SE Symposium-Endocrine (1-5

SE1-1

CUSHING’S SYNDROME: UPDATE AND REVIEW

due to prolonged exposure to cortisol. Signs and symptoms may include abdominal obesity with thin arms and legs, a round red face, a fat lump between the shoulders, purplish stretch marks (striae), acne, fragile skin with heals poorly, muscles weakness, osteoporosis and high blood pressure. Women may have more hair and irregular menstruation. Occasionally there may be changes in mood, headaches, and a chronic feeling of tiredness.

Cushing’s syndrome is generally considered a rare disease. It occurs an incidence of 0·2–5·0 per million people per year with a prevalence of 39–79 per million in various populations. However, a mild degree of overproduction of cortisol without obvious symptoms is more common. Endogenous Cushing’s syndrome is divided between ACTH-dependent (about 80%) and ACTH-independent (about 20%) causes. Among ACTH-dependent forms, pituitary corticotroph adenoma (Cushing’s disease) is the most common, followed by ectopic ACTH syndrome, and CRH syndrome is rare. Cortisol excess from primary unilateral adrenal adenomas or carcinomas suppresses ACTH. Rarely, Cushing’s syndrome is caused by primary bilateral macronodular adrenal hyperplasia (BMAH), ACTHindependent macronodular adrenal hyperplasia (AIMAH) or primary pigmented nodular adrenocortical disease (PPNAD) and its non-pigmented variant, isolated micronodular adrenocortical disease. The second step is screening and confirmation of diagnosis: 24 h urine free cortisol (UFC), the 1 mg overnight (or two-day, 2 mg) dexamethasone suppression test, and late night salivary cortisol are recommended. To optimize sensitivity, guidelines recommend using the upper limit of the dexamethasone as the cut-off for healthy responses. Patients with two abnormal screening test results can be diagnosed with Cushing’s syndrome. Once Cushing’s syndrome is diagnosed, the cause should syndrome is measurement of plasma ACTH. A decreased plasma ACTH concentration in a patient usually suggests an adrenal cause and CT scan for adrenal gland is necessary. For ACTH-dependent Cushing’s syndrome, MRI of pituitary is the investigation of choice. If the differentiated diagnostic testing is ectopic ACTH syndrome, further image should include high-resolution CT scanning of the chest and abdomen.

SE1-2

MEDICAL MANAGEMENT OF CUSHING'S SYNDROME

HUNG-YU CHANG

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taiwan, R.O.C.

The main indications for medical therapy of Cushing's syndrome(CS) are (1) when surgery being contraindicated, (2) control of hypercortisolism in preparation for surgery, (3) persistence or recurrence of hypercortisolism after surgery, (4) control of hypercortisolism while waiting for the effect of pituitary radiation in patients with Cushing's disease(CD), and (5) treatment of occult ectopic ACTH syndrome. Ketoconazole and metyrapone have been the most frequently used medical therapies for CS. Ketoconazole has been used worldwide for more than 30 years in CS. A retrospective ketoconazole study comprising 200 patients with CD showed that almost 50% of patients who continued on ketoconazole therapy achieved biochemical control and clinical improvement and 20.5% of patients stopped the treatment due to poor tolerance. Metyrapone is a pharmacologic agent used survey including 195 patients with CS, metyrapone therapy achieved a control rate ranged between 43 and 76% in reference to different criteria of biochemical control. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness. Fluconazole inhibited 11-deoxycortisol and cortisol production. There are few reports of fluconazole use in CS patients. Mitotane is an antineoplastic agent used in the treatment of adrenocortical carcinoma but also rarely used to treat CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects, could control hypercortisolism in the majority of CD patients. Etomidate is the only drug available for intravenous use and a significant suppression of serum cortisol levels occurs after 5 hours. As a glucocorticoid receptor blocker, Mifepristone acts directly at the cortisol glucocorticoid receptor and the progesterone receptor. The US FDA approved mifepristone for the treatment of hyperglycemia associated with CS in 2012. The D2-receptor agonist cabergoline, induces long-term biochemical remission in about 30% of patients with CD, although escape occurs .Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor–binding profile, with high binding affinity for somatostatin-receptor subtype 5. Pasireotide is the only agent approved by Taiwan FDA for treatement of CD. In a 12-month phase 3 study of Pasireotide in CD, the median urinary free cortisol level decreased by approximately 50% but hyperglycemia-related adverse events developed in 118 of 162 patients. There is still a need for a medical therapy that is more effective and with less adverse effects for patients with CS. A longacting, once-monthly formulation of pasireotide is under clinical development for CD and novel steroidogenesis inhibitors are being developed, such as levoketoconazole and osilodrostat (LCI699). Retinoic acid decreases ACTH secretion through action on POMC gene transcription, and normalises UFC concentrations in some patients with CD.

SE2-1

MICRORNA-MEDIATED NETWORKS UNDERLIE IMMUNE RESPONSE REGULATION IN PAPILLARY THYROID CARCINOMA

1C-T HUANG, 1Y-J OYANG, 4H-C HUANG, 1,2,3H-F JUAN

1 Graduate Institute of Biomedical Electronics and Bioinformatics, 2 Department of Life Science, 3 Institute of Molecular and Cellular Biology, National Taiwan University, 4 Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.

Papillary thyroid carcinoma (PTC) is a common endocrine malignancy with low death rate but increased incidence and recurrence in recent years. MicroRNAs (miRNAs) are small non-coding RNAs with diverse regulatory capacities in eukaryotes and have been frequently implied in human cancer. Despite current progress, however, a panoramic overview concerning miRNA regulatory networks in PTC is still lacking. Here, we analyzed the expression datasets of PTC from The Cancer Genome Atlas (TCGA) Data Portal and demonstrate for the first time that immune responses are significantly enriched and under specific regulation in the direct miRNA2target network among distinctive PTC variants to different extents. Additionally, considering the unconventional properties of miRNAs, we explore the protein-coding competing endogenous RNA (ceRNA) and the modulatory networks in PTC and unexpectedly disclose concerted regulation of immune responses from these networks. Interestingly, miRNAs from these conventional and unconventional networks share general similarities and differences but tend to be disparate as regulatory activities increase, coordinately tuning the immune responses that in part account for PTC tumor biology. Together, our systematic results uncover the intensive regulation of immune responses underlain by miRNA-mediated networks in PTC, opening up new avenues in the management of thyroid cancer.

SE2-2

LYMPHOCYTIC THYROIDITIS AND PAPILLARY THYROID CARCINOMA

Lymphocytic (Hashimoto’s) thyroiditis is an autoimmune disease in thyroid. The pathogenesis of

Hashimoto's thyroiditis is due to a combination of genetic and environmental factors. This disease occurs in 0.3-1.5 per 1000 individuals worldwide and is more predominant in females with gender prevalence ratios of 5 to 20:1.

Papillary thyroid carcinoma is the most common type of thyroid cancer representing > 80% of all thyroid cancer cases. It occurs more frequently in women and presents in the 20-55 years of age. The driver mutations, including BRAF, RAS and PAX8-PPARG, are associated with different histologic variants of papillary thyroid carcinoma and confer distinct patterns of gene expression, signaling and clinical characteristics.

Some reports demonstrate lymphocytic thyroiditis is associated with the development of papillary thyroid carcinoma and is a predictive factor of prognosis. Though this is still a subject of debate. More prospective studies are needed to clarify these correlations.

SE2-3

IMMUNE-RELATED ENDOCRINE ADVERSE EVENTS

CHIA-CHI LIN, MD, PHD

Department of Oncology, National Taiwan University Hospital; Department of Urology, National Taiwan University College of Medicine

Four monoclonal antibodies targeting immune checkpoint proteins are available for the treatment of patients with melanoma, non-small cell lung, head and neck, kidney, and urothelial cancer as well as Hodgkin lymphoma, and their use will likely expand in the future to additional tumor types.

Immune checkpoint inhibition may trigger autoimmune syndromes involving different organs, including several endocrine glands (pituitary, thyroid, adrenals, and endocrine pancreas). Hypophysitis is more frequently associated with ipilimumab (anti-CTLA4 antibody), whereas the incidence of thyroid dysfunction is higher with nivolumab / pembrolizumab / atezolizumab (anti-PD1 / PDL1 antibodies). Primary adrenal insufficiency can rarely occur with either treatment. Autoimmune diabetes is very rare. As hypophysitis and adrenalitis may be life-threatening, endocrinological evaluation is essential particularly in patients developing fatigue and other symptoms consistent with adrenal insufficiency. Corticosteroids should be promptly used when hypophysitis-induced adrenal insufficiency or adrenalitis are diagnosed, but not in thyroiditis or diabetes. No impact of

In absence of predicting factors, accurate information to patients provided by the oncology care team is essential for early diagnosis and to limit the consequences of checkpoint inhibition-related endocrine toxicity.

SE3-1

GENETICS OF ENDOCRINE AND METABOLIC DISEASES- OVERVIEW AND COMPLEX DISEASE GENETICS

WEI-SHIUNG YANG, MD., PHD.

Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, and Department of Internal Medicine, NTU Hospital

The genetics of human diseases are generally categorized into monogenic or polygenic (a trendy term is complex disease) in etiology. The monogenic disorders usually reveal a compatible mode of be linked to the disease phenotypes. Therefore, looking for a genotype can lead to the diagnosis of a disease. On the other hand, the number of candidate genes for a complex disease can be huge, from ten to hundreds. The predictive value of a genotype is usually very low. However, it is still important not diabetes mellitus and autoimmune thyroiditis will be given to illustrate these issues in this talk.

SE3-2

MENDELIAN DISEASE IN ENDOCRINE PRACTICE

TJIN-SHING JAP, M.D.

Division of Endocrinology and Metabolism, Taipei-Veterans General Hospital, School of Medicine, National Yang Ming University, Taipei, Taiwan 112

Single gene inheritance, also referred to as a Mendelian inheritance is a straight forward in pathogenesis and can be utilized in daily endocrine practice because a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene may cause association (GWA) studies, the primary investigation method for monogenic disease was through inheritance studies by using positional cloning in the families. The phenotype studies are crucial in a

From the experience we earned, early detection of the mutated gene is warranted because surgical intervention may be avoided from one to the other with a proper treatment regimen being administered early in the course of the disease, or even may stop the medication or shift the therapeutic regimen, respectively.

With the recent advance in Genome wide sequencing by using next generation sequencing in hand, scientists right now easily to match monogenic disease phenotypes to their corresponding genes e.g., Allan--Herndon--Dudley syndrome, SHORT syndrome, etc. To keep this in mind, once a disease corresponding gene product (protein) might work in a manner that alters its biological function. The nature of disease-associated changes in protein structure and function enable the drug hunter in turn to design drugs specifically targeting corresponding proteins in patients with rare disease in which Familial Renal Gucosuria and SGLT2 inhibitor as the example. rate of mutations. Early diagnosis of monogenic endocrine disease is necessary, not luxury one. The patients with rare disease may provide a clue for drug discovery. Genetic counseling is a part of practice

SE3-3

Precision Medicine and Clinical Genetic Testing

1,2,3,4PEI-LUNG CHEN,MD, PHD

1Department of Internal Medicine, 2Department of Medical Genetics, National Taiwan University Hospital; 3Graduate Institute of Medical Genomics and Proteomics, 4Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taiwan

Precision medicine, according to the National Institutes of Health (NIH), USA, is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”. Under this approach, diagnostic testing is often employed for diagnosis and/or for selecting appropriate therapies based on the patient’s genetic content. Given that the genetic models of diseases (for example, single gene disease vs. complex disease) can vary from diseases to diseases, the most appropriate method for genetic testing therefore will also keep evolving. In addition to traditional platforms (such as Sanger sequencing, multiplex ligation precision medicine and the state-of-the-art methodologies of clinical genetic testing will be illustrated.

SE4-1

CHROMOGRANIN A AND NEUROENDOCRINE TUMORS

Gastroenteropancreatic neuroendocrine tumor (GEP NET) is the second prevalent malignancy in gastrointestinal tract. The prevalence rate was twice higher than pancreatic cancer in United State. The incidence and prevalence of NETs increased approximately 500% over the past 30 year, which may be partially due to improvement of diagnosis and clinical awareness. The diagnosis of GEP NET is difficult because of confusion nomenclature and the varieties of cell differentiated in pathologic specimen, from poorly differentiated carcinoma to well-differentiated tumors. GEP NET also exhibits a wide spectrum of clinical behavior. The initial clinical symptoms are often indolent and some of

An accurate diagnosis in GEP NET is important because their diverse tumor behavior, drug of choice for systemic therapy and the predicted tumor response under systemic therapy, which are very different to exocrine carcinoma in gastrointestinal tract. Additionally, classic biomarkers such as CEA and CA199, which were widely used in exocrine carcinoma in evaluate disease status and monitor response to systemic therapy, were useless in GEP NET.

Chromogranin A (CgA) is a 439 amino acid protein and belongs to one of granin family, which is a principle component of dense-core granule in neuroendocrine cells (7). CgA expression generally correlates with dense-core granule numbers within neuroendocrine cells. Neuroendocrine cells cosecrete CgA and hormone during the secretory granule exocytotic process, thus CgA had been reported as a marker of neuroendocrine cell activity (9). Serum CgA had been used as a biomarker in diagnosis, evaluation of tumor status and evaluate tumor response under systemic therapy in GEP NET. However, the experiences and clinical values of CgA in GEP NET were limited out of western countries. The purpose of this section was to evaluate the clinical roule of serum CgA levels with disease status and treatment response in GEP NET patients in Taiwan.

SE4-2

MEDICAL TREATMENT FOR NEUROENDOCRINE TUMORS (NET): FOCUSING ON PANCREATIC/MIDGUT NET AND TARGETED THERAPY

CHIUN HSU

Graduate Institute of Oncology, National Taiwan University College of Medicine; Department of Oncology, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei, Taiwan

Pancreatic NET and other midgut-derived NET are used to be considered as distinct disease entities because of their different clinical presentation and responses to systemic therapy. Results from molecular genetics also implied that they have distinct pathogenic processes. Molecular targeted agents, including the mTOR inhibitor everolimus and the multikinase inhibitor sunitinib, are approved for the treatment of low-grade, advanced pancreatic NET, whereas somatostatin analogues are used for other midgut NETs. In this presentation updated results from clinical trials of molecular targeted agents, along or in combination, and radiolabeled somatostatin analogue therapy will be summarized and the evolving landscape of clinical trials will be discussed.

SE4-3

FUTURE OUTLOOK OF GEP-NETS IN TAIWAN AND TREATMENT PARADIGMS UPDATE

YAN-SHEN SHAN MD, PHD

Distinguished Professor and Director; Department of Clinical Medicine Research; Division of General Surgery, Department of Surgery, NCKUH; Institute of Clinical Medicine, College of Medicine, NCKU, Tainan, Taiwan ROC

Since introduction of new classification of GEP-NET on 2010, there is a great change in the improve patient survival and quality of life. Aggressive surgical resection for primary NETs and metastatic NETs were done based on the advanced image studies and improvement of surgical technique and postoperative care. TCOG has launched a registry trial for recording of NETs since 2013. After management of this rare tumor, we found several emergent needs in management of GEPNET should be discussed in future. 1. The role and regimen as neoadjuvant therapy for metastatic biological therapy/ target therapy after resection in metastatic GEP-NETs 4. The exact role CgA in the following of GEP-NETs. Here, we will present our experience in the management of GEP-NETs based on these points.

SE4-4

NEUROENDOCRINE TUMOR AND MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

S-R S

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

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with an estimated incidence of 0.25%. It is characterized by the occurrence of parathyroid adenomas, gastropancreatic neuroendocrine tumors (NET) and anterior pituitary tumors. Diagnosis of MEN1 is established in an individual by one of three criteria: the occurrence of two or more MEN1-associated endocrine tumors; MEN1 mutation. Respective tumors occurring in MEN1 patients tend to be larger, more aggressive and resistant to treatment than those occurring in non-MEN1 patients.

Individuals having a high risk of developing MEN1-associated tumors should be offered a program of combined clinical, biochemical and radiological screening. According to the guidelines, screening of gastropancreatic NET should include an annual plasma biochemical evaluation of a (VIP), pancreatic polypeptide, chromogranin A, and insulin. Annual pancreatic and duodenal visualization with magnetic resonance imaging, computed tomography, or endoscopic ultrasound was also suggested. However, the nature and timing of screening will depend on local resources, clinical judgement and patient preferences. Patients with MEN1 should be managed by a multidisciplinary team. The main aim of treatment is to maintain disease- and symptom-free and to maintain a good quality of life.

On the other hand, the association of MEN1 is 25-40% in gastrinoma, 5% in insulinoma, 20% in non-syndromic NET, 45% in somatostatinoma, 10% in gastrinoma, and 5% in VIPoma. Clinical examination and family history survey to exclude complex cancer syndromes including MEN1 were suggested to be performed in all cases of NETs in guidelines. Screening strategy including appropriate biochemical and radiological investigations also depends on local resource and clinical judgement.

SE5-1

DEBATE AND CONSENSUS OF THYROID TUMOR MANAGEMENT IN TAIWAN

S-T CHEN

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taiwan, R.O.C.

Up to 30% of well-differentiated thyroid cancer (WDTC) patients may experience a clinically significant recurrence throughout their lifetime. Since that the currently used AJCC/UICC staging and/or disease persistence. The truth of the ongoing and dynamic risk of WDTC recurrence led to the in AJCC/UICC staging were incorporated in 2009 by the American Thyroid Association (ATA). The risk of disease recurrence to classify patients as low, intermediate, or high risk for recurrence. After a follow-up for a median of 7 years after their original treatment, Tuttle et al. added in a response-to likely to recur versus those likely to remain disease-free. Accordingly, management algorithms for low, intermediate and high risk WDTC were illustrated in the 2015 ATA guideline; even so, topics such as management of micropapillary thyroid cancer, the need of postoperative radioactive iodine ablation, the need of central neck dissection, etc. still remains room for debate.

Additional tools such as biochemical markers (for example, the expression of NIS, VEGF receptors, etc), genetic mutations (RAS, RET/PTC, BRAF) and molecular markers for distant validity.

SE5-2

NUCLEAR MEDICINE-RELATED DEBATES AND CONSENSUSES OF DIFFERENTIATED THYROID CANCER MANAGEMENT IN TAIWAN

1,2, 3DHY SHEN

1Department of Nuclear Medicine and PET Center, 2Integrated thyroid cancer management group, TSGH TriService General Hospital (TSGH), National Defense Medical Center (NDMC), Taipei, Taiwan; 3Society of Nuclear Medicine, Taiwan, R.O.C.

Follicular-epithelial origin thyroid cancers including papillary and follicular cancers constitutes about ~90% of thyroid malignancies and are collectively named as differentiated thyroid cancers (DTCs). The majority of DTCs are avid for radioactive iodine (RAI) and thus allow RAI to be used as therapeutic or diagnostic modality. I-131 treatment is mainly (1) to eradicate post-thyroidectomy remnants, (2) to abolish microscopic lesions if any and (3) to control macroscopic tumors as possible. RAI, such as I-123, I-124 and I-131 can provide functional imaging to delineate the whole body tumor involvement and differentiation status (i.e. functioning Na+/I- symporter expression). Recently the DTC management paradigm has been evolving to be more conservative regarding RAI use: recommendation of routine I-131 treatment has been weakened and pre-therapy diagnostic RAI scan been proposed to justify or defy RAI use while such implementation needs to be agreed by different specialties involved in thyroid tumor management. Furthermore, ever-lasting controversy regarding with the adequate dose or activity of RAI use for DTCs has not been well solved. Either dosimetrybased or empiric practice is still of controversial. Also the treatment interval of repeated RAI treatment and maximally cumulative dose limit has not been well addressed. In very recent days, the term of RAI-refractory DTC has emerged and calls for more attention to realize the appropriate use of RAI treatment.

Conventionally RAI whole body scans (WBS) in conjunction to serum thyroglobulin (Tg) checkup are used for tumor surveillance and, in certain situation, cross-section imaging (i.e. CT and MRI) and PET/CT might be needed. The intensity of RAI WBS follow up has also been challenged by ATA proven useful to detect de-differentiation of DTCs. Thus its indication might need to extend to (1) advanced staged tumor (e.g. pT4 or M1 disease) or (2) unproportionally elevated serum Tg level in DTCs.

SE5-3

MANAGEMENT OF WELL DIFFERENTIATED THYROID CANCER TAILORED THROUGH RISK STRATIFICATION

HURNG-SHENG WU

Asia Institute Tele-Surgery; Chang-Bing Show-Chwan Memorial Hospital National Defense Medical Center and Tri-Service General Hospital Taiwan Association of Endocrine Surgeons

Thyroid cancer is the most common malignancy of endocrine disease, the incidence of thyroid cancer and the number of patients are increasing globally. Well-differentiated thyroid cancer(WDTC) of follicular cell origin represent more than 90% of thyroid malignancies, which involve two major histological types, papillary thyroid cancer(PTC) and follicular thyroid cancer(FTC). For patients with WDTC have an excellent prognosis, some patients die from progressive tumor.

Well established prognostic factors including metastases, age, tumor size, extrathyroid extension, complete of resection and gender. According to these risk factors, the extent of surgical resection of the thyroid and neck lymph node dissection is decided preoperatively. After surgery thyroid remnant ablation with 131I and TSH suppression with L-thyroxine were the triad of initial therapy recommended for most patients. However, recently several approaches were reported that risk recurrence and death from thyroid cancer in individual patients with various clinical parameters that become available postoperatively. These factors include histological subtype, 131I whole body scintigraphy findings, response to 131I treatment. Serum thyroglobulin(Tg) levels under TSH stimulated or not stimulated conditions and change in serum Tg antibody(TgAb) concentration after surgery. WDTC with no detectable TgAb, Tg-doubling time seems to be the most powerful predictor of prognosis, whereas, WDTC with TgAb, change in serum TgAb concentration seems to be the best predictor of outcome.

Three-level stratification to assess risk of recurrence after surgery. Low-risk patients: no local or distant metastases; all macroscopic tumor has been resected; there is no tumor invasion of locoregional tissue or structures, the tumor did not have aggressive histology or vascular invasion and no 131I uptake outside the thyroid.

Intermediate-risk patients have any of the following: microscopic invasion of tumor into the perithyroidal soft tissue; cervical lymph node metastases or 131I uptake outside the thyroid bed or tumor with aggressive histology or vascular invasion. High-risk patients have macroscopic tumor invasion, incomplete tumor resection, distant metastases, and 131I high serum Tg level to what is seen on posttreatment scan.

Molecular testing in BRAF mutation as a risk factor that is an important tool guidance toward the personalization surgery in PTC.

Depend on the risk assessment in individual patients with these approached, concerning risks of recurrence and death from WDTC are better predicted, large dose 131I may be avoided in low risk patients and more appropriate intensity and methods for follow-up studies.