIa Family.: Jae Hoon Chung, Kwang Won Kim, Ji Eun Kim, Byoung Joon Kim, Sung Hoon Kim, Kyung Ah Kim, Myung Sik Lee, Moon Gyu Lee; J Korean Endocr Soc. 1998;13(2):230-239. Published online January 1, 2001

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Abstract PDF: Multiple endocrine neoplasia (MEN) Ila is an inherited disease characterized by the development of medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. It has been shown to be associated with germ-line mutatians in the RET proto-oncogene. Presymptomatic screening of medullary thyroid carcinoma in MEN IIa families enables the early diagnosis of this tumor with its significant morbidity, We describe a 19-year-old woman fmm a MEN IIa family who was founded by DNA analysis to be a gene carrier of MEN IIa and then was diagnosed, using a pentagastrin stimulation test, as having presymptomatie medullary thyroid carcinoma She underwent thyroidectomy and histologic examination confirmed medullary thyroid carcinoma. It is cancluded that direct genetic analysis for mutations in the RET proto-oncogene should be the diagnstlc test of choice for identifying family members at risk for MEN IIa and thyroidectomy on the basis of genetic analysis is a rational course of action.

Case Report

A Case of Multiple endocrine neoplasia type 2a.: Seung Jae Hong, In Myung Yang, Jeong Taek Woo, Jin Woo Kim, Young Seol Kim, Young Kil Choi, Yong Sun Yun, Chung Hwan Lee, Seong Ho Lee, Deok Yoon Kim, Sung Weon Kim; J Korean Endocr Soc. 1997;12(2):328-337. Published online January 1, 2001

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Abstract PDF: Multiple endocrine neoplasia type2a (MEN type2a) is a dominantly inherited cancer syndrome which is characterized by medullary thyroid carcinoma, pheochromocytoma and parathyroid hyperplasia or adenoma. Recent reports show that DNA analysis will be introduced into screening of MEN type2a families. Regular prospective screening and appropriate surgical intervention can reduce the morbidity and mortality due to MEN type2a. We experienced a case of MEN type 2a in a 46-year-old female patient. She had undergone bilateral adrenalectomy due to pheochromocytoma, followed by a total radical thyroidectomy, which revealed medullary thyroid carcinoma of the both thyroid gland and parathyroid hyperplasia.

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