Faculty Profiles - SHIEN Tadahiko

Clinicopathological Features of Tumors as Predictors of the Efficacy of Primary Neoadjuvant Chemotherapy for Operable Breast Cancer Reviewed

Tadahiko Shien, Sadako Akashi-Tanaka, Kunihisa Miyakawa, Takashi Hojo, Chikako Shimizu, Kunihiko Seki, Masashi Ando, Tsutomu Kohno, Naruto Taira, Hiroyoshi Doihara, Noriyuki Katsumata, Yasuhiro Fujiwara, Takayuki Kinoshita

WORLD JOURNAL OF SURGERY 33 ( 1 ) 44 - 53 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Neoadjuvant chemotherapy (NC) is standard therapy for patients with locally advanced breast cancer and is increasingly used for early-stage operable disease. Clinical and pathological responses are important prognostic parameters for NC, which aims to achieve a pathological complete response or tumor reduction to reduce the volume of subsequent breast resection. Clinicopathological markers that predict patient response to NC are needed to individualize treatment.
From 1998 to 2006, 368 patients with primary breast cancer underwent curative surgical treatment after NC (anthracycline and/or taxane without trastuzumab). We retrospectively evaluated the clinicopathological features and classification of the tumors using computed tomography (CT) before NC and analyzed the correlation with the pathological complete response (pCR) and reduction of tumor size after treatment.
The overall response and pCR rates in these patients were 86% and 17%, respectively. In multivariate analysis, classification as a scirrhous-type tumor was an independent predictor of reduced likelihood of pCR (p = 0.0115; odds ratio 0.21). For tumor reduction, histological grade 3 (p = 0.0002; odds ratio 3.3) and localized tumors identified by using CT imaging (p = 0.0126; odds ratio 2.4) were independent predictors in multivariate analysis.
In this study, NC often did not result in pCR for breast cancers classified as scirrhous. Furthermore, tumor type classification using CT imaging and histological grading was effective to predict tumor reduction in response to NC that included an anthracycline and/or a taxane.

DOI： 10.1007/s00268-008-9800-9

Evaluation of axillary status in patients with breast cancer using thin-section CT Reviewed

Tadahiko Shien, Sadako Akashi-Tanaka, Miwa Yoshida, Takashi Hojo, Eriko Iwamoto, Kunihisa Miyakawa, Takayuki Kinoshita

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 13 ( 4 ) 314 - 319 2008.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

Background. In recent years, the surgical management of patients with breast cancer has shifted to a locoregional approach, and evaluating the patient's axillary lymph node status is of the greatest importance in determining the appropriate treatment strategy. We evaluated on the efficacy of preoperative axillary staging using contrast-enhanced computed tomography (CE-CT).
Methods. Between 2000 and 2003, 235 patients with operable breast cancer who underwent CE-CT before surgery and 137 patients who received neoadjuvant chemotherapy (NAC) and underwent CE-CT before NAC and surgery were enrolled in this study. The axillary status was evaluated based on three criteria (short-axis diameter, shape, and enhancement type), and the diagnosis was correlated with the histopathological results.
Results. In patients who did not receive NAC, the size criterion of a short-axis diameter of more than 5 mm provided a sensitivity of 78%, a specificity of 75%, and an accuracy of 76% in predicting node-positive status. According to the size criterion of a short-axis diameter of more than 5 mm and the shape criterion of the absence of intranodal fat density, the specificity and accuracy were 90% and 81%, respectively, and according to the enhancement type criterion of early enhancement, the corresponding values were 89% and 78%. Evaluation was more difficult in patients who received NAC and the sensitivity of the size-based criterion in the patients who received NAC was lower than in those who did not.
Conclusion. These findings suggest that CE-CT based on size criteria is useful for evaluating the preoperative axillary status of breast cancer patients, but that evaluation is more difficult and the sensitivity is reduced in patients who have received NAC.

DOI： 10.1007/s10147-007-0753-z

Clinical efficacy of S-1 in pretreated metastatic breast cancer patients Reviewed

Tadahiko Shien, Chikako Shimizu, Sadako Akashi-Tanaka, Kan Yonemori, Tsutomu Kohno, Takashi Hojo, Masashi Ando, Noriyuki Katsumata, Takayuki Kinoshita, Yasuhiro Fujiwara

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 38 ( 3 ) 172 - 175 2008.3

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Background: S-1, an oral fluoropyrimidine carbamate, is an active and well-tolerated agent against solid cancer. However, the clinical efficacy of S-1 in patients with metastatic breast cancer has not been determined.
Methods: We retrospectively evaluated the efficacy of S-1 and identified its adverse effects in patients with metastatic breast cancer who had failed to respond to prior chemotherapy regimens. All the patients were treated at the National Cancer Center Hospital and received S-1 twice daily at a dose of 80 mg/m(2) for 4 weeks, followed by a 2-week rest interval.
Results: Between 2003 and 2007, 37 women with metastatic breast cancer received S-1 as a third line or greater chemotherapy regimen. All the patients had been previously treated with both anthracyclines and taxanes prior to S-1 chemotherapy. The median order of S-1 administration was as a fifth-line treatment, and 23 patients (62%) received S-1 as their final anticancer drug. One (3%) partial response and two (5%) stable diseases were observed. The median time to progression (TTP) was 84 days. Grade 2 adverse events, such as diarrhea, stomatitis and neutropenia occurred in 5 (16%), 1 (3%) and 1 (3%) patients, respectively.
Conclusions: S-1 was safety administered to heavily treated metastatic breast cancer patients with limited efficacy. Further evaluation of S-1 is necessary to elucidate its clinical role in breast cancer treatment.

DOI： 10.1093/jjco/hyn001

Favorable outcome in patients with breast cancer in the presence of pathological response after neoadjuvant endocrine therapy Reviewed

Sadako Akashi-Tanaka, Mutsuko Omatsu, Chikako Shimizu, Masashi Ando, Kotoe Terada, Tadahiko Shien, Takayuki Kinoshita, Yasuhiro Fujiwara, Kunihiko Seki, Tadashi Hasegawa, Takashi Fukutomi

BREAST 16 ( 5 ) 482 - 488 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：CHURCHILL LIVINGSTONE

Neoadjuvant endocrine therapy (NAET) can expand the number of breast cancer patients who can be treated with breast-conserving surgery and can predict benefit from adjuvant endocrine therapy. Because no validated surrogate markers for long-term outcome have been established, we conducted prospective trials to evaluate pathological response and Ki-67 index following treatment with tamoxifen or anastrozole. The study population included postmenopausal women with operable breast tumors that were both estrogen and progesterone receptor-positive and larger than 3 cm. Response was classified as pathological response (minimal response or better) and non-response. Non-responding (25.5%, vs. response 85.9%, p = 0.002), axillary node-positive (58.4% vs. node negative 100%, p=0.045), and high pretreatment Ki-67 index (41.4% vs. low Ki-67 87.1%, p=0.03) patients were significantly associated with poor 5-year relapse-free survival. Multivariate analysis of relapse-free survival indicated that pathological response was independent. Therefore, pathological response may be a favorable prognostic factor after NAET. (c) 2007 Elsevier Ltd. Alt rights reserved.

DOI： 10.1016/j.breast.2007.02.003

[Diagnosis using contrast-enhanced CT for breast cancer and pathological diagnosis]. Reviewed

Sakemura N, Akashi-Tanaka S, Shien T, Kinoshita T, Iwamoto E, Miyakawa K

Nihon rinsho. Japanese journal of clinical medicine 65 Suppl 6 348 - 352 2007.6

Tumor inhibitory effect of gefitinib (ZD1839, Iressa) and taxane combination therapy in EGFR-overexpressing breast cancer cell lines (MCMADR, MDA-MB-231) Reviewed

Daisuke Takabatake, Takeo Fujita, Tadahiko Shien, Kensuke Kawasaki, Naruto Taira, Seiji Yoshitomi, Hirotoshi Takahashi, Yoichi Ishibe, Yutaka Ogasawara, Hiroyoshi Doihara

INTERNATIONAL JOURNAL OF CANCER 120 ( 1 ) 181 - 188 2007.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

Some kinds of breast cancer cell lines, similar to several types of solid tumors, express epidermal growth factor receptor (EGFR). However, gefitinib, an EGFR tyrosine kinase inhibitor, is not effective for all these cell lines. Similarly, taxane is effective for many of the cell lines, although some, such as the multidrug-resistant MCF7/ADR cell line, show taxane-resistance. Here, we examined the growth inhibitory effect of combination treatment with gefitinib and taxane on the breast cancer cell lines MDA-MB-231 (EGFR-positive) and MCF7/ADR (EGFR- and HER2-positive). To estimate the combined effect, a Combination Index was calculated for each cell line. The combination of gefitinib and taxane showed a strong synergistic effect on MCF7/ADR cells, but an in vitro additive-antagonistic effect on MDA-MB-231 cells. Similarly, the combination treatment showed a significantly increased tumor inhibitory effect on MCF7/ADR xenografts, but not on MDA-MB-231 xenografts. Regarding the mechanism of the synergistic effect, Western blotting analysis revealed that taxane activated the EGFR-Akt pathway in MCF7/ADR cells but not in MDA-MB-231. To determine the optimal sequential administration of gefitinib and taxane for MCF7/ADR cells, we used flow cytometry to analyze the cell cycle and apoptosis; finding that taxane treatment followed by gefitinib produced a higher rate of G2 arrest and apoptosis than gefitinib treatment followed by taxane. These results suggest gefitinib overcomes the drug-resistance of these cells, thereby increasing the effects of taxane on MCF7/ADR cells. Further, activation of the EGFR-Akt pathway by taxane is related to this synergistic effect. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.22187

Brain metastases after achieving local pathological complete responses with neoadjuvant chemotherapy. Reviewed

Tsukamoto S, Akashi-Tanaka S, Shien T, Terada K, Kinoshita T

Breast cancer (Tokyo, Japan) 14 ( 4 ) 420 - 424 2007

Language：English Publisher：The Japanese Breast Cancer Society

Background: We encountered two patients with inflammatory breast carcinoma who developed symptomatic brain metastases after achieving local pathological complete responses (pCR) with neoadjuvant chemotherapy (NAC).<BR>Case presentations: The first patient is a 39-year-old woman (Case 1), who underwent NAC with AC (doxorubicin + cyclophosphamide)followed by weekly paclitaxel. After achieving a clinical CR (cCR), we conducted a modified radical mastectomy. Pathological evaluation confirmed no residual malignant cells within the breast tissue or lymph nodes. However, she developed neurological symptoms from brain metastases one month postoperatively. The second patient is a 44-year-old woman (Case 2). Again, no residual malignant cells were detected within the breast tissue or lymph nodes following NAC, but the patient developed symptomatic brain metastases eight months postoperatively. When primary breast tumors are locally advanced, it may be worthwhile to rule out brain metastases even if pCR is obtained after NAC.

DOI： 10.2325/jbcs.14.420

Other Link： http://search.jamas.or.jp/link/ui/2008154599

乳房Paget's病の特徴と治療方針

久野博文, 木下貴之, 明石定子, 寺田琴江, 枝園忠彦, 岩本恵理子

日本臨床外科学会雑誌 67 ( 増刊 ) 593 - 593 2006.10

Development of a Japanese version of the BREAST-Q and the traditional psychometric test of the mastectomy module for the assessment of HRQOL and patient satisfaction following breast surgery.

Saiga M, Taira N, Kimata Y, Watanabe S, Mukai Y, Shimozuma K, Mizoo T, Nogami T, Iwamoto T, Motoki T, Shien T, Matsuoka J, Doihara H

Breast Cancer EPub 2006.5

Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro Reviewed

N Taira, H Doihara, T Oota, F Hara, T Shien, H Takahashi, S Yoshitomi, Y Ishibe, N Shimizu

ACTA MEDICA OKAYAMA 60 ( 1 ) 25 - 34 2006.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Human esophageal cancers have been shown to express high levels of epidermal growth factor receptor (EGFR) and a relationship between high EGFR expression and local advance, the number of lymph node metastases, life expectancy, and sensitivity to chemo-radiotherapy has been demonstrated. We examined the use of gefitinib, an orally active EGFR-selective tyrosine kinase inhibitor, as a new strategy for treatment of esophageal carcinoma. The effects of gefitinib were evaluated in monotherapy and in combination with radiotherapy in human esophageal carcinoma cell lines. Gefitinib produced a dose-dependent inhibition of cellular proliferation in all of the 8 esophageal carcinoma cell lines examined, with IC50 values ranging from 5.7 mu M to 36.9 mu M. In combination, gelitinib and radiotherapy showed a synergistic effect in 2 human esophageal carcinoma cell lines and an additive effect in 5 cell lines. Western blotting demonstrated that gefitinib blocked activation of the EGFR-extracellular signal-regulated kinase (Erk) pathway and the EGFR-phosphoinositide-3 kinase (PI3K)-Akt pathway after irradiation. These results suggest that further evaluation of EGFR blockade as a treatment for esophageal cancer should be performed, and that radiotherapy combined with EGFR blockade may enhance the response of esophageal carcinoma to therapy.

DOI： 10.18926/AMO/30755

Frequent overexpression of epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation Reviewed

T Shien, T Tashiro, M Omatsu, T Masuda, K Furuta, N Sato, S Akashi-Tanaka, M Uehara, E Iwamoto, T Kinoshita, T Fukutomi, H Tsuda, T Hasegawa

JOURNAL OF CLINICAL PATHOLOGY 58 ( 12 ) 1299 - 1304 2005.12

Language：English Publishing type：Research paper (scientific journal) Publisher：B M J PUBLISHING GROUP

Aims: To evaluate the expression of common biological markers and the epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation (DCMDs).
Materials/methods: Thirty DCMDs were clinicopathologically and immunohistochemically analysed and compared with 36 control cases of high grade conventional invasive ductal carcinoma (IDC).
Results: EGFR, HER2/neu, oestrogen receptor, progesterone receptor, and p53 expression was seen in 21, one, three, four, and 20 of the 30 DCMDs, compared with eight, nine, 18, 17, and five of the 36 conventional IDCs (p < 0.05), respectively. In 16 of the 30 DCMDs, metastases were found in the brain, lung, bone, and liver, within a maximum of 47 months (mean, 13.9) after initial surgery, whereas only four of the 36 conventional IDCs metastasised to the lung and bone within a maximum of 27 months (mean, 18.0) after initial surgery (p = 0.0001). There was a significant difference in disease free survival between DCMD and conventional IDC (p = 0.001). EGFR was frequently overexpressed in DCMD compared with conventional IDC, whereas the expression of HER2/neu and hormone receptors was lower in DCMD. Fluorescent in situ hybridisation revealed that the mean EGFR to chromosome 7 centromere (CEP7) ratio of the 24 DCMD cases available for evaluation was 1.03, and EGFR gene amplification was not detected in the 21 DCMD cases with EGFR overexpression.
Conclusion: Immunohistochemistry for myoepithelial markers and EGFR is useful for the accurate diagnosis and molecular target treatment of high grade DCMD.

DOI： 10.1136/jcp.2005.026096

Diagnosis of complete response to neoadjuvant chemotherapy using diagnostic Imaging in primary breast cancer patients Reviewed

T Kanazawa, S Akashi-Tanaka, E Iwamoto, M Takasugi, T Shien, T Kinoshita, K Miyakawa, C Shimizu, M Ando, N Katsumata, Y Fujiwara, T Fukutomi

BREAST JOURNAL 11 ( 5 ) 311 - 316 2005.9

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Advances in the therapeutic agents used for neoadjuvant chemotherapy (NAC) have recently achieved higher response rates and induced a greater number of pathologic complete responses (pCR) than ever before. The aim of this study is the diagnosis of pCR after NAC by diagnostic imaging of clinical complete response (cCR) patients. This study included 35 breast cancer patients who demonstrated cCR after receiving NAC with a combination of anthracycline and taxane from May 1998 to August 2003. Surgical treatment included breast-conserving therapy followed by radiotherapy or mastectomy. The identity of post-NAC lesions as either a complete response (CR) or partial response (PR) were made by mammography, ultrasonography, and contrast-enhanced computed tomography (CT). Among the 35 patients, 11 achieved pCR, including the disappearance of both invasive and intraductal components. Of the patients achieving pCR, eight were defined as CR and three were determined to be PR by CT There was a significant relationship between the pCR and the determination of CR by CT The determination of CR by ultrasonography was indicative of the disappearance of pathologic invasive components. While mammography appeared to reflect the observed histologic results, we did not observe any statistical differences. A subset of cases exhibited discrepancies between the imaging and pathologic results, likely due to the replacement of destroyed tumor cells by fibrosis and granulomatous tissue. The evaluation of CR by CT was significantly indicative of pCR. The positive predictive value, however, was not large enough to avoid surgical treatment. Further studies will be needed to establish a diagnosis of pCR.

DOI： 10.1111/j.1075-122X.2005.00003.x

Antitumor effect of gefitinib ('Iressa') on esophageal squamous cell carcinoma cell lines in vitro and in vivo Reviewed

F Hara, M Aoe, H Doihara, N Taira, T Shien, H Takahashi, S Yoshitomi, K Tsukuda, S Toyooka, T Ohta, N Shimizu

CANCER LETTERS 226 ( 1 ) 37 - 47 2005.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

High expression of epidermal growth factor receptor (EGFR) is thought to be correlated with cell proliferation, invasion, metastasis, resistance to chemoradiotherapy, and poor prognosis in Various kinds of human cancers. Blockade of EGFR signal transduction can be a promising strategy for cancer therapy. Approximately 40-70% of esophageal squamous cell carcinomas (ESCCs) show high expression of EGFR. In this study, we examined the antitumor effect of gefitinib, an EGFR tyrosine kinase inhibitor, against ESCC cells in vitro and in vivo. In three ESCC cell lines (TE8, T.T and T.Tn), cell proliferation had been inhibited in a dose-dependent manner and IC(50) Values (respectively, 8.49, 18.9 and 17.3 mu M). Gefitinib inhibited EGF-induced autophosphorylation of EGFR and its downstream signaling pathways, Ras/Raf/MAPK and PI3K/Akt, and caused G(1) arrest of cell cycle and apoptosis confirmed with flow cytometry. We examined the effect of gefitinib on nude mice bearing established TE8 and T.T xenografts. Gefitimb (100 or 200 mg/kg once-daily, p.o.) showed antitumor activity in a dose-dependent manner, resulting in a significantly improved survival of treated mice as compared with untreated mice. Immunohistochemical examination of the harvested tumor was performed to examine the status of phosphorylated EGFR, PCNA, Factor VIII and apoptosis. We found inhibition of EGFR phosphorylation, cell cycle arrest (by PCNA staining), decrease of microvessel density (Factor VIII) and induction of apoptosis by TUNEL staining. In conclusion, our findings demonstrate that gefitinib is effective for growth inhibition of ESCC cell lines in vitro and in vivo and suggest that gefitinib may be one of the new therapeutic options for ESSC. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2004.12.025

PLC and PI3K pathways are important in the inhibition of EGF-induced cell migration by gefitinib ('Iressa', ZD1839) Reviewed

Tadahiko Shien, Hiroyoshi Doihara, Humikata Hara, Hirotoshi Takahashi, Seiji Yoshitomi, Naruto Taira, Youiti Ishibe, Jyun Teramoto, Motoi Aoe, Nobuyoshi Shimizu

Breast Cancer 11 ( 4 ) 367 - 373 2004.11

Language：English Publishing type：Research paper (scientific journal)

Background: Expression of epidermal growth factor receptor (EGFR) by human breast cancer tissues is associated with poor clinical response. The EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib ('Iressa', ZD1839), is a leading example of a molecular targeted agent, and has an anti-proliferative effect on various cancer cells. But the details of the anti-cancer effect and mechanism have not been elucidated. We studied the anti-cancer effect of gefitinib in breast cancer cell lines and the intracellular pathway downstream of EGFR associated with cell migration. Methods: In this study, we analysed the anti-proliferative and anti-migratory effect of gefitinib in EGFR (+) breast cancer cell lines by WST-1 analysis and chemotaxis chamber analysis. We analyzed several intracellular phosphorylated pathways which are activated by mitogen activated kinases (extracellular signal-regulated protein kinase 1 and 2: MEK), phosphatidylinositol 3'-kinase (PI3K) and phpspholipase C (PLC), by blocking those pathways using inhibitors of each kinase, and also investigated the effects on the phosphorylation of myosin light chain (MLC). Results: Gefitinib inhibited proliferation in most of these cell lines. MDA-MB231 was shown to be resistant. Furthermore, proliferation of MDA-MB231 cells was not affected by EGF stimulation, but migration of MDA-MB231 cells was significantly inhibited. PI3K and PLC inhibitors blocked EGF-stimulated cell migration and MLC phosphorylation, but the MEK inhibitor did not influence cell migration. Conclusions: Gefitinib has an anti-migratory effect on MDA-MB231 that results in an anti-proliferative effect. PI3K and PLC are important for the migration of MDA-MB231 cells, and gefitinib may inhibit migration by blocking these signalling pathways.

DOI： 10.1007/BF02968044

Scopus

Less invasive surgery for primary hyperparathyroidism based on preoperative Tc-99m-hexakis-2-methoxyisobutylisonitrile imaging findings Reviewed

N Taira, H Doihara, F Hara, T Shien, D Takabatake, H Takahashi, S Yoshitomi, Y Ishibe, N Shimizu

SURGERY TODAY 34 ( 3 ) 197 - 203 2004

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER-VERLAG

Purpose. The clinical benefits acquired by introducing hexakis-2-methoxyisobutylisonitrile (MIBI), the reliability of MIBI, and the adequacy of applying less invasive surgeries based on MIBI imaging were retrospectively investigated.
Methods. The surgical results before introducing Tc-99m-MIBI scintigraphy (MIBI) in 10 patients with primary hyperparathyroidism were compared with those after introducing MIBI in 22 patients.
Results. Surgical failure occurred in two patients (20.0%) before introducing MIBI, and in one (4.5%) after introducing MIBI, thus suggesting that the surgical results improved after introducing MIBI. This was because the diagnosis of ectopic adenoma improved with MIBI. Less invasive surgeries were performed in two patients before introducing MIBI, and in 13 patients after introducing MIBI. Consequently, the operation time decreased significantly. The sensitivity of MIBI,. ultrasonography, and computed tomography to adenoma was 100%, 72.2%, and 57.1%, respectively, thus indicating MIBI to have the highest sensitivity. The positive predictive value of MIBI was 85.7%, and all false-positive results were caused by nodular lesions of the thyroid gland. However, the preoperative differentiation of false-positive results could be successfully performed by combining MIBI with neck ultrasonography.
Conclusion. The sensitivity of MIBI to adenoma was thus found to be highly satisfactory. As a result, it might be possible to perform less invasive surgeries based on MIBI imaging without any decrease in the surgical results.

DOI： 10.1007/s00595-003-2687-z