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Owing to low incidence rates, population-based breast cancer screening is not recommended by many municipalities in Japan for women aged 40 years. To evaluate the usefulness of screening in women aged 40 years, we investigated the results of population-based breast cancer screening among young women performed in the Ibaraki Prefecture.Data regarding histological characteristics, recall rates, cancer detection rates, positive predictive values, tumor categories, and status of lymph node metastases were obtained from population-based screening data from Ibaraki Health Service Association Institute. The "number needing to be screened" (NNS) was determined; using Pearson's chi-squared test, these data were compared between women aged 40 years and 40 years.The data of 428,560 women were evaluated. Cancer detection rates were significantly lower and the NNS and proportion of women with tumor category T2 or higher was significantly increased in women aged 40 years than in those aged 40 years (0.06% vs. 0.21%, 1505 vs. 281-439, and 28.9% vs. 6.3%, respectively; all, p 0.05). The proportion of early-stage cancers was lower in women aged 40 years than in those 40 years, but this was not significant.These results suggest that population-based breast cancer screening should not be recommended for women aged 40 years. To reduce the breast cancer-related mortality rate in young women and ensure efficient use of limited medical resources in Japan, a more efficient surveillance system, based on genetic propensity and family history, needs to be established.

Introduction: Hyperthermia (HT) is a non-invasive cancer therapy. Treatment temperature between 41°C to 44°C has no cytotoxic damage in normal cells, however shows cytotoxicity in cancer cells because of the underdeveloped vascular system. HT often used with other cancer therapy such as radiation therapy and chemotherapy. However mechanism of synergistic effect using these therapies remains unclear. Compared to 37°C, 42°C is mild heat stress for cells, thus superoxide anion is released from tissue. Superoxide anion is produced by mitochondrial electron transport chain. Reactive oxygen species (ROS), produced by mild heat stress, can be released from mitochondria. We have previously reported that ATP-binding cassette sub-family G member 2 (ABCG2) expression was suppressed by increasing mitochondrial ROS, and induction of the cancer specific porphyrin accumulation. ABCG2 is a transporter of doxorubicin (DOX), therefore we hypothesized that synergistic effect of HT and chemotherapy would be induced by down-regulation of ABCG2 expression via intracellular ROS increase. In this study, we investigated if cytotoxic effect of breast cancer cell using DOX can be enhance by HT via intracellular ROS increase. Materials and methods: The murine breast cancer cell line, 4T1E was incubated at 37°C or 42°C for 1h. Intracellular ROS generation after HT treatment was detected by electron spin resonance (ESR). Twenty four hours after HT treatment, cells were incubated in medium containing 0, 0.1 and 1 μM DOX for 24 h. Cell viability was measured using the Cell Counting Kit 8, a water-soluble tetrazolium-8 based colorimetric assay. ABCG2 expression in whole cells was analyzed by Western blotting. Results and discussion: ESR signal peak with HT treatment became high as compared to without HT treatment, indicating intracellular ROS level was increased by HT treatment. Cell viability and ABCG2 expression were decreased by DOX exposure and by HT treatment. The enhancement of HT treatment effect by DOX is considered to be result of down-regulation of ABCG2 expression by ROS. When cells were exposed to DOX with 5-aminolevulinic acid (ALA), cell viability reduced further. Since it is known that porphyrin is introduced by ALA and is transported by ABCG2, we speculate that ALA worked as a competitive inhibitor of DOX excretion transporter to enhance cell death. ESR signal peak in ALA treatment cells was higher than that in non-ALA treatment cells. Significant increase in cellular damage by HT treatment was shown by adding ALA, but not without ALA. Moreover, cell death induced by HT and ALA treatment was suppressed by adding N-acetylcysteine (NAC), which is an antioxidant. These results suggest that cellular damage of HT treatment is due to ROS production induced by ALA. Conclusion: HT treatment involved intracellular ROS production and down-regulated the expression of ABCG2 protein. HT treatment also enhanced the cell damage by DOX. Cell death by DOX was enhanced by combination with HT and ALA treatment, possibly via intracellular ROS generation, and was suppressed by additing antioxidant. Citation Format: Terasaki A, Kurokawa H, Terasaki M, Ito H, Matsui H, Ichioka E, Tsushima Y, Manaka-Iguchi A, Bando H, Hara H. Hyperthermia regulates transporter expression via ROS production and enhances the cytotoxicity of doxorubicin [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-05-05.

e18049 Background: Anaplastic thyroid carcinoma (ATC) is one of the worst prognostic malignancies with a 1-year survival rate of 5-20%. ATC is thought to be originated from differentiated thyroid carcinoma (DTC) caused by undifferentiated transformation because ATCs frequently have preexisting or coexisting region of differentiated thyroid carcinoma (co-DTC), but the detailed mechanism is unclear. In this study, we analyzed mRNA expression among ATCs, DTCs and co-DTCs, and compared their molecular characteristics. Methods: Twelve patients with ATC and eight patients with DTC, who were diagnosed at Tsukuba University Hospital between 2009 to 2020, were included in this study. Of 12 ATCs, four cases had co-DTCs. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) samples of ATCs, DTCs and co-DTCs. We analyzed mRNA expression profiles among three groups using nCounter PanCancer IO 360 Panel (NanoString Technologies) and nCounter Advanced Analysis (version 2.0.134). The p-values were adjusted using Benjamini-Hochberg method and adjusted p-value < 0.05 was considered as significant. Results: The 1-year survival rate of the 12 ATC cases in this study was 37.5%. Heatmap of pathway revealed that most ATCs showed up-regulation of almost all tumor-related pathways included in the panel except for autophagy while three of ATCs didn’t show immune-related pathways up-regulation, and one co-DTC sample showed similar behavior of pathways to ATCs. The top 10 up-regulated gene in co-DTCs compare to DTCs were BATF3, TDO2, PRF1, BIRC5, MKI67, ANLN, FCGR3A/B, PPARGC1B, C2 and PFKFB3, and gene set enrichment analysis revealed that the genes with differential expression were enriched in gene set of cell proliferation. The top 10 genes with differential expression in ATCs compare to co-DTCs were CXCL5, BRCA2, MMP1, CSCL6, CXCL1, DKK1 and CXCL8, for up-regulation and ID4, ARID1A and EPM2AIP1 for down-regulation. In ATCs, gene sets of cell proliferation, cytokine and chemokine signaling, and myeloid compartment were especially up-regulated. Immune cell profiling showed that ATC had abundant inflammatory cells, especially TILs, neutrophils and macrophages, while co-DTC showed intermediate characteristics between ATC and DTC. Of note, three case of ATCs had lower inflammatory cell scores than the other ATCs except for macrophages and neutrophils, and were clustered as “DTC-like”. Conclusions: These data revealed that co-DTCs showed up-regulation of cell proliferation related genes compare to DTCs, and some ATCs had different immune cell profiles. co-DTCs showed an intermediate immune cell profile between ATC and DTC. Biological profiling of ATCs, DTCs and co-DTCs may help to understand the developmental mechanism of ATCs. In this presentation, we will report the detailed results of mRNA expression analysis with discussion of the previous reports.

Background: It is known that ER-positive breast cancer constitutes approximately 70% of all breast cancer and the particular population of these, called as luminal A breast cancer can lead to late recurrence, possibly due to the presence of dormant tumor cells. It is also argued that there are many similar biological characteristics between dormant cells and cancer stem cells (CSCs). So we hypothesized that some part of CSCs would be involved in the late recurrence of luminal type breast cancer and looked for the factors correlateing late recurrence by comparing CSC-enriched population and other population. Materials and Methods: We used the MCF-7 and HCC1500 human breast cell lines. Moreover, we isolated the BC#1 breast cancer cell from metastatic pleural effusion of a breast cancer patient (79 years old, ER+, PgR+, HER2 score 0). These cells are cultured in the adhesion culture condition or the mammosphere culture condition. The immunohistochemical characteristics such as ER, PgR, HER2, Cytokeratin (CK) 8, CK5/6 status of these cells were confirmed. The analysis of the ALDH activity and the CD44+/24- expression as the CSC marker were carried out using flow cytometry. The expression of target genes was analyzed using quantitative RT-PCR. Protein expression was determined by western-blotting. To assess the self-renewal potential of CSCs and the proliferation of immature cancer cells, we used mammosphere formation assay and colony formation assay. To investigate the effects of 4-hydroxytamoxifen(4-OHT) on mammosphere formation assay, 1µm of 4-OHT added to the medium in the particular experiment. Results: BC#1 was confirmed as luminal type by immunohistochemistry and qRT-PCR. The expression tendency between two CSC markers are almost same and correlated to the mammosphere formation capacity. We also confirmed that mammosphere culture have an increased ALDH-positive population compared with adherent culture cells. Using flow cytometry, we divided the cell lines and isolated cells into two populations, ALDH-positive and negative. By qRT-PCR analysis, ALDH-positive population showed higher expression of FOXA1 (ER expression related gene) than ALDH-negative population. In addition, we found the significantly higher expression of FOXA1 gene, and RPRM gene (p53 induced G2/M arrest related gene) in mammosphere culture samples than in adhesion culture samples. In terms of the effects of 4-OHT, 4-OHT resistant mammosphere samples showed significantly increased FOXA1 gene expression level. Finally, we established shFOXA1 MCF-7 cells to investigate the relationship between self-renewal potential and FOXA1 expression. We found that colony formation in shFOXA1 MCF-7 cells decreased compared with control while there is no significant difference in the number of mammospheres. Conclusion: CSC-enriched population showed higher FOXA1 expression and our results suggested that the expression of FOXA1 correlate to the proliferation of immature breast cancer cell rather than the induction of self-renewal potency of CSCs. Moreover, there is no report argued about the correlation between CSCs and G2/M arrest related gene like RPRM so that the biological mechanism should be investigated in future. Citation Format: Tachi K, Shiraishi A, Bando H, Yamashita T, Tsuboi I, Kato T, Ichioka E, Tsushima Y, Ikeda T, Iguchi A, Hara H, Ohneda O. The ectopic FOXA1 expression correlates to the luminal breast cancer stem cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-07-11.

Giant cell tumors of soft tissue (GCT-ST) arising in the breast are extremely rare. Herein, we report a case of a 45-year-old woman with a 5-cm mass in her left breast. Ultrasonography revealed a mainly well-circumscribed mass that contained a cystic lesion. Magnetic resonance imaging showed a fibrous capsule-covered mass that contained a high-intensity area, suggesting hemorrhaging. Ultrasound-guided core needle biopsy (CNB) revealed mononuclear histiocytic cells with a round shape or spindled appearance that was mixed with multinucleated giant cells. Immunohistochemical analysis revealed CD68-positive staining in the mononuclear and giant cells but negative staining for pancytokeratin. Preoperatively, the tumor was highly suspected of being GCT-ST. Histopathological results after a left mastectomy showed similar findings to CNB. The final diagnosis was GCT-ST in the breast. To the best of our knowledge, this is the first case report of a GCT-ST arising in the breast diagnosed by ultrasound-guided CNB.

Although postoperative serum thyroglobulin (Tg) is a prognostic indicator for papillary thyroid carcinoma (PTC), it is unreliable when Tg antibody (TgAb) is positive. We evaluated the prognostic significance of changes in serum TgAb levels of pre- and post-total thyroidectomy in TgAb-positive PTC patients. We reviewed our medical charts of 225 TgAb-positive PTC patients in whom TgAb levels were measured before and 1-2 years after total thyroidectomy, performed between April 2002 and March 2007. We divided them into 3 groups based on changes in TgAb levels. Postoperative serum TgAb levels decreased by ≥ 50% in 181 patients (80.4%) (Group 1), by

Papillary thyroid carcinoma (PTC) frequently metastasizes to and recurs in regional lymph nodes. Of the two compartments, the central compartment can be dissected through the same wound as the thyroidectomy, and the central node dissection (CND) is routinely performed in most Japanese surgical departments. However, the indications for prophylactic lateral compartment dissection (modified radical neck dissection [MND]) for low-risk PTC remain unclear. In this study, we investigated the indications for prophylactic MND for PTC patients with tumor measuring 1.1-3.0 cm without significant extrathyroid extension or distant metastasis.We investigated the lymph node disease-free survival (LN-DFS) rates of 829 patients who underwent CND and of 414 patients who underwent MND and CND between 2005 and 2007 at Kuma Hospital.The LN-DFS of these two groups was not significantly different. In the subset of patients with CND only, clinical central node metastasis (N1a) significantly predicted a worse LN-DFS. All N1a patients recognized as showing recurrence developed such recurrence in the lateral compartment. Other conventional prognostic factors, such as sex and age, were not related to LN-DFS.Taken together, N1a patients with low-risk PTC measuring 1.1-3.0 cm can be considered as candidates for prophylactic MND.

Preoperative localization study is difficult in patients with primary hyperparathyroidism (PHPT) caused by intrathyroidal parathyroid adenoma. The objective of this study was to evaluate the usefulness of ultrasonography (US) in the diagnosis of intrathyroidal parathyroid adenoma. Between January 2004 and December 2009, seven of 373 patients who underwent parathyroidectomy because of PHPT in our hospital were found to have intrathyroidal parathyroid adenoma. The ultrasonographic features of intrathyroidal parathyroid adenoma were examined retrospectively. The most characteristic feature of intrathyroidal parathyroid adenoma was a hyperechoic line on the ventral surface of the parathyroid gland. A hyperechoic line was clearly detected even in small adenomas in which feeding vessels could not be detected on color Doppler sonography. In comparison with feeding vessels, a hyperechoic line was frequently detected in normally located parathyroid adenoma. (99m)Tc-sestamibi (MIBI) scintigraphy and computed tomography (CT) could show parathyroid adenoma in the intrathyroidal position in only three of five and in only one of three patients examined, respectively. Since a hyperechoic line is characteristic of parathyroid adenoma, an intrathyroidal parathyroid adenoma could be suspected by only non-invasive US.

症例は62歳，女性．直腸癌穿孔に対しハルトマン手術を施行．術後9カ月で腫瘍マーカーの上昇があり，腹部造影CTで門脈臍部に低吸収域を認め転移性肝癌と診断，尾状葉温存肝左葉切除術を施行した．術後の病理組織学的所見では，門脈内に直腸の原発巣と類似した腺癌を認め，門脈腫瘍栓と診断した．また，摘出標本の肉眼所見および病理組織学的所見では肝実質には明らかな病変を認めず，肝実質転移を伴わない門脈腫瘍栓と診断した．術後の腫瘍マーカーは正常化し，術後10カ月の現在，再発の徴候を認めていない．大腸癌の肝実質転移を伴わない門脈腫瘍栓の報告は少なく，稀と考えられるため，文献的考察も含め報告する．

This is an account of a case of primary adenocarcinoma of the small intestine successfully treated with chemotherapy. A 46-year-old man was admitted with a complaint of severe abdominal distension. Abdominal computerized tomography revealed bowel obstruction, and this was found at surgery to be due to a tumor at the jejunum 100 cm distal from the Treitz ligament. Pathological diagnosis of the resected specimen was adenocarcinoma. Although adjuvant chemotherapy with doxifluridine 800 mg/day was given, a recurrent lesion at the abdominal wall was detected 19 months after surgery. Colonoscopy simultaneously revealed stenosis at the descending colon. The patient was subsequently treated with resection of the mass at the abdominal wall, and colostomy was made at the transverse colon to circumvent the stenosis due to peritoneal carcinomatosis. It was not long before another recurrence developed at the abdominal wall with a subsequent rise in tumor markers. mFOLFOX6 (oxaliplatin 85 mg/m2, levofolinate calcium 200 mg/m2, 5-FU 400/2,400 mg/m2) was given, and the patient responded. Primary small intestinal adenocarcinoma is a rare disease with a dismal prognosis. Due to rarity of the disease, clinical trials have not been performed, and little is known about the effect of chemotherapy. The current patient survived for 4 years and 5 months after the diagnosis, owing at least partially to the mFOLFOX6 which was found to be the only active regimen.

The present experiment was designed to determine the relation between examination failure-stress and anxiety inventory scores. The stress was produced through failure and success reports on class-room examinations, specially made for this purpore. The anxiety tests used were Cattell's I.P.A.T. Anxiety Questionnaire and three from the Objective-Analytic Anxiety Test Eattery. The subjects were eighty-five college students divided into three groups-success, failure, and control. The failure and success groups were subjected to the experimental treatments of getting failure and success in a course achievement test. The effect of these situations upon anxiety scores was tested. As an additional problem, the change of anxiety scores from the pre-stress to the post-stress for groups high and low in pre-stress (usual) level of anxiety was tested. 1. The analysis of covariance adjusted to the pre-stress anxiety scores and grade point averages yielded no significant difference between the three groups in any of the anxiety tests at the 5% level of significance. A difference in the hypothesized direction was seen in the mean scores of two anxiety tests. 2. For the second hypothesis, there was no consistant difference across the four anxiety tests, but there were trends for high anxiety groups to decrease more than the lower groups between pre-test, and post-test, and their variances tended to be higher than those of the lower groups in all the situations.

本実験においては, 失敗ストレスの反応を不安テストで測定する試みがなされた。ストレスは作為的に行われたクラスでの試験の失敗点の呈示によって実験的に作られたものである。それを測定する不安テストはCattellのI.P.A.T. Anxiety ScaleとObjective-analytic anxiety test batteryの内の3つのテストである。被験者は85名のイリノイ大学学生で, 成功, 失敗, コントロールの3群にわけられ, 成功, 失敗の両群には学課試験を行い, それについての成功点, 失敗点を呈示, 反応を不安テストで測定した。次に第二の問題として, 平常の不安レベルの高低により各グループを2群に分け, ストレス場面に対する反応の差を検討した。以上二つの課題の結果は, (1)ストレス前の不安点と学校平均成績にアジヤストした共分散分析の結果では, I.P.A.T. Anxiety Scaleにおいて危険率10%レベルで有意差があった。しかし他のテストにおいては有意差が見られなかった。(2)第2の問題では4テスト全部にわたる一定した傾向は見られなかった。