Familial medullary thyroid carcinoma (FMTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. An identifiable RET mutation can be detected in about 85% of FMTC families. The majority of germline mutations in FMTC have been found in exons 10 and 11 of the RET proto-oncogene, specifically within the cysteine codons 609, 611, 618, 620, and 634. We screened members of a large Korean family that had a history of FMTC by genetic analyses, and propose a therapeutic approach for managing the disorder. We report a RET mutation in exon10, codon 618 that causes substitution of a cysteine by a serine in the cysteine-rich domain of the RET receptor in a three-generation FMTC family composed of 30 members with 11 carriers. Nine of the gene carriers were clinically affected. The FMTC with cysteine RET mutations found in the Korean population is consistent with the clinical pattern reported worldwide; to date there have been no ethnic differences identified for FMTC. Our results suggest that this genetic profile might be associated with usually aggressive clinical course with regional lymph node metastasis but late onset of MTC.
Adolescent ; Adult ; Aged ; Amino Acid Substitution ; Carcinoma, Medullary/*genetics/pathology/secondary ; Exons ; Female ; Genetic Predisposition to Disease ; Genetic Testing ; Genotype ; *Germ-Line Mutation ; Humans ; Male ; Middle Aged ; Pedigree ; Proto-Oncogene Proteins c-ret/*genetics ; Republic of Korea ; Thyroid Neoplasms/*genetics/pathology

The lateral septum (LS) is a forebrain structure that has been implicated in a wide range of behavioral and physiological responses to stress. However, the specific populations of neurons in the LS that mediate stress responses remain incompletely understood. Here, we show that neurons in the dorsal lateral septum (LSd) that express the somatostatin gene (hereafter, LSd Sst neurons) are activated by diverse stressors. Retrograde tracing from LSd Sst neurons revealed that these neurons are directly innervated by neurons in the locus coeruleus (LC), the primary source of norepinephrine well-known to mediate diverse stress-related functions in the brain. Consistently, we found that norepinephrine increased excitatory synaptic transmission onto LSd Sst neurons, suggesting the functional connectivity between LSd Sst neurons and LC noradrenergic neurons. However, optogenetic stimulation of LSd Sst neurons did not affect stress-related behaviors or autonomic functions, likely owing to the functional heterogeneity within this population. Together, our findings show that LSd Sst neurons are activated by diverse stressors and suggest that norepinephrine released from the LC may modulate the activity of LSd Sst neurons under stressful circumstances.

PURPOSE: Tumor markers are often used to monitor the response to therapy and to detect recurrences in patients with resected breast cancer. Here we evaluated the prognostic value of the preoperative serum concentrations of tumor markers in patients with breast cancer. METHODS: The preoperative serum concentrations of tumor markers (CEA, CA15-3 and TPS) were measured in 670 patients who were treated via potentially curative surgical resection for breast cancer from 2001 to 2004. We investigated the association of the serum concentrations of tumor markers with the disease-free survival and overall survival at the time of the primary diagnosis in relation to the established prognostic factors such as tumor size, lymph node status, hormonal receptor status, age and menopausal status. RESULTS: The established prognostic factors and the elevated preoperative serum tumor marker values were correlated with disease-free survival (CEA: P=0.014, CA15-3: P=0.002 and TPS: P<0.001) and overall survival (CEA: P=0.045, CA15-3: P=0.002 and TPS: P<0.001) on univariate analysis. On multivariate analysis, tumor size, lymph node status, hormone receptor status and TPS (P=0.03) were independent prognostic factors for recurrence and the lymph node status, hormone receptor status and TPS serum level (P<0.001) were independent prognostic factors for overall survival. CONCLUSION: The preoperative serum concentrations of tumor makers (CEA, CA15-3 and TPS) are strong independent prognostic factors for recurrence and survival in patients with breast cancer. The tests for the preoperativeserum concentrations of tumor markers have convenient and reproducible advantages while the others require tumor tissue. Patients with elevated preoperative serum tumor marker values need appropriate adjuvant therapy, careful monitoring and detection of recurrences during the follow-up period.
Biomarkers, Tumor ; Breast Neoplasms* ; Breast* ; Diagnosis ; Disease-Free Survival ; Follow-Up Studies ; Humans ; Lymph Nodes ; Multivariate Analysis ; Prognosis ; Recurrence

PURPOSE: Medullary thyroid cancer (MTC) is a rare disease and the clinical course of MTC many vary. In this study, we analyzed the factors influencing the prognosis of MTC. METHODS: The study group consisted of 37 patients with MTC seen at KNUH between July 1985 and July 2003. We analyzed the medical records of MTC surgical cases in a retrospective study to analyze treatment results and utilized the Kaplan-Meier and chi-squred tests to determine the correlation of prognosis and recurrence. RESULTS: The median age of patients was 39 years and 7 patients had a family history and accompanying disease. No metastases were detected at the time of diagnosis. The majority of the sizes of tumors were under 4 cm in 22 cases and 24 cases (64.9%) showed unilateral tumor locations. Twenty cases (48.6%) showed lymph node metastasis, and invasion of the surrounding organs was seen in 5 cases (13.5%) of these cases. A total thyroidectomy and central neck dissection was performed in all cases. In 17 cases, a modified radical neck dissection was performed initially. Recurrence was detected in 13 out of 37 cases. The most common site of recurrence was the neck, followed by the lung and liver. We analyzed the factors that affected recurrence and it was found that lymph node metastasis and the TNM stage had a statistically significant relationship. No factor showed relevance to prognosis by multivariate analysis. The survival rates were 89.2% for 5 years and 83.8% for 10 years. CONCLUSION: We could not find any statistical significance for a factor relevant to the prognosis of the patients by multivariate analysis. However, as the 10 year-survival rate was 83.8%, we can expect improvement in the treatment of MTC with surgical management (total thyroidectomy and central neck dissection) and constant follow-up.
Diagnosis ; Follow-Up Studies ; Humans ; Liver ; Lung ; Lymph Nodes ; Medical Records ; Multivariate Analysis ; Neck ; Neck Dissection ; Neoplasm Metastasis ; Prognosis ; Rare Diseases ; Recurrence ; Retrospective Studies ; Survival Rate ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyroidectomy

IL-12 is a secretory heterodimeric cytokine composed of p35 and p40 subunits. IL-12 p35 and p40 subunits are sometimes produced as monomers or homodimers. IL-12 is also produced as a membrane-bound form in some cases. In this study, we hypothesized that the membrane-bound form of IL-12 subunits may function as a costimulatory signal for selective activation of TAA-specific CTL through direct priming without involving antigen presenting cells and helper T cells. MethA fibrosarcoma cells were transfected with expression vectors of membrane-bound form of IL-12p35 (mbIL-12p35) or IL-12p40 subunit (mbIL-12p40) and were selected under G418-containing medium. The tumor cell clones were analyzed for the expression of mbIL-12p35 or p40 subunit and for their stimulatory effects on macrophages. The responsible T-cell subpopulation for antitumor activity of mbIL-12p35 expressing tumor clone was also analyzed in T cell subset-depleted mice. Expression of transfected membrane-bound form of IL-12 subunits was stable during more than 3 months of in vitro culture, and the chimeric molecules were not released into culture supernatants. Neither the mbIL-12p35-expressing tumor clones nor mbIL-12p40-expressing tumor clones activated macrophages to secrete TNF-alpha. Growth of mbIL-12p35-expressing tumor clones was more accelerated in the CD8+ T cell-depleted mice than in CD4+ T cell-depleted or normal mice. These results suggest that CD8+ T cells could be responsible for the rejection of mbIL-12p35-expressing tumor clone, which may bypass activation of antigen presenting cells and CD4+ helper T cells.
Animals ; Antigen-Presenting Cells ; Clone Cells ; Corynebacterium ; Fibrosarcoma ; Interleukin-12 ; Interleukin-12 Subunit p35 ; Interleukin-12 Subunit p40 ; Macrophages ; Mice ; Rejection (Psychology) ; T-Lymphocytes ; T-Lymphocytes, Helper-Inducer ; Tumor Necrosis Factor-alpha

PURPOSE: The aim of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. METHODS: A total of 7 pairs of breast tumors and control tissues were taken at the time of primary surgery for array analysis. Then, performed microarray experiments in breast cancer tissues with the cDNA microarray spotted 3,063 clones of genes, were analyzed by hierachical clustering. RESULTS: Thirteen genes were over expressed in tumor samples regardless of their histopathological features and ER status, those were including, vitamin A responsive gene, proliferating cell nuclear antigen (PCNA), and signal transducer and activator of transcription 1 (STAT1). Twenty-four genes were down-regulated in tumor sites, those were including, discoidin domain receptor family mamber 2, crystallin alpha B, and myosin light polypeptide kinase. We also identified the differentially expressed genes between ER positive and negative tumors. PCNA, FLJ20500, STAT1, signal recognition particle 9 kD, and proteasome activator subunit 2 were more predominantly expressed in ER negatives. Serine protease 23, vitamin responsive gene, fibronectin 1, and SERPINA1 genes were more highly expressed in ER positive tumors. We further classified the patients according to their gene expression patterns with Cluster program. Clustering results divided patients into two distinct groups, the first group consists of only estrogen receptor (ER) negative tumors and they showed more higher gene expression levels of cell replication and cycle, invasion and metastasis, those considered poor prognosis signature. The other group mostly consists of ER positive tumors. CONCLUSION: These results support the feasibility and usefulness of this systematic approach to studying variation in gene expression patterns in human cancers as a means to dissect and classify solid tumors. We believe, this gene expression profile will outperform all currently available clinical parameters in predicting disease outcome.
Breast Neoplasms* ; Breast* ; Clone Cells ; Crystallins ; DNA, Complementary* ; Estrogens ; Fibronectins ; Gene Expression* ; Humans* ; Myosins ; Neoplasm Metastasis ; Oligonucleotide Array Sequence Analysis ; Phosphotransferases ; Prognosis ; Proliferating Cell Nuclear Antigen ; Proteasome Endopeptidase Complex ; Serine Proteases ; Signal Recognition Particle ; STAT1 Transcription Factor ; Transcriptome* ; Vitamin A ; Vitamins

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been reported to be related to certain clinical characteristics (i.e., female, non-smokers with adenocarcinoma) and gefitinib responsiveness. This exploratory analysis was performed to determine the incidence of EGFR mutations in male smokers with squamous cell carcinoma, who were treated with EGFR tyrosine kinase inhibitor, gefitinib. Sixty-nine Korean NSCLC patients were treated with gefitinib in a prospective study. For a subset of 20 male patients with squamous cell carcinoma and a history of smoking, pretreatment tumor tissue samples were obtained and analyzed for EGFR mutations (exons 18 to 21). EGFR mutations were found in 3 (15%) patients, including in-frame deletions within exon 19 (n=2) and L858R missence mutation in exon 21 (n=1). These 3 patients with EGFR mutations responded to gefitinib, whereas only one of remaining 17 patients with wild-type EGFR achieved clinical response. Trend toward longer progression-free (5.8 vs. 2.4 months; P=0.07) was noted in patients with EGFR mutations compared to those with wild-type EGFR. Although male smokers with squamous cell carcinoma have not been considered ideal candidates for gefitinib treatment, significant incidence of EGFR mutations was observed. The molecular markers should be considered to predict clinical benefits from gefitinib.
Adult ; Aged ; Antineoplastic Agents/therapeutic use ; Carcinoma, Non-Small-Cell Lung/*genetics ; Humans ; Lung Neoplasms/*genetics ; Male ; Middle Aged ; *Mutation ; Protein Kinase Inhibitors/therapeutic use ; Quinazolines/therapeutic use ; Receptor, Epidermal Growth Factor/*genetics ; *Smoking ; Treatment Outcome

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been reported to be related to certain clinical characteristics (i.e., female, non-smokers with adenocarcinoma) and gefitinib responsiveness. This exploratory analysis was performed to determine the incidence of EGFR mutations in male smokers with squamous cell carcinoma, who were treated with EGFR tyrosine kinase inhibitor, gefitinib. Sixty-nine Korean NSCLC patients were treated with gefitinib in a prospective study. For a subset of 20 male patients with squamous cell carcinoma and a history of smoking, pretreatment tumor tissue samples were obtained and analyzed for EGFR mutations (exons 18 to 21). EGFR mutations were found in 3 (15%) patients, including in-frame deletions within exon 19 (n=2) and L858R missence mutation in exon 21 (n=1). These 3 patients with EGFR mutations responded to gefitinib, whereas only one of remaining 17 patients with wild-type EGFR achieved clinical response. Trend toward longer progression-free (5.8 vs. 2.4 months; P=0.07) was noted in patients with EGFR mutations compared to those with wild-type EGFR. Although male smokers with squamous cell carcinoma have not been considered ideal candidates for gefitinib treatment, significant incidence of EGFR mutations was observed. The molecular markers should be considered to predict clinical benefits from gefitinib.
Adult ; Aged ; Antineoplastic Agents/therapeutic use ; Carcinoma, Non-Small-Cell Lung/*genetics ; Humans ; Lung Neoplasms/*genetics ; Male ; Middle Aged ; *Mutation ; Protein Kinase Inhibitors/therapeutic use ; Quinazolines/therapeutic use ; Receptor, Epidermal Growth Factor/*genetics ; *Smoking ; Treatment Outcome

PURPOSE: Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid and BRAFV600E mutation is the most frequent genetic alteration in PTC. BRAFV600E mutation has been demonstrated as a prognostic biomarker for prediction of poor clinicopathological outcomes, such as increased incidence of extrathyroidal extension, lymph node metastasis, and advanced stage. However, there is conflicting literature regarding the association of BRAFV600E mutation and aggressive clinicopathological features. In this study, we investigated the prevalence of BRAFV600E mutation in PTC and determined the association of BRAF mutation with indicators of poor prognosis for PTC. METHODS: We reviewed 1009 patients with PTC, who underwent thyroid surgery at Kyungpook National University Hospital between January 2013 and March 2014. BRAFV600E mutation analysis was performed using real-time polymerase chain reaction based amplification of DNA extracted from paraffin-embedded tumor specimens. RESULTS: BRAFV600E mutation was detected in 863 (85.5%) patients. In univariate analysis, histologic subtype, extrathyroidal extension, and advanced stage showed significant association with BRAFV600E mutation. In addition, concurrent Hashimoto's thyroiditis showed an association with low prevalence of BRAFV600E mutation. However, no statistically significant association was observed for age, gender, multifocal or bilateral tumor, and lymph node metastasis. Multivariate analysis showed an independent association of extrathyroidal extension with BRAFV600E mutation. CONCLUSION: In this study, extrathyroidal extension of PTC is an independent prognostic factor associated with BRAFV600E mutation status. However, conduct of further large scale studies with long term follow up is required before the BRAF mutation can be conclusively recommended as a prognostic biomarker.
DNA ; Gyeongsangbuk-do ; Humans ; Incidence ; Lymph Nodes ; Multivariate Analysis ; Neoplasm Metastasis ; Prevalence ; Prognosis ; Real-Time Polymerase Chain Reaction ; Thyroid Gland ; Thyroid Neoplasms* ; Thyroiditis