PL：Plenary Lecture (1-4

PL-1 TARGET THERAPIES IN ADVANCED THYROID CANCER

ROSSELLA ELISEI

Associate Professor of Endocrinology, University of Pisa

Thyrosine kinase inhibitors (TKI) are nowadays the new drugs involved in the therapy of advanced and progressive thyroid cancer (MTC). Four of them, have been approved by both FDA and EMA for this purpose: lenvatinib and sorafenib for dedifferentiated thyroid cancer (papillary and follicular [PTC and FTC]) and vandetanib and cabozantinib for medullary thyroid cancer (MTC). As well known, TKI are cytostatic drugs that are able to block the activities of several tyrosine kinases including BRAF and RET which are the major players in the pathogenesis of both PTC/FTC and MTC. For this reason TKI must be used when there is an evident progression of the metastatic disease with the intent to block this progression. A significant increase of the serum markers, such as thyroglobulin and calcitonin, can suggest that the disease is in progression but only after a documented radiological progression according to RECIST, the TKI will be prescribed. However, all the phase III clinical trials, SELECT (for lenvatinib), DECISION (for Sorafenib), ZETA (for vandetanib) and EXAM (for cabozantinib), showed that these drugs are also able to determine a shrinkage of the lesions with a relevant objective response rate (ORR). On the basis of this objective results they can be also used with the purpose to reduce the size of lesions whose location can be dangerous for the life of our patients such as vertebral lesions that, if growing more, can rapidly compress the spinal cord determing para- or tetraplegia. Moreover, anytime there is a single lesion that is progressing or representing a clinical problem for our patient, the possibility of a local treatment, such as external radiotherapy, laser ablation, chemoembolization ecc, should be considered. Finally, anytime we decide to prescribe a TKI, the possible side effects of the drug, that are very similar among all TKI but with some peculiarities for each drug, must be considered. A very accurate, and possibly multidisciplinary, evaluation of the general health conditions and the other co-morbidities of the patient must be done before starting the systemic TKI therapy.

PL-2 PROMOTING DIABETES RESEARCH FOR BETTER DIABETES CARE IN ASIA: FOCUS ON INSULIN SECRETION AND INCRETINS

YUTAKA SEINO

Director for Kansai Electric Power Hospital, Osaka, Japan; and Director General for Kansai Electric Power Research Institute, Kobe, Japan

The global epidemic of diabetes is a serious medical and social problem in all parts of the world including East and Southeast Asia, which have the highest prevalence of the disease. Type 2 diabetes in East and Southeast Asia is characterized primarily by non-obese and b-cell dysfunction; the pathological manifestation in Europe and North America is generally insulin resistance with obesity. These differences have an immense impact on anti-diabetes prevention and treatment strategies in different populations.

Incretin-based anti-diabetic strategies including DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA) have been gaining much attention in the management of type 2 diabetes across Asia. The incretins GIP and GLP-1 are released from the gut in response to dietary nutrientsstimulate insulin secretion in a glucose-dependent manner. Meta-analyses of clinical trials on DPP4i and GLP1RA have found the drugs to be more effective in Asian patients, likely due to amelioration of b-cell dysfunction by incretins. We have recently found a potential link between dietary habits and efficacy of DPP4i. The HbA1c-lowering effect of DPP4i is attenuated by intake of saturated fats (SF), possibly because SF enhance GIP secretion and facilitate fat deposition in collaboration with GIP. Since SFconsumption is less in Asia in general compared to Europe and North America, the greater efficacy of DPP4i in Asians may therefore be partly due to dietary habits. We also succeeded in establishing incretin-based diet therapy focusing on meal sequence that ameliorates postprandial glucose elevation often found in Asians. Eating fish before rice was found to enhance GLP-1 secretion and ameliorate postprandial glucose excursion by increasing insulin secretion and delaying gastric emptying, compared to eating fish after rice. Similar reversal of rice and meat, which is rich in SF that enhance not only GLP-1 but also GIP, had similar beneficial effects but facilitated fat accumulation. Thus, the meal sequence, fish before rice, might also enhance HbA1c-lowering effects of DPP4i.

Through my career as diabetologist, I realized importance of our own research activities to understand the pathophysiology of type 2 diabetes in Asians; and to develop diet and exercise therapies as well as pharmacological interventions suitable for the management of Asian type 2 diabetes. Together with international colleagues, we established the Asian Association for the Study of Diabetes (AASD) in 2009 as a platform for active discussion of diabetes in Asia. By now, AASD has expanded rapidly, with more than 22 diabetes-related member associations across Asia and more than 3,000 individual membership globally. Furthermore, the Journal of Diabetes Investigation (JDI), which was

launched as the AASD official journal in 2010, has been receiving much attention as evidenced by its recent impact factor 3.039. By forming an alliance with international diabetes-related organizations including IDF, the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA), AASD is dedicated to improving diabetes education and care to scientifically to fight against diabetes.

In this lecture phenotype of Asian type 2 diabetes and anti-diabetes strategies for Asian type diabetes will be discussed from incretin perspectives.In addition, I will also discuss need for our diabetes research activities from AASD perspectives.

PL-3 THYROID CANCER-FROM BEDSIDE TO BENCH

JEN-DER LIN

Division of Endocrinology & Metabolism, Chang Gung Memorial Hospital in Linkou

Thyroid cancer is the most common endocrine disease, with a continuously increasing incidence in both developed and developing countries, including Taiwan. Papillary and follicular thyroid cancer account for 80–90% of the total cases and commonly originate from well-differentiated thyroid follicular cells. In the past 40 years, 4,458 thyroid cancer patients were diagnosed with thyroid cancer and underwent long-term follow-up at Chang Gung Memorial Hospital in Linkou. The clinical characteristics of well-differentiated thyroid cancer may range from indolent papillary microcarcinoma to papillary and follicular thyroid cancer with bone metastases having a poor prognosis. In this study, after a mean follow-up of 10.1 years, the disease-specific mortality (DSM) rate for papillary thyroid carcinoma with distant metastases was 70.0%. Elderly and male patients with papillary thyroid carcinoma (PTC) with distant metastasis were required more aggressive treatment. To identify novel PTC biomarkers, we herein used a GeLC-MS/MS strategy to analyze the proteome profiles of serumabundant-protein-depleted fine-needle aspirated cystic fluids in benign and PTC patients, as well as two PTC cell line secretomes. Comparative analysis revealed that 191 proteins were detected in the PTC, but none in benign cystic fluid samples, and thus may represent as potential PTC biomarkers. Immunoblot analysis confirmed the elevated expression levels of five proteins (NPC2, CTSC, GPNMB, DPP4, and ERAP2) in PTC versus benign cystic fluids. Immunohistochemical studies of nearly 100 pairs of PTC tissues and their corresponding non-tumor counterparts further showed that AGRN (n = 98), CTSC (n = 99), ERAP2 (n = 98), and GPNMB (n = 100) were significantly (p < 0.05) overexpressed in PTC, and higher expression levels of AGRN and CTSC were also significantly associated with metastasis and poor prognosis in PTC patients. In recent study, we evaluated whether the number of circulating tumor/circulating epithelial cells (CECs) expressing either epithelial cell adhesion molecule (EpCAM), podoplanin (PDPN), or thyroid-stimulating hormone receptor (TSHR) is related to remission and DSM in patients with thyroid cancer. The EpCAM+-CEC, TSHR+-CEC, and PDPN+-CEC counts in the non-remission group (n = 43) were significantly higher than the remission group (n = 85) (p < 0.001). Receiver operating characteristic (ROC) analysis showed that EpCAM+CEC, TSHR+-CEC, and PDPN+-CEC counts distinguished the mortality and survival statuses. In conclusion, new biomarkers for various thyroid cancers may improve the preoperative diagnosis. Early detection of well-differentiated thyroid carcinoma with distant metastasis and DSM may improve therapeutic outcomes.

Main related references:

1. Jen-Der Lin, Chao-Chun Huang, Hsiao-Fen Weng, Shin-Cheh Chen, Long-Bin Jeng: Comparison of cellular proteins from benign and malignant human thyroid tissues by twodimensional polyacrylamide gel electrophoresis. J Chromatogr 667: 153-60, 1995. 2. Jen-Der Lin, Tzu-Chieh Chao, Hsiao-Fen Weng, Hong-So Huang, Yat-Sen Ho: Establishment of xenografts and cell lines from well differentiated human thyroid carcinoma. J Surg Oncol 63: 112-8, 1996. 3. Jen-Der Lin, Bie-Yu Huang, Hung-Yu Chang: Clinical experience in the diagnosis of 127 papillary thyroid microcarcinomas. Endocr-Relat Cancer 5: 239-45, 1998. 4. Jen-Der Lin, Bie-Yu Huang: Comparison of the results of diagnosis and treatment between solid and cystic well differentiated thyroid carcinomas. Thyroid 8: 661-7, 1998. 5. Jen-Der Lin: The role of apoptosis in autoimmune thyroid disorders and thyroid cancer. Brit Med J 322: 1525-7, 2001. 6. Jen-Der Lin, Tzu-Chieh Chao, Shuo-Chi Chou, Chuen Hsueh: Papillary thyroid carcinomas with lung metastases. Thyroid 14: 1091-6, 2004. 7. Jen-Der Lin, Szu-Tah Chen, Tzu-Chieh Chao, Chuen Hsueh, Hsiao-Fen Weng: Diagnosis and therapeutic strategy of papillary thyroid microcarcinoma. Arch Surg 140:940-5, 2005. 8. Jen-Der Lin, Kun-Ju Lin, Tzu-Chieh Chao, Chuen Hsueh, Ngan-Ming Tsang: Therapeutic outcome of papillary thyroid carcinoma advance than T1N0M0. Radiother Oncol 89: 97-104, 2008. 9. Jen-Der Lin, Shu-Fu Lin, Szu-Tah Chen, Chuen Hsueh, Chia-Lin Li, Tzu-Chieh Chao: Longterm follow-up of papillary and follicular thyroid carcinomas with bone metastasis. PLoS One Mar. 9;12(3):e0173354. doi: 10.1371/journal.pone.0173354, 2017. 10.Hung-Chih Lin, Miaw-Jene Liou, Hsung-Ling Hsu, Jason Chia-Hsun Hsieh, Yi-An Chen, Ching-Ping Tseng, Jen-Der Lin: Combined analysis of circulating epithelial cells and serum thyroglobulin for distinguishing disease status of the patients with papillary thyroid carcinoma. Oncotarget 2016;7(13):17242-53. 11.Ching-Ping Tseng, Kong-Kit Leong, Miaw-Jene Liou, Hsung-Ling Hsu, Hung-Chih Lin, Yi-An Chen, Jen-Der Lin: Circulating epithelial cell counts for monitoring the therapeutic outcome of papillary thyroid carcinoma. Oncotarget 2017, Vol. 8, (No. 44), pp: 77453-77464

PL-4 GENETIC MANIPULATION TOWARDS IMMUNE TOLERANCE: APPROACHES BY TRANSGENIC AND KNOCKOUT/KNOCKDOWN MOUSE MODELS

HUEY-KANG SYTWU

National Health Research Institutes, Taiwan, ROC

Insulin-dependent diabetes mellitus (IDDM) is a T cell-mediated autoimmune disease. To delineate the protective roles of some immune modulatory molecules, such as soluble decoy receptor 3 (DcR3), cytotoxic T lymphocyte antigen 4 (CTLA4), program death ligand 1 and 2 (PD-L1 and 2), heme oxygenase 1 (HO-1), and chemokine receptor D6 in the autoimmune process and to search for potential preventive and/or therapeutic targets in this disease, we have generated (a) insulin promoter (pIns)-sDcR3 transgenic non-obese diabetic (NOD) mice, (b) pIns-single chain anti-CTLA4 transgenic NOD mice, (c) pIns-single chain anti-4-1BB transgenic NOD mice, (d) pIns-PD-L1 transgenic NOD mice, (e) pIns-HO-1 transgenic NOD mice, and (f) pIns-D6 transgenic NOD mice and demonstrated their immunomodulatory potential and underlying mechanisms. Meanwhile, to explore the modulatory potential of interleukin-12, 23 and 27 on autoimmune diabetes, we have generated following transgenic, knockout and knockdown NOD mice: (1) Th1 and Th2 doubly transgenic (2) IL-12 knockout (3) IL-23 knockdown (4) IL-27 knockdown NOD mice. Our results revealed that 20% IL-12deficient NOD mice still developed autoimmune diabetes, the diabetic incidence of IL-23 knockdown NOD mice is lower than that of control littermates, and the number and percentage of Th1 cells are dramatically decreased and Th17 cells are increased in IL-27 knockdown mice, indicating a differential role of IL-12 cytokine family in modulating Th1 and Th17 cell development during autoimmune diabetogenic process. Making full use of these unique mouse strains, we are quantitatively and qualitatively investigating the immunopathogenic mechanisms of autoimmune diabetes and providing valuable information for the development of novel immunotherapies.