MDPI Acta Medica Okayama 1422-0067 22 23 2021 YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development 12809 EN Miwa Fujihara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tatsuaki Takeda Departments of Pharmacy, Okayama University Hospital Yidan Zhu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tomoka Mamori Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yusuke Otani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Ryo Yoshioka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Maya Uno Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yoko Suzuki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yuko Abe Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Minami Hatono Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takahiro Tsukioki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yuko Takahashi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Mariko Kochi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takayuki Iwamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Naruto Taira Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Hiroyoshi Doihara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 5 2020 Evaluation of Prognosis of Juvenile Differentiated Thyroid Carcinoma 401 406 EN Takahiro Tsukioki Department of Breast and Endocrine Surgery, Okayama University Hospital Tadahiko Shien Department of Breast and Endocrine Surgery, Okayama University Hospital Yusuke Ohtani Department of Breast and Endocrine Surgery, Okayama University Hospital Miwa Fujihara Department of Breast and Endocrine Surgery, Okayama University Hospital Yoko Suzuki Department of Breast and Endocrine Surgery, Okayama University Hospital Yukiko Kajihara Department of Breast and Endocrine Surgery, Okayama University Hospital Minami Hatono Department of Breast and Endocrine Surgery, Okayama University Hospital Kengo Kawada Department of Breast and Endocrine Surgery, Okayama University Hospital Mariko Kochi Department of Breast and Endocrine Surgery, Okayama University Hospital Takayuki Iwamoto Department of Breast and Endocrine Surgery, Okayama University Hospital Hirokuni Ikeda Department of Breast and Endocrine Surgery, Okayama University Hospital Naruto Taira Department of Breast and Endocrine Surgery, Okayama University Hospital Hiroyoshi Doihara Department of Breast and Endocrine Surgery, Okayama University Hospital Original Article 10.18926/AMO/60799 Differentiated thyroid carcinoma (DTC) in juvenile patients is often an extensive and aggressive disease with a high frequency of recurrence. However, the prognosis is excellent, with a low mortality rate even when advanced disease is present, although prognostic factors and treatment strategy remain uncertain. Between April 2004 and March 2017, 33 juvenile patients (< 30 years old) were diagnosed with DTC and treated at our institution. We retrospectively investigated prognosis and factors including sex, reason for discovery, treatment, pathological factors and treatment progress to clarify the risk factors. All patients underwent curative surgical treatment. Pathologically, lymph node metastasis was identified in 25 patients (75%). Thirteen patients (39%) had bilateral cervical metastasis. In addition, 9 (27%) had more than 10 metastatic lymph nodes. The 2 patients with more than 20 metastatic lymph nodes were treated with radioactive iodine (RAI). Five patients (15%) had local recurrences and received surgery. There have been no further recurrences or deaths. However, no factors were determined to significantly predict the recurrence of juvenile DTC. Local recurrent disease was treated with surgery and/or RAI until remission, and survival was excellent in juvenile DTC. No potential conflict of interest relevant to this article was reported.

Springer Acta Medica Okayama 0344-5704 86 1 2020 Influences of preoperative metformin on immunological factors in early breast cancer 55 63 EN Takahiro Tsukioki Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tadahiko Shien Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takehiro Tanaka Department of Pathology, Okayama University Hospital Yoko Suzuki Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yukiko Kajihara Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Minami Hatono Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kengo Kawada Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Mariko Kochi Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takayuki Iwamoto Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hirokuni Ikeda Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Naruto Taira Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiroyoshi Doihara Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shinichi Toyooka Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Purpose Metformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer. Method We evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen. Result There was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08). Conclusion Preoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study. No potential conflict of interest relevant to this article was reported.

SpringerOpen Acta Medica Okayama 2198-7793 6 1 2020 Recurring radiation-induced angiosarcoma of the breast that was treated with paclitaxel chemotherapy: a case report 25 EN Yoko Suzuki Department of Breast and Endocrine surgery in Okayama University Japan Hospital Kohei Taniguchi Department of Pathological diagnosis, Okayama University Japan Hospital Minami Hatono Department of Breast and Endocrine surgery in Okayama University Japan Hospital Yukiko Kajiwara Department of Breast and Endocrine surgery in Okayama University Japan Hospital Yuko Abe Department of Breast and Endocrine surgery in Okayama University Japan Hospital Kengo Kawada Department of Breast and Endocrine surgery in Okayama University Japan Hospital Takahiro Tsukioki Department of Breast and Endocrine surgery in Okayama University Japan Hospital Mariko Kochi Department of Breast and Endocrine surgery in Okayama University Japan Hospital Keiko Nishiyama Department of Breast and Endocrine surgery in Okayama University Japan Hospital Takayuki Iwamoto Department of Breast and Endocrine surgery in Okayama University Japan Hospital Hirokuni Ikeda Department of Breast and Endocrine surgery in Okayama University Japan Hospital Tadahiko Shien Department of Breast and Endocrine surgery in Okayama University Japan Hospital Naruto Taira Department of Breast and Endocrine surgery in Okayama University Japan Hospital Masahiro Tabata Department of Hematology, Oncology, Respiratory, and Allergy Medicine, Okayama University Japan Hospital Hiroyuki Yanai Department of Pathological diagnosis, Okayama University Japan Hospital Hiroyoshi Doihara Department of Breast and Endocrine surgery in Okayama University Japan Hospital Background Angiosarcoma of the breast is very rare and can be divided into primary and secondary angiosarcoma. Radiation-induced angiosarcoma (RIAS) is classified as secondary angiosarcoma. Diagnosis of RIAS is difficult due to its rarity, and the interpretation of pathological imaging is complicated. In the National Comprehensive Care Network (NCCN) guidelines, the first choice of treatment is surgery with negative margins. Adjuvant radiotherapy (RT) for close soft tissue margins should be considered. Preoperative or adjuvant chemotherapy of nonmetastatic disease is not recommended for angiosarcoma. We report a case of RIAS, which was impossible to diagnose with core needle biopsy (CNB) but was diagnosed by excisional biopsy. The patient was then administered adjuvant chemotherapy using conjugated paclitaxel (PTX). Case presentation A 62-year-old woman noticed a tumor in her right breast. She had a history of right breast cancer and had undergone breast-conserving surgery, RT, and tamoxifen therapy 8 years previously. CNB, which was performed twice, was inconclusive. The tumor was surgically excised and pathological analysis yielded a diagnosis of angiosarcoma. She then underwent a right mastectomy. One month after she underwent right mastectomy, a nodule reappeared on the skin of her right breast, and excisional biopsy revealed recurrence of angiosarcoma. A few weeks later another nodule reappeared near the post-operative scar and excisional biopsy revealed recurrence of angiosarcoma. We assumed that surgical therapy was insufficient because the patient experienced relapse of angiosarcoma after complete mastectomy. After the second recurrence, we treated her with systemic chemotherapy using PTX. There was no evidence of recurrence 8 months after chemotherapy. Conclusion Although angiosarcoma is difficult to diagnose, many patients have a poor prognosis. Therefore, prompt treatment intervention is desired. Moreover, there is little evidence regarding adjuvant therapy of angiosarcoma since it is a rare disease. We consider that adjuvant therapy helped to effectively prevent recurrence in the patient after complete excision. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 1526-8209 20 2 2020 Evaluation of Therapeutic Target Gene Expression Based on Residual Cancer Burden Classification After Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer 117 124 EN Yuko Takahashi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takayuki Iwamoto Departments of Breast and Endocrine Surgery, Okayama University Hospital Yoko Suzuki Departments of Breast and Endocrine Surgery, Okayama University Hospital Yukiko Kajiwara Departments of Breast and Endocrine Surgery, Okayama University Hospital Minami Hatono Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takahiro Tsukioki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Kengo Kawada Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Mariko Kochi Departments of Breast and Endocrine Surgery, Okayama University Hospital Hirokuni Ikeda Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Naruto Taira Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Junji Matsuoka Departments of Palliative and Supportive Medicine, Okayama University Hospital Hiroyoshi Doihara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Introduction Patients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy. Patients and Methods We retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III. Results Among hormone receptor–positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node–positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II. Conclusion In hormone receptor–positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials. No potential conflict of interest relevant to this article was reported.