SE：Symposium-Endocrine (1-6

SE1-1 GRAVES’ OPHTHALMOPATHY-CLINICAL EXPERIENCES IN KOREA

JEE HEE YOON

Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea

Graves’ disease is the most common cause of thyrotoxicosis in Korea (82.7%) and up to 50% of patients with Graves’ disease develop Graves’s ophthalmopathy (GO). GO is related to the loss of immune tolerance to the thyrotropic receptor (TSHR) andorbital fibroblasts, the target cell of GO, increase connective tissue edema in the bony orbits by secreting pro-inflammatory cytokines andhydrophilic hyaluronanin early phase and lead to orbital adipose tissue expansion by differentiating to mature adipocyte in late phase. The pathogenesis of GO is becoming more clear, but some part of that is still understood incompletely. For the optimal management of GO, reducing risk factors and proper approach depending on clinical activity of GO (active inflammatory phase and chronic static phase) are necessary. The cessation of smoking and sustenance of a euthyroid state is helpful for the decreasing risk factors. For reducing inflammation in patients with active GO, systemic steroid only or with radiotherapy generally, but clinical outcome is sometimes insufficient. Other approaches for targeting immune mechanism of active GO were studied and good result of teprotumumab targeting for insulin-like growth factor-I (IGF-I) is reported recently. Surgery is indicated for emergent optic compression and management of chronic phase.

In this session, I hope to share our cases of GO and clinical data in Korea.

SE1-2 MEDICAL TREATMENT OF GRAVES’ ORBITOPATHY

SHYANG-RONG SHIH

Department of Internal Medicine, National Taiwan University School of Medicine Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital

Graves’ orbitopathy (GO) occurs in up to 50% of patients with Graves’ disease. Although GO is usually self-limiting, many patients cannot tolerate the sequelae. Proptosis, diplopia, corneal erosion, and visual loss may persist and handicap throughout life. After plateaus of active disease, a quiescent burnt out phase ensues. But reactivation of inflammation occurs in about 5%-10% of patients over their lifetime. Medication or surgery is offered in order to prevent or treat symptoms, corneal exposure, globe protruding, or optic neuropathy. Treatment plan is made according to the severity and activity of GO.

In order to treat GO, euthyroidism should be restored, and smoking should be quitted. All patients should be treated with nonpreserved artificial tears with osmoprotective properties. Selenium supplementation and oral pentoxifylline may offer some improvement in mild GO. In active and moderate to severe TED, high-dose intravenous glucocorticoids (GCs) therapy is recommended. However, adverse effects such as hypertension, hyperglycemia, hypokalemia, infections, peptic ulcer, osteoporosis, hepatitis, and abnormal behavior (including mood alteration, hyperactivity, psychosis, disorientation, sleep disturbances) may occur. Thirty-one percent of the patient would suffer from disease reactivation. If high dose intravenous GCs is not effective, second line of treatment include second course of high-dose intravenous GCs, oral GCs with orbital radiotherapy, oral GCs with cyclosporine, and Rituximab. Orbital radiotherapy may improve diplopia, but may induce transient exacerbation of ocular symptoms which can be controlled by oral GCs. But some studies suggest that radiotherapy has no significant effect compared with natural course of GO. Radiotherapy should be avoided in patients with diabetes or vasculitis, as the radiation may exacerbate retinopathy. Combination therapy with cyclosporine and oral GCs is another choice for partial responder of high dose intravenous GCs. About 60% of the patients have response. Adverse events of cyclosporine are dose-dependent renal and liver toxicities, and gingival hyperplasia. Rituximab has a direct-B-celldepleting action and can modulated B-cell function. Some study showed that rituximab has 100% effect on GO and disease activity never recurs, but other study failed to demonstrate an improved outcome compared with placebo. Infusion-related reactions are the most frequent side effect, and transient and significant periorbital edema and inflammation may occur. Rehabilitative surgery such as orbital decompression, squint surgery, and lid surgery may be offered after active inflammation subsided.

SE1-3 THE STRATEGY FOR THE MANAGEMENT OF GRAVES’ OPHTHALMOPATHY

YI-HSUAN WEI

Department Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan, ROC

Graves’ ophthalmopathy (GO) is the most common extra-thyroid manifestation of Graves’ disease. The ocular manifestations represent orbital inflammation, tissue expansion, and fibrosis that often lead to substantial morbidity. The clinical signs of GO may comprise any of the following: conjunctival chemosis, periorbital soft tissue swelling, proptosis, eyelid retraction, restriction of eye movement, and decrease of vision due to exposure keratopathy or compressive optic neuropathy. The exact pathogenesis of GO has yet to be understood, and the disease remains a therapeutic challenge. Treatment strategies vary depending on disease severity and activity.

In this talk, we will introduce the clinical course of GO as well as the treatment for different stages of disease. We will focus on the surgical management of GO, including orbital decompression, strabismus correction, and eyelid repositioning. Moreover, how to recognize the problematic GO patient is very important to prevent them from irreversible visual impairment. Some complicated or intractable cases will be discussed in this talk.

Endocrinologists and ophthalmologists offer distinct contributions to the care of patients with GO. We believe that the best outcomes come from good coordination between the two specialists.

SE2-1 CONTRAST-ENHANCED ULTRASOUND (CEUS) OF THE THYROID GLAND

YI-HONG CHOU1,2, YUNG-HUI LIN2

1Yuanpei University of Medical Technology, Hsinchu, Taiwan; 2Department of Radiology, Taipei Veterans General Hospital and School of Medicine, National Yang Ming University, Taipei, Taiwan

High resolution US (US) has been widely used in the diagnosis of small part disorders. Conventional US has been reported to be associated with a sensitivity of 71.32%, a specificity of 77.04%, a positive predictive value of 69.78%, a negative predictive value of 78.33%, and an accuracy of 74.60% in the diagnosis of thyroid malignancy. The typical US appearances of malignancy include hypoechogenicity, poorly defined boundary/irregular margin, and microcalcifications. However, not all malignancies show typical US features. Contrast-enhanced US (CEUS) may be helpful in some instances.

A uniform high contrast enhancement on CEUS is suggestive of a benign thyroid nodule, especially in favor of an adenomatous nodule. A small hypoechoic lesion with a regular boundary on US and hypo-enhancement (without significant marginal enhancement) on CEUS is suggestive of a papillary carcinoma. A hypoechoic lesion with a regular boundary on US and apparent marginal enhancement on CEUS is more likely to be an adenomatous thyroid nodule with eosinophilic change or hemorrhage. The time-intensity curve (TIC) obtained at CEUS can be also used. As compared with normal thyroid tissue, a malignant thyroid nodules exhibit low peak intensity.

Representative features for thyroid adenomas and nodular goiters on US are either no wash-out or wash-out with persistent edge enhancement in late phase, while thyroid carcinomas show a complete wash-out in late phase. The sensitivity, specificity, positive and negative predictive value of 81%, 92%, 97% and 63%, respectively, have been reported for the differentiation of benignity and malignancy. Dynamic evaluation of microcirculation using CEUS may provide a more reliable preoperative discrimination between thyroid adenomas and thyroid carcinomas. (Clinical Hemorheology and Microcirculation, 2015;61:13-22). However, a prospective study is necessary for further confirmation on the usefulness of CEUS in the differentiation of benign and malignant thyroid nodules.

To date, US-guided fine needle aspiration cytology and core-needle biopsy are still the most important preoperative diagnostic tools. The role of CEUS in the evaluation of diffuse thyroid disorders is not yet defined. CEUS of the thyroid gland may be of help in the evaluation of minimally invasive therapeutic procedure (e.g., RFA) of thyroid nodules.

SE2-2 MOLECULAR TESTING FOR THYROID NODULES

RUE-TSUAN LIU

Tsuan-Huey Clinic

Thyroid nodules are common in adults with a prevalence of approximately 70%. Fine needle aspiration (FNA) with cytologic examinationremains the diagnostic test of choice to distinguish benign from malignant thyroid nodules. However, it fails to discriminate as benign or malignant in up to onethird of cases.To reduce the burden of repeat diagnostic testing and unnecessary surgery, there has been extensive investigation into molecular markers that can be detected on FNA specimens to more accurately stratify a patient’s risk of malignancy. Over the last 2 decades, our understanding of the genetic mechanisms of thyroid cancer has dramatically expanded. This knowledge provides the basis for establishing and further improving molecular tests for thyroid nodules and cancer. In this talkI will discuss the limitation of current cytopathologic evaluation, the development of thyroid molecular testing, and the strengths and limitations of commercially available tests, taking into the consideration of my previous work on the molecular genetics of thyroid nodules in Taiwan.

SE2-3 CURRENT CONCEPT FOR THYROID RADIOFREQUENCY ABLATION

WEI-CHE LIN

Department Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital

Ultrasound-guided RFA has shown good results for benign thyroid nodules, including autonomously functioning thyroid nodules. For benign thyroid nodules, RFA effectively ameliorates symptoms and cosmetic problems by reducing the thyroid nodule volume. Recent case series also suggest ultrasound-guided RFA as an alternative treatment for recurrent thyroid carcinoma in patients who are at a high risk of complications from surgery or who refuse to undergo repeated surgeries. According to a recent meta-analysis of ultrasound-guided RFA treatment for locally recurrent thyroid cancer, the therapeutic success is very high with a significant serum thyroglobulin reduction. The revised American Thyroid Association guideline suggests ultrasound-guided RFA as a useful alternative to surgical resection of metastatic thyroid cancer. Although RFA has been shown to be an excellent treatment modality for benign thyroid nodules and recurrent thyroid cancers, several RFAassociated complications have been reported, including voice change, skin burns, hematoma formation, and hypothyroidism. In this talk, we will brief introduce the indication for thyroid RFA, some technique for the procedure and the possible complication associated with RFA. In the end, we will also like to share the biggest result of Taiwan in the treatment of benign thyroid goiter in Kaohsiung Chang Gung Memorial Hospital.

SE2-4 NEW APPLICATION OF GENETIC TESTING IN CLINICAL DIAGNOSIS

YI-NING SU

Dianthus Maternal Fetal Medicine Clinic, Taipei, Taiwan; Sofiva Genomics Co., Ltd., Taipei, Taiwan.

With the rapidly changing technological platforms in the genetic testing and clinical diagnostics fields, the next-generation sequencing (NGS) has been the major player in non-invasive prenatal screening (NIPS), and liquid biopsy. NIPS and liquid biopsy share the similar mechanism by testing the cell-free fetal DNA (cffDNA) and circulating tumor DNA (ctDNA) in the bloodstream, respectively. The major advantage of NIPS and liquid biopsy is non-invasive procedure. In NIPS, the fetus shed fetal DNA into mother’s bloodstream as well as in liquid biopsy, the tumor cells release tumor DNA into patient’s bloodstream, and the genetic testing can thus detect by drawing blood from the mother or patient. The major difference is NIPS applies in the pregnancy to detect fetal chromosomal aneuploidy while liquid biopsy is for cancer to identify tumor DNA mutations. Unlike the invasive chorionic villus sampling (CVS) or amniocentesis that needs insert a needle through the cervix or abdomen, and biopsy needs to remove a piece of tissue by a surgeon.

NIPS used NGS-whole exome sequencing based and covers the whole fetal genome, i.e 23 pairs of chromosomes. Moreover, NIPS especially focus on the most common chromosomal disorders, including trisomy 13 (Patau Syndrome), trisomy 18 (Edwards Syndrome), and trisomy 21 (Down Syndrome). Furthermore, NIPS now can detect microdeletion syndromes, and also apply to testing for single gene disorders, for example, skeletal dysplasia genetic mutations.

Liquid biopsy can be used to early cancer detection, tumor genotyping, identification of drug resistance markers and monitor the tumor situation during the treatment. Liquid biopsy uses a sensitive NGS-based targeted assay, and detects four relevant mutation classes, including single nucleotide variations (SNVs), insertions/deletions, copy number variations (CNV) and structural rearrangements. It allows detecting tumor-specific alterations and monitoring tumor heterogeneity. Moreover, by noninvasive blood-based monitoring mutation dynamics during therapy enables to have better temporal sampling of tumor evolution. Besides, it can monitor treatment response, disease progression and reoccurrence.

NIPS and liquid biopsy are the most advanced non-invasive genetic testing, and available in routine clinical testing. Both NIPS and liquid biopsy hold great potential in the future for further applications.

SE3-1 NATIONAL PA REGISTRY-BASED EVIDENCE FORCLINICAL PRACTICE OF PRIMARY ALDOSTERONISMIN JAPAN

MITSUHIDE NARUSE1 , JPAS STUDY GROUP1

1Clinical Research Institute of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Primary aldosteronism (PA) is a representative cause of endocrine hypertension characterized by an excess production of aldosterone, hypertension, and various cardiovascular complications. Although clinical practice guidelines have been published, details of each diagnostic stephave not been standardized and heterogeneous clinical practice between institutes and countries remain to be resolved. The aim of the study was to produce evidence to improve clinical practiceof PA in Japan through National registry. Methods: We established the National PA registry by multicenter collaboration of 28 referral centers (Japan PA Study: JPAS). 2800 patients who were diagnosed as PA by positive case detection and at least one positive result in confirmatory testing and underwent AVS between 2006 and 2016 were registered.Results:1) Prevalence of cardiovascular diseases, especially stroke, was significantly higher in PA patients than essential hypertension. Hypokalemia, unilateral subtype and/or PAC larger than 125pg/ml were at greater risk of cardiovascular diseases and had greater need for PA-specific treatment, 2) Since clinical manifestation of PA in the elderly waslike that in younger patients, diagnostic process of PA should follow the same clinical practice guideline even in the elderly, 3) Saline infusion test as a confirmatory testing was useful also for subtype diagnosis,4) More than 90% of PA patients with normokalemia and bilateral disease on CThad bilateral subtype on AVS and AVS is recommended less weakly, while thoseyounger than 35 years with marked PA (hypokalemia and unilateral disease on adrenal CT) could be spared, 5) While biochemical benefit after ADX was achieved solely with Lateralization Index larger than 4 of AVS, clinical benefit was affected not only by LI but also clinical findings such as age, BMI, and blood pressure, 6) Prevalence of cortisol co-secretion was significantly increased in PA with adrenal tumor larger than 2 cm in diameter, suggestingan importance of dexamethasone suppression test. LI larger than 4 was applicable for PA subtype diagnosis even in patients with PA with subclinical cortisol co-secretion, but not in those with overt Cushing syndrome, 7) Although effects of ADX and medical therapy in unilateral PA were comparable in the reno- and cardiovascular events during the 1 year follow up after treatment, ADX provided superior results in correcting hypertension and hypokalemia.Conclusions: Various evidence for elaboration and simplification of clinical practiceof PA was created by excluding institutional bias through National PA registry in Japan. PA registry could serve as a unique infrastructure for future research and development of new diagnostic methods and treatment of PA.(This research was supported by AMED, Japan Agency for Medical Research and development, for the Practical Research Project for Rare/Intractable Diseaseunder Grant Number JP17ek0109122).

SE3-2 ADRENAL VENOUS SAMPLING IN NTUH

CHIN-CHEN CHANG

Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan

Hypokalemia and refractory hypertension usually lead to an increased likelihood of primary aldosteronism (PA), which is the most common cause of secondary hypertension. The main causes of PA are aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH). Unilateral laparoscopic adrenalectomy is usually the treatment of choice for patients with APA, whereas patients with IAH are normally treated with medicines. Adrenal venous sampling (AVS) was introduced in late 1960s as a test to distinguish unilateral from bilateral primary aldosteronism. AVS is held to be the “gold standard” diagnostic procedure for assessing lateralization of aldosterone secretion and thereby identifying the surgically curable forms of primary aldosteronism.

The successful cannulation of both adrenal veins continues to be challenging clinical issues. Adequate adrenal sampling is based on higher cortisol concentration compared with peripheral sampling. We introduced Dyna-CT into the AVS procedure since 2012 and on-site quick cortisol assay (QCA) since 2015. The successful rate had been improved to 97% in non-stimulated AVS.

The development of AVS relies on cooperation with teammates in Taiwan Primary Aldosteronism Investigation (TAIPAI) study group. We have gradually improved the performance on AVS that can be dedicated to the academic research.

SE3-3 CASE DETECTION AND DIAGNOSIS OF PRIMARY ALDOSTERONISM -THE CONSENSUS OF TAIWAN SOCIETY OF ALDOSTERONISM

YA HUI HU

Division of Endocrine and Metabolism, Department of Internal Medicine, Taipei Tzu Chi Hospital, The Buddhist Medical Foundation, Taiwan, ROC

臨床上有懷疑 PA 的病人，需要進行 ARR (aldosterone/PRA) 篩檢，到底哪些人應該被篩檢？ 日本內分泌學會發表的原發性醛固酮症指引中，建議所有高血壓的病人都應該篩檢，在台灣臨床 工作中，對任何疑似 PA 的病人，都可以進行篩檢，例如低血鉀或病患使用 ACEI/ARB 其鉀離子 不如預期那麼高、阻抗性高血壓、電腦斷層意外發現腎上腺腫瘤、太過年輕發病高血壓、病患或 是家族有年輕中風病史等等。我們針對疑似 PA 的病人進行 ARR 篩檢，如果篩檢陽性則需要進一 步做確定診斷，確定診斷的檢測方法很多，在台灣比較常被使用的是生理食鹽水灌注試驗 (saline infusion test, SIT)、captopril 試驗 (captopril challenge test, CCT) 或 ARB 抑制試驗。需要注意的是， 進行 ARR 篩檢時，應盡可能地先矯正低血鉀，倘若 ARR 篩檢正處於低血鉀之際，篩檢可能呈 現假陰性，但如果這時候篩檢呈現陽性，且血漿腎素活性 (plasma renin activity) 低到無法偵測、 血漿醛固酮濃度高 (plasma aldosterone concentration, PAC ＞ 20 ng/dL)，那麼此患者可以不需要再

進行確診試驗。確診試驗陽性的病人需進行亞型分析，先執行腎上腺電腦斷層影像檢查，具有明 顯腫瘤的患者，如果年齡小於 35 歲並且具足原發性醛固酮瘤特質 ( 血鉀低，ARR 很高，電腦斷 層呈現均質富含脂肪的腎上腺腫瘤 ) 可以直接進入手術，但是如果沒有把握或年齡大於等於 35 歲，最好先做功能性的定位，確定醛固酮大量分泌是來自於哪一側，如果是單側功能性的醛固酮 瘤 (APA)，建議進行後腹腔內視鏡腎上腺摘除手術，如果是雙側增生，建議病人長期服用礦物性 皮質素受體拮抗劑 (mineralocorticoid receptor antagonist, MR 拮抗劑 ) 治療。目前台灣有兩項檢查可 以用來執行功能性定位，用以區分醛固酮瘤 (APA) 與雙側增生，第一種是非侵襲性的核子醫學造 影 (NP-59 SPECT/CT)，第二種是腎上腺靜脈採血檢測 (adrenal venous sampling, AVS)，這是目前全 球公認區分亞型的黃金標準檢測，是一項侵入性的檢查，需要把導管置入兩側腎上腺靜脈採血， 此項檢查需要訓練精良的醫師執行，因為右側的腎上腺靜脈採血非常困難，NP-59 SPECT/CT 或 AVS 執行後，如果檢查結果不夠明確，可以兩項都做。當電腦斷層沒有明顯腫瘤，倘若臨床醫師 仍懷疑患者可能有醛固酮瘤 ( 低血鉀、血壓特高、ARR 特高等 )，可以執行 AVS 檢測，以偵測小 的醛固酮瘤。對於電腦斷層沒有明顯腫瘤且臨床上沒有高度懷疑醛固酮瘤的患者，建議長期服用 MR 拮抗劑治療。

SE4-1

從偶發性的甲狀腺結節談起

陳涵栩

臺北榮民總醫院內分泌新陳代謝科

甲狀腺結節是一種常見的臨床問題。流行病學的研究顯示：甲狀腺結節的盛行率在婦女約 5% 而在男性約 1%。然而，高解像力的超音波可以在 40-60% 隨機選擇的個人發現甲狀腺結節。 甲狀腺結節的臨床重要性是需要排除甲狀腺癌。 所有已知或疑似甲狀腺結節的患者應該以血清甲促素 (TSH) 的測定以及甲狀腺超音波 做為初步的檢查。如果血清 TSH 低於正常，應考慮進行放射性同位素甲狀腺掃描。稍高的 血清 TSH 濃度與甲狀腺結節中惡性腫瘤的風險增加相關，需要進行細針穿刺細胞學檢查。 另外血清 TSH 如果正常或升高，放射性同位素掃描不應作為初始的影像評估，以免將囊腫 (Cyst) 誤判成冷結節。應在所有已知或疑似甲狀腺結節的患者中進行甲狀腺超音波檢查， 並且應該包含頸部淋巴結的檢查。 細針穿刺細胞學檢查是在評估甲狀腺結節時重要的臨床檢查，而根據甲狀腺超音波檢查的 甲狀腺結節超音波圖譜，對於甲狀腺結節是否需要進行診斷性的細針穿刺細胞學檢查，可以提 供很好的建議。根據甲狀腺超音波檢查的甲狀腺結節的超音波圖，可以先將甲狀腺結節分成高 度懷疑、中度懷疑、低度懷疑、以及非常低度懷疑是惡性的超音波圖譜，然後根據甲狀腺結節 的超音波圖的懷疑等級訂出需要穿刺的最小直徑。

FDG-PET 掃描可以作為甲狀腺結節是否需要接受細針穿刺細胞學檢查的參考。如果 18FDG-PET 是局部性 (focal) 的攝取增加，甲狀腺癌風險的機會也增加，所以建議對於 > 1cm 的結節進行細針穿刺細胞學檢查。瀰漫性 (diffuse) 的 18FDG-PET 攝取，連同慢性淋巴 細胞性甲狀腺炎的甲狀腺超音波和臨床證據，則不需要進一步影像學檢查或進行細針穿刺 細胞學檢查。

SE4-2 THE ROLE OF FINE NEEDLE ASPIRATION, CYTOLOGY INTERPRETATION, AND MOLECULAR TESTING FOR THYROID NODULES

SHU-FU LIN

Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Taoyuan, Taiwan

Thyroid nodules are a common clinical disease, and differentiated thyroid cancer is becoming increasingly prevalent. Diagnostic thyroid ultrasound (US) should be performed in all patients with a suspected thyroid nodule. Fine needle aspiration (FNA) is a simpleprocedurewithhighaccuracy for evaluating thyroid nodules. US-guided FNA is preferredfor nodules with a higher likelihood of a nondiagnostic cytology or sampling error. The FNA may be performed using palpation if the diagnostic US confirms the presence of a predominantlysolid nodule corresponding to what is palpated.

According to American Thyroid Association guideline 2015,thyroid nodule FNA cytology should be reported using diagnostic groups outlined in the Bethesda System for Reporting Thyroid Cytopathology. This system consistsof six diagnostic categories, including (i) nondiagnostic/ unsatisfactory; (ii) benign; (iii) atypia of undetermined significance/follicular lesion of undetermined significance; (iv) follicular neoplasm/suspicious for follicular neoplasm, a category that also encompasses the diagnosisof Hu¨rthle cell neoplasm/suspicious for Hu¨rthle cellneoplasm; (v) suspicious for malignancy, and (vi)malignant, and provides an estimation of cancer riskwithin each category.

Molecular markers are frequently used for diagnostic,prognostic or predictive purposes. The proposeduse of molecular markers in indeterminate thyroid FNA specimens is diagnostic and with the implication of a companion use to informdecision-making on primary surgical treatment.A number of molecular approaches have been studied in the clinical setting of indeterminate FNA cytologic interpretation.

SE4-3

細胞學檢查後的部份對策

施翔蓉

臺大醫學院內科／臺大醫院代謝內分泌科

當細針穿刺細胞學檢查結果為不確定良惡性 (indeterminate: AUS/FLUS, FN, SUSP) 時，並不建 議常規使用正子掃描檢查去判別結節的良惡性。 關於手術方式，當細針穿刺細胞學檢查結果為不確定良惡性時，如果結節只有一顆，建議一 開始採用甲狀腺單側切除術。但這也不是一定的，可依照臨床狀況、超音波影像、病人需求、分 子生物學檢查等等來調整。在有惡性機率增加的狀況，且若之後甲狀腺單側切除病理檢查結果為 惡性時將建議雙側甲狀腺全切除的話，在一開始細針穿刺細胞學檢查結果為不確定良惡性時，會 建議甲狀腺全切除比較合適。若之後甲狀腺單側切除後病理檢查結果發現為惡性時將建議雙側甲 狀腺全切除的話，當病人有雙側結節、或有明顯的其他疾病、或是病人希望接受雙側甲狀腺切除 術以避免之後還有需要再切除另一側甲狀腺的狀況，可考慮在一開始細針穿刺細胞學檢查結果為 不確定良惡性時，接受甲狀腺全切除術。 關於細針穿刺細胞學檢查結果為良性的甲狀腺結節長期追蹤計畫，建議應依超音波影像特徵 而異。若結節有高度懷疑惡性的超音波影像特徵，應在一年內接受超音波和超音波導引細針穿刺 細胞學檢查。若結節有低到中度懷疑惡性的超音波影像特徵，建議應每 1 到 2 年接受一次超音波 檢查。若超音波影像顯示結節有明顯增大或有產生新的疑似惡性的超音波影像特徵，則應接受細 針穿刺細胞學檢查；或是繼續以超音波觀察追蹤，若結節持續增大，則安排細針穿刺細胞學檢查。 若結節具有非常低度懷疑惡性的超音波影像特徵，追蹤超音波觀察結節有無變大以決定是否需要 安排細針穿刺細胞學檢查的效果很有限。 若結節沒有達到細針穿刺細胞學檢查的標準而沒有接受穿刺檢查，則追蹤計畫應也是依超音 波影像特徵而異。

SE4-4

懷孕期間發現的結節的處置

蘇登煌

遠東聯合診所醫護部

懷孕婦女的結節的盛行率大約 3 到 21% 間，隨著其懷孕的年紀次而增加，大多數在懷孕期 間發現的結節為原先在懷孕前已存在的結節，而懷孕會跟原先已存在的結節的大小增加有關，並 跟部分的新結節的生成有關。目前並無研究顯示懷孕期間發現的結節的惡性可能性並不比沒有懷 孕期間發現的結節為高。懷孕期間發現的惡性結節很少見。過去研究中顯示第二妊娠期進行行甲 狀腺手術，並沒有任何母親或新生兒的後遺症。如果要在懷孕期間進行手術，為了最小化流產的 風險，手術應在妊娠 24 週前的第二妊娠期內進行，且應由熟練的外科醫師執行，以減少第一妊 娠期進行手術所可能導致胎兒的器官病變及自動流產和第三妊娠期進行手術所可能導致的早產。 對於分化型甲狀腺癌的手術時間，延後手術時間到產後對預後沒有影響，而懷孕對於分化型甲狀 腺癌的預後的影響並沒有定論。細針穿刺在懷孕期間仍是一個安全的診斷工具，可在任一妊娠期 內進行。標準的細胞診斷標準可適用於懷孕期間發現的結節。 對於甲狀腺功能正常或低能的懷孕婦女，如遇到臨床上有意義的結節，細針穿刺可於任一 妊娠期內執行或延到懷孕結束後執行細針穿刺檢查。但對於超音波追踨中快速長大或有症狀的 結節，細針穿刺應該執行。對於細胞學檢查為良性的懷孕婦女，懷孕期間並不需要特別的監測 策略，其處置同未懷孕的婦女，且不建議使用甲狀腺素壓抑治療。如結節的細胞學結果為不確 定時，若無嚴重的局部症狀或令人擔心的現象 ( 如妊娠 24-26 週前急速長大或超音波下有疑似淋 巴結轉移 )，手術應延到產後進行，相反地，若臨床上呈現侵略性的行為，則應考慮手術。分子 標誌分析的角色在懷孕中為不確定。如結節的細胞學結果為惡性時，若於早期懷孕時，經由細胞 學檢查診斷為甲狀腺癌之婦女應該用超音波監測。假如它在妊娠 24-26 週前急速長大 ( 即結節的 長寬高其中有兩個象限增大 20% 以上且至少增大 2 mm 以上，或是結節的體積增大 50% 以上 ) 或 超音波下有疑似淋巴結轉移的現象，手術應在第二妊娠期間進行。反之，若此腫瘤在妊娠中期都 很穩定，手術應延至生產後。但如細胞學檢查診斷為髓質癌或未分化癌，則應進行手術。如於第 三妊娠期間診斷為甲狀腺癌之婦女，手術應延至生產後。如遇到懷孕期間發現甲狀腺結節的婦女， 可依上述建議及超音波變化擬定合適的方針。

SE4-5 POST-OPERATIVE RISK ASSESSMENT AND RADIOIODINE THERAPY OF DIFFERENTIATED THYROID CANCER

YEN-HSIANG CHANG

Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan, ROC

In 2015, the American Thyroid Association (ATA) renewed the guidelines regarding the management of differentiated thyroid carcinoma (DTC) based on the results of studies published since 2009. According to the new evidences, the treatment of DTC has continued to modify and evolve.

Post-surgical radioactive iodine (RAI) ablation is almost routinely performed, however, recent studies showed that ablation is not beneficial for survival in low-risk patients. Recombinant human thyroid-stimulating hormone (rhTSH) has been recommended as the first line mode of TSH stimulation except for high risk patients or those with recurrent/metastatic disease. Although low-dose (30mCi) ablation showed similar ablation rate to high-dose ablation, long-term outcome has not yet been established.

According to the follow-up of DTC patients, no single factor is capable of completely predicting the long-term outcomes. The concepts of “dynamic risk assessment” have important implications on DTC management during follow-up.

Recently, policy for treating DTCs has changed in many aspects and tends to be more “personalized”. We have to continue to capture the new information with time to present the best treatments for DTC patients.

SE5-1 UP-TO-DATE OF CLINICAL PRACTICE OF PHEOCHROMOCYTOMA/ PARAGANGLIOMA

MITSUHIDE NARUSE1, MIKA TSUIKI1,2, HIRONOBU UMAKOSHI1,2, TETSUYA TAGAMI1,2, AKIYO TANABE3, PHEO-J STUDY GROUP1, ACPA-JSTUDY GROUP3

1Clinical Research Institute of Endocrinology and Metabolism, 2Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto,3Department of Diabetes and Endocrinology, National Center for Global Health and Medicine, Tokyo, Japan

A tumor of chromaffin cells of the adrenal medulla is termed as pheochromocytoma and that of the extra-adrenal paraganglion system is termed as paraganglioma with a general term of pheochromocytoma/paraganglioma(PPGL).While bilateral, extra-adrenal, multiple, or malignant disease is about 10% of PPGL, germline mutation has been demonstrated in about 30%.PPGL has 2 unique clinical aspects, hypersecretion of catecholamine (CA) and malignant potential, requiring comprehensive clinical practice among the related departments. Diagnosis of treatment of PPGL follows the Clinical Practice Guidelines of the task force group for Pheochromocytoma by Ministry of Health, Labor and Welfare in Japan (2012) andClinical Practice Guideline for Pheochromocytoma and Paraganglioma of Endocrine Society (2014).Major chances of making diagnosis are 1) various symptom termed ‘Spell’, 2) hypertension (paroxysmal, crisis, treatment-resistant, complication of diabetes mellitus) and 3) adrenal incidentaloma, which can be designated as ‘PPGL-high risk’ group. Clinical practice of PPGL consists of 3 major steps: functional diagnosis of excess CA excretion, imaging diagnosis of tumor localization, and choice of treatment.Functional diagnosis includes measurement of plasma CA levels, fractionated metanephrines in spot urine, and 24 hrs urinary CA excretion. Determination of plasma and urine CA during paroxysmal hypertension is also useful. Plasma free-metanephrines accounting for 10% of the total has been recommended as the most sensitive and specific confirmatory test. Diagnostic imaging includes adrenal CT scan and MRI. Since 90% of PPGL is pheochromocytoma, the primary tumor is readily recognized in the adrenal. Combination of CT, MRI, and 123I-MIBG scintigraphy is indicated if the primary tumor is not found.18F-FDG-PET is usefulin detecting metastatic lesions of malignant PPGL.Laparoscopic tumor resection after enough amount and period of treatment with alphablocker doxazocin is the principle choice of treatment. The lecture will focus on current topicsincluding the new WHO classification, asymptomatic PPGL, genetic testing, pathological grading of malignancy, CA synthase inhibitor metyrosine, and new radionucleotide therapy in addition to the general aspects of clinical practice of PPGL.(Funding: Supported by the Health Labor Sciences Research Grant for the Research on Measures for Intractable Diseases from Ministry of Health Labor and Welfare in Japan, the National Center for Global Health and Medicine, Japan,27-1402)

SE5-2 GENETICS AND DIAGNOSIS OF PHEOCHROMOCYTOMA/ PARAGANGLIOMA

PEI-LUNG CHEN

Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Departments of Medical Genetics and Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan, ROC

Pheochromocytoma (PCC) and paraganglioma (PGL) are catecholamine-secreting tumors of neural crest origin, derived from the adrenal medulla or extra-adrenal ganglia, respectively. They are very important diseases drawing high attention. Clinically, although often benign tumors, they are associated with high morbidity and mortality because of mass effect and high blood circulating catecholamines. Roughly one quarter of PCC/PGL are malignant. Furthermore, high recurrence rate in family members, but lack of a reliable prediction which members to be affected, makes the diseases daunting. Scientifically, PCC/PGL are tumors related to the hypoxia pathway, and many known causative genes are also key players of neoplasia syndromes, such as multiple endocrine neoplasia, neurofibromatosis, etc. Therefore, basic research on PCC/PGL often shed light on the mechanism of fundamental pathways. PCC/PGL are actually not rare, and the prevalence figures approximate 0.2% in autopsy series. The mean age at diagnosis is about 40 years, with slight female preponderance. Clinical manifestations can vary widely, depending on the predominant type of catecholamine secreted (epinephrine, norepinephrine, dopamine), the presence of co-secreted neuropeptides and whether secretion is sustained or episodic. A characteristic presentation is intermittent paroxysms of symptoms and signs related to episodic catecholamine release, including hypertension, headache, anxiety, sweats, pallor, flushing or palpitation. Traditional diagnosis relies on clinical presentations, biochemistry data (VMA, catecholamines, metanephrine, normetanephrine, etc.) and image examinations. However, variable and non-specific manifestations make early diagnosis a real challenge.

There are at least 15 well-documented genes (NF1, RET, VHL, SDHD, SDHC, SDHB, SDHAF2, SDHA, TMEM127, MAX, FH, KIF1B, EGLN1, RASH1 and EPAS1) that can cause PCC/PGL with an autosomal dominant transmission. Other additional genes were recently reported to cause PCC/PGL through somatic mutation (ARNT, ATRX, BRAF, CSDE1, FGFR1, IDH1, SETD2 and TP53) or gene fusion (BRAF, MAML3 and NGFR). NGS disease panel is a powerful tool for genetic diagnosis. Better databases are needed to clarify the pathogenicity of certain identified variants. Progress in genetics/ genomics can provide better genetic diagnosis and counseling, as well as guide the treatment strategy. Furthermore, identification of novel PCC/PGL-causing genes has the potential to shed light on the pathophysiology of PCC/PGL, which could potentially lead to new therapeutic breakthrough.

SE5-3 SURGICAL TREATMENT OF PHEOCHROMOCYTOMA

KUO-HOW HUANG

Department Radiation Urology, National Taiwan University Hospital, Taipei, Taiwan, ROC

Pheochromocytomas are relatively uncommon tumors among adrenal tumors. Patients with pheochromocytomas are potentially curable by surgical treatment; however, pheochromocytomas present a substantial risk of morbidity and mortality during or after surgical procedures. In recent decades, most pheochromocytoma could be surgically treated by minimally invasive methods. In this speech, I will talk about pre-operative preparation, principles of surgery, anesthetic management, intra-operative considerations, surgical outcomes and post-operative follow-up and share with the experiences on surgical outcomes of pheochromocytoma in our institute.

SE6-1 CURRENT CHALLENGES IN THE TREATMENT OF PATIENTS WITH HYPERLIPIDEMIA

WEI-SHIUNG YANG

Department Internal Medicine, National Taiwan University Hospital Taipei,, Taiwan,

Hyperlipidemia is a major modifiable risk factor in the pathogenesis of atherosclerosis. In the past decades, we have witnessed a huge progress in the management of hypercholesterolemia. With the use of statins and ezetimibe, we are able to reduce blood LDL-C and consequently the CV risk in patients with hyperlipidemia. Recent introduction of PCSK9 inhibitors further moves this field into a new era in which we can even bring down the LDL-c to a level which we could hardly imagine before. But the questions remain, first whether there is still residual CV risk after this and how we can manage it; second how low the bottom of LDL-C lowering will be. Should we continue to explore the bottom of LDL-C lowering and hope that this may reduce the CV risk further?

Aside from the treatment of LDL-C, not much progress has been made in the treatment of hypertriglyceridemia and low HDL-C. The management of extreme high triglycerides probably caused by various genetic etiologies is still difficult. The development of HDL-C raising drugs, such as CETP inhibitors has not been always successful. Nonetheless, a recent trial of IL-1β inhibitor targeting on the inflammatory pathway shed light on the reduction of residual CV risk beyond lipid lowering therapy. Future exploration of the science and the clinical management of the residual CV risk in the future is expected to be very exciting!

SE6-2 PCSK9 INHIBITORS, A NEW THERAPEUTIC REGIMEN FOR PATIENTS WITH DYSLIPIDEMIA- FROM JAPAN’S PERSPECTIVE

MASATO ODAWARA

The Department of Diabetes, Endocrinology, Metabolism and Rheumatology, Tokyo Medical University

Diabetes is a major risk factor for cardiovascular diseases (CVD) and vulnerable plaques associated with dyslipidemia are less likely to regress in patients with diabetes.The Japan Atherosclerosis Society Guideline was revised in 2017, which recommend the reduction of LDLcholesterol (LDL-C) below 70 mg/dLin diabetic patients associated with additional risk factor. The claims database analysis in Japan, however, showed low achievement rate of LDL-C goal in a CVhigh risk population in a routine care setting. Alirocumab,a PCSK9 inhibitor, has been shown to be safeand highly effective in Japanese population in Phase 3 trial,ODYSSEY Japan and has been on the market since July, 2016.

In this symposium, I would like to discussthe value of alirocumabas a new therapeutic regimen for the management of dyslipidemia from Japan perspective.

SE6-3 THE ROLE OF PCSK9 INHIBITORS FOR LDL-C REDUCTION IN DIABETIC PATIENT WITH ASCVD- FROM ENDOCRINOLOGIST POINT OF VIEW

HORNG-YIH OU

Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan City, Taiwan, ROC

Patients with type 2 diabetes have increased cardiovascular risk. Individuals with type 2 diabetes often have elevated levels of non-high-density lipoprotein cholesterol, triglycerides, and small, dense low-density lipoprotein, which further increase their cardiovascular risk.

Statin therapy is commonly used to manage dyslipidaemia, particularly with the goal of reducing LDL-C and non-HDL-C levels. Although significant reductions in cardiovascular events have been observed in individuals with diabetes treated with statins, real-world studies often report underutilisation of statins and suboptimal dosing in high-risk patients. Even with maximally tolerated statin, many diabetic patients continue to have persistent lipid abnormalities, and are therefore exposed to residual cardiovascular risk.

PCSk9 inhibitor is a new class of lipid-lowering agent which showed significant benefit in reducing LDL cholesterol and cardiovascular outcomes in high-risk patients, but specific efficacy for patients with diabetes is unknown. It is until recently that PCSK9 inhibitor’s LDL-reduction effect been reported in diabetic patients. In this talk, the focus will be on the efficacy and safety of PCSK9 inhibitor, alirocumab, in randomized trials of diabetic patients (ODYSSEY DM-insulin and ODYSSEY-DM-Dyslipidemia). These studies prove the primary efficacy endpoints on reductions of LDL (ODYSSEY DM-insulin) and non-HDL cholesterol (ODYSSEY-DM-Dyslipidemia) as expected, without alterations in glycemia. Further validation of PCSK9 inhibitor regarding MACE outcome reductions will be promising to reduce cardiovascular risk in diabetes.

SE6-4 EVIDENCE-BASED PCSK9 INHIBITORS: FROM BENCH TO CLINIC AND ITS PROSPECT

WEI-WEN LIN

Cardiovascular center, Taichung Veteran Hospital, Taichung, Taiwan

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have been approved by FDA for the treatment of high risk cardiovascular disease patients with inadequately treated levels of LDL-C. They are capable of lowering LDL-C by as much as 60 percent in patients on statin therapy. PCSK9 binds to LDL-R on the surface of hepatocytes, leading to the degradation of the LDL-R and higher levels. Antibodies to PCSK9 interfere with its binding of the LDL-R leading to higher hepatic LDL-R expression and lower plasma LDL-C levels. Alirocumab and evolocumab are fully humanized monoclonal antibodies approved for clinical used.

Following an initial subcutaneous injection of PCSK9i, the onset of inactivation of PCSK9 enzyme occurs within four to eight hours following the first subcutaneous injection, elimination is expected to occur via saturable binding to PCSK9 enzyme and nonsaturable proteolysis to small peptides and amino acids. The effective elimination half-life of the available PCSK9 inhibitors is 11 to 20 days. PCSK9i studies are landmark trials providing formal evidence that treatment targeted at PCSK9 receptor confers additional cardiovascular benefit beyond that achieved by lipid-lowering treatment alone. The side effects of treatment with monoclonal antibodies against PCSK9 appear to be generally mild but are being meticulously evaluated in separate sub studies. It is anticipated that the results of the PCSK9i trial will soon be implemented in international guidelines regarding the treatment of high-risk patients, directing clinicians in the use of this new and expensive class of drugs.