Faculty Profiles - KAGAWA Shunsuke

Papers - KAGAWA Shunsuke

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Experimental Curative Fluorescence-guided Surgery of Highly Invasive Glioblastoma Multiforme Selectively Labeled With a Killer-reporter Adenovirus

Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Michael Bouvet, Yasuo Urata, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

MOLECULAR THERAPY 23 ( 7 ) 1182 - 1188 2015.7

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

Fluorescence-guided surgery (FGS) of cancer is an area of intense current interest. However, although benefits have been demonstrated with FGS, curative strategies need to be developed. Glioblastoma multiforme (GBM) is one of the most invasive of cancers and is not totally resectable using standard bright-light surgery (BLS) or current FGS strategies. We report here a curative strategy for FGS of GBM. In this study, telomerase-dependent adenovirus OBP-401 infection brightly and selectively labeled GBM with green fluorescent protein (GFP) for FGS in orthotopic nude mouse models. OBP-401-based FGS enabled curative resection of GBM without recurrence for at least 150 days, compared to less than 30 days with BLS.

DOI： 10.1038/mt.2015.63

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer

Kunitoshi Shigeyasu, Takeshi Nagasaka, Yoshiko Mori, Naosuke Yokomichi, Takashi Kawai, Tomokazu Fuji, Keisuke Kimura, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

PLOS ONE 10 ( 6 ) e0130409 2015.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background
To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown.
Methods
This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1methylation status in relation to overall survival (OS).
Results
By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis.
Conclusions
CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer.

DOI： 10.1371/journal.pone.0130409

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

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

ACTA MEDICA OKAYAMA 69 ( 3 ) 173 - 176 2015.6

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

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 (type IIIB1 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

Feasibility of oral administration of S-1 as adjuvant chemotherapy in gastric cancer: 4-week S-1 administration followed by 2-week rest vs. 2-week administration followed by 1-week rest. International journal

Tomoki Yamatsuji, Yasuhiro Fujiwara, Hideo Matsumoto, Shinji Hato, Tsutomu Namikawa, Kazuhiro Hanazaki, Munenori Takaoka, Jiro Hayashi, Kaori Shigemitsu, Kazuhiro Yoshida, Atsushi Urakami, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Motoki Ninomiya, Toshiyoshi Fujiwara, Toshihiro Hirai, Masafumi Nakamura, Minoru Haisa, Yoshio Naomoto

Molecular and clinical oncology 3 ( 3 ) 527 - 532 2015.5

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

In 2006, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated that S-1 is an effective adjuvant therapy for gastric cancer. Following that study, S-1 has been used as the standard adjuvant therapy for gastric cancer in Japan. However, the 1-year completion rate was only 65.8% in the ACTS-GC study and feasibility remains a critical issue. We conducted a study to evaluate the feasibility of 2 weekly administration regimens of S-1 as adjuvant chemotherapy in gastric cancer. The criteria for eligibility included histologically proven stage II (excluding T1), IIIA or IIIB gastric cancer with D2 lymph-node dissection. The patients were randomly assigned to either arm A (S-1 administration for 4 weeks followed by 2 weeks of rest) or arm B (S-1 administration for 2 weeks followed by 1 week of rest). In each arm, treatment was continued for 12 months unless recurrence or severe adverse events were observed. The primary endpoint was feasibility (protocol treatment completion rate). The secondary endpoints were safety, relapse-free survival and overall survival. A total of 47 patients were assigned to arms A or B between May, 2008 and February, 2010. During the first interim analysis, the protocol treatment completion rates in arms A and B were 83 and 100%, respectively at 6 months and 49 and 89%, respectively, at 12 months (P=0.0046). Therefore, S-1 administration for 2 weeks followed by 1 week rest was more feasible as adjuvant chemotherapy in gastric cancer. Grade 3 adverse events in arm A included fatigue (8.0%), anorexia (8.0%), nausea (4.0%), vomiting (4.0%) and hand-foot syndrome (4.0%), whereas none were observed in arm B. There were no reported grade 4 adverse events in either arm. In conclusion, the 2-week S-1 administration followed by 1-week rest regimen appears to be a more feasible oral administration regimen for S-1 as adjuvant chemotherapy in gastric cancer.

Targeting tumors with a killer-reporter adenovirus for curative fluorescence-guided surgery of soft-tissue sarcoma

Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Fuminari Uehara, Hiroshi Tazawa, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 6 ( 15 ) 13133 - 13148 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：IMPACT JOURNALS LLC

Fluorescence-guided surgery (FGS) of cancer is an area of intense interest. However, FGS of cancer has not yet been shown to be curative due to residual microscopic disease. Human fibrosarcoma HT1080 expressing red fluorescent protein (RFP) was implanted orthotopically in the quadriceps femoris muscle of nude mice. The tumor-bearing mice were injected with high and low-dose telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401, which labeled the tumor with GFP. Fluorescence-guided surgery (FGS) or bright light surgery (BLS) was then performed. OBP-401 could label soft-tissue sarcoma (STS) with GFP in situ, concordant with RFP. OBP-401-based FGS resulted in superior resection of STS in the orthotopic model of soft-tissue sarcoma, compared to BLS. High-dose administration of OBP-401 enabled FGS without residual sarcoma cells or local or metastatic recurrence, due to its dual effect of cancer-cell labeling with GFP and killing. High-dose OBP-401 based-FGS improved disease free survival (p = 0.00049) as well as preserved muscle function compared with BLS. High-dose OBP-401-based FGS could cure STS, a presently incurable disease. Since the parent virus of OBP-401, OBP-301, has been previously proven safe in a Phase I clinical trial, it is expected the OBP-401-FGS technology described in the present report should be translatable to the clinic in the near future.

Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics

Kunitoshi Shigeyasu, Hiroshi Tazawa, Yuuri Hashimoto, Yoshiko Mori, Masahiko Nishizaki, Hiroyuki Kishimoto, Takeshi Nagasaka, Shinji Kuroda, Yasuo Urata, Ajay Goel, Shunsuke Kagawa, Toshiyoshi Fujiwara

GUT 64 ( 4 ) 627 - 635 2015.4

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

Background Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs.
Methods We developed a new approach to capture live CTCs among millions of peripheral blood leukocytes using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan).
Results Our biological capturing system can image epithelial and mesenchymal tumour cells with telomerase activities as GFP-positive cells. After sorting, direct sequencing or mutation-specific PCR can precisely detect different mutations in KRAS, BRAF and KIT genes in epithelial, mesenchymal or epithelial-mesenchymal transition-induced CTCs, and in clinical blood samples from patients with colorectal cancer.
Conclusions This fluorescence virus-guided viable CTC capturing method provides a non-invasive alternative to tissue biopsy or surgical resection of primary tumours for companion diagnostics.

DOI： 10.1136/gutjnl-2014-306957

腹腔鏡補助下幽門側胃切除後の腹腔内膿瘍に対して内視鏡的経残胃ドレナージが有効であった1例

久保田哲史, 香川俊輔, 菊地覚次, 黒田新士, 西崎正彦, 母里淑子, 岸本浩行, 永坂岳司, 加藤博也, 藤原俊義

日本消化器外科学会雑誌 48 ( 3 ) 208 - 214 2015.3

Language：Japanese Publisher：(一社)日本消化器外科学会

胃切除後の合併症としてまれながら腹腔内膿瘍があり,治療にはドレナージが必要であることが多い.CT・US下の経皮ドレナージが低侵襲で第一選択となるが,腹腔内臓器に囲まれた深部の膿瘍は穿刺がしばしば困難である.今回,我々は腹腔鏡補助下幽門側胃切除術後,腹腔内膿瘍を合併した症例を経験した.膿瘍は残胃の背側にありCT・US下の経皮ドレナージが困難であったが,超音波内視鏡により膿瘍ならびに近接する総肝動脈も明瞭に観察され,超音波内視鏡ガイド下に経残胃ドレナージを安全に施行可能であった.胃切除後であっても腹腔内膿瘍に対する経胃的ドレナージの施行は,低侵襲な治療手段としての一選択肢となりうると考えられたので報告する.(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01117&link_issn=&doc_id=20150420350006&doc_link_id=10.5833%2Fjjgs.2014.0054&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.2014.0054&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

高齢化社会に向けたこれからの胃癌治療戦略治療すべきか経過観察かサルコペニアが高齢胃癌患者の予後に及ぼす影響

桑田和也, 高木弘誠, 菊地覚次, 黒田新士, 吉田龍一, 西崎正彦, 香川俊輔, 藤原俊義

日本胃癌学会総会記事 87回 175 - 175 2015.3

Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells

Kyoko Shimoyama, Shunsuke Kagawa, Michihiro Ishida, Shinichiro Watanabe, Kazuhiro Noma, Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Shunsuke Tanabe, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara

BREAST CANCER RESEARCH AND TREATMENT 149 ( 3 ) 597 - 605 2015.2

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

The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25 % of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.

DOI： 10.1007/s10549-015-3265-y

Endoscopic transgastric drainage of postoperative abdominal abscess after laparoscopic-assisted distal gastrectomy Reviewed

Tetsushi Kubota, Shunsuke Kagawa, Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Yoshiko Mori, Hiroyuki Kishimoto, Takeshi Nagasaka, Hironari Kato, Toshiyoshi Fujiwara

Japanese Journal of Gastroenterological Surgery 48 ( 3 ) 208 - 214 2015

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Gastroenterological Surgery

Although rare, intra-abdominal abscess is one possible postoperative complication of gastrectomy for gastric cancer that requires proper management. Generally, CT-guided or echo-guided percutaneous drainage is the first choice as a less-invasive approach, but percutaneous puncture is sometimes difficult because of surrounding viscera. In our case, an obese woman developed intra-abdominal abscess after laparoscopic distal gastrectomy for gastric cancer. The abscess was surrounded by abdominal organs and was difficult to puncture percutaneously. The patient was therefore treated by endoscopic ultrasonography (EUS)-guided drainage through the wall of the remnant stomach. We successfully achieved safe EUS-guided drainage, because EUS clearly showed perigastric abscess and the common hepatic artery. This case demonstrates trans-gastric drainage of perigastric abscess as a safe, less-invasive procedure, even for the remnant stomach after laparoscopic distal gastrectomy.

DOI： 10.5833/jjgs.2014.0054

MicroRNA as a molecular target for gastrointestinal cancers

Tazawa H, Nagasaka T, Kagawa S, Fujiwara T

Transl Gastrointest Cancer 4 ( 3 ) 219 - 235 2015

宿主正常細胞である癌関連線維芽細胞を標的とした新たな食道癌治療法の開発

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

Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Takehara K, Tazawa H, Okada N, Hashimoto Y, Kikuchi S, Kuroda S, Kishimoto H, Shirakawa Y, Narii N, Mizuguchi H, Urata Y, Kagawa S, Fujiwara T

Mol Cancer Ther DOI: 10.1158/1535-7163 DOI: 10.1158/1535-7163 2015

早期胃癌に対する腹腔鏡下幽門側胃切除術における左胃静脈異常分枝と左肝動脈異常分枝の同時発生に対する戦略的アプローチ 1症例報告(Strategic approach to concurrent aberrant left gastric vein and aberrant left hepatic artery in laparoscopic distal gastrectomy for early gastric cancer: A case report)

Kuwada Kazuya, Kuroda Shinji, Kikuchi Satoru, Hori Naoto, Kubota Tetsushi, Nishizaki Masahiko, Kagawa Shunsuke, Fujiwara Toshiyoshi

Asian Journal of Endoscopic Surgery 8 ( 4 ) 454 - 456 2015

Language：English Publisher：John Wiley & Sons Australia, Ltd

症例は60歳女性で、早期胃癌に対する治療目的で紹介来院となった。内視鏡検査では胃下体部に潰瘍を伴う陥凹性病変が認められ、組織診により印環細胞癌と診断した。腹部造影CTでは、リンパ節転移および遠隔転移は認められず、早期癌と判断したが、肝外側区に流入する左胃静脈異常分枝(ALGV)と左肝動脈異常分枝(ALHA)の同時発生が認められた。D1リンパ節郭清と腹腔鏡下幽門側胃切除術が予定された。最初の術中観察で、造影CT所見と同様に肝外側区に流入するALGVおよびALHAが観察された。そのため、治療可能性と安全性を考慮して、肝流入部でALGVを分割し、さらに基部で左胃動脈(LGA)を分割する代わりに、LGA周囲の全リンパ節と胃に向けてALHAの各分枝を分割し、ALHAを温存した。腹腔鏡下リンパ節郭清後、上腹部を5cm切開し、Billroth I再建術を施行した。手術時間は204分で、推定出血量は0mLであった。胃癌は、病理学的にステージIA、T1N0M0と診断した。術後に肝胆道酵素の軽度上昇が認められたが、経過は全体的に良好で、術後10日目に退院となった。6ヵ月間のフォローアップで再発は認めていない。

DOI： 10.1111/ases.12203

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J06174&link_issn=&doc_id=20160527140014&doc_link_id=10.1111%2Fases.12203&url=https%3A%2F%2Fdoi.org%2F10.1111%2Fases.12203&type=Crossref&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00002_2.gif

Precise navigation surgery of tumours in the lung in mouse models enabled by in situ fluorescence labelling with a killer-reporter adenovirus

Shuya Yano, Yong Zhang, Shinji Miwa, Hiroyuki Kishimoto, Yasuo Urata, Michael Bouvet, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

BMJ Open Respiratory Research 2 ( 1 ) 1 - 6 2015

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

Background: Current methods of image-guided surgery of tumours of the lung mostly rely on CT. A sensitive procedure of selective tumour fluorescence labelling would allow simple and high-resolution visualisation of the tumour for precise surgical navigation. Methods: Human lung cancer cell lines H460 and A549 were genetically transformed to express red fluorescent protein (RFP). Tumours were grown subcutaneously for each cell line and harvested and minced for surgical orthotopic implantation on the left lung of nude mice. Tumour growth was measured by fluorescence imaging. After the tumours reached 5 mm in diameter, they were injected under fluorescence guidance with the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus, OBP-401. Viral labelling of the lung tumours with GFP precisely colocalised with tumour RFP expression. Three days after administration of OBP-401, fluorescence-guided surgery (FGS) was performed. Results: FGS of tumours in the lung was enabled by labelling with a telomerase-dependent adenovirus containing the GFP gene. Tumours in the lung were selectively and brightly labelled. FGS enabled complete lung tumour resection with no residual fluorescent tumour. Conclusions: FGS of tumours in the lung is feasible and more effective than bright-light surgery.

DOI： 10.1136/bmjresp-2015-000096

Eradication of osteosarcoma by fluorescence-guided surgery with tumor labeling by a killer-reporter adenovirus

Yano S, Miwa S, Kishimoto H, Urata Y, Tazawa H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

J Orthop Res doi: 10.1002/jor.23073. [Epub ahead of print] 2015

Multidisciplinary cancer therapy with telomerase-specific oncolytic adenovirus

Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

Current Cancer Therapy Reviews 11 ( 3 ) 178 - 187 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：Bentham Science Publishers B.V.

A multidisciplinary approach of combining surgery, chemotherapy and radiotherapy has remained the accepted standard management for various types of human cancer. However, many new treatment options have recently become available, including molecular targeted therapies, immunotherapies and oncolytic virotherapies. Replication-selective tu-mor-specific viruses have been designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. We constructed an attenuated adenovirus 5 vector, telomelysin (OBP-301), in which the telomerase-specific promoter drives expression of viral replication-inducible E1 genes. Although telomelysin alone exhibited substantial antitumor effects both in animal models and in clinical trials, telomelysin has the potential to be the first-in-class oncolytic virus for combination therapy based on our current understanding of the molecular mechanisms. Telomelysin sensitizes human cancer cells to ionizing radiation by inhibiting the radiation-induced DNA repair machinery, and also eliminates radio-resistant quiescent cancer stem-like cells by promoting cell cycle entry. A clinical trial of intratumoral administration of telomelysin with radiotherapy in esophageal cancer patients is currently underway. This article reviews recent highlights in the rapidly evolving field of multidisciplinary therapy with telomelysin.

DOI： 10.2174/1573394712666160128201822

Molecular diagnosis and therapy for occult peritoneal metastasis in gastric cancer patients

Shunsuke Kagawa, Kunitoshi Shigeyasu, Michihiro Ishida, Megumi Watanabe, Hiroshi Tazawa, Takeshi Nagasaka, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

WORLD JOURNAL OF GASTROENTEROLOGY 20 ( 47 ) 17796 - 17803 2014.12

Language：English Publisher：BAISHIDENG PUBLISHING GROUP INC

To apply an individualized oncological approach to gastric cancer patients, the accurate diagnosis of disease entities is required. Peritoneal metastasis is the most frequent mode of metastasis in gastric cancer, and the tumor-node-metastasis classification includes cytological detection of intraperitoneal cancer cells as part of the staging process, denoting metastatic disease. The accuracy of cytological diagnosis leaves room for improvement; therefore, highly sensitive molecular diagnostics, such as an enzyme immunoassay, reverse transcription polymerase chain reaction, and virus-guided imaging, have been developed to detect minute cancer cells in the peritoneal cavity. Molecular targeting therapy has also been spun off from basic research in the past decade. Although conventional cytology is still the mainstay, novel approaches could serve as practical complementary diagnostics to cytology in near future. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i47.17796

Establishment of a Non-Invasive Semi-Quantitative Bioluminescent Imaging Method for Monitoring of an Orthotopic Esophageal Cancer Mouse Model

Shinji Kuroda, Tetsushi Kubota, Katsuyuki Aoyama, Satoru Kikuchi, Hiroshi Tazawa, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

PLOS ONE 9 ( 12 ) e114562 2014.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Orthotopic models of various types of tumors are widely used in anti-tumor therapeutic experiments in preclinical studies. However, there are few ways to appropriately monitor therapeutic effect in orthotopic tumor models, especially for tumors invisible from the outside. In this study we aimed to establish a non-invasive semi-quantitative bioluminescent imaging method of monitoring an orthotopic esophageal cancer mouse model. We confirmed that the TE8 esophageal cancer cell line implanted orthotopically into the abdominal esophagus of nu/nu mice (n=5) developed not only a main tumor at the implanted site, but also local lymph node metastases and peritoneal disseminations within 6 weeks after inoculation. We established a TE8 cell line that stably expressed the firefly luciferase gene (TE8-Luc). We showed that TE8-Luc cells implanted subcutaneously into nu/nu mice (n=5) grew over time until 5 weeks after inoculation. Tumor volume was strongly correlated with luminescent intensity emitted from the tumor, which was quantified using the IVIS imaging system. We then showed that TE8-Luc cells implanted orthotopically into the mouse abdominal esophagus (n=8) also formed a tumor and that the luminescent intensity of such a tumor, as detected by IVIS, increased over time until 7 weeks after inoculation and was therefore likely to reflect tumor progression. We therefore propose that this orthotopic esophageal cancer model, monitored using the non-invasive semi-quantitative IVIS imaging system, will be useful for in vivo therapeutic experiments against esophageal cancer. This experimental setting is expected to contribute to the development of novel therapeutic technologies for esophageal cancer in preclinical studies.

DOI： 10.1371/journal.pone.0114562

Two cases of stage IV gastric cancer responding to chemotherapy and leading to pathological complete response Reviewed

Tetsushi Kubota, Shunsuke Kagawa, Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 41 ( 12 ) 2308 - 2310 2014.11

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

Case 1: A 76-year-old man presented with advanced gastric cancer in the esophagogastric junction with para-aortic lymph node metastasis (HER2 positive CT4N1M1 [LYM], cStage IV). After 3 courses of chemotherapy consisting of S-1+docetaxel + trastuzumab were completed, we performed surgery. No cancer cells were revealed during histopathological examination, indicating pathological complete response (pCR). At present, 12 months after treatment, the patient is well, with no signs of recurrence. Case 2: A 74-year-old man presented with advanced gastric cancer with peritoneal metastasis (cT4b [Panc] N1M1 [P], cStage IV). After 2 courses of chemotherapy consisting of S-1+CDDP were completed, we performed surgery. Histopathological examination revealed no cancer cells, indicating pCR. At present, 13 months after treatment, the patient is incident-free, with no signs of recurrence.

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