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Background: It infrequently occurs that cytologic diagnosis of papillary thyroid carcinoma (PTC) cannot be confirmed by histology after surgery. This phenomenon may be a false-positive cytology or a true disappearing tumor. Objectives: We evaluated patients who had consistent findings of PTC at fine needle aspiration cytology (FNAC) and no evidence of PTC in surgical specimens. Methods: Positive cytology findings and a negative histological diagnosis of PTC in the thyroid was defined as thyroid nodules with FNAC findings of PTC prior to surgery and no evidence of malignancy on histological examination of surgically removed thyroids. We retrospectively reviewed patients who underwent fine needle aspiration (FNA) and thyroidectomy in Asan Medical Center from 2004 to 2012. Results: Six patients were found who fit the definition of positive cytology findings and a negative histological diagnosis of PTC in the thyroid. The FNAC diagnosis of 6 patients was ‘malignancy' suggesting PTC according to the Bethesda system. All patients underwent thyroidectomy with central neck dissection. Three patients had reactive changes after FNA due to needle passage. Among these 3 patients, 2 had pathologically confirmed metastatic PTC in dissected lymph nodes. These 2 patients could be defined as true disappearing PTC in the thyroid after FNA. The remaining 3 patients had neither histologic alterations nor evidence of PTC in the thyroid and lymph nodes specimens. Conclusions: Both disappearing PTC and a false-positive result of FNAC should be considered in patients with positive cytology findings and a negative histological diagnosis of PTC in the thyroid.

The objective of this study was to evaluate the usefulness of American Thyroid Association (ATA) risk classification and dynamic risk stratification (DRS) based on the response to initial therapy in pediatric patients with differentiated thyroid cancer (DTC).This historical cohort study included 77 pediatric patients with DTC who underwent thyroid surgery. Clinical outcomes during median 5.3 years of follow up were assessed according to 3 ATA risk groups and 4 DRS groups.In ATA risk classification, 22%, 48%, and 30% of patients were in the low-, intermediate-, and high-risk groups, respectively. There was no significant difference in disease-free survival (DFS) between the indeterminate and the low-risk group. The risk of recurrent/persistent disease was significantly higher only in the high risk group [hazard ratio (HR), 18.4; P = 0.005]. In DRS, 49%, 13%, 6%, and 31% of patients were classified in the excellent, indeterminate, biochemical incomplete, and structural incomplete response groups, respectively. The risk of recurrent/persistent disease was significantly higher in the indeterminate group (HR, 10.2; P = 0.045) and in the structural incomplete group (HR, 98.7; P = 0.005) compared with the excellent response group.DRS based on the response to initial therapy could be useful in addition to initial ATA pediatric risk classification to predict recurrent/persistent disease in pediatric patients with DTC.

The short-chain fatty acid, α-lipoic acid (ALA) is a powerful antioxidant used for treatment of diabetic neuropathy. Recent studies suggested the possibility of ALA as a potential anti-cancer agent, because it could activate adenosine monophosphate activated protein kinase (AMPK) and inhibit transforming growth factor-β (TGFβ) pathway. We evaluate the effects of ALA on thyroid cancer cell proliferation, migration, and invasion. We performed in vitro cell proliferation analysis with BCPAP, HTH-83, CAL-62, and FTC-133 cells. ALA suppressed cell proliferation through activation of AMPK and subsequent down-regulation of mammalian target of rapamycin (mTOR)-S6 signaling pathway. Low-dose ALA, which had minimal effects on cell proliferation, also decreased cell migration and invasion of BCPAP, CAL-62, and HTH-83 cells. ALA inhibited epithelial mesenchymal transition (EMT) evidently by increase of E-cadherin and decreases of activated β-catenin, vimentin, snail, and twist in these cells. ALA suppressed TGFβ production and inhibited induction of p-Smad2, and twist by TGFβ1 or TGFβ2. These findings indicate that ALA reduces thyroid cancer cell migration and invasion through suppression of TGFβ production and inhibition of TGFβ signaling pathways. ALA also significantly suppressed tumor growth in mouse xenograft model using BCPAP and FTC-133 cells. This is the first study to show anti-cancer effect of ALA on thyroid cancer cells. ALA could be a potential therapeutic agent for advanced thyroid cancer, as an adjuvant therapy with other systemic therapeutic agents. Citation Format: Hyemi Kwon, Min Ji Jeon, Won Gu Kim, Seonhee Lim, Soyoung Sim, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1816.

Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Identification of clinicopathological features and molecular prognostic markers is important for the treatment of ACC. The aim of this study was to evaluate the clinical and histopathological features of ACC for prognostic prediction. This retrospective cohort study included 86 patients pathologically confirmed with ACC in a single center. Ki-67 index was evaluated by immunohistochemical staining of paraffin-embedded samples. The median age of the 86 (46 male and 40 female) patients with ACC was 49 years old (range 21–78), and the mean primary tumor size was 12.2 ± 5.2 cm. ACCs were incidentally found in 29 patients (34%). Three patients (3%) had bilateral ACC, and 59 patients (69%) had distant metastasis (37 synchronous and 22 metachronous). Twenty-four patients (28%) had symptoms from hormone excess or mass effects, and 25 patients (29%) had nonspecific symptoms. The 5-year survival rate for ACC was 28%. Sixty patients underwent surgical treatment, including 37 patients with an R0 resection. Tumor size, Ki-67 index, stage, and resection status were independently associated with overall survival by multivariate analysis. In patients with R0 resection, recurrence was significantly associated with larger tumor size and functional tumor. Tumor size, Ki-67 index, stage, and resection status are important prognostic indicators of survival in ACC patients.

Background: Transcriptional activating mutations of telomerase reverse transcriptase (TERT) are associated with more aggres- sive thyroid cancer. We evaluated the significance of TERT promoter mutations in Korean patients with classic papillary thyroid cancer (PTC). Methods: Genomic DNA was isolated from four thyroid cancer cell lines and 35 fresh-frozen PTC tissues. TERT promoter muta- tions (C228T and C250T) and the BRAF V600E mutation were evaluated by polymerase chain reaction amplification and direct sequencing. Results: The CC228229TT mutation in the TERT promoter was detected in BCPAP cells and the C250T mutation was found in 8505C cells. No TERT promoter mutation was observed in Cal-62 or ML-1 cells. The C228T mutation was found in only 1 of 35 (2.8%) PTCs and no C250T mutations were detected in any of the study subjects. The BRAF V600E mutation was found in 20 of 35 (57.1%) PTCs. One patient with the C228T TERT mutation also harbored the BRAF V600E mutation and developed a recur- rence. Conclusion: The prevalence of somatic TERT promoter mutations was low in Korean patients with classic PTC. Therefore, the prognostic role of TERT promoter mutations might be limited in this patient cohort.

Purpose: Src is overexpressed or hyperactivated in a variety of human cancers, including thyroid carcinoma. Src is a central mediator in multiple signaling pathways that are important in oncogenesis and cancer progression. In this study, we evaluated the effects of an Src inhibitor, SKI-606 (bosutinib), in a spontaneous metastatic thyroid cancer model with constitutively activated Src (ThrbPV/PVPten+/− mice). Experimental Design: ThrbPV/PVPten+/− mice were treated with SKI-606 or vehicle controls, beginning at 6 weeks of age until the mice succumbed to thyroid cancer. We assessed the effects of SKI-606 on thyroid cancer progression and analyzed the impact of SKI-606 on aberrant Src-mediated signaling. Results: SKI-606 effectively inhibited aberrant activation of Src and its downstream targets to markedly inhibit the growth of thyroid tumor, thereby prolonging the survival of treated mice. While Src inhibition did not induce cell apoptosis, it decreased cell proliferation by affecting the expression of key regulators of cell-cycle progression. Importantly, SKI-606 dramatically prevented dedifferentiation, vascular invasion, and lung metastasis of thyroid cancer cells. These responses were meditated by downregulation of mitogen-activated protein kinase pathways and inhibition of the epithelial–mesenchymal transition. Conclusions: Our findings suggest that Src is critical in the progression of thyroid cancer, making oral SKI-606 a promising treatment strategy for refractory thyroid cancer. Clin Cancer Res; 18(5); 1281–90. ©2012 AACR.

Signal transducer and activator of transcription-1 (STAT1) plays a critical role in tumorigenesis by controlling several functions in both tumor cells and the immune system, and is considered to be a tumor suppressor. The present study evaluated the activity of STAT1 in human papillary thyroid carcinomas (PTC).STAT1 activity was measured in nuclear extracts of tumor tissues from 35 PTC patients using an ELISA-based kit.STAT1 activity was significantly lower in tumors than in the surrounding normal thyroid tissues (P0.01). The association between STAT1 activity and clinicopathologic factors was analyzed in PTC tissues. STAT1 activity was significantly lower in tumors that measured 2 cm or more than in tumors that measured 2 cm or less (P = 0.044). Moreover, tumor size was inversely correlated with STAT1 activity (Spearman's rank correlation coefficient (rho) = -0.34, P = 0.048). In addition, tumors with BRAF mutations showed lower STAT1 activity than wild-type BRAF tumors [0.064 (0.056-0.124) vs. 0.108 (0.073-0.153) arbitrary units, P = 0.048].STAT1 activity is suppressed in PTCs (as measured by DNA-binding activities). The tumor with T1799A BRAF mutation and tumor sizes of 2 cm or more were clinicopathologic parameters associated with lower STAT1 activity. STAT1 activity of tumor might be one of potential biomarkers for PTC's.

Central diabetes insipidus (DI), characterized by unexpected fatal hypernatremia, is a rare complication after successful cardiopulmonary resuscitation with therapeutic hypothermia, but may be potentially fatal if recognition is delayed. We describe here a patient who experienced cardiac arrest due to a pulmonary embolism, followed by successful resuscitation after induction of therapeutic hypothermia. The patient, however, suddenly developed unexpected hypernatremia with increased urine output and was diagnosed with central DI as a complication of cerebral edema, and eventually died. Our findings suggest that central DI should be considered as a possible complication following unexpected hypernatremia with increased urine output during therapeutic hypothermia and that desmopressin acetate should be used to treat central DI.

5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of 5′-AMP-activated protein kinase (AMPK), which plays a role in the maintenance of cellular energy homeostasis. Activated AMPK inhibits the protein kinase mechanistic target of rapamycin, thereby reducing the extent of protein translation and suppressing both cell growth and cell cycle entry. Recent reports indicate that AMPK-mediated growth inhibition is achieved via an action of the RAF–MEK–ERK mitogen-activated protein kinase pathway in melanoma cells harboring the V600E mutant form of the BRAF oncogene. In this study, we investigated the anti-cancer efficacy of AICAR by measuring its effects on proliferation, apoptosis, and cell cycle progression of BRAF wild-type and V600E-mutant thyroid cancer cell lines. We also explored the mechanism underlying these effects. AICAR inhibited the proliferation of BRAF V600E-mutant thyroid cancer cell lines more strongly than was the case with wild-type cell lines. The suppressive effect of AICAR on cell proliferation was associated with increased S-phase cell cycle arrest and apoptosis. Interestingly, AICAR suppressed phosphorylation of ERK and p70S6K in BRAF V600E-mutant thyroid cancer cells, but rather increased phosphorylation in wild-type cells. Together, the results indicate that AICAR-induced AMPK activation in BRAF V600E-mutant thyroid cancer cell lines resulted in increases in apoptosis and S-phase arrest via downregulation of ERK and p70S6K activity. Thus, regulation of AMPK activity may be potentially useful as a therapy for thyroid cancer if the cancer harbors a BRAF V600E mutation.

The primary treatment of locoregionally recurrent/persistent papillary thyroid cancer (PTC) is surgical removal by reoperation. However, there had been only limited number of reports on the outcome of reoperation.This study was to evaluate the efficacy of the first reoperation for locoregionally recurrent/persistent papillary thyroid carcinoma and the usefulness of stimulated thyroglobulin for evaluating efficacy of reoperation.This was a retrospective observational cohort study in a tertiary referral hospital.A total of 83 patients, who underwent initial total thyroidectomy and nodal dissection with radioactive iodine remnant ablation, received reoperation for locoregionally recurrent/persistent PTC and were included in this study. Stimulated thyroglobulin levels were assessed before and after reoperation.We assessed biochemical remission (stimulated thyroglobulin1 ng/ml) after reoperation and evaluated second clinical recurrence-free survival rate according to stimulated thyroglobulin value.There was a significant positive correlation between the numbers of resected malignant lymph nodes and the reduction in stimulated thyroglobulin level after reoperation. Biochemical remission was achieved in 51% of patients who underwent first reoperation. Patients with stimulated thyroglobulin level greater than 5 ng/ml after first reoperation had a greater chance of a second clinical recurrence (the estimated 5 yr clinical recurrence free survival rate, 94 ± 3 vs.74 ± 9%, log rank statistics 15.8, df = 1, P0.001).Surgery is an effective option for managing locally recurrent/persistent PTC. Stimulated thyroglobulin is a useful marker for evaluating efficacy of reoperation and predicting second recurrence in locoregionally recurrent/persistent PTC.

X-linked inhibitor of apoptosis protein (XIAP) is associated with tumor genesis, growth, progression and metastasis, and acts by blocking caspase-mediated apoptosis. In the present study, we sought to evaluate the expression patterns of XIAP in various neoplastic thyroid disorders and determine the association between XIAP expression and clinicopathologic factors. Expression of XIAP was evaluated with immunohistochemical staining using monoclonal anti-XIAP in 164 specimens of conventional papillary thyroid carcinoma (PTC) and 53 specimens of other malignant or benign thyroid tumors. XIAP positivity was observed in 128 (78%) of the 164 conventional PTC specimens. Positive rates of XIAP expression in follicular variant PTC, follicular, medullary, poorly differentiated, and anaplastic thyroid carcinoma specimens were 20%, 25%, 38%, 67%, and 38%, respectively. Six nodular hyperplasia specimens were negative and 1 of 7 follicular adenomas (8%) was positive for XIAP. Lateral neck lymph node metastases were more frequent in patients negative for XIAP expression (P = 0.01). Immunohistochemical staining for XIAP as a novel molecular marker may thus be helpful in the differential diagnosis of thyroid cancer. Moreover, high XIAP expression in conventional PTC is strongly associated with reduced risk of lateral neck lymph node metastasis.

Little is known about the kinetics of viral shedding of pandemic influenza A/H1N1 2009 virus. Influenza RNA, as a surrogate for viral clearance, was therefore measured on days 1, 5, 7, and 10 or more in patients admitted to hospital with pandemic influenza A/H1N1 2009 infection. A total of 72 patients who were admitted to hospital with confirmed pandemic influenza A/H1N1 2009 at a tertiary care hospital, Seoul, South Korea, between 1 September and 11 November 2009 were evaluated. The median duration of viral shedding, as assessed by RT-PCR, was 9 days, as determined by the Kaplan-Meier method. Patients who were positive by RT-PCR at their last assay, but who were discharged before the next RT-PCR test due to symptom improvement, were censored from the analysis. If such patients were included, with the assumption that they had negative viral status at discharge, the median duration of viral shedding was 5 days (interquartile range, 2-8 days). These calculations thus suggest that the true median duration of viral shedding is between 5 and 9 days. Univariate analysis showed that delayed administration of antiviral therapy and comorbidity were associated with slower viral clearance. Multivariate analysis showed that oseltamivir started after the first day of symptoms (OR 2.7, 95% CI 1.2-5.7) was associated independently with slower viral clearance. These findings indicate that, in about 50% of patients admitted to hospital with pandemic influenza A/H1N1 2009, virus can be positive as tested by RT-PCR on the eighth day after developing symptoms of influenza. The present findings also indicate that starting antiviral therapy within 24 hr of the onset of symptoms is associated with more rapid viral clearance.

During the early stages of the pandemic influenza A H1N1 2009 (pH1N1) outbreak in South Korea, the government recommended antiviral therapy with laboratory confirmation in specialized hospitals. Hence we had a unique opportunity to test all patients suspected to have pH1N1, including those who initially presented with a mild illness, such as those who were not in at-risk groups and who had an uncomplicated illness. We therefore evaluated the proportion and clinical features of pneumonia in patients with laboratory-confirmed pH1N1. Of the 3253 patients who visited Asan Medical Center, Seoul, South Korea, between 24 August and 19 October 2009 for a suspected pH1N1 infection (temperature ≥ 37.5°C and at least 1 of the following symptoms: sore throat, cough, rhinorrhoea and nasal congestion), 553 (17%) were positive for pH1N1 by real-time reverse-transcriptase polymerase chain reaction. Chest radiographs were performed in 96 (17%) of the 553 patients. Of the 553 patients, 30 (5%; 95% confidence interval (CI) 4-8%) had pneumonia, including 26 (86%) with viral pneumonia and 4 (14%) with bacterial pneumonia. So, the proportion of pneumonia in patients with laboratory-confirmed pH1N1 was at least 5%. Multivariate analysis indicated that dyspnoea (odds ratio (OR) 57.8, p0.001), wheezing (OR 19.3, p = 0.02), vomiting (OR 18.5, p0.001) and diarrhoea (OR 11.0, p = 0.001) were independently associated with pneumonia. Antiviral therapy at48 h after the onset of symptoms (OR 2.1, p = 0.09) tended to be more common in patients with pneumonia than in those without pneumonia.

Objectives The simultaneous occurrence of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) in the same thyroid gland is documented. In this study, we evaluated the prevalence and characteristics of patients with concurrent MTC and PTC. Design Retrospective analysis of patients with MTC in a single centre and review of the literature. Patients and measurements Patients with MTC who underwent initial surgical treatment between 1996 and 2006 at Asan Medical Centre, Seoul, Korea were enrolled. We additionally reviewed the medical records of patients who initially underwent surgery for Graves' disease (GD) or follicular thyroid carcinoma (FTC) during the same period. The concurrent occurrence rate of PTC in MTC patients was compared with that in GD and FTC patients. Results Ten of 53 (19%) MTC patients displayed the concomitant PTC. In all 10 cases, the MTC and PTC components were separated by normal thyroid tissue, with the maximal diameters of PTC being less than 1.0 cm in the majority of patients. The rates of concurrent PTC in patients with MTC, GD and FTC were 19%, 15% and 19%, respectively, which were not significantly different. Conclusions Our results suggest that the occurrence of concurrent MTC/PTC is generally a simple reflection of incidental papillary microcarcinoma.

Summary Objectives To evaluate the clinical outcomes of persistent radioiodine uptake (RAIU) in the neck by diagnostic whole body scan (DxWBS) after initial therapy and the efficacy of the second ablation in patients with differentiated thyroid carcinoma (DTC). Design Patients with DTC who underwent bilateral surgery and high-dose remnant ablation between 2000 and 2004 were included. Patients with elevated serum stimulated thyroglobulin (sTg) or extensive lateral neck lymph node involvement at initial surgery underwent a second ablation, and patients with undetectable sTg or in very low-risk groups were observed. Results Among 572 patients, 25 had persistent RAIU in the neck at first DxWBS. After a median 65·7 months of follow-up, five of these patients (20%) had persistent disease, whereas another 20 patients had no abnormal findings by ultrasonography (US) or other imaging modalities. Seven of 20 patients underwent second ablation and 13 were observed. RAIU disappeared spontaneously in about half of the patients in the observation group. There were no significant between-group differences in change of RAIU at follow-up DxWBS (P = 0·62). Serum sTg decreased and eventually disappeared over a few years in both groups. Ablation failure was not an independent risk factor for recurrence (P = 0·169). Conclusions Neck US and serum sTg, but not DxWBS, were useful diagnostic tools during follow-up of patients with persistent uptake in the neck at DxWBS. A second ablation was not necessary when neck US showed no evidence of disease, especially in patients with very low sTg concentration.

We intended to determine the predictive factors of poor prognosis in cancer patients with chemotherapy-induced febrile neutropenia (FN). From January 1, 2007 to December 31, 2008, 396 episodes of FN in 346 cancer patients were retrospectively analyzed. Clinical and laboratory findings and Multinational Association of Supportive Care in Cancer (MASCC) risk-index score were analyzed and correlated with outcome. Of the 396 episodes, 73 (18.4%) had serious medical complications including 15 (3.8%) deaths. There was significant difference between unfavorable and favorable outcomes in age, gender, hypotension, tachypnea, duration of fever ≤24 h before admission (44.4% vs. 61.3%), interval of ≤7 days since last chemotherapy (34.2% vs. 16.1%), and duration of neutropenia ≥4 days (34.2% vs. 15.8%; P

The effect of coexistent chronic lymphocytic thyroiditis (CLT) on prognosis in papillary thyroid carcinoma (PTC) patients remains controversial. We evaluated the influence of coexistent CLT on prognostic outcome and the association of coexistent CLT with clinicopathological parameters.A retrospective study with a median follow-up of 70 months.Patients with PTC who underwent total thyroidectomy followed by (131)I remnant ablation between 1995 and 2003 at Asan Medical Center, Seoul, Korea were enrolled. CLT was diagnosed histopathologically.Among 1441 patients, 214 (14.9%) had coexistent CLT. A greater female preponderance was noted in the patients with CLT compared with those without CLT (P0.01). Mean tumour size in the patients with CLT was smaller than that in patients without CLT (2.0 +/- 1.2 vs. 2.2 +/- 1.4 cm; P = 0.02). One hundred and fifty-one (12.3%) patients without CLT had recurrence, whereas 14 (7.1%) patients with CLT had recurrence during the follow-up period (P = 0.016). In patients with cervical lymph node metastases, those with coexistent CLT showed a significantly lower recurrence rate than those without CLT (P = 0.012). However, this association was lost on multivariate analysis adjusting for other clinicopathological predictors for recurrence.In this study, CLT was commonly associated with PTC and was associated with smaller size of the primary tumour at presentation. CLT was also associated with a reduced risk of recurrence during follow-up, although this was not significant after adjustment for other prognostic factors.

The aim of the study was to evaluate the usefulness of the antithyroglobulin autoantibody (TgAb) value at 6-12 months after remnant ablation in predicting recurrence in differentiated thyroid carcinoma patients who had undetectable thyroglobulin (Tg) values. The change in TgAb concentration measured between the time of remnant ablation (TgAb1) and 6-12 months thereafter (TgAb2) was also evaluated as a possible prognostic indicator.Patients with differentiated thyroid carcinoma who underwent total thyroidectomy followed by (131)I remnant ablation between 1995 and 2003 at the Asan Medical Center (Seoul, Korea) were enrolled. Of these, 824 patients with undetectable Tg at 6-12 months after remnant ablation during thyroid hormone withdrawal were the subjects of this study.TgAb2 was positive in 56 patients. Ten of 56 patients (18%) with positive TgAb2 had recurrence, whereas only 10 of 768 patients (1%) with negative TgAb2 had recurrence during 73.6 months of follow-up (P0.001). The change between TgAb1 and TgAb2 levels was evaluated in patients with positive TgAb2. TgAb concentration decreased by more than 50% in 21 patients (group 1) and by less than 50% in 16 patients (group 2), and it increased in 19 patients (group 3). The recurrence rates in groups 1, 2, and 3 were 0, 19, and 37%, respectively (P = 0.016).Serum TgAb levels measured at 6-12 months after remnant ablation could predict recurrence in patients with undetectable Tg values. In patients with undetectable Tg and positive TgAb values, a change in TgAb concentration during the early postoperative period may be a prognostic indicator of recurrence.

Background and Objectives: It is important to analyze right-sided chest electrocardiograms (ECGs) to rule out combined right ventricular infarction in patients with inferior wall infarction. However, the patterns of rightsided chest ECGs in healthy adults have not been thoroughly investigated. This study was conducted to analyze the normal patterns of ECGs and the prevalence of ST segment elevation (STE) in the right-sided precordial leads (V3R and V4R) in healthy adult Koreans. Subjects and Methods: One hundred thirty healthy male volunteers who registered at the Armed Forces Daejeon Hospital for military recruitment were enrolled between December 2006 and April 2007. Standard 12-lead ECGs and right-sided precordial ECGs were obtained. The characteristic features of the QRS complex configuration, STE, and T wave morphology from right-sided precordial ECGs were analyzed. Results: The most common QRS configuration in right-sided precordial leads was the rS pattern. The Q waves were present in lead V4R in 4.6% of the study population. STEs of 0.5-1 mm were present in 25.4% of V3R recordings and 6.2% of V4R recordings. T waves were usually negative in the right-sided precordial leads. However, if there was a STE in V4R, the associated T waves were usually positive. There were statistically significant correlations between STEs in V4R and STEs in II, III, aVF, V1, V3, and V6 (p

Context: Slits, representative axon guidance molecules, and their Roundabout (Robo) transmembrane receptors are identified as key regulators of many cancers. One genome-wide liknage analysis suggested Slit-Robo Rho GTPase activating protein 1 gene as a candidate gene in papillary thyroid carcinoma (PTC) susceptibility. Objective: To identify the role of Slit-Robo signaling in PTC. Results : Slits(Slit 1-3) and Robos (Robo 1-4) were expressed in all of thyroid cancer cells and Slit2, Slit3, Robo1 and Robo4 presented higher expression than others. The mRNA expression of Slits and Robos was higher in fresh frozen PTC tissues than matched normal tissues. When we conducted immunohistochemical staining of Slit2 and Robo1 in thyroid tissues, the positivity of Slit2 and Robo1 were higher in PTC tissues than benign or normal tissues. However, negative Slit2 expression was significantly associated with cervical lymph node (LN) metastasis, distant metastasis and cervical recurrence of PTC (P Conclusions : Low expression of Slit2 was associated with poor prognostic factors in PTC. This present study demonstrated the potential of Slit2 as a novel prognostic and therapeutic factor in PTC. Citation Format: MinJi Jeon, Won Gu Kim, Seonhee Lim, Eun Kyung Jang, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Low Slit2 expression is associated with the aggressiveness of papillary thyroid carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2042. doi:10.1158/1538-7445.AM2015-2042

Metabolic reprogramming of cancer cell is one of essential hallmarks of cancer. Otto Warburg first demonstrated that cancer cells utilized more glucose and enhanced glycolytic pathway in the presence of oxygen in 1926. Scientific observ ations of basic and clinical research in several decades supported that cancer-specific metabolism can be an emerging target for treatment of cancer. Metabolic reprogramming is regulated by both oncogenic signaling and tumor suppressor genes associated with critical signaling pathways in metabolism. These changes provided energy, substrat es for cell growth and proliferation, favoring microenvironment, and important for redox balancing for cancer cells. Recent advance of several tools for evaluation comprehensive metabolic profiles of cancer cells provided us to identification of metabolic Achilles’ heel of cancers including thyroid cancer. This approach can be a useful strategy for advance in treatment of cancer patients.

Endocrinol Metab 2014;29:530-5 http://dx.doi.org/10.3803/EnM.2014.29.4.530 Corrections for Figure 2 in page 534 are needed. The bar graphs of male and female are drawn as same graphs. We apologize for any inconvenience that this may have caused.

Objective: Ghrelin is a novel peptide hormone, which exerts somatotropic, orexigenic and adipogenic effects. Recent studies have shown that the preproghrelin Leu72Met polymorphism is associated with serum creatinine (Scr) concentration in type 2 diabetes; 72Met carriers exhibited lower Scr levels as compared with the 72Met non-carriers. We hypothesized that the preproghrelin Leu72Met polymorphism is associated with a lower rate of developing renal dysfunction in patients with type 2 diabetic nephropathy. Design: The preproghrelin Leu72Met polymorphism was investigated using PCR techniques in 138 patients with diabetic nephropathy divided into two groups, one with normal renal function and the other with renal dysfunction. Methods: Determination of the frequency of the preproghrelin Leu72Met polymorphism was the main outcome measure. Results: The frequency of the Leu72Met polymorphism in diabetic nephropathy was significantly lower in patients with renal dysfunction (15.9%, PP Conclusion: These data suggest that 72Met carrier status may be used as a marker predicting a lower chance of developing renal dysfunction in diabetic nephropathy.

Objective The outcome evaluation for the revascularization of intracranial vascular stenoses has not been fully described due to the highly technical nature of the procedure. We report here on the early and late clinical outcomes of angioplasty and/or stenting of symptomatic severe intracranial vascular stenoses at a single institute. Materials and Methods Since 1995, we have treated 35 patients with symptomatic intracranial vascular stenosis (more than 70% stenosis, mean stenosis: 78.6% ± 6.2%). Angioplasty (n = 19) was performed for the horizontal segment of the middle cerebral artery (M1) (n = 16) and the basilar artery (BA) (n = 1), the intradural vertebral artery (VA) (n = 1), and the cavernous internal carotid artery (ICA) (n = 1). Stenting (n = 16) was performed for the cavernous or petrous ICAs (n = 9), the intradural VA (n = 3), BA (n = 2), and M1 (n = 2) artery. We assessed the angiographic success (defined as residual stenosis < 50%) rate, the periprocedural complications during the 30-day periprocedural period, the symptomatic recurrence and restenosis during a mean 22-month follow-up (FU) period. The Kaplan-Meier estimate of the cumulative event-free rate of the major cerebrovascular events, i.e. death, stroke or restenosis, was also done. Results Angiographic success was achieved in 97% of our patients (34/35). There were four procedure-related complications (11%) including a death and a minor stroke. During the mean 22-month FU, the asymptomatic restenosis rate was 9% and the symptomatic restenosis rate was 6% in the target lesion and 9% in all the vascular territories. The Kaplan-Meier estimate was 70.6% (95% confidence interval = 46.5-94.7) after 33 months of FU. Conclusion In addition to a high angiographic success rate and an acceptable periprocedural complication rate, intracranial angioplasty and/or stenting revealed a relatively low symptomatic recurrence rate. Hemorrhage is a rare, but the physician must aware that potentially fatal periprocedural complications can occur.

Distant metastasis is a main cause of death in follicular thyroid carcinoma (FTC) patients. Factors related to distant metastasis in FTC had been known as age, primary tumor size, and invasiveness. Ras mutations were also supposed to be associated with poor clinical outcomes. We analyzed Ras mutations in FTC with a distant metastasis (FTC M1, n=28), size matched-FTC without a distant metastasis (FTC M0, n=28), follicular adenoma (FA, n=17), and nodular hyperplasia (NH, n=12) to figure out the roles of Ras mutations in follicular thyroid carcinogenesis and metastasis. In addition, we assess the relationship between Ras mutations and clinical outcomes in FTC patients. NRAS, HRAS, and KRAS mutations were assessed using direct sequencing method. Among 85 patients, 39 patients (46%) had Ras mutations. NRAS codon 61 mutation (n=21; 25%) was the most common point mutation. HRAS codon 61, KRAS codon 12/13, and KRAS codon 61 mutations were found in 7, 6, and 4 patients, respectively. NRAS codon 12/13 mutation was found in only 1 patient, and HRAS codon 12/13 mutation was not found. Ras mutations were significantly more common in the FTC than FA or NH groups. Especially, NRAS codon 61 mutation was associated with distant metastasis in patients with FTC. However, there was no significant difference in survival between the Ras mutation positive-FTC and Ras mutation negative-FTC patients. Ras mutation, especially NRAS codon 61 mutation, was significantly associated with the presence of distant metastases. NRAS codon 61 mutation status might be a potential prognostic factor in FTC patients. Citation Format: MinJi Jeon, Eun Kyung Jang, Dong Eun Song, So Young Sim, Eui Young Kim, Yun Mi Choi, Ji Min Han, Won Gu Kim, Tae Yong Kim, Young Kee Shong, Won Bae Kim. N-ras codon 61 mutation is associated with distant metastasis in patients with follicular thyroid carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4009. doi:10.1158/1538-7445.AM2014-4009

Received June 24, 2014 / Revised 1st October 13, 2014, 2nd October 20, 2014 / Accepted October 23, 2014 Correspondence: Min Ji Jeon, MD, Division of Endocrinology & Metabolism, Department of Internal Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Tel: 82-2-3010-1317, Fax: 82-2-3010-6962, E-mail: mj080332@gmail.com Bukwang/Dalim Award from the Korean Thyroid Association, 2013.

Background/Aims 5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a cellular energy sensor that monitors intracellular AMP/adenosine triphosphate (ATP) ratios and is a key regulator of the proliferation and survival of diverse malignant cell types. In the present study, we investigated the effect of activating AMPK by 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR) in thyroid cancer cells. Methods We used FRO thyroid cancer cells harboring the BRAFV600E mutation to examine the effect of AICAR on cell proliferation and cell survival. We also evaluated the involvement of mitogen-activated protein kinase (MAPK) pathways in this effect. Results We found that AICAR treatment promoted AMPK activation and suppressed cell proliferation and survival by inducing p21 accumulation and activating caspase-3. AICAR significantly induced activation of p38 MAPK, and pretreatment with SB203580, a specific inhibitor of the p38 MAPK pathway, partially but significantly rescued cell survival. Furthermore, small interfering RNA targeting AMPK-α1 abolished AICAR-induced activation of p38 MAPK, p21 accumulation, and activation of caspase-3. Conclusions Our findings demonstrate that AMPK activation using AICAR inhibited cell proliferation and survival by activating p38 MAPK and proapoptotic molecules in FRO thyroid cancer cells. These results suggest that the AMPK and p38 MAPK signaling pathways may be useful therapeutic targets to treat thyroid cancer.

A solitary skin metastasis is a rare manifestation of papillary thyroid carcinoma (PTC). A 55-year-old woman presented with a movable subcutaneous nodule in her anterior neck for several months. Three years ago, she underwent total thyroidectomy and remnant ablation for classical PTC (pT3N0M0) and was under thyroxine suppression therapy without any evidence of recurrent disease. The subcutaneous nodule was 0.4 cm in size, firm, and movable without any change in the overlying skin. Recurrent PTC was confirmed after excision biopsy. Eight months after, she got a new nodule along the previous excision site. After punch biopsy, metastatic PTC was confirmed in the deep dermis and was re-excised with a clear resection margin. This is the first report of a case of solitary skin metastasis of PTC in Korea. Although solitary skin metastasis of PTC is rare, it should be considered in patients with a skin nodule.

The present study was designed to determine the spatial correlation among extent of DNA synthetic activity, expressions of G1/S phase cyclins, cyclin-dependent kinases (CDKs) and CIP/KIP family of CDK inhibitors (CKIs), and activities of G1/S phase CDKs in glomeruli and outer medullae of kidneys during the active regeneration period after ischemic injury. DNA synthetic activity was measured using [3H]-thymidine autoradiogram in the kidney sections. Cyclin, CDK, and CKI proteins were determined by Western blot analysis. CDK activities were determined by phosphorylation amount using specific substrate. The protein levels of cyclins (D1, D3, E, A) and activities of CDK4 and CDK2 were increased concomitant with the induction of DNA synthetic activity in outer medullae, but not in glomeruli, in adult kidneys during DNA synthetic period after ischemic injury. The p27KIP1 protein, but not the p21CIP1 protein, increased equally in total kidney, glomeruli, and outer medullae after ischemic injury. These results indicate that renal tubules have an active cyclin/CDK system, while glomeruli, do not have a cyclin/CDK system during active regeneration of kidneys after ischemic injury.

To evaluate angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism in nephrotic syndrome, 85 patients (minimal-change nephrotic syndrome, MCNS: 55 cases; focal segmental glomerulosclerosis, FSGS: 30 cases) and 61 control subjects were examined. The distribution of ACE genotype in the control group was II 44%, ID 41% and DD 15%. The distribution of ACE genotypes in MCNS was similar to that in controls. However, the distribution of ACE genotypes in FSGS was markedly different from those of MCNS. The DD genotype was more frequent (p0.05) in FSGS than in MCNS. Patients with the DD genotype tended to present clinical symptoms at an earlier age. They also showed a lower responsiveness to corticosteroid therapy and a higher incidence of chronic renal failure than those with other genotypes. Our results indicate that the ACE DD genotype in FSGS may be a risk factor for the poor responsiveness to steroid therapy and the development of chronic renal failure.