The recent prevalence of ultrasound-guided fine-needle aspiration biopsy has resulted in a marked increase in the number of patients with papillary microcarcinoma (maximum diameter,

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Aromatase inhibitors have played a central role in endocrine therapy for estrogen receptor (ER)-positive breast cancer in postmenopausal women. However, factors predictive of the efficacy of aromatase inhibitors, and prognostic factors, both for early and late recurrence in women treated with adjuvant aromatase inhibitors have not been identified. Whole genome analysis identified that a TP53 gene mutation exists in ER-positive breast cancers, although the frequency of TP53 gene mutation in luminal tumors is lower compared with basal-like or human epidermal growth factor receptor type 2 (HER2)-positive breast cancers. We examined expression of p53, as well as ER, progesterone receptor, HER2 and Ki-67 using immunohistochemistry in postmenopausal ER-positive breast cancer patients who were treated with aromatase inhibitors as adjuvant endocrine therapy. There were 53 (21%) tumors that contained 10% or more p53-positive cells. High p53 expression was positively correlated with tumor grade, HER2 score and Ki-67 expression. Significant association was observed between disease-free survival and high p53 expression in multivariate analysis (P < 0.0001). Compared with women without recurrence, women with early recurrence had significantly higher p53 expression (P < 0.0001), as did women with late recurrence (P = 0.037). The present study demonstrates that p53 accumulation is a strong predictor of both early and late recurrence in ER-positive breast cancer patients treated with aromatase inhibitors as adjuvant endocrine therapy. TP53 gene alteration might be a key biological characteristic of ER-positive breast cancer.

Evaluation of immune dysfunction during the tumor-bearing state is a critical issue in combating cancer. In this study, we initially found that IL-6, one of the cachectic factors, suppressed CD4+ T cell–mediated immunity through downregulation of MHC class II by enhanced arginase activity of dendritic cells (DC) in tumor-bearing mice. We demonstrated that administration of Ab against IL-6R (anti–IL-6R mAb) greatly enhanced T cell responses and inhibited the growth of tumor in vivo. We also found that IL-6 upregulated the expression of arginase-1 and arginase activity of DC in vitro. Tumor-infiltrating CD11c+ DC exhibited upregulated mRNA expression of arginase-1 but reduced expression of MHC class II in parallel with the increase in serum IL-6 levels at the late stage in tumor-bearing hosts. However, the administration of anti–IL-6R mAb into tumor-bearing mice inhibited both the downmodulation of MHC class II and the upregulation of arginase-1 mRNA levels in DC. Furthermore, we noted that Nω-hydroxy-L-arginine or L-arginine, an arginase-1 inhibitor, blocked the reduction in MHC class II levels on CD11c+ DC during the tumor-bearing state. Finally, we demonstrated that the administration of Nω-hydroxy-L-arginine at the peritumor site significantly enhanced CD4+ T cell responses and inhibited tumor growth. Thus, IL-6–mediated arginase activation and the subsequent reduction in MHC class II expression on DC appeared to be critical mechanisms for inducing dysfunction of the immune system in the tumor-bearing state. Blockade of the IL-6–arginase cascade is a promising tool to overcome the dysfunction of antitumor immunity in tumor-bearing hosts.

Abstract. After the Fukushima nuclear power plant accident on March 11, 2011, the public of Japan became particularly concerned about the possibility of an increased risk of childhood thyroid cancer, similar to what was observed after the Chernobyl's accident. Due to serious public health perception, there was an urgency to evaluate the baseline levels of childhood thyroid status in Fukushima prefecture. Therefore we have commenced a thyroid ultrasound examination (TUE) survey of the approximately 360,000 pediatric inhabitants (0 to 18 years of age) who lived in Fukushima at the time of the accident in October 2011. The subjects were divided into three categories according to the standardized diagnostic criteria of ultrasound findings. Category A contained the subjects whose TUE findings were intact or benign. Category B were recommended a confirmatory TUE. Category C was recommended an immediate confirmatory TUE. Results: The survey of 40,302 subjects in the first year was completed in March, 2013. There were 40,097 (99.5%), 205 (0.50%) and 0 subjects in categories A, B and C, respectively. Of the 82 category B subjects who underwent fine needle aspiration cytology (FNAC), 12 were diagnosed with a malignant tumor or were suspected to have malignancy. The 12 subjects received thyroid surgery and 11 thyroid cancers and one benign nodule were confirmed histologically after surgery. This is the first largescaled TUE survey to employ sophisticated ultrasound screening and aim to evaluate the baseline frequency of childhood thyroid nodules and cysts. The results will become the golden standard of future comparative TUE in Fukushima, Japan.Key words: Fukushima, Chernobyl, Ultrasound examination, Nodules, Thyroid cancer first few months after the Fukushima disaster.Due to the issue of concern and a strong request from the central and local governments, the Fukushima Health Management survey (FHM) body initiated several health protection surveys [5], including one that involved thyroid ultrasound examinations (TUE) of all pediatric inhabitants who lived or were staying in Fukushima at the time of the accident. The first objective of this survey was to evaluate the baseline rates of childhood thyroid nodules and cancer in Fukushima as this information was not yet available. The baseline survey commenced on October 9, 2011 [6,7] and was conducted by Fukushima Medical University (FMU). Since it is essentially important to follow the standardized ultrasound diagnostic criteria as a part of quality control when any large-scaled screening, the protocol and the initial data of the baseline TUE survey in Fukushima are reported concretely here for the first time.

These results indicate that the up-regulation of COX-2 may contribute predominantly in the early phase of papillary carcinoma progression, whereas it plays a more adjuvant role in follicular carcinoma progression.

Although sporadic medullary thyroid carcinoma (MTC) tends to be unicentric and confined to one lobe, total thyroidectomy is usually performed because of the risk of a hereditary or bilateral process. Germline RET mutation analysis can discriminate hereditary MTC and truly sporadic, nonhereditary MTC. We analyzed 72 of 94 patients with MTC to establish the genetic nature and the clinical features of nonhereditary MTC. Since 1996 we have prospectively treated 15 patients with nonhereditary MTC (prospective study group, or PSG) according to a unilateral surgery policy. A group of 22 previously operated patients in whom the nonhereditary nature was established served as controls (retrospective study group, or RSG). Systematic central and ipsilateral neck dissection was performed in both groups. Outcome was assessed using postoperative stimulated serum calcitonin levels; a normal value was considered a biochemical cure. All 24 hereditary MTC patients carried germline RET mutations: 8 of 48 patients with apparently sporadic MTC had the mutations, and 6 of the 8 had bilateral MTC. All 40 patients without mutations had a unilateral tumor. In the RSG group 15 of 22 (68%) patients underwent total thyroidectomy, and the biochemical cure rate was 68%. Although only 3 of 15 (20%) of the PSG patients underwent total thyroidectomy, 12 of the 15 (80%) achieved biochemical cure. Univariate analyses revealed that pathologic node involvement- high T and N stages-was adversely related to biochemical cure. The extent of thyroid resection was not related to biochemical cure. Of 20 patients with node involvement, 10 achieved biochemical cure, indicating the importance of systematic neck dissection. Hemithyroidectomy with systematic central and ipsilateral neck dissection is appropriate surgery for nonhereditary MTC.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive neoplasms in humans and myeloid-derived suppressor cells (MDSCs) contribute to the negative regulation of immune responses in the context of cancer and inflammation. In order to investigate the pathophysiology of thyroid cancer, peripheral blood mononuclear cells (PBMCs) were obtained from 49 patients with thyroid cancer, 18 patients with non-cancerous thyroid diseases and 22 healthy volunteers. The MDSC levels were found to be higher in patients with any type of thyroid cancer (P<0.05), patients with ATC (P<0.001) and patients with medullary thyroid carcinoma (P<0.05), when compared to patients with non-cancerous thyroid diseases. The MDSC levels were also higher in patients with stage III-IV thyroid cancer compared to those in patients with non-cancerous thyroid diseases (P<0.05). The stimulation index (SI) of phytohemagglutinin (PHA)-induced lymphocyte blastogenesis was significantly lower, the C-reactive protein (CRP) levels were significantly higher and the serum albumin levels were significantly lower in patients with ATC compared to those in patients with non-cancerous thyroid diseases. The SI was significantly lower in stage III and IV thyroid cancer compared to that in non-cancerous thyroid disease (P<0.05). Furthermore, the CRP levels were higher and the concentration of albumin was lower in stage IV thyroid cancer compared to those in non-cancerous thyroid disease (P<0.05). Patients with thyroid carcinoma were then classified into one of two groups according to a %PBMC of MDSC cut-off level of 1.578, which was the average %PBMC of MDSC of patients with any type of thyroid carcinoma. In patients with higher MDSC levels, the production of CRP and interleukin (IL)-10 was significantly higher (P<0.05) and the albumin levels were significantly lower (P<0.05) compared to those in patients with lower MDSC levels. These data indicate that MDSCs are increased in patients with ATC. Furthermore, these patients exhibited suppression of cell-mediated immune responses, chronic inflammation and nutritional impairment.