Faculty Profiles - OHARA Toshiaki

Papers - OHARA Toshiaki

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Molecular Subtypes of Breast Cancers from Myanmar Women: A Study of 91 Cases at Two Pathology Centers Reviewed International journal

Thar Htet San, Masayoshi Fujisawa, Soichiro Fushimi, Lamin Soe, Ngu Wah Min, Teizo Yoshimura, Toshiaki Ohara, Myint Myint Yee, Shinsuke Oda, Akihiro Matsukawa

Asian Pacific journal of cancer prevention : APJCP 18 ( 6 ) 1617 - 1621 2017.6

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

Background: Breast cancer is the most common cancer in Myanmar women. Revealing the hormonal receptor
status, human epidermal growth factor receptor 2 (HER2) and Ki-67 expression is useful for estimating patient
prognosis as well as determination of treatment strategy. However, immunohistochemical features and classification of
molecular subtypes in breast cancers from Myanmar remain unknown. Methods: The clinicopathological features of
91 breast cancers from Myanmar women were examined. Immunohistochemistry was performed on tissue specimens
with antibodies to estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67, cytokeratin (CK)5/6 and CK14.
Immunohistochemistry-based molecular subtyping was conducted. Results: Breast cancers in Myanmar women were
relatively large, high grade with frequent metastatic lymph nodes. Of the 91 patients, tumors with ER positive, PgR
positive, and HER2 positive were 57.1%, 37.4%, and 28.6%, respectively. The most prevalent subtype was luminal B
(HER2-) (39.6%), followed by HER2 (22.0%), triple negative (TN)-basal-like (12.1%), luminal A (11.0%), TN-null
(8.8%) and luminal B (HER2+) (6.6%). The mean Ki-67 expression of 91 cases was 33.9% (33.9% ± 19.2%) and the
median was 28% (range; 4%-90%). The mean Ki-67 expression of luminal A, luminal B, HER2 and TN-basal-like/
null was 7%, 30%, 40%, and 57%/43%, respectively. A higher Ki-67 expression significantly correlated with a higher
grade, larger size and higher stage of malignancy. Conclusions: We, for the first time, investigated the histopathological
features of breast cancers from Myanmar women. Myanmar breast cancers appeared to be aggressive in nature, as
evidenced by high frequency of poor-prognosis subtypes with high level of Ki-67 expression.

DOI： 10.22034/APJCP.2017.18.6.1617

Low prevalence of human mammary tumor virus (HMTV) in breast cancer patients from Myanmar. Reviewed International journal

Thar Htet San, Masayoshi Fujisawa, Soichiro Fushimi, Teizo Yoshimura, Toshiaki Ohara, Lamin Soe, Ngu Wah Min, Ohnmar Kyaw, Xu Yang, Akihiro Matsukawa

Infectious agents and cancer 12 20 - 20 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

BACKGROUND: Human mammary tumor virus (HMTV) is 90-95% homologous to mouse mammary tumor virus (MMTV), one of the causal agents of murine mammary tumors. HMTV (MMTV-like) sequences were reported to be present in human breast cancers from several populations with a prevalence range of 0-78%; however, the prevalence of HMTV in breast cancers from Myanmar remains unknown. METHODS: Fifty-eight breast cancer samples from Myanmar women were examined in this study. DNA was isolated from formalin-fixed paraffin-embedded specimens, and HMTV envelope sequences were detected by semi-nested PCR. The sequence of the PCR products was also confirmed. RESULTS: Only 1.7% (1 of 58) of the breast cancers were positive for HMTV, and the sequence of PCR products was 98.9% identical to the reference HMTV sequence (GenBank accession No. AF243039). The tumor with HMTV was grade III invasive ductal carcinoma, 7.0 cm in size with lymph node metastasis (T3, N1, M0). CONCLUSIONS: We, for the first time, investigated the presence of HMTV in Myanmar breast cancer patients. In accordance with other Asian studies, the prevalence of HMTV in Myanmar was quite low, supporting the hypothesis that Asian breast cancers have different etiologies than in Western countries, where HMTV is more prevalent.

DOI： 10.1186/s13027-017-0130-0

Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer. Reviewed International journal

Seishi Nishitani, Kazuhiro Noma, Toshiaki Ohara, Yasuko Tomono, Shinichiro Watanabe, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

International journal of oncology 49 ( 4 ) 1351 - 9 2016.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, iron depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased iron conditions were made using an iron-depletion diet in mice and the iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere-formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased iron conditions. In vitro study showed that decreased iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.

DOI： 10.3892/ijo.2016.3640

Iron depletion enhances the effect of sorafenib in hepatocarcinoma. Reviewed International journal

Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Kazuhiro Nouso, Akihiro Matsukawa, Kazuhide Yamamoto, Toshiyoshi Fujiwara

Cancer biology & therapy 17 ( 6 ) 648 - 56 2016.6

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

ABSTACT Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that iron depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed iron depletion therapy including iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of iron depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar®) and/or deferasirox (EXJADE®) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both iron depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by iron depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.

DOI： 10.1080/15384047.2016.1177677

Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion. Reviewed International journal

Satoru Kikuchi, Shunsuke Kagawa, Toshiaki Ohara, Tetsushi Kubota, Kazuya Kuwada, Tetsuya Kagawa, Shinji Kuroda, Yasuhiro Shirakawa, Masahiko Nishizaki, Toshiyoshi Fujiwara

Acta medica Okayama 70 ( 3 ) 213 - 216 2016.6

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

A 69-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) at the lesser curvature in the angle of stomach. Histological examination revealed tub1, pM, ly0, v0, pLM(-), pVM(-), and the resection was considered curative. The scar after ESD was followed by esophagogastroduodenoscopy (EGD) and biopsy. Twenty months later, EGD showed an ulcerative lesion in the vicinity of the ESD scar, and histological examination of the biopsy specimen showed adenocarcinoma. A distal gastrectomy with lymph node dissection was then performed. Postoperative pathology showed tub1, pM, pN0, ly0, v0, and Stage 1A. Skip lesions were seen in the specimen resected by ESD, and the histological review confirmed so-called "dysplasia-like atypia" (DLA) between the lesions. It has been reported recently that in DLA, the dysplasia-like change involves only the bases of the pits, without upper pit or surface epithelium involvement, and it is said that the rate of DLA is higher in gastric cancer patients. We speculated that a precancerous lesion close to the resected cancer developed into a local recurrence.

DOI： 10.18926/AMO/54421

Therapeutic Potential of Targeting Cancer-Associated Fibroblasts in Esophageal Cancer Reviewed

野間和広, 賀島肇, 二宮卓之, 勝部亮一, 渡邉伸一郎, 大原利章, 田澤大, 香川俊輔, 白川靖博, 藤原俊義

癌と化学療法 42 ( 10 ) 1228 - 1230 2015.10

Language：Japanese

Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00296&link_issn=&doc_id=20151027380020&doc_link_id=%2Fab8gtkrc%2F2015%2F004210%2F021%2F1228-1230%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2015%2F004210%2F021%2F1228-1230%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Prone-position thoracoscopic resection of posterior mediastinal lymph node metastasis from rectal cancer Reviewed International journal

Yasuhiro Shirakawa, Kazuhiro Noma, Takeshi Koujima, Naoaki Maeda, Shunsuke Tanabe, Toshiaki Ohara, Toshiyoshi Fujiwara

WORLD JOURNAL OF SURGICAL ONCOLOGY 13 45 - 45 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Mediastinal lymph node metastasis from colorectal cancer is rare, and barely any reports have described resection of this pathology. We report herein a successful thoracoscopic resection of mediastinal lymph node metastasis in a prone position. A 65-year-old man presented with posterior mediastinal lymph node metastasis after resection of the primary rectal cancer and metachronous hepatic metastasis. Metastatic lymph nodes were resected completely using thoracoscopic surgery in the prone position, which provided advantages of minimal invasiveness, good surgical field, and reduced ergonomic burden on the surgeon. Thoracoscopic resection in the prone position was thought to have the potential to become the standard procedure of posterior mediastinal tumors.

DOI： 10.1186/s12957-015-0466-0

Operative technique of antethoracic esophageal reconstruction with pedicled jejunal flap Reviewed International journal

Yasuhiro Shirakawa, Kazuhiro Noma, Takeshi Koujima, Naoaki Maeda, Shunsuke Tanabe, Toshiaki Ohara, Kazufumi Sakurama, Toshiyoshi Fujiwara

Esophagus 12 ( 1 ) 57 - 64 2015.1

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

Esophageal reconstruction using intestine is often performed for esophageal cancer patients in cases where the stomach cannot be used. We have previously performed reconstruction using ileocolon with supercharge and drainage as our first choice in those cases. However, a less invasive, simpler, and safer reconstructive technique using jejunum without vascular anastomosis has recently become popular at our facility. This study describes the technique of esophageal reconstruction with jejunum, compares the surgical outcomes to those of standard reconstruction using ileocolon, and discusses the clinical significance of this new concept.Subjects comprised 53 patients (52 males, 1 female) who underwent esophageal reconstruction using jejunum between January 2008 and July 2013. Patient characteristics, technical details, and outcomes were compared with those of 51 subjects who had undergone esophageal reconstruction using ileocolon. When making the pedicled jejunal flap, the first jejunal vascular arcade was preserved, which in most cases allowed it to be pulled up to the cervical region by processing and transection up to the second jejunal vascular branch.The vascular anastomosis techniques were used in 80.4 % (41/51) of esophageal reconstructions using colon, compared with only 24.5 % (13/53) of reconstructions using jejunum. No difference in the frequency of postoperative adverse effects was seen between groups, but the frequency of diarrhea was significantly lower with reconstruction using jejunum.Esophageal reconstruction using jejunum with the blood vessel processing technique results in both simpler and safer pulling up. Thus the need to perform supercharge and superdrainage is reduced.

DOI： 10.1007/s10388-014-0455-3

Prone-Position Thoracoscopic Ligation of the Thoracic Duct for Chyle Leak Following Radical Neck Dissection in a Patient with a Right Aortic Arch. Reviewed International journal

Yasuhiro Shirakawa, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Naoaki Maeda, Shunsuke Tanabe, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 69 ( 3 ) 173 - 6 2015

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

A chyle leak can occur as a complication after neck or chest surgery. Such a leak prolongs the hospital stay and is sometimes life-threatening. The treatment options are conservative management, interventional radiologic embolization, and surgery. Thoracoscopic ligation of the thoracic duct has emerged as a promising and definitive treatment. The case of a 65-year-old Japanese male patient with a rare congenital right aortic arch (typeⅢB1 of Edward's classification) and a severe chyle leak that occurred after a total pharyngolaryngo-esophagectomy (TPLE) is described. The chyle leak was successfully managed by thoracoscopic ligation of the thoracic duct via a left-side approach with the patient in the prone position.

DOI： 10.18926/AMO/53524

腫瘍血管新生抑制療法に対する鉄欠乏の新規の相乗効果(A novel synergistic effect of iron depletion on antiangiogenic cancer therapy)

大原利章

岡山医学会雑誌 126 ( 2 ) 182 - 183 2014.8

手術手技食道癌手術における用手補助的腹腔鏡下胃管作成の工夫

白川靖博, 前田直見, 田辺俊介, 大原利章, 野間和広, 藤原俊義

手術 68 ( 7 ) 951 - 954 2014.6

術前DCF療法が著効した食道原発内分泌細胞癌の1切除例

前田直見, 白川靖博, 國府島健, 大原利章, 田邊俊輔, 野間和広, 櫻間教文, 藤原俊義

岡山医学会雑誌 126 ( 1 ) 39 - 43 2014.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：岡山医学会

66歳男。心窩部痛を主訴とした。上部消化管造影検査所見で胸部中部食道(Mt)左-前壁に70mm大の周堤隆起明瞭な2型病変が認められた。上部消化管内視鏡検査所見で切歯より25cm〜33cmの食道左-前壁に半周性の2型病変を認められた。同部位の生検を施行し、内分泌細胞癌(小細胞型)と診断された。造影CT検査所見およびPET/CT検査より、胸部食道内分泌細胞癌(小細胞型)cT3cN1cM0:cStage IIIと診断し、術前補助化学療法2コースの後、手術の方針とした。化学療法は、docetaxel、cisplatin、5-fluorouracilの三剤を併用した。手術は腹臥位胸腔鏡下食道亜全摘、用手補助的腹腔鏡下胃管作製、3領域リンパ節郭清、胸骨後経路再建、頸部吻合を施行した。組織所見にて潰瘍部では加療による影響と考えられる線維化とヘモジデリンの沈着を認め、Grade 3と判定した。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00175&link_issn=&doc_id=20140415220008&doc_link_id=10.4044%2Fjoma.126.39&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.126.39&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

食道原発悪性黒色腫の1切除例 Reviewed

前田直見, 白川靖博, 國府島健, 大原利章, 田邊俊輔, 野間和広, 櫻間教文, 藤原俊義

岡山医学会雑誌 126 ( 1 ) 45 - 48 2014.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：岡山医学会

61歳男。食物つかえ感を主訴とした。上部消化管造影検査所見にて胸部中部下部食道(MtLt)前から右壁に、60mm大の周堤隆起明瞭な2型病変が認められた。上部消化管内視鏡検査所見で切歯より30cm〜36cmの食道前〜右壁に半周性の2型病変が認められた。口側には1型隆起部分も認めた。2型部分は黒紫色であったが、1型部分はピンクから白色調で一部血腫を形成していた。以上より、胸部食道原発悪性黒色腫cT3cN0 cM0:cStage IIと診断した。手術は腹臥位胸腔鏡下食道亜全摘、用手補助的腹腔鏡下胃管作製、2領域リンパ節郭清(胸部、腹部)、胸骨後経路再建、頸部吻合を施行した。組織所見よりpT2N0M0 pStage IIと診断し、術後補助化学療法として高用量DTIC療法を6コース行った。術後1年5ヵ月経過しているが無再発生存中である。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00175&link_issn=&doc_id=20140415220009&doc_link_id=10.4044%2Fjoma.126.45&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.126.45&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Assistant-based standardization of prone position thoracoscopic esophagectomy. Reviewed International journal

Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Ryoichi Katsube, Shunsuke Tanabe, Toshiaki Ohara, Kazufumi Sakurama, Toshiyoshi Fujiwara

Acta medica Okayama 68 ( 2 ) 111 - 7 2014

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

Thoracoscopic esophagectomy in the prone position (TEPP) might enable solo-surgery in cases requiring resection of the esophagus and the surrounding lymph nodes due to the associated advantages of good exposure of the surgical field and ergonomic considerations for the surgeon. However, no one approach can be for all patients requiring extensive lymphadenectomy. We recently developed an assistant-based procedure to standardize exposure of the surgical field. Patients were divided into 1 of 2 groups:a pre-standardization group (n=37) and a post-standardization group (n=28). The thoracoscopic operative time was significantly shorter (p=0.0037) in the post-standardization group (n=28; 267 ± 31 min) than in the pre-standardization group (n=37;301 ± 53 min). Further, learning curve analysis using the moving average method showed stabilization of the thoracoscopic operative time after the standardization. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the 2 groups. There were also no significant differences in the complication rate. Assistant-based surgery and standardization of the procedure resulted in a well-exposed and safe surgical field. TEPP decreased the operative time, even in patients requiring extensive lymphadenectomy.

DOI： 10.18926/AMO/52407

The 2013 Incentive Award of the Okayama Medical Association in Cancer Research (2013 Hayashibara Prize and Yamada Prize) Invited

Ohara Toshiaki

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 126 ( 2 ) 93 - 94 2014

Advanced hepatocellular carcinoma with lymph node metastases showing epithelial to mesenchymal transition effectively treated with systemic chemotherapy: Report of a case. Reviewed International journal

Hiroshi Sadamori, Takahito Yagi, Kunitoshi Shigeyasu, Yuzo Umeda, Masahiro Sugihara, Naosuke Yokomichi, Toshiaki Ohara, Naoshi Nishida, Takeshi Nagasaka, Ajay Goel, Toshiyoshi Fujiwara

Hepatology research : the official journal of the Japan Society of Hepatology 43 ( 12 ) 1368 - 73 2013.12

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

We present a case in which combination chemotherapy was used to successfully treat hepatocellular carcinoma (HCC) with rapid progression of lymph node (LN) metastases after liver resection. In addition, epithelial to mesenchymal transition (EMT) markers were examined immunohistochemically. A 43-year-old man who had been diagnosed with HCC showed an enlarged LN near the hepatic artery proper. After extended left lobectomy with lymphadenectomy in the hepatoduodenal ligament, he experienced rapid progression of metastases to the para-aortic and mediastinal LN. Partial remission was achieved after induction and maintenance of combination chemotherapy using etoposide, carboplatin, epirubicin and 5-fluorouracil. As a consequence of this treatment, the patient survived 10 months. Immunohistochemical studies demonstrated that HCC cells in the metastatic LN showed low expression of E-cadherin and high expression of N-cadherin and vimentin, indicating EMT. Combination chemotherapy may prove effective for patients with HCC accompanied by LN metastases that show features of EMT.

DOI： 10.1111/hepr.12080

Direct observation diverticulectomy for Zenker’s diverticulum carcinoma Reviewed International journal

Toshiaki Ohara, Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Ryouichi Katsube, Shunsuke Tanabe, Toshiyoshi Fujiwara

Esophagus 10 ( 4 ) 235 - 238 2013.12

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/s10388-013-0376-6

Other Link： http://link.springer.com/article/10.1007/s10388-013-0376-6/fulltext.html

Current Status of Neoadjuvant Chemotherapy for Advanced Esophageal Cancer Reviewed

田辺俊介, 白川靖博, 前田直見, 勝部亮一, 大原利章, 櫻間教文, 野間和広, 藤原俊義

癌と化学療法 40 ( 12 ) 1612 - 1614 2013.11

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

Since reported in the JCOG9907 trial, neoadjuvant chemotherapy prior to surgery has become the standard treatment for advanced (Stage II/III) esophageal cancers. However, more powerful neoadjuvant chemotherapy is required for the treatment of locally advanced cases or cases involving multiple lymph node metastases. At our institute, DCF therapy (docetaxel, cisplatin, and 5-fluorouracil) is administered selectively for the treatment of patients with far-advanced esophageal cancer. We treated 53 thoracic esophageal cancer patients who underwent surgery following neoadjuvant chemotherapy between January 2010 and December 2012. FP therapy (cisplatin and 5-fluorouracil) was administered to 43 patients, and DCF therapy to 7 patients who had far-advanced esophageal cancer. All patients treated with DCF therapy experienced grade 3 and 4 adverse events. With the exception of 1 patient, all patients who received DCF therapy could undergo curative surgery. DCF therapy could become an effective preoperative chemotherapy.

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A novel synergistic effect of iron depletion on antiangiogenic cancer therapy. Reviewed International journal

Toshiaki Ohara, Kazuhiro Noma, Shinichi Urano, Shinichiro Watanabe, Seishi Nishitani, Yasuko Tomono, Fumiaki Kimura, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

International journal of cancer 132 ( 11 ) 2705 - 13 2013.6

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce iron levels has been shown to suppress tumor growth in vivo. However, iron depletion monotherapy by iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that iron depletion may induce angiogenesis. Therefore, we hypothesized that iron depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An iron-deficient diet and an iron chelator were used to simulate an iron-depleted condition. The antitumor effects of iron depletion and antiangiogenic therapy were determined on A549 xenograft mice. The iron-depleted condition produced by an iron-deficient diet suppressed tumor growth. Tumor tissue from the iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the iron-depleted antitumor effect. Treatment to deplete iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.

DOI： 10.1002/ijc.27943

Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice. Reviewed International journal

Toshio Nishikawa, Munenori Takaoka, Toshiaki Ohara, Yasuko Tomono, Huifang Hao, Xiaohong Bao, Takuya Fukazawa, Zhigang Wang, Kazufumi Sakurama, Yasuhiro Fujiwara, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

Cancer biology & therapy 14 ( 3 ) 230 - 6 2013.3

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

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

DOI： 10.4161/cbt.23294

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