Lateral Septum Somatostatin Neurons are Activated by Diverse Stressors

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.

Role of BRAFV600E Mutation as a Marker for Prognostic Stratification of Papillary Thyroid Carcinoma / 대한내분비외과학회지

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.

A Korean Family of Familial Medullary Thyroid Cancer with Cys618Ser RET Germline Mutation

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.

Prognostic Value of the Preoperative CEA, CA15-3 and TPS Serum Levels in Patients with Breast Cancer

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.

The Clinical Characteristics, Prognostic of Medullary Thyroid Cancer / 대한내분비외과학회지

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.