Abstract. Recent studies have demonstrated that BRAF V600E mutation is a common event in papillary thyroid carcinoma and a majority of these lesions have shown a direct relationship between BRAF V600E mutation and aggressive characteristics, including a worse patient prognosis. However, there are no studies from Japan regarding this issue in a large series with adequate postoperative follow-up periods. We investigated BRAF V600E mutation in 631 patients with papillary carcinoma having median follow-up periods of 83 months. The prevalence of BRAF V600E mutation was 38.4%, and the rate was higher in carcinoma larger than 1.0 cm but did not successively increase with tumor size. Furthermore, the prevalence did not significantly increase in cases demonstrating high-risk biological features such as clinically apparent lymph node metastasis, massive extrathyroid extension, advanced age, distant metastasis at surgery, and advanced Stage. The disease-free survival of patients with BRAF V600E mutation did not differ from that of those without BRAF V600E mutation. These findings indicate that, although BRAF V600E mutation may play some roles in local carcinoma development, there is no evidence that BRAF V600E mutation significantly reflects the aggressive characteristics and poor prognosis of patients with papillary carcinoma in Japan.Key words: BRAF mutation, Papillary carcinoma, Thyroid, Prognosis (Endocrine Journal 56: 89-97, 2009) PAPILLARY carcinoma of the thyroid is the most common malignancy arising from thyroid follicular cells. Although papillary carcinoma frequently metastasizes to the regional lymph node, it generally shows an indolent character and grows slowly. However, cases displaying certain characteristics are progressive, show a dire prognosis and are considered highrisk. There are several classification systems evaluating the progression of thyroid carcinoma and among these, the UICC/AJCC TNM staging system is the most widely adopted [1]. It consists of three components; T factor, tumor size and extrathyroid extension; N factor, lymph node metastasis; M factor, distant metastasis. Then, each case is staged based on the TNM classification and patient age. This system is evaluated on preoperative imaging studies (TNM and Stage) and also on postoperative pathological examination (pTNM and pStage). We previously demon-

Highlights d Qualitative changes in plasma neutralizing antibody are longitudinally analyzed d Affinity-matured antibodies with resistance to variants are durably maintained d Neutralizing potency and breadth to SARS-CoV-2 variants increase with time d Serological immunity evolves with time to counter SARS-CoV-2 variants

Multiple SARS-CoV-2 variants have mutations in the spike receptor binding domain (RBD) with potential to evade neutralizing antibody. In particular, the Beta and Omicron variants escape from antibody neutralizing activity in those who received two doses of BNT162b2 mRNA vaccine. Nonetheless, boosting with a third vaccine dose or by breakthrough infection improves the overall breadth of the neutralizing antibodies, but the mechanism remains unclear. Here, we longitudinally profiled the cellular composition of RBD-binding memory B cell subsets and their antibody binding and neutralizing activity against SARS-CoV-2 variants after the second dose of mRNA vaccine. Two doses of the mRNA vaccine elicited plasma neutralizing antibodies with a limited activity against Beta and Omicron but induced an expanded antibody breadth overtime, up to 4.9 months after vaccination. In contrast, more than one-third of RBD-binding IgG + memory B cells with a resting phenotype initially bound the Beta and Omicron variants and steadily increased the B cell receptor breadth overtime. As a result, a fraction of the resting memory B cell subset secreted Beta and Omicron-neutralizing antibody when stimulated in vitro. The neutralizing breadth of the resting memory B cell subset helps us understand the prominent recall of Omicron-neutralizing antibodies after an additional booster or breakthrough infection in fully vaccinated individuals.

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Abstract. Thyroid cancers have long been considered to arise in middle age and, after their repeated proliferation, resulting in further damage to the genome, they progress to more aggressive and lethal cancers. However, in 2014, some studies were reported that might lead to a marked change in our understanding of the natural history of thyroid cancer. A high prevalence of papillary carcinoma in the young suggested that the first initiation of thyroid cancer is likely to occur in the infantile period. Such a conclusion was also supported by a very slow growth rate of papillary microcarcinomas (PMCs) in an observation trial. The proliferation rate of PMCs was negatively correlated with the age, and surgery to remove PMCs did not contribute to reduce mortality from thyroid cancer. These findings strongly suggested the existence of self-limiting cancers, which are truly malignant but do not progress to lethal cancers, for the first time in human history. The early detection of self-limiting cancers results in overdiagnosis. Ultrasonographic screening of the thyroid in the young should be avoided. Lethal thyroid cancers, whose origin is still unknown, appear suddenly after middle age. In the elderly, thyroid cancers are a mixture of self-limiting and lethal cancers; thus, when thyroid cancer is detected, careful follow-up with examination of its growth rate is required.