Faculty Profiles - FUJIWARA Toshiyoshi

MISC - FUJIWARA Toshiyoshi

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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 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.

Effect of methionine-depletion via methioninase-treatment on cancer cells in S/G2 phase and chemosensitivity.

Shuya Yano, Shukuan Li, Qinghong Han, Yuying Tan, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

JOURNAL OF CLINICAL ONCOLOGY 33 ( 15 ) 2015.5

MicroRNA as a molecular target for gastrointestinal cancers

Hiroshi Tazawa, Takeshi Nagasaka, Shunsuke Kagawa, Toshiyoshi Fujiwara

TRANSLATIONAL GASTROINTESTINAL CANCER 4 ( 3 ) 219 - 235 2015.5

Language：English Publishing type：Book review, literature introduction, etc. Publisher：AME PUBL CO

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally suppress the expression of many target genes, thereby contributing to the modulation of diverse cellular fates in tumor biology. Recent accumulating evidences have demonstrated that aberrant expression of miRNAs is highly associated with tumor initiation, progression and metastasis in various types of cancers including gastrointestinal (GI) cancers. Exploration of precise miRNA-based gene regulatory networks in the pathogenesis of GI cancers will provide important information for the development of novel anticancer strategies aimed at normalizing the critical miRNAs that are deregulated in GI cancers. Recent reports using clinical samples have shown the potential of upregulation of oncogenic miR-21 and of downregulation of the tumor-suppressive miR-34 family as novel molecular biomarkers for the diagnostic and prognostic prediction of GI cancers. In this review, we have focused on the functional roles of these two cancer-related miRNAs, miR-21 and miR-34, that are commonly deregulated during the development and progression of GI cancers. Moreover, the therapeutic potential of miRNA-targeting anticancer therapy is discussed for clinical application as novel anticancer therapy for GI cancers.

DOI： 10.3978/j.issn.2224-4778.2015.04.01

Aggressive Multimodality Treatment for Advanced Rectal Cancer

Ryo Inada, Takeshi Nagasaka, Toshiaki Toshima, Yoshiko Mori, Yoshitaka Kondo, Hiroyuki Kishimoto, Takao Hiraki, Taihei Oshiro, Yukihide Kanemitsu, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 69 ( 2 ) 113 - 118 2015.4

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

A case of advanced rectal cancer treated by aggressive local and systemic treatment who has survived more than 7 years from initial recurrence is presented. A 55-year-old woman was diagnosed with advanced lower rectal cancer and underwent a low anterior resection with complete removal of all regional lymph nodes and total mesorectal excision. The tumor was diagnosed as a moderately differentiated adenocarcinoma, pStage IIIB (T3, N2a, M0). Twenty-six months after the initial surgery, local recurrence in the pelvis was detected by computed tomography, and total pelvic exenteration with distal sacrectomy (TPES) was performed after systemic chemotherapy with a molecular-targeted drug. Six months after the TPES, multiple lung metastases were detected. Consequently, the patient underwent radiofrequency ablation (RFA) and chemotherapy. The disease has since been controlled for 38 months. As volume control is essential for cancer treatment, it may be important to combine appropriate local therapy with systemic therapy to metastatic or recurrent sites in order to achieve much longer disease control.

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 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

Correlation of Computed Tomography Imaging Features and Pathological Features of 41 Patients with Pancreatic Neuroendocrine Tumors

Masashi Utsumi, Yuzo Umeda, Kosei Takagi, Kuise Takashi, Daisuke Nobuoka, Ryuichi Yoshida, Susumu Shinoura, Hiroshi Sadamori, Takahito Yagi, Toshiyoshi Fujiwara

HEPATO-GASTROENTEROLOGY 62 ( 138 ) 441 - 446 2015.3

Language：English Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Background:/Aims: Pancreatic neuroendocrine tumors (PNET) are relatively rare. Here, we present clinical and pathological characteristics of PNETs to show a relationship between computed tomography (CT) imaging and the 2010 World Health Organization (WHO) classification. Methodology: We retrospectively reviewed the records of 41 PNET patients who were treated between 2002 and 2012. All tumors were classified as neuroendocrine tumor (NET) grade 1 (121), NET grade 2 (G2), or neuroendocrine carcinoma (NEC) grade 3 (G3) on the basis of the 2010 WHO classification system. Results: Twenty-five tumors were classified as G1, 11 as G2, and five as G3. Mean sizes of the G1, G2 and G3 tumors were 1.84 +/- 0.54, 4.90 +/- 0.84, and 5.62 +/- 1.18 cm, respectively, (P < 0.01). A PNET is typically hypervascular and exhibits contrast enhancement on enhanced CT. Higher percentage of G1 tumors demonstrated typical imaging and showed a significantly greater distinct mass compared with G2 and G3 tumors. Conclusions: Although PNET has many imaging features that appear on CT, G2 and G3 tumors often show atypical imaging features, particularly with large sizes and/or ill-defined features, when compared with G1 tumors. If a PNET has atypical imaging features, possibility of malignancy should be considered.

DOI： 10.5754/hge14388

Cancer cells mimic in vivo spatial-temporal cell-cycle phase distribution and chemosensitivity in 3-dimensional Gelfoam (R) histoculture but not 2-dimensional culture as visualized with real-time FUCCI imaging

Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminaru Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 14 ( 6 ) 808 - 819 2015.3

Language：English Publisher：TAYLOR & FRANCIS INC

The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We previously reported monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor, intravitally in live mice, using a fluorescence ubiquitination-based cell-cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after cessation of chemotherapy. These results suggested why most drugs currently in clinical use, which target cancer cells in S/G(2)/M, are mostly ineffective on solid tumors. In the present report, we used FUCCI imaging and Gelfoam (R) collagen-sponge-gel histoculture, to demonstrate in real time, that the cell-cycle phase distribution of cancer cells in Gelfoam (R) and in vivo tumors is highly similar, whereby only the surface cells proliferate and interior cells are quiescent in G(0)/G(1). This is in contrast to 2D culture where most cancer cells cycle. Similarly, the cancer cells responded similarly to toxic chemotherapy in Gelfoam (R) culture as in vivo, and very differently than cancer cells in 2D culture which were much more chemosensitive. Gelfoam (R) culture of FUCCI-expressing cancer cells offers the opportunity to image the cell cycle of cancer cells continuously and to screen for novel effective therapies to target quiescent cells, which are the majority in a tumor and which would have a strong probability to be effective in vivo.

DOI： 10.1080/15384101.2014.1000685

ARID1A expression in gastric adenocarcinoma: Clinicopathological significance and correlation with DNA mismatch repair status

Ryo Inada, Shigeki Sekine, Hirokazu Taniguchi, Hitoshi Tsuda, Hitoshi Katai, Toshiyoshi Fujiwara, Ryoji Kushima

WORLD JOURNAL OF GASTROENTEROLOGY 21 ( 7 ) 2159 - 2168 2015.2

Language：English Publisher：BAISHIDENG PUBLISHING GROUP INC

AIM: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.
METHODS: We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables.
RESULTS: The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6 +/- 9.2 vs 60.4 +/- 11.7, P < 0.001), a female sex (55.3% vs 31.3%, P = 0.004), an antral location (44.7% vs 25.7%, P = 0.021), and a differentiated histology (57.9% vs 39.7%, P = 0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P = 0.022) and lymph node metastasis (83.5% vs 73.7%, P = 0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P < 0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR = 1.36, 95% CI: 1.01-1.84; P = 0.040).
CONCLUSION: Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.

DOI： 10.3748/wjg.v21.i7.2159

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 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

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

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

WORLD JOURNAL OF SURGICAL ONCOLOGY 13 ( 45 ) doi:10.1186/s12957-015-0466-0 2015.2

Language：English 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

Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging

Shinji Miwa, Shuya Yano, Hiroaki Kimura, Mako Yamamoto, Makoto Toneri, Yasunori Matsumoto, Fuminari Uehara, Yukihiko Hiroshima, Takashi Murakami, Katsuhiro Hayashi, Norio Yamamoto, Michael Bouvet, Toshiyoshi Fujiwara, Hiroyuki Tsuchiya, Robert M. Hoffman

CELL CYCLE 14 ( 4 ) 621 - 629 2015.2

Language：English Publisher：TAYLOR & FRANCIS INC

Essentially every population of cancer cells within a tumor is heterogeneous, especially with regard to chemosensitivity and resistance. In the present study, we utilized the fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging system to investigate the correlation between cell-cycle behavior and apoptosis after treatment of cancer cells with chemotherapeutic drugs. HeLa cells expressing FUCCI were treated with doxorubicin (DOX) (5M) or cisplatinum (CDDP) (5M) for 3h. Cell-cycle progression and apoptosis were monitored by time-lapse FUCCI imaging for 72h. Time-lapse FUCCI imaging demonstrated that both DOX and CDDP could induce cell cycle arrest in S/G(2)/M in almost all the cells, but a subpopulation of the cells could escape the block and undergo mitosis. The subpopulation which went through mitosis subsequently underwent apoptosis, while the cells arrested in S/G(2)/M survived. The present results demonstrate that chemoresistant cells can be readily identified in a heterogeneous population of cancer cells by S/G(2)/M arrest, which can serve in future studies as a visible target for novel agents that kill cell-cycle-arrested cells.

DOI： 10.4161/15384101.2014.991604

The rare BRAF VK600-601E mutation as a possible indicator of poor prognosis in rectal carcinoma - a report of a case

Yoshiko Mori, Takeshi Nagasaka, Hideyuki Mishima, Yuzo Umeda, Ryo Inada, Hiroyuki Kishimoto, Ajay Goel, Toshiyoshi Fujiwara

BMC MEDICAL GENETICS 16 ( 1 ) 10.1186/s12881-015-0144-7 2015.1

Language：English Publisher：BIOMED CENTRAL LTD

Background: The BRAF V600E mutation is reportedly associated with inferior survival among colon cancer patients. Here we report a patient with rectal cancer who carried the novel BRAF mutation VK600-601E, which has analogous molecular functions to those of the conventional BRAF mutation V600E, and may have potential as a prognostic marker for colorectal cancer (CRC).
Case presentation: The present 65-year-old male patient was diagnosed with recurrent rectal adenocarcinoma (stage II by AJCC TNM staging 7th edition) 14 months after surgery and was treated with modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin), radiation, and FOLFIRI (fluorouracil, leucovorin, and irinotecan). The tumor progressed before further treatment could be initiated, resulting in death after 15 months. This survival period was similar to the median overall survival among patients with metastatic CRC and BRAF mutations who were treated with the FOLFIRI regimen with or without cetuximab.
Conclusions: Thus, the BRAF VK600-601E mutation may lead to an aggressive clinical course in CRC patients suffering from rapid progression and potential resistance to multiple therapeutic modalities.

DOI： 10.1186/s12881-015-0144-7

Operative technique of antethoracic esophageal reconstruction with pedicled jejunal flap

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 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

Enlarging lymphoepithelial cyst of the pancreas during 12 months of observation: report of a case

Daisuke Satoh, Hiroshi Sadamori, Takahito Yagi, Toshiyoshi Fujiwara

SURGERY TODAY 45 ( 1 ) 101 - 104 2015.1

Language：English Publisher：SPRINGER

Pancreatic lymphoepithelial cysts (LECs) are rare benign pancreatic cystic lesions, the etiology of which is unknown. We report a case of a pancreatic LEC, discovered incidentally in a 63-year-old man during a follow-up clinic visit for an abdominal aneurysm. Computed tomography showed a multilocular cyst, 60-mm diameter in the body of the pancreas. This cyst increased from 6.0 to 6.5 cm during 12 months of observation. Part of the cyst was also visualized on positron emission tomography imaging. Since a pancreatic cystic neoplasm could not be ruled out, we performed distal pancreatectomy and postoperative pathological examination confirmed that the lesion was an LEC of the pancreas. Despite the conclusive postoperative findings, resection is unavoidable when a true pancreatic neoplasm cannot be excluded.

DOI： 10.1007/s00595-014-0960-y

A Case of Intra-Abdominal Desmoid Tumor Treated by Laparoscopic Surgery

Yagi Tomohiko, Inada Ryo, Nagasaka Takeshi, Watanabe Ayako, Matsumoto Hijiri, Toshima Toshiaki, Mori Yoshiko, Kondo Yoshitaka, Kishimoto Hiroyuki, Fujiwara Toshiyoshi

Nihon Gekakei Rengo Gakkaishi (Journal of Japanese College of Surgeons) 40 ( 1 ) 111 - 115 2015

Language：Japanese Publisher：Japanese College of Surgeons

A woman in her 60s had undergone partial nephrectomy for right renal cell carcinoma in 2009. Three years after that resection, a tumor measuring 40mm in diameter was identified near the ascending colon on follow-up computed tomography (CT), and she was referred to our department for management. Positron emission tomography (PET)-CT revealed both abnormal uptake of fluorodeoxyglucose by the tumor and absence of distant metastases. Colonoscopy showed a moderately elevated lesion like a submucosal tumor in the ascending colon. On suspicion of malignancy, laparoscopy-assisted right colectomy with lymphadenectomy was performed for diagnosis and treatment of the tumor. Histopathologically, the tumor was diagnosed as a desmoid tumor occurring in the mesentery of the ascending colon, and surgical margins were negative for tumor cells. The patient is doing well without recurrence as of 13 months postoperatively. We describe herein a relatively rare case of intra-abdominal desmoid tumor treated by laparoscopic surgery. Early surgical intervention should be considered for diagnosis and treatment.

DOI： 10.4030/jjcs.40.111

Other Link： http://search.jamas.or.jp/link/ui/2015308089

A Case of Primary Small Intestinal Adenocarcinoma with Difficult Preoperative Diagnosis

Matsumoto Hijiri, Inada Ryo, Kondo Yoshitaka, Watanabe Ayako, Yagi Tomohiko, Toshima Toshiaki, Mori Yoshiko, Kishimoto Hiroyuki, Nagasaka Takeshi, Fujiwara Toshiyoshi

Nihon Gekakei Rengo Gakkaishi (Journal of Japanese College of Surgeons) 40 ( 1 ) 61 - 65 2015

Language：Japanese Publisher：Japanese College of Surgeons

A 66-year-old man visited an initial hospital with a complaint of abdominal pain, and intra-abdominal abscess near the sigmoid colon was detected by abdominal CT scan. He got well by antibiotic medication. One year later, abdominal abscess recurred, and he was referred to our hospital for management. We performed capsule and double balloon endoscopy, indicating no malignant tumor at the small intestine. Intraoperatively small intestinal cancer with invasion to the rectum, metastases of lymph nodes and peritoneum was firstly diagnosed.Primary small intestinal adenocarcinoma is e a relatively rare disease with poor prognosis. Recently, capsule and double balloon endoscopy was reported to make contribution to get early diagnosis and improve prognosis. On the other hand, some cases remains to be difficult to make an early diagnosis like the case we described.

DOI： 10.4030/jjcs.40.61

Other Link： http://search.jamas.or.jp/link/ui/2015308079

遺伝子組換えアデノウイルスを用いたCirculating Tumor Cell検出系の開発と臨床応用

櫻井文教, 水口裕之, 藤原俊義

大和証券ヘルス財団研究業績集38号 108 - 112 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 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

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

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 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

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