Background: The question of how to manage patients with low-risk papillary thyroid microcarcinoma (PTMC; T1aN0M0) has recently become an important clinical issue. Two Japanese centers have conducted prospective clinical trials of active surveillance (AS) for low-risk PTMC since the 1990s, reporting favorable outcomes. This policy has thus seen gradual adoption worldwide to avoid overtreatment. Not all PTMCs are suitable for AS, however, and many physicians still hesitate to apply the management policy in daily clinical practice. A task force on management for PTMC created by the Japan Association of Endocrine Surgery collected and analyzed bibliographic evidence and has produced the present consensus statements regarding indications and concrete strategies for AS to facilitate the management of adult patients diagnosed with low-risk PTMC. Summary: These statements provide indications for AS in adult patients with T1aN0M0 low-risk PTMC. PTMCs with clinical lymph node metastasis, distant metastasis, recurrent laryngeal nerve (RLN) paralysis due to carcinoma invasion, or protrusion into the tracheal lumen warrant immediate surgery. Tumors suspected of aggressive subtypes on cytology are recommended for immediate surgery. Immediate surgery is also recommended for tumors adherent to the trachea or located along the course of the RLN. Practical strategies include diagnosis, decision-making, follow-up, and monitoring related to the implementation of AS. The rate of low-risk PTMC progression is lower in older patients. However, we recommend continuing AS as long as circumstances permit. Future tasks in optimizing management for low-risk PTMC are also described, including molecular markers and patient-reported outcomes. Conclusions: An appropriate multidisciplinary team is necessary to accurately evaluate primary tumors and lymph nodes at the beginning of and during AS, and to adequately reach a shared-decision with individual patients. If appropriately applied, AS of low-risk PTMC is a safe management strategy offering favorable outcomes and preserves quality of life at low cost.

Formation of coated carrier vesicles, such as COPIcoated vesicles from the cis-Golgi, is triggered by membrane binding of the GTP-bound form of ADP-ribosylation factors. This process is blocked by brefeldin A, which is an inhibitor of guanine nucleotide exchange factors for ADP-ribosylation factor. GBF1 is one of the guanine nucleotide-exchange factors for ADPribosylation factor and is localized in the Golgi region. In the present study, we have determined the detailed subcellular localization of GBF1. Immunofluorescence microscopy of cells treated with nocodazole or incubated at 15 aeC has suggested that GBF1 behaves similarly to proteins recycling between the cis-Golgi and the endoplasmic reticulum. Immunoelectron microscopy has revealed that GBF1 localizes primarily to vesicular and tubular structures apposed to the cisface of Golgi stacks and minor fractions to the Golgi stacks. GBF1 overexpressed in cells causes recruitment of class I and class II ADP-ribosylation factors onto Golgi membranes. Furthermore, overexpressed GBF1 antagonizes various effects of brefeldin A, such as inhibition of membrane recruitment of ADP-ribosylation factors and the COPI coat, and redistribution of Golgi-resident and itinerant proteins. These observations indicate that GBF1 is involved in the formation of COPI-coated vesicles from the cis-Golgi or the preGolgi intermediate compartment through activating ADP-ribosylation factors.

BIG2 is a guanine nucleotide exchange factor (GEF) for the ADP-ribosylation factor (ARF) family of small GTPases, which regulate membrane association of COPI and adaptor protein (AP)-1 coat protein complexes. A fungal metabolite, brefeldin A (BFA), inhibits ARF-GEFs and leads to redistribution of coat proteins from membranes to the cytoplasm and membrane tubulation of the Golgi complex and the trans-Golgi network (TGN). To investigate the function of BIG2, we examined the effects of BIG2-overexpression on the BFA-induced redistribution of ARF, coat proteins, and organelle markers. The BIG2 overexpression blocked BFA-induced redistribution from membranes of ARF1 and the AP-1 complex but not that of the COPI complex. These observations indicate that BIG2 is implicated in membrane association of AP-1, but not that of COPI, through activating ARF. Furthermore, not only BIG2 but also ARF1 and AP-1 were found as queues of spherical swellings along the BFA-induced membrane tubules emanating from the TGN. These observations indicate that BFAinduced AP-1 dissociation from TGN membranes and tubulation of TGN membranes are not coupled events and suggest that a BFA target other than ARF-GEFs exists in the cell.

Background: Clinical practice guidelines have endorsed both active surveillance and surgery as viable management options for papillary thyroid microcarcinoma (PTMC). However, patients' perceptions on the options have rarely been addressed. Methods: A cross-sectional survey was conducted on 50 patients with PTMC who were under either active surveillance (n = 20) or postoperative follow-up (n = 30). The primary outcome was anxiety, which was measured using the State-Trait Anxiety Inventory (STAI). A questionnaire that comprised six items about PTMCrelated symptoms and concerns, which were measured with a visual analog scale, was also administered. Cohen's d effect size was calculated to express group differences. Multiple regression analysis was used to examine the relationships between state anxiety and other variables. Results: The median age and observation period were 61.5 years (range, 40-83 years) and 4.1 years (range, 0-8.6 years), respectively. The female/male ratio was 38/12. Compared with the surgery group, the active surveillance group showed higher scores in both state anxiety and trait anxiety, with corresponding effect sizes of 0.55 (confidence interval [CI]-0.03 to 1.1; p = 0.068) and 0.63 (CI 0.02-1.2; p = 0.037), respectively. Trait anxiety (b = 0.83) and observation time (b =-1.57) were the significant predictors of state anxiety. Moderate effect sizes were observed for ''discomfort in the neck'' (-0.53; CI-1.11 to 0.04); ''weak voice'' (-0.46; CI-1.03 to 0.12); and ''nervous about neck appearance'' (-0.64; CI-1.23 to-0.07), in favor of active surveillance. Conclusions: State anxiety among patients with PTMC seemed to be a reflection of an individual's trait rather than management. Understanding the patients' view appears to be key to improve shared decision-making.