Faculty Profiles - KAGAWA Shunsuke

Papers - KAGAWA Shunsuke

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ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer. International journal

Hibiki Umeda, Kunitoshi Shigeyasu, Toshiaki Takahashi, Kazuya Moriwake, Yoshitaka Kondo, Kazuhiro Yoshida, Sho Takeda, Shuya Yano, Yuki Matsumi, Hiroyuki Kishimoto, Tomokazu Fuji, Kazuya Yasui, Hideki Yamamoto, Kosei Takagi, Masashi Kayano, Hiroyuki Michiue, Keiichiro Nakamura, Yoshiko Mori, Fuminori Teraishi, Hiroshi Tazawa, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

Molecular cancer 24 ( 1 ) 116 - 116 2025.4

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

BACKGROUND: Colorectal cancer (CRC) is considered the third most common type of cancer worldwide. Tumor-associated macrophages (TAMs) have been shown to promote drug resistance. Adenosine-to-inosine RNA-editing, as regulated by adenosine deaminase acting on RNA (ADAR), is a process that induces the posttranscriptional modification of critical oncogenes. The aim of this study is to determine whether the signals from cancer cells would induce RNA-editing in macrophages. METHODS: The effects of RNA-editing on phenotypes in macrophages were analyzed using clinical samples and in vitro and in vivo models. RESULTS: The intensity of the RNA-editing enzyme ADAR1 (Adenosine deaminase acting on RNA 1) in cancer and mononuclear cells indicated a strong positive correlation between the nucleus and cytoplasm. The ADAR1-positive mononuclear cells were positive for CD68 and CD163, a marker for M2 macrophages. Cancer cells transport pro-inflammatory cytokines or ADAR1 protein directly to macrophages via the exosomes, promoting RNA-editing in AZIN1 (Antizyme Inhibitor 1) and GLI1 (Glioma-Associated Oncogene Homolog 1) and resulting in M2 macrophage polarization. GLI1 RNA-editing in the macrophages induced by cancer cells promotes the secretion of SPP1, which is supplied to the cancer cells. This activates the NFκB pathway in cancer cells, promoting oxaliplatin resistance. When the JAK inhibitors were administered, oncogenic RNA-editing in the macrophages was suppressed. This altered the macrophage polarization from M2 to M1 and decreased oxaliplatin resistance in cancer cells. CONCLUSIONS: This study revealed that ADAR1-high TAMs are crucial in regulating drug resistance in CRC and that targeting ADAR1 in TAMs could be a promising treatment approach for overcoming drug resistance in CRC.

DOI： 10.1186/s12943-025-02312-y

Short-term Safety of Robot-assisted Rectal Surgery in Patients Aged ≥75 Years: A Single-center Retrospective Study. International journal

Fuminori Teraishi, Yusuke Yoshida, Ryohei Shoji, Nobuhiko Kanaya, Yuki Matsumi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 45 ( 3 ) 1291 - 1299 2025.3

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

BACKGROUND/AIM: The aging population challenges surgical management of rectal cancer. This study evaluated the short-term safety of robot-assisted rectal surgery (RARS) in patients aged 75 years and older, examining perioperative complications and surgical outcomes in this vulnerable population. PATIENTS AND METHODS: A single-center retrospective cohort study was conducted at Okayama University Hospital from September 2020 to December 2024, including 109 patients undergoing RARS. Patients were divided into older (≥75 years, n=19) and non-older (<75 years, n=90) groups. Surgical procedures utilized the da Vinci Xi system, with comprehensive assessment of perioperative characteristics and complications using the Clavien-Dindo classification. RESULTS: The older group demonstrated significantly higher American Society of Anesthesiologists classification (89.5% ≥2 vs. 58.9% in non-older group, p=0.036). Postoperative complications were more frequent in the older group (8 vs. 18 cases, p=0.04), though severe complications were similar to those in the non-older group. Median postoperative hospital stay was longer in the older group (12 vs. 9 days, p=0.01), but this difference disappeared when excluding stoma cases. Critically, no postoperative mortality was observed within 30 days in either group. CONCLUSION: Robot-assisted rectal surgery appears safe for patients aged 75 years and older. While the older group experienced more complications, these were predominantly manageable. The findings suggest that careful patient selection and experienced surgical teams can successfully employ robotic techniques in older patients while maintaining oncological standards.

DOI： 10.21873/anticanres.17516

Tailoring Neoadjuvant Therapy for Rectal Cancer: A Single-center Study of Local Recurrence Patterns. International journal

Ryohei Shoji, Fuminori Teraishi, Yoshitaka Kondo, Yusuke Yoshida, Nobuhiko Kanaya, Yuki Matsumi, Kunitoshi Shigeyasu, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 45 ( 3 ) 1261 - 1271 2025.3

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

BACKGROUND/AIM: Postoperative local recurrence remains an important issue in rectal cancer, and the optimal treatment strategy, surgical approach, and prognosis after treatment are yet to be addressed. PATIENTS AND METHODS: We reviewed 21 patients who underwent surgical resection at our department for postoperative pelvic local recurrence of rectal cancer between January 2013 and December 2022, and performed a retrospective analysis of outcomes in terms of preoperative treatment and surgical approach. RESULTS: Of the 21 patients, four (19%) were treated with upfront surgery (Upfront surgery group), 13 (62%) with chemotherapy (Chemotherapy group), and four (19%) with neoadjuvant chemoradiotherapy (NACRT; NACRT group). The surgical approach was open laparotomy (Open group) in 10 (47.6%) patients and minimally invasive surgery (MIS, MIS group) in 11 (52.4%). Seventeen (81.0%) had a negative resection margin (RM). Overall median postoperative survival was 71 months and median relapse-free survival was 6.2 months. The most common form of recurrence was pelvic local re-recurrence in seven patients (33.3%). By preoperative treatment type, the RM securement rate was higher in the Chemotherapy and NACRT groups than in the Upfront surgery group, and the postoperative recurrence rate was lowest in the NACRT group. By surgical approach, intraoperative blood loss and incidence of Clavien-Dindo Grade 3 or higher postoperative adverse events were both significantly lower in the MIS group than in the Open group. CONCLUSION: Surgical intervention for postoperative recurrence of rectal cancer results in good survival, but short relapse-free survival. NACRT can deter local re-recurrence after resection, and MIS may contribute to reducing complications.

DOI： 10.21873/anticanres.17513

Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone. International journal

Tomohiko Yagi, Shunsuke Kagawa, Shohei Nogi, Atsuki Taniguchi, Masashi Yoshimoto, Kanto Suemori, Yasuo Nagai, Shuto Fujita, Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Fuminori Teraishi, Kosei Takagi, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 74 ( 3 ) 96 - 96 2025.2

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

BACKGROUND: The mechanisms by which neutrophils acquire pro-tumor properties remain poorly understood. In pancreatic cancer, cancer-associated fibroblasts (CAFs) may interact with neutrophils, directing them to promote tumor progression. METHODS: To validate the association between CAFs and neutrophils, the localization of neutrophils was examined in clinically resected pancreatic cancer specimens. CAFs were produced by culturing in cancer-conditioned media, and the effects of these CAFs on neutrophils were examined. In vitro migration and invasion assays assess the effect of CAF-activated neutrophils on cancer cells. The factors secreted by the activated neutrophils were also explored. Finally, pirfenidone (PFD) was tested to determine whether it could suppress the pro-tumor functions of activated neutrophils. RESULTS: In pancreatic cancer specimens, neutrophils tended to co-localize with IL-6-positive CAFs. Neutrophils co-cultured with CAFs increased migratory capacity and prolonged life span. CAF-affected neutrophils enhance the migratory and invasive activities of pancreatic cancer cells. IL-8 is the most upregulated cytokine secreted by the neutrophils. PFD suppresses IL-8 secretion from CAF-stimulated neutrophils and mitigates the malignant traits of pancreatic cancer cells. CONCLUSION: CAFs activate neutrophils and enhance the malignant phenotype of pancreatic cancer. The interactions between cancer cells, CAFs, and neutrophils can be disrupted by PFD, highlighting a potential therapeutic approach.

DOI： 10.1007/s00262-025-03946-z

Short-Term and Long-Term Outcomes of Robotic Gastrectomy for Gastric Cancer: A Single-Center, Single-Arm Prospective Study. International journal

Nobuhiko Kanaya, Shinji Kuroda, Yoshihiko Kakiutchi, Hajime Kashima, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Cureus 17 ( 2 ) e79063 2025.2

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

BACKGROUND: Robotic gastrectomy (RG) has emerged as a promising approach for gastric cancer (GC) treatment, offering advantages such as enhanced dexterity, improved visualization, and increased precision. However, its widespread adoption remains limited due to technical complexity, high costs, limited applications, and insufficient evidence. METHODS: We conducted a single-center, prospective study to evaluate the safety and feasibility of RG, including robotic total gastrectomy (RTG), robotic proximal gastrectomy (RPG), and robotic distal gastrectomy (RDG) with D1+ or D2 lymphadenectomy, in clinical stage I/II GC. The primary endpoint was the incidence of intraoperative and postoperative complications, while the secondary endpoints included surgical outcomes and long-term prognosis. RESULTS: Seven patients were enrolled. No intraoperative complications or conversions to open surgery occurred. The primary endpoint was met, with no major postoperative complications. RTG had a longer operative time and more lymph nodes dissected than RDG and RPG. The median postoperative hospital stay was 10 days. Recurrence was observed in two cases, one of which achieved long-term survival without chemotherapy. CONCLUSION: Our findings demonstrate the safety and feasibility of RG for early and advanced GC. Further multicenter studies with larger cohorts are needed to establish its oncological benefits and cost-effectiveness, facilitating broader clinical adoption.

DOI： 10.7759/cureus.79063

閉塞・穿通を伴う進行左側大腸癌に対する術前化学療法の治療成績

寺石文則, 伊木道子, 吉田有佑, 庄司良平, 松三雄騎, 重安邦俊, 近藤喜太, 香川俊輔, 藤原俊義

日本大腸肛門病学会雑誌 78 ( 2 ) 107 - 107 2025.2

Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer. International journal

Ema Mitsui, Satoru Kikuchi, Tomohiro Okura, Hiroshi Tazawa, Yuta Une, Noriyuki Nishiwaki, Shinji Kuroda, Kazuhiro Noma, Shunsuke Kagawa, Toshiaki Ohara, Junko Ohtsuka, Rieko Ohki, Toshiyoshi Fujiwara

Scientific reports 15 ( 1 ) 3267 - 3267 2025.1

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

Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC) and assessed whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. We conducted immunohistochemical analysis of IL-6 and α-smooth muscle (α-SMA) expressions in clinical samples of GC and PM, and investigated the interactions between CAFs and GC cells in vitro. Anti-tumor effects of anti-IL-6R Ab on PM of GC were investigated in an orthotopic murine PM model. IL-6 expression was significantly correlated with α-SMA expression in clinical samples of GC, and higher IL-6 expression in the primary tumor was associated with poor prognosis of GC. Higher IL-6 and α-SMA expressions were also observed in PM of GC. In vitro, differentiation of fibroblasts into CAFs and chemoresistance were observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM in GC cells cocultured with fibroblasts in the orthotopic mouse model but could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in the TME was associated with poor prognosis of GC, and CAFs were associated with establishment and progression of PM via IL-6. Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of GC.

DOI： 10.1038/s41598-025-88033-0

Predictive marker for response to trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer patients. International journal

Toshiaki Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Sho Takeda, Hibiki Umeda, Kazuya Moriwake, Masashi Kayano, Yuya Sakurai, Shunsuke Nakamura, Masafumi Takahashi, Kaori Nitta, Kazuhiro Yoshida, Yuki Matsumi, Hiroyuki Michiue, Hideki Yamamoto, Hiroyuki Kishimoto, Fuminori Teraishi, Ryohei Shoji, Nobuhiko Kanaya, Hajime Kashima, Yoshihiko Kakiuchi, Shinji Kuroda, Shunsuke Kagawa, Toshiyoshi Fujiwara

BMC cancer 25 ( 1 ) 1 - 1 2025.1

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

OBJECTIVE: Trifluridine/tipiracil (FTD/TPI) is one of the options for late-line treatment of colorectal cancer (CRC). However, the specific patient populations that would particularly benefit from it remain unclear. This study attempted to identify predictive markers of chemotherapy efficacy with trifluridine/tipiracil (FTD/TPI), focusing on the RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) expression and neutrophil-lymphocyte ratio (NLR). METHODS: To assess the effectiveness of FTD/TPI in CRC patients, we retrospectively analyzed 72 CRC patients at Okayama University Hospital from 2014 to 2022. RESULTS: Adding bevacizumab to FTD/TPI resulted in a more prolonged progression-free survival (PFS), consistent with the SUNLIGHT study findings (p = 0.0028). Among the participants, those with a high NLR had a shorter PFS (p = 0.0395). Moreover, high ADAR1 expression was associated with longer PFS (p = 0.0151). In multivariate analysis, low ADAR1 (HR = 3.43, p = 0.01) and absence of bevacizumab (HR = 4.25, p = 0.01) were identified as factors shortening PFS. The high ADAR1 group demonstrated fewer cases of progressive disease and a higher proportion of stable disease than the low ADAR1 group (p = 0.0288). Low NLR and high ADAR1 were predictive markers of prolonged PFS in the bevacizumab-treated group (p = 0.0036). CONCLUSION: Low NLR and high ADAR1 were predictive markers for a positive response to the FTD/TPI plus bevacizumab regimen associated with prolonged PFS. The FTD/TPI plus bevacizumab regimen should be proactively implemented in the low NLR and high ADAR1 subgroups.

DOI： 10.1186/s12885-024-13370-8

An effective surgical educational system in the era of robotic surgery: "Double-Surgeon Technique" in robotic gastrectomy for minimally invasive surgery. International journal

Yoshihiko Kakiuchi, Shinji Kuroda, Yusuke Yoshida, Nobuhiko Kanaya, Hajime Kashima, Satoru Kikuchi, Shunsuke Kagawa, Toshiyoshi Fujiwara

Langenbeck's archives of surgery 410 ( 1 ) 20 - 20 2024.12

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

PURPOSE: Gastric cancer (GC) remains a major malignancy. Robotic gastrectomy (RG) has gained popularity due to various advantages. Despite those advantages, many hospitals lack the necessary equipment for RG and are still performing laparoscopic gastrectomy (LG) due to its established minimal invasiveness and safety. METHODS: This study assessed the effectiveness of the "Double-Surgeon Technique" (DST) for improving surgical education and proficiency with LG. The DST involves both a console-side surgeon and a patient-side surgeon working actively in RG, enhancing the skill acquisition needed for LG and potentially reducing surgical time. Assessment of this method was performed by surgical time, and cases were divided into three groups: first half (Phase 1: P1) and second half (P2) before the introduction of DST, and after the introduction of DST (P3). RESULTS: Two surgical trainees were trained using the DST. The learning curve in both reached a plateau in P2, but descended again in P3. For one trainee, surgical time for P3 was significantly reduced compared to P1 (p = 0.001) and P2 (p = 0.0027) despite the intervals between laparoscopic distal gastrectomy as the main surgeon in P3 being significantly longer than in P2 (p = 0.0094). Other surgical results in both trainees did not differ significantly. Further, no difference in induction phase results of RG were evident between surgeons and trainees with or without DST experience. CONCLUSION: Surgical education using the DST could be effective in the current context of the need for RG and LG.

DOI： 10.1007/s00423-024-03593-5

Optimization of workflow processes for sustainable paternal involvement: case study of an academic "daddy surgeon" in Japan.

Nobuhiko Kanaya, Shinji Kuroda, Yoshitaka Kondo, Yuko Takehara, Yoshihiko Kakiuchi, Hitoshi Minagi, Masaki Sakamoto, Shunsuke Kagawa, Hitomi Kataoka, Toshiyoshi Fujiwara

Surgery today 2024.12

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

Work-life balance is often discussed in Japan. Yet surgeons find it challenging to take paternity leave because of their demanding surgical duties and a strong sense of responsibility. One Japanese male surgeon had his first paternity experience as a research fellow in the US. When he returned to Japan, he resumed his surgical training and started a research project to become an academic surgeon. When he and his wife were expecting their second child, they discussed his paternity participation before the delivery and decided on a sustainable paternity participation plan. By coordinating his responsibilities with his co-workers, he limited his attendance at work to daytime hours only for 1 month to manage paternity duties. This adjustment did not affect the number of main and assistant operations conducted that month and effective optimization of workflow processes decreased the extra workload for other team members. His experience suggests that the optimization of workflow processes can enhance personal life, including paternity participation. (150/150).

DOI： 10.1007/s00595-024-02959-y

Subjective global assessment for nutritional screening and its impact on surgical outcomes: A prospective study in older patients with colorectal cancer. Reviewed International journal

Fuminori Teraishi, Yusuke Yoshida, Ryohei Shoji, Nobuhiko Kanaya, Yuki Matsumi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Shunsuke Kagawa, Rie Tamura, Yoshikazu Matsuoka, Hiroshi Morimatsu, Toshiharu Mitsuhashi, Toshiyoshi Fujiwara

Langenbeck's archives of surgery 409 ( 1 ) 356 - 356 2024.11

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

PURPOSE: Our perioperative management center provides preoperative intervention and functional and nutritional assessments for colorectal cancer patients aged over 75 years. This study evaluated the associations of preoperative nutritional status with postoperative outcomes and prognosis in colorectal cancer patients aged 75 years or older. METHODS: This was a prospective, observational study of 71 colorectal cancer patients aged 75 years or older who underwent surgery between July 2020 and September 2022. The Subjective Global Assessment (SGA) was evaluated as a nutritional index. The patients were classified into three groups: SGA-A (well nourished), B (moderately malnourished), and C (severely malnourished), and the correlations with postoperative outcomes and prognosis were examined. RESULTS: The median age of the 71 patients (34 males, 37 females) was 78 (75-92) years, and their median body mass index (BMI) was 22.3 (13.4-31.9) kg/m2. Forty-eight patients had colon cancer, and 23 had rectal cancer. On the SGA, 28 patients were SGA-A, 25 SGA-B, and 18 SGA-C. The SGA-B/C group had significantly higher BMI (p < 0.01) and more ICU admissions (p = 0.02). The G8 score was significantly lower (p = 0.03) in the SGA-B/C group, suggesting coexisting functional decline. In terms of postoperative outcomes, the SGA-B/C group had a significantly longer postoperative hospital stay (p = 0.04). The 3-year OS rates for all stages were 100% in the SGA-A group and 49.7% in the SGA-B/C group (p = 0.03), while the 3-year OS rates for patients excluding Stage IV were 100% in the SGA-A group and 68.5% in the SGA-B/C group, not significantly different (p = 0.14). The 3-year RFS rate was 95.5% in the SGA-A group and 65.3% in the SGA-B/C group (p = 0.15). CONCLUSION: The SGA is a promising nutritional index associated with short-term outcomes in older patients undergoing colorectal cancer surgery. The SGA can be assessed in a few minutes during an outpatient visit, making it useful for routine clinical use.

DOI： 10.1007/s00423-024-03548-w

Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity. Reviewed International journal

Tomoko Ohtani, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kento Kumon, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 74 ( 1 ) 12 - 12 2024.11

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

Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. However, their effects on DCs remained unclear. In the present study, the aim was to elucidate the mechanisms of DC activation by OBP-702, focusing particularly on tumor-derived exosomes. Exosomes (Exo53, Exo301, or Exo702) were isolated from conditioned media of human or murine pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and PAN02) after treatment with Ad-p53, OBP-301, or OBP-702. Exo702 derived from Panc-1 and MiaPaCa-2 cells significantly upregulated CD86, CD80, CD83 (markers of DC maturation), and IFN-γ in DCs in vitro. Similarly, Exo702 derived from PAN02 cells upregulated CD86 and IFN-γ in bone marrow-derived DCs in a bilateral PAN02 subcutaneous tumor model. This DC maturation was inhibited by GW4869, an inhibitor of exosome release, and anti-CD63, an antibody targeting the exosome marker. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect.

DOI： 10.1007/s00262-024-03849-5

Primary ileal myeloid sarcoma presenting with bowel obstruction: a case report. Reviewed International journal

Hitoshi Minagi, Nobuhiko Kanaya, Yoshitaka Kondo, Yoshihiko Kakiuchi, Shinji Kuroda, Ryohei Shoji, Hajime Kashima, Yuki Matsumi, Satoru Kikuchi, Kunitoshi Shigeyasu, Fuminori Teraishi, Shunsuke Kagawa, Toshiyoshi Fujiwara

Surgical case reports 10 ( 1 ) 229 - 229 2024.10

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

BACKGROUND: Myeloid sarcoma (MS) is an extramedullary tumor constituted by myeloid blasts or immature myeloid cells. It frequently occurs in conjunction with acute myeloid leukemia (AML); however, it can exceptionally manifest in patients without leukemia. Here, we present a rare case of primary MS originating in the small bowel without evidence of bone marrow involvement. CASE REPRESENTATION: A 33 year-old female with no relevant medical history was admitted to our hospital with recurrent abdominal pain. Computed tomography (CT) revealed bowel obstruction due to thickening of the ileum wall, which was suspected to be an ileal tumor. Initially, ectopic endometriosis was suspected because of abdominal pain associated with the menstrual cycle and changes observed on a follow-up CT scan. The lesion could not be detected by double-balloon endoscopy. Despite conservative treatment, the obstruction persisted, and laparoscopic partial ileal resection was performed, which revealed extensive involvement of the ileum and mesentery. Additionally, the mesentery of the resected ileum was extremely thickened. Histopathological and immunohistochemical examinations of the surgical specimen indicated ileal MS. Bone marrow aspiration after discharge was negative for cytological findings of leukemia, leading to a final diagnosis of primary ileal MS. Her postoperative course was uneventful, and she is currently undergoing systemic chemotherapy tailored to AML at another hospital. CONCLUSIONS: Even though MS of the small bowel is rare and may not be considered preoperatively, similar surgical treatment to that of other small bowel malignancies can ensure proper postoperative diagnosis and appropriate chemotherapy. Given the potential need for chemotherapy, ensuring surgical safety that allows for its rapid initiation is critical.

DOI： 10.1186/s40792-024-02030-5

大腸癌に対する樹状細胞ワクチン療法と腫瘍融解アデノウイルスの併用効果

岡田尚大, 田澤大, 山田元彦, 陶守貫人, 菊地覚次, 黒田新士, 野間和広, 浦田泰生, 香川俊輔, 藤原俊義

癌と化学療法 51 ( 10 ) 1035 - 1037 2024.10

Language：Japanese Publisher：(株)癌と化学療法社

樹状細胞(DC)ワクチン療法は,細胞傷害性Tリンパ球を強力に誘導する癌免疫療法として広く研究されている。しかし臨床における有効性は十分確立されていない。著者らは,癌抑制遺伝子p53を搭載した腫瘍融解アデノウイルス製剤OBP-702を開発し,p53誘導を介した抗腫瘍効果や腫瘍免疫の活性化を明らかにしてきた。本研究では,大腸癌に対するp53導入DCワクチンとOBP-702の併用効果について検討した。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00296&link_issn=&doc_id=20241023220015&doc_link_id=%2Fab8gtkrc%2F2024%2F005110%2F016%2F1035-1037%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2024%2F005110%2F016%2F1035-1037%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

[Combined Efficacy of Dendritic Cell Vaccine and Oncolytic Adenovirus in Colorectal Cancer].

Naohiro Okada, Hiroshi Tazawa, Motohiko Yamada, Kanto Suemori, Satoru Kikuchi, Shinji Kuroda, Kazuhiro Noma, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 51 ( 10 ) 1035 - 1037 2024.10

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

Dendritic cell(DC)vaccine therapy has been widely studied as cancer immunotherapy that potently induces cytotoxic T lymphocytes. However, their efficacy in clinical practice has not yet been established. We have developed an oncolytic adenovirus OBP-702 carrying the tumor suppressor gene p53 and have demonstrated its therapeutic potential to induce cytopathic effect and activate antitumor immunity via p53 induction. In this study, we investigated the combined effect of p53-transduced DC vaccine and OBP-702 in colorectal cancer.

膵癌が誘導する癌関連線維芽細胞サブタイプは腫瘍融解ウイルスに異なる感受性を示す

永井康雄, 田澤大, 藤田修斗, 高橋洋祐, 菊地覚次, 黒田新士, 大原利章, 野間和広, 浦田泰生, 香川俊輔, 藤原俊義

日本癌治療学会学術集会抄録集 62回 O66 - 4 2024.10

マクロピノサイトーシスは膵癌関連膵星細胞の腫瘍融解ウイルスへの感受性を増強する

西山岳芳, 田澤大, 永井康雄, 庄司良平, 菊地覚次, 黒田新士, 大原利章, 野間和広, 田中啓祥, 狩野光伸, 浦田泰生, 香川俊輔, 藤原俊義

日本癌治療学会学術集会抄録集 62回 O66 - 6 2024.10

発生部位からみた肉腫の適切な外科的切除縁とは?-領域横断的な認識の統合- 後腹膜脂肪肉腫に対する外科的切除縁の最適化

近藤喜太, 金谷信彦, 庄司良平, 松三雄騎, 垣内慶彦, 重安邦俊, 菊地覚次, 黒田新士, 田辺俊介, 野間和広, 寺石文則, 香川俊輔, 藤原俊義

日本癌治療学会学術集会抄録集 62回 OWS3 - 2 2024.10

NTRK融合遺伝子とERBB2 amplificationが合併したマイクロサテライト安定型大腸癌

重安邦俊, 高橋利明, 山本英喜, 垣内慶彦, 松三雄騎, 近藤喜太, 寺石文則, 黒田新士, 香川俊輔, 藤原俊義

日本癌治療学会学術集会抄録集 62回 ICCJ3 - 6 2024.10

高齢がん患者に対するがん診療高齢大腸癌患者における主観的包括的栄養評価(SGA)の有用性単施設前向き観察研究

寺石文則, 吉田有佑, 庄司良平, 松三雄騎, 重安邦俊, 近藤喜太, 香川俊輔, 田村利枝, 松岡義和, 藤原俊義

日本癌治療学会学術集会抄録集 62回 CCWS1 - 6 2024.10

食道癌の集学的治療～高齢化社会とICI時代の先鞭をつける～高齢者食道癌患者に対する免疫チェックポイント阻害薬+化学療法

橋本将志, 野間和広, 松本聖, 河崎健人, 國友知義, 田上幸憲, 前田直見, 菊地覚次, 重安邦俊, 田辺俊介, 近藤喜太, 黒田新士, 寺石文則, 香川俊輔, 藤原俊義

日本癌治療学会学術集会抄録集 62回 OSY8 - 7 2024.10

p53-armed oncolytic virotherapy induces abscopal effect in osteosarcoma by promoting immunogenic cell death. Reviewed International journal

Koji Demiya, Hiroshi Tazawa, Hiroya Kondo, Miho Kure, Yusuke Mochizuki, Tadashi Komatsubara, Aki Yoshida, Koji Uotani, Joe Hasei, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Molecular therapy. Oncology 32 ( 3 ) 200845 - 200845 2024.9

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

Osteosarcoma (OS), the most frequent primary malignant tumor of bone in children and adolescents, is refractory to immune checkpoint inhibitors due to its poor antitumor immune response. Chemotherapy and virotherapy induce immunogenic cell death (ICD) and antitumor immune responses, leading to the abscopal effect in untreated tumors. We previously demonstrated the antitumor activity of the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 in human OS cells. Here, we show the therapeutic potential of chemotherapeutic drugs (doxorubicin, cisplatin) and telomerase-specific oncolytic adenoviruses (OBP-301, p53-armed OBP-702) to induce ICD in human OS cells (U2OS, MNNG/HOS, SaOS-2) and murine OS cells (NHOS). OBP-702 induced more profound ICD via the secretion of adenosine triphosphate (ATP) and high-mobility group box protein B1 (HMGB1) compared with chemotherapy and OBP-301 in human OS cells. Murine NHOS cells were also more sensitive to OBP-702 than OBP-301. Subcutaneous NHOS tumor models demonstrated that intratumoral injection of OBP-702 significantly increased the tumor infiltration of cytotoxic CD8+ T cells and induced the abscopal effect against non-treated tumors compared with OBP-301. Our results suggest that OBP-702 is a promising antitumor reagent to induce ICD with secretion of ATP and HMGB1 and the abscopal effect against OS.

DOI： 10.1016/j.omton.2024.200845

間質のコラーゲン産生は胃癌における腫瘍融解ウイルス療法の治療抵抗性を増強する(Stromal collagen type 1 deposition promotes resistance to oncolytic virotherapy in gastric cancer)

大倉友博, 田澤大, 菊地覚次, 黒田新士, 大原利章, 野間和広, 大塚旬子, 大木理恵子, 浦田泰生, 香川俊輔, 藤原俊義, 藤原俊義

日本癌学会総会記事 83回 P - 2252 2024.9

Comprehensive geriatric assessment as an indicator of postoperative recovery in older patients with colorectal cancer. Reviewed International journal

Fuminori Teraishi, Ryohei Shoji, Yoshitaka Kondo, Shunsuke Kagawa, Rie Tamura, Yoshikazu Matsuoka, Hiroshi Morimatsu, Toshiharu Mitsuhashi, Toshiyoshi Fujiwara

Journal of geriatric oncology 101837 - 101837 2024.7

BRAF-mutant microsatellite-stable rectal cancer with acquired KRAS mutation leading to drug resistance in liver metastasis. Reviewed International journal

Kunitoshi Shigeyasu, Hideki Yamamoto, Toshiaki Takahashi, Kazuya Moriwake, Masashi Kayano, Sho Takeda, Yuki Matsumi, Yuzo Umeda, Yoshitaka Kondo, Fuminori Teraishi, Kazuya Yasui, Tomokazu Fuji, Shunsuke Kagawa, Toshiyoshi Fujiwara

International cancer conference journal 13 ( 3 ) 189 - 192 2024.7

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

BRAF-mutant microsatellite-stable colorectal cancer (CRC), metastasized to distant sites, is associated with a poor prognosis. However, the BEACON CRC regimen, comprising a BRAF inhibitor, MEK inhibitor, and anti-EGFR antibody, offered a prolonged prognosis. Nonetheless, resistance to this regimen may occur, as observed in our reported case of CRC, where a KRAS mutation was identified in addition to the BRAF V600E mutation. Here, we present a case of 74-year-old woman with rectal cancer (pT4bN1bM0 Stage IIIc) harboring the BRAF V600E mutation. After resection of the primary tumor and during adjuvant chemotherapy using CAPOX (capecitabine and oxaliplatin), liver and lung metastases became apparent, and a companion diagnosis test revealed the presence of a BRAF V600E mutation. The new lesions were deemed resistant to the CAPOX regimen, and we decided to introduce encorafenib and cetuximab. After resection of liver metastases, encorafenib and cetuximab were reintroduced, but a new lesion appeared in hepatic S7, indicating resistance to the encorafenib and cetuximab regimen. The resistant liver metastasis was subsequently resected. To elucidate the resistance mechanism, we conducted a comprehensive analysis using the FoundationOne CDx cancer gene panel test, revealing the presence of a KRAS Q61H mutation alongside the BRAF V600E mutation. Subsequent liquid biopsy after liver recurrence confirmed the persistence of the KRAS Q61H mutation. Our results highlight the significance of cancer genome profiling tests (CGP tests) and liquid biopsies in guiding treatment strategies for BRAF-mutant colorectal cancer. Therefore, CGP testing offers valuable information for treatment, even if it does not lead to new drug administrations.

DOI： 10.1007/s13691-024-00678-2

私が目指すScientific Surgeonとその現状と未来

金谷信彦, 黒田新士, 近藤喜太, 坂本真樹, 垣内慶彦, 菊地覚次, 香川俊輔, 藤原俊義

日本消化器外科学会総会 79回 668 - 668 2024.7

上部消化管上部消化管癌に対する更なる低侵襲・機能温存治療観音開き法再建後の吻合部狭窄および狭窄症状のリスク因子分析から見えた再建手技の理想型

黒田新士, 垣内慶彦, 菊地覚次, 賀島肇, 田辺俊介, 野間和広, 楳田祐三, 寺石文則, 香川俊輔, 藤原俊義

日本消化器外科学会総会 79回 573 - 573 2024.7

Functional remodeling of intraperitoneal macrophages by oncolytic adenovirus restores anti-tumor immunity for peritoneal metastasis of gastric cancer. Reviewed International journal

Motoyasu Tabuchi, Satoru Kikuchi, Hiroshi Tazawa, Tomohiro Okura, Toshihiro Ogawa, Ema Mitsui, Yuta Une, Shinji Kuroda, Hiroki Sato, Kazuhiro Noma, Shunsuke Kagawa, Toshiaki Ohara, Junko Ohtsuka, Rieko Ohki, Yasuo Urata, Toshiyoshi Fujiwara

Molecular therapy. Oncology 32 ( 2 ) 200806 - 200806 2024.6

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

Intraperitoneal tumor-associated macrophages (TAMs) are involved in evading anti-tumor immunity and promoting the peritoneal metastasis (PM) of gastric cancer (GC). Oncolytic viruses are known to induce the activation of host anti-tumor immunity in addition to tumor lysis. This study investigated whether a wild-type p53-loading telomerase-specific oncolytic adenovirus (OBP-702) could elicit the remodeling of intraperitoneal macrophages and enhance the efficacy of immune therapy. Increased numbers of CD163 TAMs and few CD8+ lymphocytes were immunohistochemically observed in clinical samples with PM, which suggested that TAMs were associated with the suppression of anti-tumor immunity. OBP-702 induced immunogenic cell death and upregulated PD-L1 expression in human and murine GC cell lines. Intraperitoneal administration of OBP-702 increased recruitment of CD8+ lymphocytes into the PM via the functional remodeling of intraperitoneal macrophages from TAM toward a pro-inflammatory phenotype, resulting in significantly suppressed tumor growth for the in vivo model. Furthermore, the combination of intraperitoneal OBP-702 with anti-programmed cell death-1 antibody enhanced anti-tumor immunity and prolonged the survival of mice bearing PM. Intraperitoneal immunotherapy using OBP-702 restores anti-tumor immunity via the remodeling of intraperitoneal macrophages in addition to direct tumor lysis and cooperates with immune checkpoint inhibitors to suppress PM in GC.

DOI： 10.1016/j.omton.2024.200806

Senescent Fibroblasts Potentiate Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells via IL-8-mediated Crosstalk. Reviewed International journal

Yuncheng Li, Hiroshi Tazawa, Yasuo Nagai, Shuto Fujita, Tomohiro Okura, Ryohei Shoji, Motohiko Yamada, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 44 ( 6 ) 2497 - 2509 2024.6

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

BACKGROUND/AIM: Diffuse-type gastric cancer (DGC) often forms peritoneal metastases, leading to poor prognosis. However, the underlying mechanism of DGC-mediated peritoneal metastasis is poorly understood. DGC is characterized by desmoplastic stroma, in which heterogeneous cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) and senescent CAFs (sCAFs), play a crucial role during tumor progression. This study investigated the CAF subtypes induced by GC cells and the role of sCAFs in peritoneal metastasis of DGC cells. MATERIALS AND METHODS: Conditioned medium of human DGC cells (KATOIII, NUGC-4) and human intestinal-type GC (IGC) cells (MKN-7, N87) was used to induce CAFs. CAF subtypes were evaluated by analyzing the expression of α-smooth muscle actin (α-SMA), senescence-associated β-galactosidase (SA-β-gal), and p16 in human normal fibroblasts (GF, FEF-3). A cytokine array was used to explore the underlying mechanism of GC-induced CAF subtype development. The role of sCAFs in peritoneal metastasis of DGC cells was analyzed using a peritoneally metastatic DGC tumor model. The relationships between GC subtypes and CAF-related markers were evaluated using publicly available datasets. RESULTS: IGC cells significantly induced α-SMA+ myCAFs by secreting transforming growth factor-β, whereas DGC cells induced SA-β-gal+/p16+ sCAFs by secreting interleukin (IL)-8. sCAFs further secreted IL-8 to promote DGC cell migration. In vivo experiments demonstrated that co-inoculation of sCAFs significantly enhanced peritoneal metastasis of NUGC-4 cells, which was attenuated by administration of the IL-8 receptor antagonist navarixin. p16 and IL-8 expression was significantly associated with poor prognosis of DGC patients. CONCLUSION: sCAFs promote peritoneal metastasis of DGC via IL-8-mediated crosstalk.

DOI： 10.21873/anticanres.17056

局所環境とがん免疫膵臓癌のMHC低発現を改善するエピジェネティック制御剤の同定と樹状細胞併用p53ウイルス免疫療法への応用

陶守貫人, 田澤大, 山田元彦, 岡田尚大, 菊地覚次, 黒田新士, 野間和広, 浦田泰生, 香川俊輔, 藤原俊義

日本がん免疫学会総会・日本バイオセラピィ学会学術集会総会合同大会プログラム・抄録集 28回・37回 78 - 78 2024.6

A multi-center, prospective, clinical study to evaluate the anti-reflux efficacy of laparoscopic double-flap technique (lD-FLAP Study). Reviewed

Shinji Kuroda, Michihiro Ishida, Yasuhiro Choda, Atsushi Muraoka, Shinji Hato, Tetsuya Kagawa, Norimitsu Tanaka, Toshiharu Mitsuhashi, Yoshihiko Kakiuchi, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Annals of gastroenterological surgery 8 ( 3 ) 374 - 382 2024.5

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

BACKGROUND: Double-flap technique (DFT) is a reconstruction procedure after proximal gastrectomy (PG). We previously reported a multi-center, retrospective study in which the incidence of reflux esophagitis (RE) (Los Angeles Classification ≥Grade B [LA-B]) 1 year after surgery was 6.0%. There have been many reports, but all of them were retrospective. Thus, a multi-center, prospective study was conducted. METHODS: Laparoscopic PG + DFT was performed for cT1N0 upper gastric cancer patients. The primary endpoint was the incidence of RE (≥LA-B) 1 year after surgery. The planned sample size was 40, based on an estimated incidence of 6.0% and an upper threshold of 20%. RESULTS: Forty patients were recruited, and 39, excluding one with conversion to total gastrectomy, received protocol treatment. Anastomotic leakage (Clavien-Dindo ≥Grade III) was observed in one patient (2.6%). In 38 patients, excluding one case of postoperative mortality, RE (≥LA-B) was observed in two patients (5.3%) 1 year after surgery, and the upper limit of the 95% confidence interval was 17.3%, lower than the 20% threshold. Anastomotic stricture requiring dilatation was observed in two patients (5.3%). One year after surgery, body weight change was 88.9 ± 7.0%, and PNI <40 and CONUT ≥5, indicating malnutrition, were observed in only one patient (2.6%) each. In the quality of life survey using the PGSAS-45 questionnaire, the esophageal reflux subscale score was 1.4 ± 0.6, significantly better than the public data (2.0 ± 1.0; p = 0.001). CONCLUSION: Laparoscopic DFT showed anti-reflux efficacy. Taken together with the acceptable incidence of anastomotic stricture, DFT can be an option for reconstruction procedure after PG.

DOI： 10.1002/ags3.12783

「多様な外科医が活躍する社会」の実現に向けて Academic daddy surgeonを目指した一外科医の試み

金谷信彦, 黒田新士, 坂本真樹, 垣内慶彦, 近藤喜太, 竹原裕子, 香川俊輔, 藤原俊義

日本外科系連合学会誌 49 ( 3 ) 276 - 276 2024.5

p53-Armed Oncolytic Virotherapy Improves Radiosensitivity in Soft-Tissue Sarcoma by Suppressing BCL-xL Expression. Reviewed

Tadashi Komatsubara, Hiroshi Tazawa, Joe Hasei, Toshinori Omori, Kazuhisa Sugiu, Yusuke Mochizuki, Koji Demiya, Aki Yoshida, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Acta medica Okayama 78 ( 2 ) 151 - 161 2024.4

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

Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities including radiotherapy, STSs are often refractory to antitumor modalities, and novel strategies that improve the prognosis of STS patients are needed. We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. Here, we demonstrate in vitro and in vivo antitumor effects of OBP-702 in combination with ionizing radiation against human STS cells (HT1080, NMS-2, SYO-1). OBP-702 synergistically promoted the antitumor effect of ionizing radiation in the STS cells by suppressing the expression of B-cell lymphoma-X large (BCL-xL) and enhancing ionizing radiation-induced apoptosis. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors' growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors.

DOI： 10.18926/AMO/66924

Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic adenovirus. Reviewed International journal

Masashi Hashimoto, Shinji Kuroda, Nobuhiko Kanaya, Daisuke Kadowaki, Yusuke Yoshida, Masaki Sakamoto, Yuki Hamada, Ryoma Sugimoto, Chiaki Yagi, Tomoko Ohtani, Kento Kumon, Yoshihiko Kakiuchi, Kazuya Yasui, Satoru Kikuchi, Ryuichi Yoshida, Hiroshi Tazawa, Shunsuke Kagawa, Takahito Yagi, Yasuo Urata, Toshiyoshi Fujiwara

British journal of cancer 130 ( 7 ) 1187 - 1195 2024.4

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

BACKGROUND: Pancreatic cancer is an aggressive, immunologically "cold" tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). METHODS: We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). RESULTS: First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. CONCLUSION: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.

DOI： 10.1038/s41416-024-02583-0

高齢者大腸癌における周術期リハビリテーションの個別化を目指した術前機能評価の有用性の検証

寺石文則, 庄司良平, 賀島肇, 松三雄騎, 近藤喜太, 黒田新士, 野間和広, 香川俊輔, 藤原俊義

日本外科学会定期学術集会抄録集 124回 PS - 8 2024.4

術後障害の評価と対策術後継続的な栄養指導による胃切除術後障害の軽減効果

菊地覚次, 半澤俊哉, 賀島肇, 庄司良平, 松三雄騎, 垣内慶彦, 黒田新士, 田辺俊介, 野間和広, 香川俊輔, 藤原俊義

日本胃癌学会総会記事 96回 175 - 175 2024.2

Perioperative and Postoperative Continuous Nutritional Counseling Improves Quality of Life of Gastric Cancer Patient Undergoing Gastrectomy. Reviewed International journal

Shunya Hanzawa, Satoru Kikuchi, Shinji Kuroda, Ryohei Shoji, Hajime Kashima, Yuki Matsumi, Ayako Takahashi, Yoshihiko Kakiuchi, Kosei Takagi, Shunsuke Tanabe, Kazuhiro Noma, Shunsuke Kagawa, Kenichi Shikata, Toshiyoshi Fujiwara

Nutrition and cancer 76 ( 6 ) 476 - 485 2024

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

Post-gastrectomy syndrome (PGS) and body weight loss (BWL) decrease quality of life (QOL) and survival of the patient undergoing gastrectomy. We have introduced perioperative and post-discharge continuous nutritional counseling (CNC) to prevent BWL and improve QOL after gastrectomy. In the present study, we evaluated the effect of CNC on QOL using the Post-gastrectomy Syndrome Assessment Scale-45 (PGSAS-45). Eighty-three patients with gastric cancer (GC) who underwent curative gastrectomy between March 2018 and July 2019 were retrospectively analyzed. Patients received either pre-discharge nutritional counseling alone (control group, n = 45) or CNC (CNC group, n = 38) after gastrectomy. QOL at 12 months after gastrectomy was compared between the two groups. In QOL assessment, change in body weight (-7.98% vs. -12.77%, p = 0.0057), ingested amount of food per meal (7.00 vs. 6.07, p = 0.042) and ability for working (1.89 vs. 2.36, p = 0.049) were significantly better in CNC group than control group. Multiple regression analysis showed that CNC was a significantly beneficial factor for abdominal pain subscale (p = 0.028), diarrhea subscale (p = 0.047), ingested amount of food per meal (p = 0.012), Ability for working (p = 0.031) and dissatisfaction at the meal (p = 0.047). Perioperative and postoperative CNC could improve QOL in the patient undergoing gastrectomy in addition to preventing postoperative BWL.

DOI： 10.1080/01635581.2024.2340782

Clinical Impact of Prehabilitation on Elective Laparoscopic Surgery in Frail Octogenarians With Colorectal Cancer. Reviewed International journal

Fuminori Teraishi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Shunsuke Kagawa, Rie Tamura, Yoshikazu Matsuoka, Hiroshi Morimatsu, Toshiyoshi Fujiwara

Anticancer research 43 ( 12 ) 5597 - 5604 2023.12

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

BACKGROUND/AIM: The aim of the present study was to clarify the clinical impact of prehabilitation by the perioperative management center (PERIO) at our hospital in severely frail octogenarians with colorectal cancer. PATIENTS AND METHODS: We compared the clinicopathological characteristics of octogenarians who underwent surgery for colorectal cancer before the establishment of PERIO intervention (Control group) with those who received prehabilitation (PERIO group). All patients were classified as American Society of Anesthesiologists (ASA) class 3 or higher. The primary outcome was the incidence of postoperative complications. RESULTS: There were 21 patients in the Control group and 19 patients in the PERIO group. Operative time was significantly longer in the PERIO group (Control group, 200 min vs. PERIO group, 230 min; p=0.03) and blood loss was significantly higher in the PERIO group (Control group, 5 ml vs. PERIO group, 30 ml; p=0.02). Postoperative complications occurred in 10 patients (47.6%) in the Control group and 3 patients (15.8%) in the PERIO group and were significantly lower in the PERIO group (p=0.03). Postoperative hospital stay was 13 days (range=7-31 days) in the Control group and 11 days (range=8-70 days) in the PERIO group (p=0.39). The rate of discharge directly to home was 81% in the Control group and 93.3% in the PERIO group (p=0.29). CONCLUSION: In frail octogenarians with colorectal cancer of ASA class 3 or higher, the incidence of postoperative complications was significantly lower after PERIO intervention.

DOI： 10.21873/anticanres.16762

Intraperitoneal Administration of p53-armed Oncolytic Adenovirus Inhibits Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells. Reviewed International journal

Naoto Hori, Hiroshi Tazawa, Yuncheng Li, Tomohiro Okura, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 43 ( 11 ) 4809 - 4821 2023.11

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

BACKGROUND/AIM: Diffuse-type gastric cancer (GC) frequently exhibits peritoneal metastasis, leading to poor prognosis. However, efforts to develop antitumor strategies for preventing the peritoneal metastasis of GC have been unsuccessful. As diffuse-type GC cells often carry a genetic alteration in the tumor suppressor p53 gene, p53 restoration may be a potent strategy for preventing peritoneal metastasis of GC. In this study, we investigated the therapeutic potential of p53-expressing adenoviral vectors against peritoneal metastasis of diffuse-type GC cells. MATERIALS AND METHODS: Three diffuse-type human GC cell types with different p53 statuses (p53-wild type NUGC-4, p53-mutant type GCIY, and p53-null type KATOIII) were used to evaluate the therapeutic potential of p53 activation induced by the p53-expressing, replication-deficient adenovirus Ad-p53 and oncolytic adenovirus OBP-702. Viability, apoptosis, and autophagy of virus-treated GC cells were analyzed under normal and sphere-forming culture conditions using the XTT assay and western blot analysis. The in vivo antitumor effects of OBP-702 and Ad-p53 were assessed using xenograft tumor models involving peritoneal metastasis of NUGC-4 and GCIY cells. RESULTS: Under normal and sphere-forming culture conditions, OBP-702 induced a significantly greater antitumor effect in GC cells compared with Ad-p53 by strongly inducing p53-mediated apoptosis and autophagy and receptor tyrosine kinase suppression. In vivo experiments demonstrated that intraperitoneal administration of OBP-702 significantly suppressed the peritoneal metastasis of NUGC-4 and GCIY cells compared with Ad-p53, leading to prolonged survival of mice. CONCLUSION: Intraperitoneal administration of OBP-702 inhibits the peritoneal metastasis of GC cells by inducing p53-mediated cytopathic activity.

DOI： 10.21873/anticanres.16678

米国留学中に経験した出産育児と共稼ぎから見えた外科医のワークライフバランスへの提言

金谷信彦, 黒田新士, 竹原裕子, 皆木仁志, 垣内慶彦, 近藤喜太, 香川俊輔, 藤原俊義

日本臨床外科学会雑誌 84 ( 増刊 ) S65 - S65 2023.10

Exosomes as a drug delivery tool for cancer therapy: a new era for existing drugs and oncolytic viruses. Reviewed International journal

Yoshihiko Kakiuchi, Shinji Kuroda, Nobuhiko Kanaya, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

Expert opinion on therapeutic targets 1 - 10 2023.9

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

INTRODUCTION: Exosomes are cell-derived nanovesicles involved in cell-to-cell communications. These nanovesicles are generally considered to contain important carriers of information such as DNA and RNA, and show specific tropism. AREAS COVERED: The combination of existing therapeutic agents with exosomes enhances therapeutic effects by increasing uptake into the tumor. Induction of immunogenic cell death (ICD) may also be triggered more strongly than with the drug alone. Oncolytic viruses (OVs) are even more effective as a drug in combination with exosomes. Although OVs are more likely to cause immune activity, combination with exosomes can exert synergistic effects. OVs have potent anti-tumor effects, but many limitations, such as being limited to local administration and vulnerability to attack by antibodies. Incorporation into exosomes can overcome these limitations and may allow effects against distant tumors. EXPERT OPINION: Novel therapies using exosomes are very attractive in terms of enhancing therapeutic efficacy and reducing side effects. This approach also contains elements overcoming disadvantages in OVs, which have not been used clinically until now, and may usher in a new era of cancer treatments.

DOI： 10.1080/14728222.2023.2259102

Dual antiplatelet therapy inhibits neutrophil extracellular traps to reduce liver micrometastases of intrahepatic cholangiocarcinoma. Reviewed International journal

Masashi Yoshimoto, Shunsuke Kagawa, Hiroki Kajioka, Atsuki Taniguchi, Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Tomohiko Yagi, Shohei Nogi, Fuminori Teraishi, Kunitoshi Shigeyasu, Ryuichi Yoshida, Yuzo Umeda, Kazuhiro Noma, Hiroshi Tazawa, Toshiyoshi Fujiwara

Cancer letters 567 216260 - 216260 2023.7

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

The involvement of neutrophil extracellular traps (NETs) in cancer metastasis is being clarified, but the relationship between intrahepatic cholangiocarcinoma (iCCA) and NETs remains unclear. The presence of NETs was verified by multiple fluorescence staining in clinically resected specimens of iCCA. Human neutrophils were co-cultured with iCCA cells to observe NET induction and changes in cellular characteristics. Binding of platelets to iCCA cells and its mechanism were also examined, and their effects on NETs were analyzed in vitro and in in vivo mouse models. NETs were present in the tumor periphery of resected iCCAs. NETs promoted the motility and migration ability of iCCA cells in vitro. Although iCCA cells alone had a weak NET-inducing ability, the binding of platelets to iCCA cells via P-selectin promoted NET induction. Based on these results, antiplatelet drugs were applied to these cocultures in vitro and inhibited the binding of platelets to iCCA cells and the induction of NETs. Fluorescently labeled iCCA cells were injected into the spleen of mice, resulting in the formation of liver micrometastases coexisting with platelets and NETs. These mice were treated with dual antiplatelet therapy (DAPT) consisting of aspirin and ticagrelor, which dramatically reduced micrometastases. These results suggest that potent antiplatelet therapy prevents micrometastases of iCCA cells by inhibiting platelet activation and NET production, and it may contribute to a novel therapeutic strategy.

DOI： 10.1016/j.canlet.2023.216260

Collagenous Colitis in a Patient With Gastric Cancer Who Underwent Chemotherapy. Reviewed International journal

Masaya Iwamuro, Takehiro Tanaka, Shunsuke Kagawa, Shoko Inoo, Motoyuki Otsuka

Cureus 15 ( 5 ) e39466 2023.5

Language：English

Herein, we present a case of collagenous colitis in a patient who underwent chemotherapy for gastric cancer, comprising five cycles of S-1 plus oxaliplatin and trastuzumab, followed by five cycles of paclitaxel and ramucirumab and seven cycles of nivolumab. The subsequent initiation of trastuzumab deruxtecan chemotherapy led to the development of grade 3 diarrhea after the second cycle of treatment. Collagenous colitis was diagnosed via colonoscopy and biopsy. The patient's diarrhea improved following the cessation of lansoprazole. This case highlights the importance of considering collagenous colitis as a differential diagnosis, in addition to chemotherapy-induced colitis and immune-related adverse event (irAE) colitis, in patients with similar clinical presentations.

DOI： 10.7759/cureus.39466

Locally Advanced Rectal Cancer Invading the Gluteus Maximus Muscle Completely Responded to Total Neoadjuvant Therapy. Reviewed

Masaki Sakamoto, Fuminori Teraishi, Kunitoshi Shigeyasu, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 77 ( 2 ) 209 - 213 2023.4

Language：English

A 70-year-old male with anal pain and fever was diagnosed with rectal cancer perforation and abscess in the right gluteus maximus (GM) muscle. He underwent a transverse colon colostomy followed by preoperative capecitabine+oxaliplatin. Some local control was achieved but a residual abscess was observed in the right GM muscle. To secure circumferential resection margin by tumor reduction, he received chemoradiotherapy as total neoadjuvant therapy (TNT) and underwent laparoscopic abdominoperineal resection, D3 lymph node dissection, combined coccyx resection, and partial resection of the right GM muscle. The skin defect and pelvic dead space were filled with a right lateral vastus lateral great muscle flap. Histopathologically, the resected specimen showed no tumor cells in the primary tumor or lymph nodes, indicating a pathological complete response (pCR). This case suggests that TNT might improve the R0 resection and pCR rates and overall survival.

DOI： 10.18926/AMO/65152

Removing the Esophageal Stump During Reconstruction for Esophagojejunostomy in Total Gastrectomy for Gastric Cancer: the Modified Overlap Method. Reviewed International journal

Yoshihiko Kakiuchi, Shinji Kuroda, Satoru Kikuchi, Hajime Kashima, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 27 ( 3 ) 643 - 645 2023.3

A Case Report of Non-typical Annular Pancreas Diagnosed during Laparoscopic Gastric Surgery. Reviewed

Toshiaki Takahashi, Yoshihiko Kakiuchi, Satoru Kikuch, Shinji Kuroda, Sho Takeda, Kunitoshi Shigeyasu, Yoshitaka Kondo, Fuminori Teraishi, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 77 ( 1 ) 91 - 95 2023.2

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

An annular pancreas is a rare anomaly of the pancreas, defined as pancreatic tissue that totally or partly encircles the duodenum, usually the descending portion. A 76-year-old man who was diagnosed with gastric cancer cT3N0M0 Stage IIB underwent laparoscopic distal gastrectomy with D2 lymph node dissection. Intraoperatively, the dorsal half of the duodenal bulb was seen to be half surrounded by the pancreas, and a non-typical annular pancreas was diagnosed. Because of the risk to the pancreas, it was considered impossible to perform anastomosis by a linear stapler as in the usual laparoscopic procedure. Therefore, we performed laparoscopically assisted distal gastrectomy and Billroth-I reconstruction using a circular stapler, and the surgery was completed without difficulties. His postoperative course was good despite the development of a pancreatic fistula, which was an International Study Group for Pancreas Fistula biochemical leak. Some APs can be diagnosed preoperatively, but the rarer subtypes such as ours are more difficult to visualize on imaging. In gastrectomy, it is both oncologically important and technically challenging to perform lymph node dissection around the pancreas. In this case with an especially proximal pancreas, a circular stapler was considered better suited for gastroduodenal anastomosis and required a broader field than that afforded by laparoscopy. A case of non-typical annular pancreas diagnosed during laparoscopic gastric surgery is described.

DOI： 10.18926/AMO/64368

【こだわりの体腔内縫合・吻合術】胃外科腹腔鏡下/ロボット支援下噴門側胃切除後の観音開き法による再建 Reviewed

黒田新士, 菊地覚次, 垣内慶彦, 香川俊輔, 藤原俊義

手術 77 ( 2 ) 189 - 195 2023.2

Survival Impact of Postoperative Skeletal Muscle Loss in Gastric Cancer Patients Who Underwent Gastrectomy. Reviewed International journal

Kazuya Kuwada, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Kosei Takagi, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yuzo Umeda, Toshiyoshi Fujiwara

Anticancer research 43 ( 1 ) 223 - 230 2023.1

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

BACKGROUND/AIM: It has recently been recognized that preoperative sarcopenia contributes to postoperative complications and overall survival in gastric cancer (GC). However, few studies have investigated the relationship between postoperative skeletal muscle loss (SML) and survival in GC, despite the inevitability of body weight loss after gastrectomy in most GC patients. Herein, we studied the impact of postoperative SML on GC prognosis. PATIENTS AND METHODS: A total of 370 patients with GC who underwent curative gastrectomy were retrospectively evaluated in this study. Postoperative SML was assessed on computed tomography (CT) images taken before surgery and 1 year after surgery. The impact of postoperative SML on survival was evaluated. RESULTS: Postoperative severe SML was significantly associated with presence of comorbidities, higher tumor stage, higher postoperative complication rate and longer hospital stay. Univariate and multivariate analyses of prognostic factors for overall survival revealed that SML was an independent indicator of poor prognosis, along with age, tumor stage, preoperative sarcopenia, and operation time (hazard ratio, 2.65; 95% confidence interval, 1.68-4.20, p<0.0001). There was a strong association of severe postoperative SML with decreased overall survival in patients with preoperative sarcopenia. CONCLUSION: To improve the prognosis of GC patients after surgery, it is important to prevent postoperative SML as well as preoperative sarcopenia. Perioperative multimodal interventions including nutritional counseling, oral nutritional supplements, and exercise are required to prevent SML after gastrectomy.

DOI： 10.21873/anticanres.16153

A Case of a Transwoman with Colorectal Cancer after Flap Vaginoplasty Reviewed

Shiho Watanabe, Fuminori Teraishi, Sari Fujimoto, Toshiyuki Watanabe, Sho Takeda, Shuhei Narita, Koya Yamashita, Kunitoshi Shigeyasu, Shunsuke Kagawa, Yuzaburo Namba, Yoshihiro Kimata

Journal of Plastic and Reconstructive Surgery 2 ( 3 ) 98 - 101 2023

p53-armed oncolytic adenovirus induces autophagy and apoptosis in KRAS and BRAF-mutant colorectal cancer cells. Reviewed International journal

Shuta Tamura, Hiroshi Tazawa, Naoto Hori, Yuncheng Li, Motohiko Yamada, Satoru Kikuchi, Shinji Kuroda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

PloS one 18 ( 11 ) e0294491 2023

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

Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF-wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF-mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed. We recently demonstrated that the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 exhibit therapeutic potential against KRAS-mutant human pancreatic cancer cells. In this study, we evaluated the therapeutic potential of OBP-301 and OBP-702 against human CRC cells with differing KRAS/BRAF status. Human CRC cells with wild-type KRAS/BRAF (SW48, Colo320DM, CACO-2), mutant KRAS (DLD-1, SW620, HCT116), and mutant BRAF (RKO, HT29, COLO205) were used in this study. The antitumor effect of OBP-301 and OBP-702 against CRC cells was analyzed using the XTT assay. Virus-mediated modulation of apoptosis, autophagy, and the EGFR-MEK-ERK and AKT-mTOR signaling pathways was analyzed by Western blotting. Wild-type and KRAS-mutant CRC cells were sensitive to OBP-301 and OBP-702, whereas BRAF-mutant CRC cells were sensitive to OBP-702 but resistant to OBP-301. Western blot analysis demonstrated that OBP-301 induced autophagy and that OBP-702 induced autophagy and apoptosis in human CRC cells. In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis.

DOI： 10.1371/journal.pone.0294491

Oncolytic virus-mediated p53 overexpression promotes immunogenic cell death and efficacy of PD-1 blockade in pancreatic cancer. Reviewed International journal

Hiroyuki Araki, Hiroshi Tazawa, Nobuhiko Kanaya, Yoshinori Kajiwara, Motohiko Yamada, Masashi Hashimoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Yuzo Umeda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Molecular therapy oncolytics 27 3 - 13 2022.12

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

Immune checkpoint inhibitors, including anti-programmed cell death 1 (PD-1) antibody, provide improved clinical outcome in certain cancers. However, pancreatic ductal adenocarcinoma (PDAC) is refractory to PD-1 blockade therapy due to poor immune response. Oncolytic virotherapy is a novel approach for inducing immunogenic cell death (ICD). We demonstrated the therapeutic potential of p53-expressing telomerase-specific oncolytic adenovirus OBP-702 to induce ICD and anti-tumor immune responses in human PDAC cells with different p53 status (Capan-2, PK-59, PK-45H, Capan-1, MIA PaCa-2, BxPC-3) and murine PDAC cells (PAN02). OBP-702 significantly enhanced ICD with secretion of extracellular adenosine triphosphate and high-mobility group box protein B1 by inducing p53-mediated apoptosis and autophagy. OBP-702 significantly promoted the tumor infiltration of CD8+ T cells and the anti-tumor efficacy of PD-1 blockade in a subcutaneous PAN02 syngeneic tumor model. Our results suggest that oncolytic adenovirus-mediated p53 overexpression augments ICD and the efficacy of PD-1 blockade therapy against cold PDAC tumors. Further in vivo experiments would be warranted to evaluate the survival benefit of tumor-bearing mice in combination therapy with OBP-702 and PD-1 blockade.

DOI： 10.1016/j.omto.2022.09.003

Involvement in the tumor-infiltrating CD8+ T cell expression by the initial disease of remnant gastric cancer. Reviewed International journal

Yoshihiko Kakiuchi, Satoru Kikuchi, Shinji Kuroda, Shunsuke Kagawa, Toshiyoshi Fujiwara

World journal of surgical oncology 20 ( 1 ) 374 - 374 2022.11

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

BACKGROUND: Remnant gastric cancer (RGC) has been increasing for various reasons such as a longer life span, medical progress, and others. It generally has a poor prognosis, and its mechanism of occurrence is unknown. The purpose of this study was to evaluate the clinicopathological features of and clarify the oncological features of RGC. METHODS: Between January 2002 and January 2017, 39 patients with RGC following distal gastrectomy underwent curative surgical resection at the Okayama University Hospital; their medical records and immunohistochemically stained extracted specimens were used for retrospective analysis. RESULTS: On univariate analysis, initial gastric disease, pathological lymph node metastasis, and pathological stage were the significant factors associated with poor overall survival (p=0.014, 0.0061, and 0.016, respectively). Multivariate analysis of these 3 factors showed that only initial gastric disease caused by malignant disease was an independent factor associated with a poor prognosis (p=0.014, hazard ratio: 4.2, 95% confidence interval: 1.3-13.0). In addition, tumor-infiltrating CD8+ T cells expression was higher in the benign disease group than in the malignant group (p=0.046). CONCLUSIONS: Initial gastrectomy caused by malignant disease was an independent poor prognostic factor of RGC, and as one of the causes, lower level of tumor-infiltrating CD8+ T cells in RGC may involve in.

DOI： 10.1186/s12957-022-02853-2

Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer. Reviewed International journal

Yoshinori Kajiwara, Hiroshi Tazawa, Motohiko Yamada, Nobuhiko Kanaya, Takuro Fushimi, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Ryuichi Yoshida, Yuzo Umeda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 72 ( 5 ) 1285 - 1300 2022.11

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

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.

DOI： 10.1007/s00262-022-03334-x

Dual-targeted near-infrared photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in the tumor microenvironment. Reviewed International journal

Hiroaki Sato, Kazuhiro Noma, Toshiaki Ohara, Kento Kawasaki, Masaaki Akai, Teruki Kobayashi, Noriyuki Nishiwaki, Toru Narusaka, Satoshi Komoto, Hajime Kashima, Yuki Katsura, Takuya Kato, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

Scientific reports 12 ( 1 ) 20152 - 20152 2022.11

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

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment.

DOI： 10.1038/s41598-022-24313-3

OBP-702を用いたウイルス治療による膵癌の長期抗腫瘍免疫賦活効果

橋本将志, 黒田新士, 金谷信彦, 垣内慶彦, 菊地覚次, 田澤大, 香川俊輔, 浦田泰生, 藤原俊義

癌と化学療法 49 ( 10 ) 1127 - 1129 2022.10

Language：Japanese Publisher：(株)癌と化学療法社

膵癌は予後不良な癌であり,近年話題の癌免疫療法に対しても免疫細胞の浸潤が乏しい腫瘍として知られている。また,近年術前化学療法の有効性が注目されている。我々は,腫瘍特異的に増殖する腫瘍融解アデノウイルス製剤(OBP-301)を開発し,食道癌において放射線療法+OBP-301治療の臨床試験が進行中である。臨床試験のなかで腫瘍浸潤リンパ球やPD-L1の発現増強を認め,免疫学的な治療効果も期待されている。次世代の薬剤としてOBP-301にp53遺伝子を搭載したOBP-702を開発し,膵癌に対して強力な治療効果を発揮することを確認した。今回,膵癌におけるOBP-702の有効性に関し,長期抗腫瘍免疫の指標としてCD8陽性メモリーT細胞に注目して検討した。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00296&link_issn=&doc_id=20221021370020&doc_link_id=%2Fab8gtkrc%2F2022%2F004910%2F021%2F1127-1129%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2022%2F004910%2F021%2F1127-1129%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

RNA editing facilitates the enhanced production of neoantigens during the simultaneous administration of oxaliplatin and radiotherapy in colorectal cancer. Reviewed International journal

Yasuhiro Komatsu, Kunitoshi Shigeyasu, Shuya Yano, Sho Takeda, Kazutaka Takahashi, Nanako Hata, Hibiki Umeda, Kazuhiro Yoshida, Yoshiko Mori, Kazuya Yasui, Ryuichi Yoshida, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teraishi, Yuzo Umeda, Shunsuke Kagawa, Hiroyuki Michiue, Hiroshi Tazawa, Ajay Goel, Toshiyoshi Fujiwara

Scientific reports 12 ( 1 ) 13540 - 13540 2022.8

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

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability-high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX-CRT regimen. CRT can promote proteomic diversity via RNA editing.

DOI： 10.1038/s41598-022-17773-0

Impact of Amino Acids Nutrition Following Gastrectomy in Gastric Cancer Patients. Reviewed International journal

Satoru Kikuchi, Nobuo Takata, Shinji Kuroda, Hibiki Umeda, Shunsuke Tanabe, Naoaki Maeda, Kosei Takagi, Kazuhiro Noma, Yuko Hasegawa, Kumiko Nawachi, Shunsuke Kagawa, Yuzo Umeda, Kenichi Shikata, Toshiyoshi Fujiwara

Anticancer research 42 ( 7 ) 3637 - 3643 2022.7

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

BACKGROUND/AIM: Postoperative body weight loss (BWL) and skeletal muscle loss (SML) after gastrectomy are associated with a decline in quality of life and worse longterm prognosis in gastric cancer (GC) patients. This study aimed to evaluate the efficacy of amino acids nutrition on BWL and SML in the early period following gastrectomy. PATIENTS AND METHODS: The parameters of body composition were measured by bioelectrical impedance analysis in the patients undergoing radical gastrectomy for GC and analyzed retrospectively. Patients received either peripheral parenteral nutrition (PPN) of 4.3% glucose fluid with regular diet (control group, n=43) or PPN of 7.5% glucose fluid containing amino acids plus oral nutritional supplement (ONS) rich in protein with regular diet (amino acids group, n=40) following gastrectomy. The percentages of BWL and SML from preoperative values to those at 7 days and 1 month after surgery were compared between the two groups. RESULTS: The %BWL and %SML at 7 days after surgery were significantly lower in the amino acids group than those in the control group (%BWL, -2.4±1.7% vs. -4.2±1.8%; p<0.0001, %SML, -4.1±3.8 vs. -6.5±3.8; p=0.006). Moreover, the %BWL at 1 month after surgery was significantly lower in the amino acids group compared to that in the control group (- 4.6±2.9% vs. -6.1±2.6%; p=0.01); however, the %SML was similar between the two groups. The hematological nutritional parameters were similar between the two groups. CONCLUSION: Amino acids nutrition by PPN and ONS following gastrectomy prevented postoperative BWL and SML in the early period after surgery in GC patients.

DOI： 10.21873/anticanres.15852

Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer. Reviewed International journal

Toshihiro Ogawa, Satoru Kikuchi, Motoyasu Tabuchi, Ema Mitsui, Yuta Une, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Toshiaki Ohara, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

Molecular therapy oncolytics 25 249 - 261 2022.6

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

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are associated with the establishment and progression of peritoneal metastasis. This study investigated the efficacy of replicative oncolytic adenovirus-mediated p53 gene therapy (OBP-702) against CAFs and peritoneal metastasis of gastric cancer (GC). Higher CAF expression in the primary tumor was associated with poor prognosis of GC, and higher CAF expression was also observed with peritoneal metastasis in immunohistochemical analysis of clinical samples. And, we found transcriptional alteration of p53 in CAFs relative to normal gastric fibroblasts (NGFs). CAFs increased the secretion of cancer-promoting cytokines, including interleukin-6, and gained resistance to chemotherapy relative to NGFs. OBP-702 showed cytotoxicity to both GC cells and CAFs but not to NGFs. Overexpression of wild-type p53 by OBP-702 infection caused apoptosis and autophagy of CAFs and decreased the secretion of cancer-promoting cytokines by CAFs. Combination therapy using intraperitoneal administration of OBP-702 and paclitaxel synergistically inhibited the tumor growth of peritoneal metastases and decreased CAFs in peritoneal metastases. OBP-702, a replicative oncolytic adenovirus-mediated p53 gene therapy, offers a promising biological therapeutic strategy for peritoneal metastasis, modulating CAFs in addition to achieving tumor lysis.

DOI： 10.1016/j.omto.2022.04.009

Tumor-targeted fluorescence labeling systems for cancer diagnosis and treatment. Reviewed International journal

Hiroshi Tazawa, Kunitoshi Shigeyasu, Kazuhiro Noma, Shunsuke Kagawa, Fuminori Sakurai, Hiroyuki Mizuguchi, Hisataka Kobayashi, Takeshi Imamura, Toshiyoshi Fujiwara

Cancer science 113 ( 6 ) 1919 - 1929 2022.6

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

Conventional imaging techniques are available for clinical identification of tumor sites. However, detecting metastatic tumor cells that are spreading from primary tumor sites using conventional imaging techniques remains difficult. In contrast, fluorescence-based labeling systems are useful tools for detecting tumor cells at the single-cell level in cancer research. The ability to detect fluorescent-labeled tumor cells enables investigations of the biodistribution of tumor cells for the diagnosis and treatment of cancer. For example, the presence of fluorescent tumor cells in the peripheral blood of cancer patients is a predictive biomarker for early diagnosis of distant metastasis. The elimination of fluorescent tumor cells without damaging normal tissues is ideal for minimally invasive treatment of cancer. To capture fluorescent tumor cells within normal tissues, however, tumor-specific activated target molecules are needed. This review focuses on recent advances in tumor-targeted fluorescence labeling systems, in which indirect reporter labeling using tumor-specific promoters is applied to fluorescence labeling of tumor cells for the diagnosis and treatment of cancer. Telomerase promoter-dependent fluorescence labeling using replication-competent viral vectors produces fluorescent proteins that can be used to detect and eliminate telomerase-positive tumor cells. Tissue-specific promoter-dependent fluorescence labeling enables identification of specific tumor cells. Vimentin promoter-dependent fluorescence labeling is a useful tool for identifying tumor cells that undergo epithelial-mesenchymal transition (EMT). The evaluation of tumor cells undergoing EMT is important for accurately assessing metastatic potential. Thus, tumor-targeted fluorescence labeling systems represent novel platforms that enable the capture of tumor cells for the diagnosis and treatment of cancer.

DOI： 10.1111/cas.15369

[The Chugoku-Shikoku GanPro Produces Advanced Cancer Specialists to Provide Whole Person Medical Care]. Invited

Shunsuke Kagawa, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 49 ( 6 ) 638 - 641 2022.6

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

The 3rd Chugoku-Shikoku GanPro has set a plan to train advanced cancer specialists to provide whole person medical care, and 11 partner universities have formed a consortium, and 18 working groups have been working to provide graduate school education. Through a unique e-learning system and an exercise to learn team medicine, we trained medical professionals who have advanced expertise and can provide cancer care through multidisciplinary team medicine. The project has produced a wide range of personnel including doctors, dentists, pharmacists, nurses, radiologists, medical physicists, and nutritionists. The graduates who have acquired various specialized cancer qualifications practice at regional cancer treatment centers, contributing to the enhancement and improvement of cancer treatment in the Chugoku and Shikoku regions.

Anorectal leiomyoma with GLUT1 overexpression mimicking malignancy on FDG-PET/CT. Reviewed International journal

Fuminori Teraishi, Kunitoshi Shigeyasu, Shunsuke Kagawa, Toshiyoshi Fujiwara

Journal of surgical case reports 2022 ( 5 ) rjac101 2022.5

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

A 43-year-old female underwent pelvic magnetic resonance imaging for uterine myoma that incidentally revealed a 4.6 × 2.8 cm soft tissue mass in the anorectal region. Rectal endoscopy showed a submucosal tumor just above the anal canal. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed an anorectal tumor with very high FDG uptake. Aspiration cytology and needle biopsy were inconclusive, and the patient underwent trans-perineal tumor resection. The excised tumor was a 4.6 × 3.5 × 2.7 cm gray-white bifurcated nodular tumor. Light microscopy revealed fenestrated growth of poorly dysmorphic short spindle-shaped cells with eosinophilic sporophytes. Immunohistochemical staining was positive for αSMA and desmin, negative for CD117 (KIT) and S100, and the patient was diagnosed with benign leiomyoma. Tumor cells were also positive for glucose transporter-1 (GLUT1) immunohistochemically. It is important to keep in mind that FDG-PET/CT may show false-positive results even in benign anal leiomyoma for various reasons, including GLUT1 overexpression.

DOI： 10.1093/jscr/rjac101

Overexpression of Adenovirus E1A Reverses Transforming Growth Factor-β-induced Epithelial-mesenchymal Transition in Human Esophageal Cancer Cells. Reviewed

Tomoya Masuda, Hiroshi Tazawa, Yuuri Hashimoto, Takeshi Ieda, Satoru Kikuchi, Shinji Kuroda, Kazuhiro Noma, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 76 ( 2 ) 203 - 215 2022.4

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

The epithelial-mesenchymal transition (EMT), a normal biological process by which epithelial cells acquire a mesenchymal phenotype, is associated with migration, metastasis, and chemoresistance in cancer cells, and with poor prognosis in patients with esophageal cancer. However, therapeutic strategies to inhibit EMT in tumor environments remain elusive. Here, we show the therapeutic potential of telomerase-specific replication- competent oncolytic adenovirus OBP-301 in human esophageal cancer TE4 and TE6 cells with an EMT phenotype. Transforming growth factor-β (TGF-β) administration induced the EMT phenotype with spindleshaped morphology, upregulation of mesenchymal markers and EMT transcription factors, migration, and chemoresistance in TE4 and TE6 cells. OBP-301 significantly inhibited the EMT phenotype via E1 accumulation. EMT cancer cells were susceptible to OBP-301 via massive autophagy induction. OBP-301 suppressed tumor growth and lymph node metastasis of TE4 cells co-inoculated with TGF-β-secreting fibroblasts. Our results suggest that OBP-301 inhibits the TGF-β-induced EMT phenotype in human esophageal cancer cells. OBP-301-mediated E1A overexpression is a promising antitumor strategy to inhibit EMT-mediated esophageal cancer progression.

DOI： 10.18926/AMO/63425

Surgical technique of suprapancreatic D2 lymphadenectomy focusing on the posterior hepatic plexus for advanced gastric cancer. Reviewed International journal

Nobuhiko Kanaya, Shinji Kuroda, Yoshihiko Kakiuchi, Sho Takeda, Satoru Kikuchi, Kazuhiro Noma, Ryuichi Yoshida, Yuzo Umeda, Fuminori Teraishi, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Langenbeck's archives of surgery 407 ( 2 ) 871 - 877 2022.3

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

PURPOSE: Although D2 lymphadenectomy is currently considered a standard procedure for advanced gastric cancer (GC) worldwide, there is room for discussion about the appropriate range of suprapancreatic D2 lymphadenectomy. Focusing on the posterior hepatic plexus (PHP), which is not well recognized, we developed a surgical technique of suprapancreatic D2 lymphadenectomy, which we have called PHP-D2, and its short-term and long-term efficacies were evaluated in comparison with non-PHP-D2. METHODS: GC patients who underwent distal gastrectomy with D2 lymphadenectomy between July 2006 and May 2013 were enrolled, from which patients who had peritoneal metastasis and/or were peritoneal cytology-positive during surgery were excluded. Their medical records were retrospectively reviewed. RESULTS: Ninety-two patients (non-PHP-D2: 48, PHP-D2: 44) were enrolled. Shorter operation time (330 min vs 275 min, p < 0.0001) and less blood loss (290 mL vs 125 mL, p < 0.0001) were observed in PHP-D2, and no pancreatic fistulas were observed in PHP-D2. More lymph nodes of #11p (1 vs 1.5, p = 0.0328) and #12a lymph nodes (0 vs 1, p = 0.0034) were retrieved in PHP-D2, with no significant differences in #8a and #9 lymph nodes. Lymphatic recurrence was significantly less in PHP-D2 (p = 0.0166), and univariate and multivariate analyses showed that non-PHP-D2 was a significant risk factor for lymphatic recurrence (p = 0.0158), although there were no significant differences between non-PHP-D2 and PHP-D2 in 5-year overall survival and 5-year relapse-free survival. CONCLUSION: PHP-D2 was a safe and feasible procedure that had the potential to reduce lymphatic recurrence, and it can be a standard procedure of D2 lymphadenectomy for advanced GC.

DOI： 10.1007/s00423-022-02437-4

Association between Advanced T Stage and Thick Rectus Abdominis Muscle and Outlet Obstruction and High-Output Stoma after Ileostomy in Patients with Rectal Cancer Reviewed

Yasuhiro Komatsu, Kunitoshi Shigeyasu, Sho Takeda, Yoshiko Mori, Kazutaka Takahashi, Nanako Hata, Kokichi Miyamoto, Hibiki Umeda, Yoshihiko Kakiuchi, Satoru Kikuchi, Shuya Yano, Shinji Kuroda, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teraishi, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

International Surgery 106 ( 3 ) 102 - 111 2022

Publishing type：Research paper (scientific journal)

Objective: This study aimed to identify factors associated with outlet obstruction and high-output stoma (HOS) after ileostomy creation. Summary of background data: Ileostomy creation is effective in preventing leakage among patients undergoing low anterior resection for rectal cancer. However, major complications such as outlet obstruction and HOS can occur after surgery. Moreover, these complications cannot be prevented. Methods: This retrospective study included 34 patients with rectal cancer who underwent low anterior resection and ileostomy creation at Okayama University Hospital from January 2015 to December 2018. Then, the risk factors associated with outlet obstruction and HOS were analyzed. Results: Of 34 patients, 7 (21%) experienced outlet obstruction. In a multivariate logistic regression analysis, advanced T stage (P ¼ 0.10), ileostomy with a short horizontal diameter (P ¼ 0.01), and thick rectus abdominis (RA) muscle (P ¼ 0.0005) were considered independent risk factors for outlet obstruction. There was a significant correlation between outlet obstruction and HOS (P ¼ 0.03). Meanwhile, the independent risk factors of HOS were advanced T stage (P ¼ 0.03) and thick RA muscle (P ¼ 0.04). Conclusions: Thick RA muscle and advanced T stage were the common risk factors of outlet obstruction and HOS. Therefore, in high-risk patients, these complications can be prevented by choosing an appropriate ileostomy location according to RA muscle thickness and by preventing tubing into the ileostomy.

DOI： 10.9738/INTSURG-D-21-00012.1

Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation Reviewed

Atene Ito, Shunsuke Kagawa, Shuichi Sakamoto, Kazuya Kuwada, Hiroki Kajioka, Masashi Yoshimoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara

BMC Cancer 21 ( 1 ) 2021.12

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

<title>Abstract</title><sec>
<title>Background</title>
Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated.

</sec><sec>
<title>Methods</title>
The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored.

</sec><sec>
<title>Results</title>
Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein.

</sec><sec>
<title>Conclusion</title>
EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.

</sec>

DOI： 10.1186/s12885-021-07816-6

Other Link： http://link.springer.com/article/10.1186/s12885-021-07816-6/fulltext.html

Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression. Reviewed International journal

Kazuhisa Sugiu, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Yusuke Mochizuki, Hiroya Kondo, Shuhei Osaki, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Koji Ueda, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Cancer chemotherapy and pharmacology 88 ( 3 ) 513 - 524 2021.9

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

BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells. MATERIALS AND METHODS: The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model. RESULTS: DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model. CONCLUSION: Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.

DOI： 10.1007/s00280-021-04310-5

Longitudinal observation of insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes mellitus: A report of two cases. Reviewed International journal

Noriko Fujiwara, Mayu Watanabe, Akihiro Katayama, Yohei Noda, Jun Eguchi, Hitomi Kataoka, Shunsuke Kagawa, Jun Wada

Clinical case reports 9 ( 9 ) e04574 2021.9

Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments. Reviewed International journal

Yasuhiro Shirakawa, Hiroshi Tazawa, Shunsuke Tanabe, Nobuhiko Kanaya, Kazuhiro Noma, Takeshi Koujima, Hajime Kashima, Takuya Kato, Shinji Kuroda, Satoru Kikuchi, Shunsuke Kagawa, Kuniaki Katsui, Susumu Kanazawa, Yasuo Urata, Toshiyoshi Fujiwara

European journal of cancer (Oxford, England : 1990) 153 98 - 108 2021.8

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

PURPOSE: OBP-301 (Telomelysin) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 sensitises human cancer cells to ionising radiation by inhibiting DNA repair, and radiation enhances coxsackievirus and adenovirus receptor-mediated OBP-301 infection on the contrary. We assessed OBP-301 with radiotherapy in oesophageal cancer patients unfit for standard chemoradiation treatments. METHODS: A phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed oesophageal cancer patients deemed unfit to undergo surgery or chemotherapy. Study treatment consisted of OBP-301 administration by intratumoural needle injection using a flexible endoscope on days 1, 18 and 32. Radiotherapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. RESULTS: Of the 13 patients, 7, 3 and 3 patients were treated with 1010, 1011 and 1012 virus particles, respectively. Study group comprised 10 males and 3 females, with a median age of 82 years (range, 53-91 years). All patients developed a transient, self-limited lymphopenia. Distribution studies revealed transient virus shedding in the plasma. Eight patients had local complete response (CR); all of them exhibited no pathologically viable malignant cells in biopsy specimens, and 3 patients had a partial response. The objective response rate was 91.7%. The clinical CR rate was 83.3% in stage I and 60.0% in stage II/III. Histopathological examination revealed massive infiltration of CD8+ cells and increased PD-L1 expression. CONCLUSION: Multiple courses of endoscopic intratumoural OBP-301 injection with radiotherapy are feasible and provide clinical benefits in patients with oesophageal cancer unfit for standard treatments.

DOI： 10.1016/j.ejca.2021.04.043

Intracorporeal semi-hand-sewn Billroth I reconstruction in total laparoscopic distal gastrectomy. Reviewed

Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Kazuya Kuwada, Nobuo Takata, Yoshihiko Kakiuchi, Shuya Yano, Kazuhiro Noma, Shunsuke Kagawa, Toshiyoshi Fujiwara

Asian journal of endoscopic surgery 14 ( 3 ) 640 - 643 2021.7

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

INTRODUCTION: Intracorporeal Billroth I (B-I) reconstruction using an endoscopic linear stapler (ELS) is widely performed in total laparoscopic distal gastrectomy. However, conventional procedures require many ELSs for anastomosis. Here, we introduce the novel intracorporeal semi-hand-sewn (SHS) B-I reconstruction. MATERIALS AND SURGICAL TECHNIQUE: After the transection of stomach and duodenum using ELS following adequate lymph node dissection, small entry holes were made on the anterior wall in the greater curvature of the stomach and the duodenal stump. The posterior walls of both the remnant stomach and the duodenum were attached with the ELS and fired to create the posterior wall of the B-I anastomosis. All the transection line of the duodenum and one-third of the transection line of the stomach were dissected; finally the anterior wall suturing at the anastomotic site was performed by the laparoscopic hand-sewn technique. DISCUSSION: SHS procedure was performed for 17 gastric cancer patients. There were no intraoperative complications or conversions to open surgery. One intra-abdominal abscess was observed although there was no anastomotic leakage. The median reconstruction time was 48 minutes (32-63). The SHS procedure was safe, feasible, and economical, although it requires sufficient laparoscopic suturing and ligation skill.

DOI： 10.1111/ases.12887

【上部消化管・こんなときどうする?高難度手術手技をマスターしよう】食道残胃吻合(観音開き法) Invited

黒田新士, 西崎正彦, 菊地覚次, 野間和広, 香川俊輔, 藤原俊義

消化器外科 44 ( 8 ) 1343 - 1351 2021.7

SMAD4 Germline Pathogenic Variant-Related Gastric Juvenile Polyposis with Adenocarcinoma Treated with Laparoscopic Total Gastrectomy: A Case Report. Reviewed International journal

Yuya Sakurai, Satoru Kikuchi, Kunitoshi Shigeyasu, Yoshihiko Kakiuchi, Takehiro Tanaka, Hibiki Umeda, Masaki Sakamoto, Sho Takeda, Shuya Yano, Mashu Futagawa, Fumino Kato, Reimi Sogawa, Hideki Yamamoto, Shinji Kuroda, Yoshitaka Kondo, Fuminori Teraishi, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Akira Hirasawa, Toshiyoshi Fujiwara

The American journal of case reports 22 e932241 2021.6

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

BACKGROUND Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases. CASE REPORT A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing. CONCLUSIONS JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.

DOI： 10.12659/AJCR.932241

Accreditation as a qualified surgeon improves surgical outcomes in laparoscopic distal gastrectomy. Reviewed

Satoru Kikuchi, Tetsuya Kagawa, Shinji Kuroda, Masahiko Nishizaki, Nobuo Takata, Kazuya Kuwada, Ryohei Shoji, Yoshihiko Kakiuchi, Toshiharu Mitsuhashi, Yuzo Umeda, Kazuhiro Noma, Shunsuke Kagawa, Toshiyoshi Fujiwara

Surgery today 51 ( 12 ) 1978 - 1984 2021.5

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

PURPOSE: The Endoscopic Surgical Skill Quantification System for qualified surgeons (QSs) was introduced in Japan to improve surgical outcomes. This study reviewed the surgical outcomes after initial experience performing laparoscopic distal gastrectomy (LDG) and evaluated the improvement in surgical outcomes following accreditation as a QS. METHODS: Eighty-seven consecutive patients who underwent LDG for gastric cancer by a single surgeon were enrolled in this study. The cumulative sum method was used to analyze the learning curve for LDG. The surgical outcomes were evaluated according to the two phases of the learning curve (learning period vs. mastery period) and accreditation (non-QS period vs. QS period). RESULTS: The learning period for LDG was 48 cases. Accreditation was approved at the 67th case. The operation time and estimated blood loss were significantly reduced in the QS period compared to the non-QS period (230 vs. 270 min, p < 0.001; 20.5 vs. 59.8 ml, p = 0.024, respectively). Furthermore, the major complication rate was significantly lower in the QS period than in the non-QS period (0 vs. 10.6%, p = 0.044). CONCLUSIONS: Experience performing approximately 50 cases is required to reach proficiency in LDG. After receiving accreditation as a QS, the surgical outcomes, including the complication rate, were improved.

DOI： 10.1007/s00595-021-02309-2

Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles. Reviewed International journal

Yoshihiko Kakiuchi, Shinji Kuroda, Nobuhiko Kanaya, Kento Kumon, Tomoko Tsumura, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Yuki Hamada, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

Molecular therapy : the journal of the American Society of Gene Therapy 29 ( 10 ) 2920 - 2930 2021.5

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

Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. Here, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.

DOI： 10.1016/j.ymthe.2021.05.015

Long-term survival without recurrence after surgery for gastric yolk sac tumor-like carcinoma: a case report. Reviewed International journal

Hibiki Umeda, Satoru Kikuchi, Shinji Kuroda, Shuya Yano, Takehiro Tanaka, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yuzo Umeda, Toshiyoshi Fujiwara

Surgical case reports 7 ( 1 ) 111 - 111 2021.5

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

BACKGROUND: Gastric yolk sac tumor (YST)-like carcinoma is extremely rare, and its prognosis is poor, because most patients have widespread metastases at the time of diagnosis. We report a case of gastric YST-like carcinoma with an adenocarcinoma component without metastases in which curative resection was performed. CASE PRESENTATION: A 77-year-old man complaining of melena and dizziness due to anemia was diagnosed with poorly differentiated adenocarcinoma in the gastric cardia, with a benign ulcer in the gastric body. He underwent total gastrectomy with D2 lymph node dissection for the tumor. Histological examination of the resected specimens revealed a mixture of reticular and glandular neoplastic components morphologically. In the reticular area, an endodermal sinus pattern and some Schiller-Duval bodies were confirmed. Gastric YST-like carcinoma with adenocarcinoma components, T2N0M0 Stage IB, was diagnosed. Immunohistochemical analysis showed that the YST was positive for carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP) and p53. In contrast, the adenocarcinoma was positive for p53 and negative for CEA and AFP. The patient remained healthy as of 7 years postoperatively, with no recurrence. CONCLUSIONS: Routine medical examinations or endoscopic examinations for accidental symptom may be helpful for early diagnosis and good prognosis for gastric YST-like carcinoma, although the prognosis is generally poor.

DOI： 10.1186/s40792-021-01199-3

Efficacy and safety of short-term (3 days) enoxaparin in preventing venous thromboembolism after gastric cancer surgery: A single-center, prospective cohort study. Reviewed International journal

Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Megumi Watanabe, Kazuya Kuwada, Tomoko Tsumura, Masahiko Nishizaki, Shunsuke Kagawa, Shiro Hinotsu, Toshiyoshi Fujiwara

International journal of surgery (London, England) 89 105946 - 105946 2021.5

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

BACKGROUND: Pharmacologic prophylaxis such as enoxaparin for venous thromboembolism (VTE) is rarely used in Japan, even following abdominal cancer surgery, for which it is recommended in relevant guidelines (at least 7 days of use) along with mechanical prophylaxis with intermittent pneumatic compression. Reasons for enoxaparin's unpopularity include concerns over postoperative bleeding and its inconvenience in clinical practice. Here, we conducted a prospective clinical study of short-term (3 days) use of enoxaparin, which is considered to minimally impact postoperative management without increasing bleeding risk. METHODS: Gastric cancer patients who underwent gastrectomy received enoxaparin for 3 days from postoperative day (POD) 1-4. The primary endpoint was the incidence of deep vein thrombosis (DVT), which was examined primarily via Doppler ultrasonography of the lower limbs between POD 8 and 14. The planned sample size was 70, which was calculated based on an estimated incidence rate of 9% and an upper limit of incidence rate of 20%, with alpha of 0.05 and beta of 0.2. RESULTS: A total of 70 gastric cancer patients were enrolled, and ultimately, 68 patients received the protocol intervention and DVT evaluation. Sixty-seven patients completed 6 enoxaparin injections, but 1 patient did not complete the course due to abdominal bleeding after initiation. The incidence of DVT was 4.4% (3/68), and the 95% upper confidence interval was 12.2%, lower than the 20% threshold we set as the upper limit of DVT incidence. DVT was detected only in the peripheral veins of the lower extremities in all 3 affected patients. The incidence of bleeding-related complications, which were not severe, was 1.5% (1/68). CONCLUSIONS: Short-term (3 days) use of enoxaparin was shown to be effective and safe for VTE prophylaxis, comparable to regular use (at least 7 days), in postoperative management of gastric cancer surgery.

DOI： 10.1016/j.ijsu.2021.105946

Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma. Reviewed International journal

Yusuke Mochizuki, Hiroshi Tazawa, Koji Demiya, Miho Kure, Hiroya Kondo, Tadashi Komatsubara, Kazuhisa Sugiu, Joe Hasei, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 70 ( 5 ) 1405 - 1417 2021.5

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

Immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1) antibody have recently improved clinical outcome in certain cancer patients; however, osteosarcoma (OS) patients are refractory to PD-1 blockade. Oncolytic virotherapy has emerged as novel immunogenic therapy to augment antitumor immune response. We developed a telomerase-specific replication-competent oncolytic adenovirus OBP-502 that induces lytic cell death via binding to integrins. In this study, we assessed the combined effect of PD-1 blockade and OBP-502 in OS cells. The expression of coxsackie and adenovirus receptor (CAR), integrins αvβ3 and αvβ5, and programmed cell death ligand 1 (PD-L1) was analyzed in two murine OS cells (K7M2, NHOS). The cytopathic activity of OBP-502 in both cells was analyzed using the XTT assay. OBP-502-induced immunogenic cell death was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). Subcutaneous tumor models for K7M2 and NHOS cells were used to evaluate the antitumor effect and number of tumor-infiltrating CD8+ cells in combination therapy. K7M2 and NHOS cells showed high expression of integrins αvβ3 and αvβ5, but not CAR. OBP-502 significantly suppressed the viability of both cells, in which PD-L1 expression and the release of ATP and HMGB1 were significantly increased. Intratumoral injection of OBP-502 significantly augmented the efficacy of PD-1 blockade on subcutaneous K2M2 and NHOS tumor models via enhancement of tumor-infiltrating CD8+ T cells. Our results suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to promote the efficacy of PD-1 blockade in OS.

DOI： 10.1007/s00262-020-02774-7

Long-term Survival with a Rare Advanced Primary Gastrointestinal Malignant Melanoma Treated with Laparoscopic Surgery/Immune Checkpoint Inhibitor. Reviewed

Motochika Endo, Shuya Yano, Hiroaki Asano, Sho Takeda, Yuki Hamada, Yoshitaka Kondo, Shinji Kuroda, Kunitoshi Shigeyasu, Satoru Kikuchi, Takehiro Tanaka, Fuminori Teraishi, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 75 ( 2 ) 231 - 238 2021.4

Language：English

Targeted therapies for malignant melanoma have improved patients' prognoses. A primary gastrointestinal malignant melanoma is very rare, with no standard treatment strategy. We treated a 78-year-old Japanese female with advanced primary gastrointestinal melanoma of the descending colon and gallbladder. We administered a multidisciplinary treatment: surgical resection of the descending colon and gallbladder tumors, resection of the metastatic lymph nodes behind the pancreas head, and immune checkpoint antibody-blockade therapy (nivolumab) for ~4 years. PET/CT demonstrated no recurrent lesion for > 3 years. Multidisciplinary therapies (e.g., surgery, chemotherapy, radiotherapy, target therapy, and immune checkpoint antibody-blockade therapy) can successfully treat primary gastrointestinal malignant melanoma.

DOI： 10.18926/AMO/61906

希少がん総論希少がんの医療者教育 Invited

香川俊輔, 藤原俊義

日本臨床 79 ( 増刊1 ) 80 - 84 2021.3

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer. Reviewed International journal

Ryoichi Katsube, Kazuhiro Noma, Toshiaki Ohara, Noriyuki Nishiwaki, Teruki Kobayashi, Satoshi Komoto, Hiroaki Sato, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

Scientific reports 11 ( 1 ) 1693 - 1693 2021.1

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

Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

DOI： 10.1038/s41598-021-81465-4

Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment. Reviewed International journal

Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M Hoffman

International journal of molecular sciences 22 ( 2 ) 2021.1

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

Oncolytic virotherapy is one of the most promising, emerging cancer therapeutics. We generated three types of telomerase-specific replication-competent oncolytic adenovirus: OBP-301; a green fluorescent protein (GFP)-expressing adenovirus, OBP-401; and Killer-Red-armed OBP-301. These oncolytic adenoviruses are driven by the human telomerase reverse transcriptase (hTERT) promoter; therefore, they conditionally replicate preferentially in cancer cells. Fluorescence imaging enables visualization of invasion and metastasis in vivo at the subcellular level; including molecular dynamics of cancer cells, resulting in greater precision therapy. In the present review, we focused on fluorescence imaging applications to develop precision targeting for oncolytic virotherapy. Cell-cycle imaging with the fluorescence ubiquitination cell cycle indicator (FUCCI) demonstrated that combination therapy of an oncolytic adenovirus and a cytotoxic agent could precisely target quiescent, chemoresistant cancer stem cells (CSCs) based on decoying the cancer cells to cycle to S-phase by viral treatment, thereby rendering them chemosensitive. Non-invasive fluorescence imaging demonstrated that complete tumor resection with a precise margin, preservation of function, and prevention of distant metastasis, was achieved with fluorescence-guided surgery (FGS) with a GFP-reporter adenovirus. A combination of fluorescence imaging and laser ablation using a KillerRed-protein reporter adenovirus resulted in effective photodynamic cancer therapy (PDT). Thus, imaging technology and the designer oncolytic adenoviruses may have clinical potential for precise cancer targeting by indicating the optimal time for administering therapeutic agents; accurate surgical guidance for complete resection of tumors; and precise targeted cancer-specific photosensitization.

DOI： 10.3390/ijms22020879

Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis Reviewed

Hiroki Kajioka, Shunsuke Kagawa, Atene Ito, Masashi Yoshimoto, Shuichi Sakamoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Yuzo Umeda, Kazuhiro Noma, Hiroshi Tazawa, Toshiyoshi Fujiwara

Cancer Letters 497 1 - 13 2021.1

Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression. Reviewed International journal

Toshinori Omori, Hiroshi Tazawa, Yasuaki Yamakawa, Shuhei Osaki, Joe Hasei, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

PloS one 16 ( 4 ) e0250643 2021

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

Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.

DOI： 10.1371/journal.pone.0250643

リアルタイムイメージングによる予後不良間葉型大腸癌の治療抵抗性EMTマーカーの発現の時空間的意義 Reviewed

三村直毅, 矢野修也, 田澤大, 家田偉史, 岡林弘樹, 重安邦俊, 武田正, 吉田一博, 寺石文則, 楳田祐三, 香川俊輔, 藤原俊義

日本分子腫瘍マーカー研究会誌 36 18 - 20 2021

Language：Japanese Publisher：日本分子腫瘍マーカー研究会

上皮間葉転換(EMT)可視化プローベを用い、間葉型大腸癌がhybrid E/Mで最も化学療法抵抗性であるかをイメージングによって明らかにするとともに、時間的にEMTマーカーを追跡した。Vimentinプロモーター下に赤色蛍光タンパク遺伝子(rfp)がドライブさせるEMT可視化プローベを作成した。大腸癌細胞株HCT116、RKOにEMT可視化プローベを導入した。大腸癌の代表的な抗癌剤5-FU、オキサリプラチン(L-OHP)、シスプラチン(CDDP)、イリノテカン(CPT-11)を曝露させた。その結果、RKOではL-OHP、CDDP、5-FUの順で赤色を呈するEMTを起こし、HCT116では5-FU、L-OHP、CDDPの順でEMTを起こした。また、時間軸では化学療法後48時間するとEMTを起こし赤色になったが、化学療法終了後48時間経過するとEMTを起こし無色に戻った。化学療法施行前にEMT阻害剤で前治療しておくと、化学療法に曝露しても赤色にならず(EMTは阻害され)、さらに化学療法への感受性も増加していた。

夢を実現するためのキャリアパス・教育システム進化する外科マネージメントセンターそれぞれの夢を実現するためのキャリアパス支援システム

菊地覚次, 黒田新士, 吉田龍一, 香川俊輔, 山根正修, 小谷恭弘, 笠原真悟, 豊岡伸一, 藤原俊義

日本外科学会雑誌 121 ( 6 ) 669 - 671 2020.11

【食道胃接合部癌update】治療噴門側胃切除後再建法食道残胃吻合の手技と成績

黒田新士, 西崎正彦, 菊地覚次, 野間和広, 香川俊輔, 藤原俊義

外科 82 ( 11 ) 1144 - 1148 2020.10

Language：Japanese Publisher：(株)南江堂

＜文献概要＞観音開き法再建は,1998年に上川らにより報告された逆流防止機構を付加した食道残胃吻合である.漿膜筋層フラップ下に埋没した食道が胃内圧の上昇に伴い押しつぶされることで,逆流防止弁としての機能を発揮することを特徴としている.多施設共同後ろ向き臨床試験において,逆流性食道炎発生予防の観点から良好な成績が報告されており,また縫合不全の発生頻度も非常に低率であることから,食道胃接合部癌などの縦隔内再建を要する症例に対しても非常に有用な再建法と考えられる.

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00393&link_issn=&doc_id=20201001100010&doc_link_id=10.15106%2Fj_geka82_1144&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_geka82_1144&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Elimination of MYCN-Amplified Neuroblastoma Cells by Telomerase-Targeted Oncolytic Virus via MYCN Suppression. International journal

Terutaka Tanimoto, Hiroshi Tazawa, Takeshi Ieda, Hiroshi Nouso, Morimichi Tani, Takanori Oyama, Yasuo Urata, Shunsuke Kagawa, Takuo Noda, Toshiyoshi Fujiwara

Molecular therapy oncolytics 18 14 - 23 2020.9

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

Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. High-risk NB is characterized by MYCN amplification and human telomerase reverse transcriptase (hTERT) rearrangement, contributing to hTERT activation and a poor outcome. For targeting hTERT-activated tumors, we developed two oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in which the hTERT promoter drives expression of the viral E1 gene for tumor-specific virus replication. In this study, we demonstrate the therapeutic potential of the hTERT-driven oncolytic adenoviruses OBP-301 and OBP-702 using four human MYCN-amplified NB cell lines (IMR-32, CHP-134, NB-1, LA-N-5) exhibiting high hTERT expression. OBP-301 and OBP-702 exhibited a strong antitumor effect in association with autophagy in NB cells. Virus-mediated activation of E2F1 protein suppressed MYCN expression. OBP-301 and OBP-702 significantly suppressed the growth of subcutaneous CHP-134 tumors. Thus, these hTERT-driven oncolytic adenoviruses are promising antitumor agents for eliminating MYCN-amplified NB cells via E2F1-mediated suppression of MYCN protein.

DOI： 10.1016/j.omto.2020.05.015

Boosting Replication and Penetration of Oncolytic Adenovirus by Paclitaxel Eradicate Peritoneal Metastasis of Gastric Cancer. International journal

Wataru Ishikawa, Satoru Kikuchi, Toshihiro Ogawa, Motoyasu Tabuchi, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

Molecular therapy oncolytics 18 262 - 271 2020.9

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

Peritoneal metastasis is the most frequent form of distant metastasis and recurrence in gastric cancer, and the prognosis is extremely poor due to the resistance of systemic chemotherapy. Here, we demonstrate that intraperitoneal (i.p.) administration of a green fluorescence protein (GFP)-expressing attenuated adenovirus with oncolytic potency (OBP-401) synergistically suppressed the peritoneal metastasis of gastric cancer in combination with paclitaxel (PTX). OBP-401 synergistically suppressed the viability of human gastric cancer cells in combination with PTX. PTX enhanced the antitumor effect of OBP-401 due to enhanced viral replication in cancer cells. The combination therapy increased induction of mitotic catastrophe, resulting in accelerated autophagy and apoptosis. Peritoneally disseminated nodules were selectively visualized as GFP-positive spots by i.p. administration of OBP-401 in an orthotopic human gastric cancer peritoneal dissemination model. PTX enhanced the deep penetration of OBP-401 into the disseminated nodules. Moreover, a non-invasive in vivo imaging system demonstrated that the combination therapy of i.p. OBP-401 administration with PTX significantly inhibited growth of peritoneal metastatic tumors and the amount of malignant ascites. i.p. virotherapy with PTX may be a promising treatment strategy for the peritoneal metastasis of gastric cancer.

DOI： 10.1016/j.omto.2020.06.021

FUCCI Real-Time Cell-Cycle Imaging as a Guide for Designing Improved Cancer Therapy: A Review of Innovative Strategies to Target Quiescent Chemo-Resistant Cancer Cells. International journal

Shuya Yano, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M Hoffman

Cancers 12 ( 9 ) 2020.9

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

Progress in chemotherapy of solid cancer has been tragically slow due, in large part, to the chemoresistance of quiescent cancer cells in tumors. The fluorescence ubiquitination cell-cycle indicator (FUCCI) was developed in 2008 by Miyawaki et al., which color-codes the phases of the cell cycle in real-time. FUCCI utilizes genes linked to different color fluorescent reporters that are only expressed in specific phases of the cell cycle and can, thereby, image the phases of the cell cycle in real-time. Intravital real-time FUCCI imaging within tumors has demonstrated that an established tumor comprises a majority of quiescent cancer cells and a minor population of cycling cancer cells located at the tumor surface or in proximity to tumor blood vessels. In contrast to most cycling cancer cells, quiescent cancer cells are resistant to cytotoxic chemotherapy, most of which target cells in S/G2/M phases. The quiescent cancer cells can re-enter the cell cycle after surviving treatment, which suggests the reason why most cytotoxic chemotherapy is often ineffective for solid cancers. Thus, quiescent cancer cells are a major impediment to effective cancer therapy. FUCCI imaging can be used to effectively target quiescent cancer cells within tumors. For example, we review how FUCCI imaging can help to identify cell-cycle-specific therapeutics that comprise decoy of quiescent cancer cells from G1 phase to cycling phases, trapping the cancer cells in S/G2 phase where cancer cells are mostly sensitive to cytotoxic chemotherapy and eradicating the cancer cells with cytotoxic chemotherapy most active against S/G2 phase cells. FUCCI can readily image cell-cycle dynamics at the single cell level in real-time in vitro and in vivo. Therefore, visualizing cell cycle dynamics within tumors with FUCCI can provide a guide for many strategies to improve cell-cycle targeting therapy for solid cancers.

DOI： 10.3390/cancers12092655

肺癌と直腸癌の同時性重複癌にpembrolizumabが著効した1例

岡凌也, 寺石文則, 杉本龍馬, 武田正, 垣内慶彦, 高田暢夫, 重安邦俊, 菊地覚次, 矢野修也, 近藤喜太, 黒田新士, 香川俊輔, 藤原俊義

日本臨床外科学会雑誌 81 ( 6 ) 1202 - 1203 2020.6

食道癌患者に対する腫瘍融解ウイルスの内視鏡的投与の実際病棟実施にむけた他部署連携

矢野朋美, 采女典子, 森隆弘, 笠原由美子, 石川貴子, 田辺俊介, 黒田新士, 野間和広, 田澤大, 香川俊輔, 白川靖博, 藤原俊義

日本消化器内視鏡技師会会報 ( 64 ) 111 - 112 2020.3

【消化器外科手術の論点2020 誌上ディベートと手術手技】胃外科噴門側胃切除後の再建法観音開き法の立場から

黒田新士, 西崎正彦, 菊地覚次, 高田暢夫, 香川俊輔, 藤原俊義

手術 74 ( 4 ) 477 - 483 2020.3

Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic Virotherapy. Reviewed International journal

Hiroshi Tazawa, Joe Hasei, Shuya Yano, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Cancers 12 ( 2 ) 2020.2

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

Adenovirus serotype 5 (Ad5) is widely and frequently used as a virus vector in cancer gene therapy and oncolytic virotherapy. Oncolytic virotherapy is a novel antitumor treatment for inducing lytic cell death in tumor cells without affecting normal cells. Based on the Ad5 genome, we have generated three types of telomerase-specific replication-competent oncolytic adenoviruses: OBP-301 (Telomelysin), green fluorescent protein (GFP)-expressing OBP-401 (TelomeScan), and tumor suppressor p53-armed OBP-702. These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT (human telomerase reverse transcriptase-encoding gene) promoter, providing tumor-specific virus replication. This review focuses on the therapeutic potential of three hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity. OBP-301 induces the antitumor effect in monotherapy or combination therapy with chemotherapeutic drugs via induction of autophagy and apoptosis. OBP-401 enables visualization of sarcoma cells within normal tissues by serving as a tumor-specific labeling reagent for fluorescence-guided surgery via induction of GFP expression. OBP-702 exhibits a profound antitumor effect in OBP-301-resistant sarcoma cells via activation of the p53 signaling pathway. Taken together, telomerase-specific oncolytic adenoviruses are promising antitumor reagents that are expected to provide novel therapeutic options for the treatment of bone and soft-tissue sarcomas.

DOI： 10.3390/cancers12020478

多発小腸GISTに対し手術を施行した神経線維腫症1型の1例 Reviewed

母里淑子, 重安邦俊, 吉岡貴裕, 永坂岳司, 原賀順子, 香川俊輔, 寺石文則, 豊岡伸一, 平沢晃, 藤原俊義

家族性腫瘍 19 ( 2 ) 77 - 82 2020.2

Language：Japanese Publisher：日本家族性腫瘍学会

症例は54歳男性.大量出血を伴う小腸多発GIST(Gastrointestinal stromal tumor)を認めて緊急入院となった.姉が神経線維腫症1型(neurofibromatosis type 1:NF1)と診断されており,患者にもおよそ20個の神経線維腫を疑う腫瘤とcafe au lait斑を6個以上認めたためNF1と診断した.出血コントロール目的に開腹手術を行ったが,GISTはおよそ20個多発しており,大量小腸切除を避けるために10mm以上の腫瘍のみ外科的切除を行い,多発微小腫瘍は経過観察とした不完全切除を選択した.切除標本の病理検査では紡錘形核と好酸性胞体を有する紡錘形細胞が密に錯綜する腫瘍を認め,免疫染色でKIT陽性.核分裂数は5以下/50HPFsであり低悪性度GISTと診断した.NF1に伴うGISTは比較的予後が良いとの報告もあるが,このような多発微小病変については明らかな治療指針がない.今後さらなる症例の集積と検討を要する.(著者抄録)

Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody. Reviewed International journal

Nobuhiko Kanaya, Shinji Kuroda, Yoshihiko Kakiuchi, Kento Kumon, Tomoko Tsumura, Masashi Hashimoto, Toshiaki Morihiro, Tetsushi Kubota, Katsuyuki Aoyama, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Hiroyuki Mizuguchi, Yasuo Urata, Toshiyoshi Fujiwara

Molecular therapy : the journal of the American Society of Gene Therapy 28 ( 3 ) 794 - 804 2020.1

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

The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.

DOI： 10.1016/j.ymthe.2020.01.003

Molecular radiosensitization of soft tissue sarcoma by oncolytic virus-mediated MCL1 ablation

Omori T, Tazawa H, Yamakawa Y, Osaki S, Hasei J, Sugiu K, Komatsubara T, Fujiwara T, Yoshida A, Kunisada T, Urata Y, Kagawa S, Ozaki T, Fujiwara T

2020.1

Short-term and long-term comparisons of laparoscopy-assisted proximal gastrectomy with esophagogastrostomy by the double-flap technique and laparoscopy-assisted total gastrectomy for proximal gastric cancer. International journal

Tomoko Tsumura, Shinji Kuroda, Masahiko Nishizaki, Satoru Kikuchi, Yoshihiko Kakiuchi, Nobuo Takata, Atene Ito, Megumi Watanabe, Kazuya Kuwada, Shunsuke Kagawa, Toshiyoshi Fujiwara

PloS one 15 ( 11 ) e0242223 2020

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

BACKGROUND: Although proximal gastrectomy (PG) is a recognized surgical procedure for early proximal gastric cancer, total gastrectomy (TG) is sometimes selected due to concern about severe gastroesophageal reflux. Esophagogastrostomy by the double-flap technique (DFT) is an anti-reflux reconstruction after PG, and its short-term effectiveness has been reported. However, little is known about the long-term effects on nutritional status and quality of life (QOL). METHODS: Gastric cancer patients who underwent laparoscopy-assisted PG (LAPG) with DFT or laparoscopy-assisted TG (LATG) between April 2011 and March 2014 were retrospectively analyzed. Body weight (BW), body mass index (BMI), and prognostic nutritional index (PNI) were reviewed to assess nutritional status, and the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45 was used to assess QOL. RESULTS: A total of 36 patients (LATG: 17, LAPG: 19) were enrolled. Four of 17 LATG patients (24%) were diagnosed with Stage ≥II after surgery, and half received S-1 adjuvant chemotherapy. BW and PNI were better maintained in LAPG than in LATG patients until 1-year follow-up. Seven of 16 LATG patients (44%) were categorized as "underweight (BMI<18.5 kg/m2)" at 1-year follow-up, compared to three of 18 LAPG patients (17%; p = 0.0836). The PGSAS-45 showed no significant difference in all QOL categories except for decreased BW (p = 0.0132). Multivariate analysis showed that LATG was the only potential risk factor for severe BW loss (odds ratio: 3.03, p = 0.0722). CONCLUSIONS: LAPG with DFT was superior to LATG in postoperative nutritional maintenance, and can be the first option for early proximal gastric cancer.

DOI： 10.1371/journal.pone.0242223

Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network. Reviewed International journal

Ieda T, Tazawa H, Okabayashi H, Yano S, Shigeyasu K, Kuroda S, Ohara T, Noma K, Kishimoto H, Nishizaki M, Kagawa S, Shirakawa Y, Saitou T, Imamura T, Fujiwara T

Scientific reports 9 ( 1 ) 16378 - 16378 2019.11

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

Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.

DOI： 10.1038/s41598-019-52816-z

トランスレーショナルリサーチとしての外科治療を補完する新たな集学的治療の開発研究

田澤大, 田辺俊介, 香川俊輔, 白川靖博, 藤原俊義

日本外科学会雑誌 120 ( 6 ) 735 - 737 2019.11

Comparison of the Effects of Epidural Analgesia and Patient-controlled Intravenous Analgesia on Postoperative Pain Relief and Recovery After Laparoscopic Gastrectomy for Gastric Cancer. International journal

Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Takashi Matsusaki, Kazuya Kuwada, Yoshikazu Kimura, Shunsuke Kagawa, Hiroshi Morimatsu, Toshiyoshi Fujiwara

Surgical laparoscopy, endoscopy & percutaneous techniques 29 ( 5 ) 405 - 408 2019.10

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

PURPOSE: Epidural analgesia (EDA) is an imperative modality for postoperative pain relief after major open abdominal surgery. However, whether EDA has benefits in laparoscopic surgery has not been clear. In this study, the effects of EDA and patient-controlled intravenous analgesia (PCIA) after laparoscopic distal gastrectomy (LDG) were compared. METHODS: This was a retrospective study that included 82 patients undergoing LDG for gastric cancer. Patients received either EDA (n=67) or PCIA (n=15) for postoperative pain relief. Postoperative outcomes and analgesia-related adverse events were compared between the two modalities. RESULTS: EDA and PCIA patients showed no differences in the incidence of complications [9 (13%) vs. 2 (13%); P=0.99] and the length of postoperative hospital stay (9.6±4.5 d vs. 9.7±4.0 d; P=0.90), although the PCIA included poorer preoperative physical status (PS) patients. The number of additional doses of analgesics was higher in the EDA than in the PCIA (1.8±2.4 vs. 0.9±1.0; P=0.01), although postoperative pain scores were similar in the 2 groups. Though the time to first passage of flatus was shorter in the EDA (P<0.05), more EDA patients developed postoperative hypotension as an adverse event (P<0.01). The full mobilization day and the day of oral intake tolerance were not significantly different between the 2 groups after surgery. CONCLUSIONS: After LDG, EDA may not be indispensable, while PCIA may be the optimal modality for providing safe and effective postoperative analgesia and recovery.

DOI： 10.1097/SLE.0000000000000605

Endoscopic Ultrasound-Guided Transgastric Drainage of an IntraAbdominal Abscess following Gastrectomy. International journal

Satoru Kikuchi, Tetsushi Kubota, Shinji Kuroda, Masahiko Nishizaki, Shunsuke Kagawa, Hironari Kato, Hiroyuki Okada, Toshiyoshi Fujiwara

Clinical endoscopy 52 ( 4 ) 373 - 376 2019.7

Language：English

Endoscopic ultrasound (EUS)-guided transgastric drainage has been performed as a less invasive procedure for pancreatic fistulas and intra-abdominal abscesses occurring after surgery in recent years. However, there are no reports of EUS-guided transgastric drainage of intra-abdominal abscesses following gastrectomy. This case report describes 2 patients who developed an intra-abdominal abscess following gastrectomy and underwent EUS-guided transgastric drainage. Both patients underwent laparoscopy-assisted distal gastrectomy with Billroth-I reconstruction for gastric cancer. The intra-abdominal abscesses were caused by postoperative pancreatic fistula that developed following gastrectomy. One patient underwent naso-cystic drainage and the other underwent only a needle puncture of the abscess cavity. EUS-guided drainage was performed safely and effectively, although 1 patient developed gastroduodenal anastomotic leakage related to this procedure. In summary, EUS-guided transgastric drainage is safe and technically feasible even in post-gastrectomy patients. However, it is necessary to be careful if this procedure is performed in the early period following gastrectomy.

DOI： 10.5946/ce.2018.134

腹腔鏡手術は開腹手術と比較して術後の筋肉量減少を予防できる可能性がある

桑田和也, 金谷信彦, 菊地覚次, 黒田新士, 吉田龍一, 西崎正彦, 香川俊輔, 藤原俊義

日本消化器外科学会総会 74回 P46 - 2 2019.7

Clinical Impact of Sarcopenia on Gastric Cancer. International journal

Kazuya Kuwada, Shinji Kuroda, Satoru Kikuchi, Ryuichi Yoshida, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 39 ( 5 ) 2241 - 2249 2019.5

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

Sarcopenia is a complex syndrome defined by progressive and generalized loss of skeletal muscle mass and strength. Although sarcopenia is mainly associated with aging, cancer is also one of its causes. Sarcopenia is now drawing attention as a poor prognostic factor in cancer. In patients with gastric cancer associated with eating disorders that often leads to loss of weight and muscle, sarcopenia is particularly important. Its definition and method of assessment, however, vary between studies, thus these need to be standardized. Nevertheless, emerging evidence suggests that sarcopenia contributes independently to postoperative complications and overall survival in gastric cancer. Interventions preventing sarcopenia with targeted nutrition and exercise are currently explored. This review aims to provide an understanding of sarcopenia, emphasizing its importance in the management of gastric cancer.

DOI： 10.21873/anticanres.13340

テロメラーゼ標的蛍光発現ウイルスを用いた腹腔内腫瘍関連マクロファージの機能解析

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

日本外科学会定期学術集会抄録集 119回 SF - 5 2019.4

PD-L1 expression combined with microsatellite instability/CD8+ tumor infiltrating lymphocytes as a useful prognostic biomarker in gastric cancer. Reviewed International journal

Toshiaki Morihiro, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Tetsushi Kubota, Katsuyuki Aoyama, Takehiro Tanaka, Satoru Kikuchi, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

Scientific reports 9 ( 1 ) 4633 - 4633 2019.3

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

While the importance of programmed death-ligand 1 (PD-L1), mutation burden caused by microsatellite instability (MSI), and CD8+ tumor infiltrating lymphocytes (TILs) has become evident, the significance of PD-L1 expression on prognosis still remains controversial. We evaluated the usefulness of combined markers of PD-L1 and MSI or CD8+ TILs as a prognostic biomarker in gastric cancer. A total of 283 patients with gastric cancer were reviewed retrospectively. PD-L1 expression on >5% tumor cells was defined as PD-L1-positive. PD-L1-positive rate was 15.5% (44/283). PD-L1 positivity was significantly correlated with invasive and advanced cancer and also significantly correlated with MSI, whereas no significance was observed with CD8+ TILs. Kaplan-Meier analysis showed that PD-L1 positivity significantly correlated with a poor prognosis (p = 0.0025). Multivariate analysis revealed that PD-L1 positivity was an independent poor prognostic factor (hazard ratio [HR]: 1.97, p = 0.0106) along with diffuse histological type and lymph node metastases. Combinations of PD-L1 and MSI (HR: 2.18) or CD8+ TILs (HR: 2.57) were stronger predictive factors for prognosis than PD-L1 alone. In conclusion, combined markers of PD-L1 and MSI or CD8+ TILs may be more useful prognostic biomarkers in gastric cancer, and better clarify the immune status of gastric cancer patients.

DOI： 10.1038/s41598-019-41177-2

Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer. Reviewed International journal

Takeda S, Shigeyasu K, Okugawa Y, Yoshida K, Mori Y, Yano S, Noma K, Umeda Y, Kondo Y, Kishimoto H, Teraishi F, Nagasaka T, Tazawa H, Kagawa S, Fujiwara T, Goel A

Cancer letters 444 127 - 135 2019.3

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

Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) and its clinical significance remains unclear. Herein, we systematically analyzed a large cohort of 627 colorectal cancer (CRC) specimens, and investigated the expression pattern of ADAR1 and its biological significance on the antizyme inhibitor 1 (AZIN1) RNA editing levels. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues vs. normal mucosa, and these findings correlated with the increased expression of mesenchymal markers, Vimentin (ρ = 0.44) and Fibroblast activation protein (ρ = 0.38). Intriguingly, ADAR1 expression was specifically upregulated in both cancer cells and fibroblasts from cancerous lesions. Conditioned medium from cancer cells led to induction of ADAR1 expression and activation of AZIN1 RNA editing in fibroblasts (p < 0.05). Additionally, edited AZIN1 enhanced the invasive potential of fibroblasts. In conclusion, we provide novel evidence that hyper-editing of AZIN1 enhances the invasive potential of CAFs within the TME in colon and is an important predictor of tumor invasiveness in CRC.

DOI： 10.1016/j.canlet.2018.12.009

A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness. Reviewed International journal

Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

Cancers 11 ( 2 ) 2019.2

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

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

DOI： 10.3390/cancers11020177

Multicenter retrospective study to evaluate the efficacy and safety of the double-flap technique as antireflux esophagogastrostomy after proximal gastrectomy (rD-FLAP Study).

Shinji Kuroda, Yasuhiro Choda, Shinya Otsuka, Satoshi Ueyama, Norimitsu Tanaka, Atsushi Muraoka, Shinji Hato, Toshikazu Kimura, Kohji Tanakaya, Satoru Kikuchi, Shunsuke Tanabe, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuhiro Shirakawa, Yasuaki Kamikawa, Toshiyoshi Fujiwara

Annals of gastroenterological surgery 3 ( 1 ) 96 - 103 2019.1

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

Aim: As a result of the difficulty in effective prevention of gastroesophageal reflux, no standard reconstruction procedure after proximal gastrectomy (PG) has yet been established. The double-flap technique (DFT), or Kamikawa procedure, is an antireflux reconstruction procedure in esophagogastrostomy. The efficacy of DFT has recently been reported in several studies. However, these were all single-center studies with a limited number of cases. Methods: We conducted a multicenter retrospective study in which patients who underwent DFT, irrespective of disease type and reconstruction approach, at each participating institution between 1996 and 2015 were registered. Primary endpoint was incidence of reflux esophagitis at 1-year after surgery, and secondary endpoint was incidence of anastomosis-related complications. Results: Of 546 patients who were eligible for this study, 464 patients who had endoscopic examination at 1-year follow up were evaluated for reflux esophagitis. Incidence of reflux esophagitis of all grades was 10.6% and that of grade B or higher was 6.0%. Male gender and anastomosis located in the mediastinum/intra-thorax were independent risk factors for grade B or higher reflux esophagitis (odds ratio [OR]: 4.21, 95% confidence interval [CI]: 1.44-10.9, P = 0.0109). Total incidence of anastomosis-related complications was 7.2%, including leakage in 1.5%, strictures in 5.5% and bleeding in 0.6% of cases. Laparoscopic reconstruction was the only independent risk factor for anastomosis-related complications (OR: 3.93, 95% CI: 1.93-7.80, P = 0.0003). Conclusion: Double-flap technique might be a feasible option after PG for effective prevention of reflux, although anastomotic stricture is a complication that must be well-prepared for.

DOI： 10.1002/ags3.12216

Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma. Reviewed International journal

Shinichiro Watanabe, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Shinichi Urano, Ryoichi Katsube, Yuuri Hashimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

Cancer biology & therapy 20 ( 9 ) 1234 - 1248 2019

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

Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy in vitro and in vivo. Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells in vitro and in vivo, without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP+ CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future.

DOI： 10.1080/15384047.2019.1617566

Intraperitoneal cancer-immune microenvironment promotes peritoneal dissemination of gastric cancer. Reviewed International journal

Shuichi Sakamoto, Shunsuke Kagawa, Kazuya Kuwada, Atene Ito, Hiroki Kajioka, Yoshihiko Kakiuchi, Megumi Watanabe, Tetsuya Kagawa, Ryuichi Yoshida, Satoru Kikuchi, Shinji Kuroda, Hiroshi Tazawa, Toshiyoshi Fujiwara

Oncoimmunology 8 ( 12 ) e1671760 - e1671760 2019

Language：English Publishing type：Research paper (scientific journal) Publisher：Informa UK Limited

A solid tumor consists of cancer and stromal cells, which comprise the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are usually abundant in the TME, contributing to tumor progression. In cases of peritoneal dissemination of gastric cancer (GC), the contribution of intraperitoneal TAMs remains unclear. Macrophages from peritoneal washings of GC patients were analyzed, and the link between intraperitoneal TAMs and GC cells was investigated to clarify the interaction between them in peritoneal dissemination. Macrophages were predominant among leukocytes constituting the microenvironment of the peritoneal cavity. The proportion of CD163-positive TAMs was significantly higher in stage IV than in stage I GC. Co-culture with TAMs potentiated migration and invasion of GC. IL-6 was the most increased in the medium of in vitro co-culture of macrophages and GC, and IL-6 elevation was also observed in the peritoneal washes with peritoneal dissemination. An elevated concentration of intraperitoneal IL-6 was correlated with a poor prognosis in clinical cases. In conclusion, intraperitoneal TAMs are involved in promoting peritoneal dissemination of GC via secreted IL-6. TAM-derived IL-6 could be a potential therapeutic target for peritoneal dissemination of GC.

DOI： 10.1080/2162402X.2019.1671760

Multiple gastrointestinal stromal tumors of the small intestine in a patient with neurofibromatosis type 1: a case report

Mori Yoshiko, Fujiwara Toshiyoshi, Shigeyasu Kunitoshi, Yoshioka Takahiro, Nagasaka Takeshi, Haraga Junko, Kagawa Shunsuke, Teraishi Fuminori, Toyooka Shinichi, Hirasawa Akira

JOURNAL OF FAMILIAL TUMORS 19 ( 2 ) 77 - 82 2019

Language：Japanese Publisher：The Japanese Society for Familial Tumors

Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder caused by germline variants in the NF1 tumor suppressor gene characterized by multiple caféau lait spots and cutaneous neurofibromas. Therefore, NF1 predisposes patients to benign and malignant tumor development. We report a 54-year-old NF1 male with multiple gastrointestinal stromal tumors (GIST) in the small intestine. We resected a part of the small intestine with larger tumors, but left the part with small tumors to avoid short bowel syndrome. Histological examination revealed spindle cells with eosinophilic cytoplasm. The tumors were positive for KIT on immunopathological examination. They were smaller than 3.5 cm and their mitotic activity was less than 5/50 in high-power fields. We left 17 GIST that were smaller than 10 mm, but no progression has been detected to date. (<250 words)

DOI： 10.18976/jsft.19.2_77

The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer Reviewed International journal

Kazuya Kuwada, Shunsuke Kagawa, Ryuichi Yoshida, Shuichi Sakamoto, Atene Ito, Megumi Watanabe, Takeshi Ieda, Shinji Kuroda, Satoru Kikuchi, Hiroshi Tazawa, Toshiyoshi Fujiwara

Journal of experimental & clinical cancer research 37 ( 1 ) 307 - 307 2018.12

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

Background: The peritoneum is one of the most frequent metastatic sites in pancreatic cancer patients, and peritoneal dissemination makes this disease refractory due to aggressive progression and chemoresistance. Although the role of the tumor microenvironment in cancer development is recognized, the correlation between the peritoneal environment and refractoriness of peritoneal dissemination remains unclear. The intraperitoneal tumor-microenvironment and its potential role in the progression of peritoneal dissemination and chemo-refractoriness, focusing especially on macrophages, were investigated.
Materials and methods: Peritoneal washes were obtained from pancreatic cancer patients, and cellular components were subjected to immunofluorescence assays. The effects of macrophages induced from monocytic THP-1 cells on pancreatic cancer cells were examined in co-culture conditions. The in vivo effects of macrophages on tumor growth and chemo-sensitivity were investigated by subcutaneously or intraperitoneally co-injecting cancer cells with macrophages into mice.
Results: CD204-positive macrophages were present along with cancer cells in the peritoneal washes. In in vitro co-culture, tumor-associated macrophages affected pancreatic cancer cells, induced the epithelial-to-mesenchymal transition (EMT), and made them more resistant to chemotherapeutic agents. M2 macrophages promoted growth of both subcutaneous tumors and peritoneal dissemination in mice. Furthermore, co-inoculation of M2 macrophages conferred chemoresistance in the peritoneal dissemination mouse model, which significantly shortened their survival.
Conclusion: Intraperitoneal tumor-associated macrophages potentially play an important role in promotion of peritoneal dissemination and chemoresistance of pancreatic cancer via EMT induction.

DOI： 10.1186/s13046-018-0981-2

taTMEを安全に導入、普及させるためのcadaver surgical trainingの役割

戸嶋俊明, 近藤喜太, 信岡大輔, 黒田新士, 前田直見, 寺石文則, 白川靖博, 香川俊輔, 藤原俊義

日本内視鏡外科学会雑誌 23 ( 7 ) OS78 - 7 2018.12

Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer. Reviewed International journal

Watanabe M, Kagawa S, Kuwada K, Hashimoto Y, Shigeyasu K, Ishida M, Sakamoto S, Ito A, Kikuchi S, Kuroda S, Kishimoto H, Tomida S, Yoshida R, Tazawa H, Urata Y, Fujiwara T

Cancer science 109 ( 10 ) 3263 - 3271 2018.10

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

Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology-positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology-positive gastric cancer patients, using a green fluorescent protein (GFP)-expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP-401). The fluorescence emitted from TelomeScan-positive cells was successfully quantified using a multi-mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology-positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus-guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.

DOI： 10.1111/cas.13760

The elucidation of tumor immunosuppression affected by cancer-associated fibroblasts

Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hiroaki Sato, Satoshi Kohmoto, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 45 ( 9 ) 1279 - 1281 2018.9

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

Development of immunotherapy, especially checkpoint inhibitors, dramatically improved the prognosis of some malignancies. However, problems on the occurrence of severe adverse effects and limited responses to these checkpoint inhibitors remain. Recently, tumor infiltrating lymphocytes (Tils) are the predictive markers of immunotherapies based on clinical evidence. The proportion of cytotoxic T cells in the tumor has been reported to affect the antitumor effect. TILs in the tumor are thought to be controlled by the interaction between cancer and tumor microenvironment. As a cause of tumor immunosuppression, cancer-associated fibroblasts (CAFs) play the main role in the tumor microenvironment. We considered the strong involvement of tumor microenvironment, particularly the role of CAFs, and reported the interaction between CAFs and proliferation, invasion, angiogenesis, and resistance in the conventional therapy. The correlation between CAFs and tumor immunity and the immunosuppression promoted by CAFs were also evaluated. Their effects will be reported in our future studies.

癌関連線維芽細胞が及ぼす腫瘍免疫逃避の解明 Reviewed

加藤卓也, 野間和広, 桂佑貴, 佐藤浩明, 河本慧, 二宮卓之, 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 45 ( 9 ) 1279 - 1281 2018.9

Language：Japanese Publisher：(株)癌と化学療法社

近年、免疫チェックポイント阻害薬をはじめがん免疫療法の発展により、飛躍的に予後の改善を認める癌腫が散見される。しかしながら、致命的な有害事象の発生や効果の得られる症例が限定的であることなど、克服すべき問題点も指摘されている。免疫チェックポイント阻害薬の治療効果予測因子として腫瘍浸潤リンパ球が注目されており、特に細胞傷害性T細胞の腫瘍内浸潤の程度が抗腫瘍効果に影響を与えていると報告されている。リンパ球の腫瘍浸潤においては、癌とがん微小環境の相互作用によって制御している可能性が指摘されている。そのなかで中心的な役割を担っている癌関連線維芽細胞(cancer-associated fibroblasts:CAFs)が注目されている。以前よりわれわれは、がん微小環境の強い関与を推測し、特にCAFsの作用に注目して癌の増殖・浸潤・血管新生・治療抵抗性について報告してきた。この度CAFsと腫瘍免疫に着目し、CAFsが寄与する腫瘍免疫抑制について検討している。今後、検討結果を随時報告する予定である。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00296&link_issn=&doc_id=20180920320008&doc_link_id=%2Fab8gtkrc%2F2018%2F004509%2F010%2F1279-1281%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2018%2F004509%2F010%2F1279-1281%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

HER2-targeted gold nanoparticles potentially overcome resistance to trastuzumab in gastric cancer Reviewed International journal

Kubota Tetsushi, Kuroda Shinji, Kanaya Nobuhiko, Morihiro Toshiaki, Aoyama Katsuyuki, Kakiuchi Yoshihiko, Kikuchi Satoru, Nishizaki Masahiko, Kagawa Shunsuke, Tazawa Hiroshi, Fujiwara Toshiyoshi

NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 14 ( 6 ) 1919 - 1929 2018.8

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

An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.

DOI： 10.1016/j.nano.2018.05.019

Clinical characteristics and management of gastric tube cancer after esophagectomy Reviewed

Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Takayuki Ninomiya, Shunsuke Tanabe, Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Shunsuke Kagawa, Yoshiro Kawahara, Hiroyuki Okada, Toshiyoshi Fujiwara

Esophagus 15 ( 3 ) 180 - 189 2018.7

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

Background: Gastric cancer is the second most common malignancy, overlapping with thoracic esophageal cancer (TEC). Among them, metachronous gastric tube cancers after TEC surgery have been increasing. The aims of this study were to examine the clinicopathological factors and treatment outcomes of gastric tube cancer (GTC) after TEC surgery. Methods: Thirty-three GTCs in 30 cases after TEC treated between 1997 and 2016 were investigated retrospectively. Results: Most cases were males. The median interval from TEC surgery to GTC occurrence was 57 (6.5–107.5) months. Almost 2/3 lesions occurred in the lower third of the gastric tube (21/33)
29 lesions (in 26 cases) were superficial cancers, and 4 lesions were advanced cancers. Twenty-two lesions of superficial cancer were differentiated type, and the remaining seven lesions were undifferentiated type. Treatment for superficial cancer had previously been performed with partial gastric tube resection (10 lesions), and the number of cases undergoing endoscopic submucosal dissection (ESD) had increased recently (19 lesions). Most cases with superficial cancer survived without relapse. Four lesions of advanced cancer were found after a relatively long interval following TEC surgery. Most lesions of advanced cancer were scirrhous, undifferentiated type, and they died due to GTC. Conclusion: GTCs may occur late in the postoperative course following TEC surgery. If they are discovered at an early stage, these lesions can be cured with ESD. Long-term periodic endoscopic examinations after TEC surgery are important.

DOI： 10.1007/s10388-018-0611-2

Sarcopenia and Comorbidity in Gastric Cancer Surgery as a Useful Combined Factor to Predict Eventual Death from Other Causes Reviewed International journal

Kazuya Kuwada, Shinji Kuroda, Satoru Kikuchi, Ryuichi Yoshida, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Annals of Surgical Oncology 25 ( 5 ) 1160 - 1166 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer New York LLC

Background: Sarcopenia is recognized as an important prognostic factor in various types of cancer, including gastric cancer. While long-term survival analyses typically focus on overall and disease-specific survival, death from other causes has received far less attention. Methods: We reviewed medical records of 491 gastric cancer patients who underwent gastrectomy from January 2005 to March 2014 and whose preoperative computed tomography (CT) images were available for evaluation of sarcopenia. Sarcopenia was defined as the SMA/BSA index (skeletal muscle area divided by body surface area) below the sex-specific lowest quartile. Results: Sarcopenia was significantly associated with age, high body mass index (BMI), presence of comorbidity, high American Society of Anesthesiologists physical status (ASA-PS), high T score, advanced stage, large blood loss, and long hospital stay, but was not significantly associated with postoperative complications. Univariate and multivariate analyses of prognostic factors for overall survival revealed that sarcopenia is an independent predictor of poor prognosis [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.01–2.09, p = 0.0454]. Our analysis of death due to other causes found that non-gastric cancer-related deaths were more frequent among sarcopenia patients with comorbidities than in the rest of our study population (p = 0.0001), while univariate and multivariate analyses revealed that sarcopenia with comorbidity was an independent risk factor for non-gastric cancer-related death (HR 1.84, 95% CI 1.31–3.61, p = 0.0308), as was age. Conclusion: For gastric cancer patients, sarcopenia increases the risk of death from other causes following surgery, which reveals the importance of developing treatment strategies based not only on cancer status but also on other clinical factors, including sarcopenia and comorbidity.

DOI： 10.1245/s10434-018-6354-4

大腸癌多発肝転移に対する肝切除多回肝切除と化学療法を見据えたParenchymal sparing & skeletonized hepatectomy

楳田祐三, 八木孝仁, 永坂岳司, 吉田龍一, 信岡大輔, 杭瀬崇, 伏見卓郎, 香川俊輔, 白川靖博, 藤原俊義

日本外科学会定期学術集会抄録集 118回 1085 - 1085 2018.4

サルコペニアは胃癌術後の予後に関連する(Sarcopenia is associated with prognosis in gastric cancer patients undergoing gastrectomy)

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

日本胃癌学会総会記事 90回 268 - 268 2018.3

A multi-institution phase II study of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study)

Shunsuke Kagawa, Atsushi Muraoka, Takeshi Kambara, Hiroshi Nakayama, Ryosuke Hamano, Norimitsu Tanaka, Kazuhiro Noma, Kohji Tanakaya, Hiroyuki Kishimoto, Kunitoshi Shigeyasu, Shinji Kuroda, Satoru Kikuchi, Kazuya Kuwada, Masahiko Nishizaki, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Cancer Chemotherapy and Pharmacology 81 ( 2 ) 387 - 392 2018.2

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

Background: Trastuzumab when combined with fluoropyrimidine and cisplatin was proven to improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) in the ToGA study. The safety and efficacy of trastuzumab in combination with docetaxel and S-1 have not yet been evaluated. Methods: This study was a multicenter, phase II study. Patients with chemotherapy-naïve HER2-positive advanced or metastatic GC were eligible. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 and 6 mg/kg in subsequent cycles. Docetaxel was administered intravenously at 40 mg/m2 on day 1 of each cycle. S-1 was administered at a dosage based on body surface area for 14 days in a 3-weekly cycle. The primary endpoint was progression-free survival (PFS). Results: A total of 23 patients were enrolled. Median PFS was 6.7 months (95% CI 4.1–10.1). The response rate (RR) was 39.1%. Median overall survival (OS) and time to treatment failure (TTF) were 17.5 and 4.4 months, respectively. Major grade 3–4 adverse events were neutropenia (39.1%), leukopenia (30.4%), and febrile neutropenia (8.7%). Conclusion: Trastuzumab in combination with docetaxel and S-1 showed effective antitumor activity and manageable toxicities as first-line treatment for patients with HER2-positive GC.

DOI： 10.1007/s00280-017-3505-4

Randomized Controlled Trial of Epidural versus Patient-controlled Intravenous Analgesia for Postoperative Pain Control after Laparoscopic Gastrectomy. Reviewed

Kikuchi S, Kuroda S, Nishizaki M, Matsusaki T, Mitsuhashi T, Kuwada K, Kagawa S, Morimatsu H, Fujiwara T

Acta medica Okayama 72 ( 1 ) 95 - 98 2018.2

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

Although epidural analgesia (EDA) is considered standard postoperative analgesia for open gastrectomy, it has been unclear whether EDA has benefits in laparoscopic gastrectomy (LG) because postoperative pain after a laparoscopic procedure is significantly reduced. We are conducting a two-arm, single-center, prospective randomized non-inferiority trial to evaluate the postoperative pain relief of patient-controlled intravenous analgesia (PCIA) compared to EDA. A total of 132 patients undergoing LG will be randomized to EDA and PCIA groups (n=64 each) for postoperative pain control. The primary endpoint is postoperative pain at 24 h after surgery. This study will clarify the optimal pain management after LG.

DOI： 10.18926/AMO/55671

Iron depletion is a novel therapeutic strategy to target cancer stem cells. International journal

Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Ryoichi Katsube, Hajime Kashima, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Ling Chen, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

Oncotarget 8 ( 58 ) 98405 - 98416 2017.11

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

Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

DOI： 10.18632/oncotarget.21846

[Radical Thoracoscopic Esophagectomy for Elderly Patients with Advanced Esophageal Cancer].

Yuki Matsumi, Yasuhiro Shirakawa, Shunsuke Tanabe, Satoshi Komoto, Naoaki Maeda, Takayuki Ninomiya, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 12 ) 1784 - 1786 2017.11

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

We report a case of an elderly patient with advanced esophageal cancer who underwent multidisciplinary treatment. An 86-year-old male consulted our hospital with complaints of pharynx discomfort and difficulty in swallowing. He was preoperatively diagnosed with esophageal cancer, T3N2M0, Stage III . We performed 2 courses of cisplatin plus 5-FU therapy as neoadjuvant chemotherapy. The primary tumor and metastatic lymph nodes reduced in size, and thoracoscopic esophagectomy in the prone position was performed. Pathological findings were esophageal cancer, pT3-Ad, INF b, ly2, v1, IM0, pPM0, pDM0, pRM1, pN3, pStage III . As the radical margin was positive, chemoradiotherapy was performed. We continued postoperative chemotherapy for approximately 1 year, and the patient has survived without relapse for 4 years from esophagectomy. Even in patients over 80 years old, long-term prognosis can be expected by performing radical surgery and chemoradiotherapy.

Novel therapeutic strategy for human epidermal growth factor receptor 2-positive gastric cancer

Nobuhiko Kanaya, Shinji Kuroda, Tetsushi Kubota, Toshiaki Morihiro, Satoru Kikuchi, Masahiko Nishizaki, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 44 ( 10 ) 883 - 885 2017.10

Language：Japanese Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

Trastuzumab (Tmab), a humanized monoclonal antibody that selectively targets human epidermal growth factor receptor 2 (HER2), is currently used in the clinical setting for the treatment of both breast and gastric cancer. While Tmab has shown improvements in patient prognoses, acquired resistance to this agent remains an issue. While some novel HER2-targeted agents have been approved for clinical use in breast cancer, no such agent has shown treatment efficacy for gastric malignancies with Tmab-resistance. Nanotechnology, which has progressed rapidly, has been applied to medical fields in recent years. Gold nanopartides, which are characterized by their in vivo stability and ease of surface modification, have been reported to show efficacy as the carriers of therapeutic agents, such as drugs, antibodies, peptides, and nucleic acids. In this work, we developed Tmab-conjugated gold nanopartides and demonstrate their efficacy for the treatment of HER2-positive, Tmab-resistant gastric cancer cell lines. Our findings demonstrate that Tmab-conjugated gold nanopartides have the potential to be a novel HER2-targeted therapeutic agent.

Clinicopathological features of gastric cancer in young patients; Multicenter retrospective study

Yoshiyasu Kono, Hiromitsu Kanzaki, Masahiro Takatani, Junichirou Nasu, Ryuta Takenaka, Hiroyuki Sakae, Ko Miura, Takehiro Tanaka, Shunsuke Kagawa, Hiroyuki Okada

ANNALS OF ONCOLOGY 28 2017.10

Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system

Katsuyuki Aoyama, Shinji Kuroda, Toshiaki Morihiro, Nobuhiko Kanaya, Tetsushi Kubota, Yoshihiko Kakiuchi, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

SCIENTIFIC REPORTS 7 ( 14177 ) doi: 10.1038/s41598-017-14717-x 2017.10

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

Oncolytic virotherapy has the disadvantage of being unsuitable for systemic delivery due to immune elimination. Liposomal encapsulation is well-recognized to reduce immune elimination and enhance the stability of drugs in the bloodstream. In the present study, the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus (TelomeScan) expressing GFP (Lipo-pTS) as an oncolytic adenoviral agent suitable for systemic delivery was investigated. Lipo-pTS, which has a diameter of 40-50 nm, showed potent antitumor effects on HCT116 colon carcinoma cells in vitro and in vivo. Tumor selectivity of Lipo-pTS was independent of coxsackie and adenovirus receptor (CAR). Importantly, Lipo-pTS reduced production of adenovirus-neutralizing antibodies (AdNAbs) after intravenous administration into immune-competent mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity. In conclusion, Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system.

DOI： 10.1038/s41598-017-14717-x

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction. Reviewed

Yamakawa Y, Tazawa H, Hasei J, Osaki S, Omori T, Sugiu K, Komatsubara T, Uotani K, Fujiwara T, Yoshida A, Kunisada T, Urata Y, Kagawa S, Ozaki T, Fujiwara T

Cancer science 108 ( 9 ) 1870 - 1880 2017.9

若き外科医からの提言わたしたちの将来の外科医療を見据えて外科研修の現状からみえた若手外科医の求めるもの大規模Surveyより

菊地覚次, 野間和広, 山根正修, 岸本浩行, 黒田新士, 香川俊輔, 新井禎彦, 佐野俊二, 三好新一郎, 藤原俊義

日本外科学会雑誌 118 ( 5 ) 588 - 590 2017.9

Training system for laparoscopy-assisted distal gastrectomy

Shinji Kuroda, Satoru Kikuchi, Naoto Hori, Shuichi Sakamoto, Tetsuya Kagawa, Megumi Watanabe, Tetsushi Kubota, Kazuya Kuwada, Michihiro Ishida, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

SURGERY TODAY 47 ( 7 ) 802 - 809 2017.7

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

Purpose Laparoscopy-assisted distal gastrectomy (LADG) is likely to become a standard procedure for gastric cancer, which highlights the importance of establishing a training system in which even inexperienced surgeons can perform this procedure safely. This study assesses our training system for LADG based on short-term surgical outcomes.
Methods We evaluated retrospectively the short-term outcomes of 100 consecutive LADGs with curative D1/D1+ lymph node dissection. Our training system was assessed based on the learning curve of trainees, and factors related to achieving good-quality operations were analyzed statistically.
Results Overall, postoperative complications developed in 10 patients (10%), and included one case of anastomotic leakage (1%) and one case of pancreatic fistula (1%). The learning curve of the trainees plateaued after 10 operator cases in terms of operation time. The importance of the trainer's position was also confirmed by the result that the operation time was significantly longer when trainees with <= 10 operator cases performed LADG with a trainer as scopist vs. a trainer as the first assistant. Univariate and multivariate analyses revealed that > 10 operator cases were the most important factor for achieving good-quality operations.
Conclusion These results show that our current LADG procedure and training system are appropriate and effective.

DOI： 10.1007/s00595-016-1439-9

Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer

Hiroshi Tazawa, Shinji Kuroda, Joe Hasei, Shunsuke Kagawa, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 18 ( 7 ) doi:10.3390/ijms18071479 2017.7

Language：English Publisher：MDPI AG

Oncolytic virotherapy has recently emerged as a promising strategy for inducing tumor-specific cell death. Adenoviruses are widely and frequently used in oncolytic virotherapy. The mechanism of oncolytic adenovirus-mediated tumor suppression involves virus-induced activation of the autophagic machinery in tumor cells. Autophagy is a cytoprotective process that produces energy via lysosomal degradation of intracellular components as a physiologic response to various stresses, including hypoxia, nutrient deprivation, and disruption of growth signaling. However, infection with oncolytic adenoviruses induces autophagy and subsequent death of tumor cells rather than enhancing their survival. In this review, we summarize the beneficial role of autophagy in oncolytic adenoviral therapy, including the roles of infection, replication, and cell lysis. Numerous factors are involved in the promotion and inhibition of oncolytic adenovirus-mediated autophagy. Furthermore, recent evidence has shown that oncolytic adenoviruses induce autophagy-related immunogenic cell death (ICD), which enhances the antitumor immune response by inducing the activation of danger signal molecules and thus represents a novel cancer immunotherapy. Understanding the precise role of oncolytic adenovirus-induced autophagy and ICD could enhance the therapeutic potential of oncolytic adenoviral therapy for treating various cancers.

DOI： 10.3390/ijms18071479

GFP labeling kinetics of triple-negative human breast cancer by a killer-reporter adenovirus in 3D GelfoamA (R) histoculture

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 53 ( 6 ) 479 - 482 2017.7

Management of early gastric cancer that meet the indication for radical lymph node dissection following endoscopic resection: a retrospective cohort analysis

Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Tetsuya Kagawa, Hiromitsu Kanzaki, Yoshiro Kawahara, Shunsuke Kagawa, Takehiro Tanaka, Hiroyuki Okada, Toshiyoshi Fujiwara

BMC SURGERY 17 ( 1 ) 687 - 694 2017.6

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

Background: Endoscopic resection (ER) has been widely accepted as the standard treatment for early gastric cancer (EGC). However, in patients considered to have undergone non-curative ER due to their potential risk of lymph node metastasis (LNM), additional gastrectomy is recommended. The aim of the present study was to identify EGC patients after non-curative ER at high risk of LNM.
Methods: A total of 150 patients who had undergone ER for EGC were diagnosed as non-curative ER due to their potential risk of LNM. Clinicopathological data and clinical outcomes were examined retrospectively.
Results: Additional gastrectomy with lymph node dissection was performed in 73 patients, and the remaining 77 patients were followed-up without additional gastrectomy. In patients who underwent additional gastrectomy, 8 patients had local residual tumor, and 8 patients had LNM, which were limited in the peritumoral nodes. Only lymphatic invasion (p = 0.012) was a statistically significant factor for LNM. The 5-year overall survival and recurrence-free survival were not significantly different between patients with and without additional gastrectomy.
Conclusion: Additional gastrectomy with lymph node dissection is recommended for patients who were diagnosed as non-curative ER with lymphatic invasion, and minimizing the extent of lymph node dissection may be allowed for these patients.

DOI： 10.1186/s12893-017-0268-0

Nonexposure laparoscopic and endoscopic cooperative surgery (closed laparoscopic and endoscopic cooperative surgery) for gastric submucosal tumor

Satoru Kikuchi, Masahiko Nishizaki, Shinji Kuroda, Shunsuke Tanabe, Kazuhiro Noma, Shunsuke Kagawa, Yasuhiro Shirakawa, Hiroshi Kato, Hiroyuki Okada, Toshiyoshi Fujiwara

GASTRIC CANCER 20 ( 3 ) 553 - 557 2017.5

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

Laparoscopic and endoscopic cooperative surgery (LECS) is increasingly applied for gastric submucosal tumors (SMTs) such as gastrointestinal stromal tumors. However, the conventional LECS procedure has the potential risk that gastric contents and even tumor cells could spread into the abdominal cavity because the gastric wall has to be opened during the resection. To avoid this problem, we have developed a modified LECS procedure named "closed LECS." Ten patients underwent closed LECS for the resection of gastric SMTs. Closed LECS consists of the following steps: endoscopic submucosal layer dissection around the tumor, laparoscopic marking of a resection line on the serosal surface along submucosal dissection line, seromuscular suturing with the marked lesion inverted into the inside of the stomach, endoscopic circumferential seromuscular dissection, and peroral retrieval. In three of the initial five cases, the closed LECS procedure was not completed as planned because of the tumor size and endoscopic inappropriate seromuscular dissection. After modification of the procedure, the entire procedure was successful in all five cases. The mean resected tumor diameter was 24.1 +/- 7.6 mm. The mean operation time was 253 +/- 45 min. One patient experienced an intra-abdominal abscess potentially related to delayed perforation as a postoperative complication. The closed LECS procedure for gastric SMTs can theoretically be applied without contamination and tumor cell dissemination into the abdominal cavity.

DOI： 10.1007/s10120-016-0641-1

Outcome of Radiation Monotherapy for High-risk Patients with Stage I Esophageal Cancer

Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Shunsuke Tanabe, Shinji Kuroda, Shunsuke Kagawa, Kuniaki Katsui, Norihisa Katayama, Susumu Kanazawa, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 71 ( 2 ) 127 - 133 2017.4

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

Currently, chemoradiation is the most widely used nonsurgical treatment for esophageal cancer. However, some patients, particularly the very elderly or those with severe vital organ dysfunction, face difficulty with the chemotherapy component. We therefore examined the outcome of radiation therapy (RT) alone for patients with esophageal cancer at our facility. Between January 2005 and December 2014, 84 patients underwent RT at our hospital, and 78 of these patients received concomitant chemotherapy. The remaining 6 patients underwent RT alone; these patients were considered to be high-risk and to have no lymph node metastasis (stage I). Five of them received irradiation up to a curative dose: 4 showed a complete response (CR) and 1 showed a partial response (PR). Of the patients exhibiting CR, 3 are currently living recurrence-free, whereas 1 patient underwent endoscopic submucosal dissection (ESD) as salvage therapy for local recurrence, with no subsequent recurrence. High-risk stage I esophageal cancer patients can be treated radically with RT alone under certain conditions. In the future, to broaden the indications for RT monotherapy to include some degree of advanced cancers, a novel concurrent therapy should be identified.

High-metastatic triple-negative breast-cancer variants selected in vivo become chemoresistant in vitro

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 53 ( 4 ) 285 - 287 2017.4

[Multiple Salvage Radiotherapies for Metachronous Lymph Node Metastasis from Gastric Cancer Contributed to Long-Term Management of Disease].

Naoto Hori, Shunsuke Kagawa, Satoru Kikuchi, Shinji Kuroda, Megumi Watanabe, Shuichi Sakamoto, Tetsuya Kagawa, Kazuya Kuwada, Tetsushi Kubota, Hiroyuki Kishimoto, Masahiko Nishizaki, Norihisa Katayama, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 2 ) 165 - 167 2017.2

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

A 70-year-old man who underwent gastrectomy for Stage III C gastric cancer developed lymph node(LN)metastasis posterior to the pancreatic head 3 years after the radical surgery.He was first treated with radiotherapy(RT)followed by chemotherapy.The irradiated tumor regressed completely.However, the cancer relapsed in a single para-aortic LN and he was treated with RT to the lesion followed by chemotherapy.Although it completely regressed, later, lung metastasis was observed.The lung lesions were well suppressed by switching to docetaxel; however, the cancer relapsed again in a mediastinal LN, and it was not responsive to docetaxel.The growing mediastinal lesion was irradiated again, which resulted in stable disease.The patient has been treated for 4 years and 7 months with all lesions being well-managed, and chemotherapy is being continued.Recurrent gastric cancer after surgery tends to present as multiple lesions; therefore, the principle therapy is systemic chemotherapy and RT is unlikely to be suitable.However, especially in cases of a solitary lesion that is chemo-resistant, RT could be an optimal option and contribute to long-term survival even in patients with recurrent gastric cancer.

Comparison of in vitro invasiveness of high- and low-metastatic triple-negative human breast cancer visualized by color-coded imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 53 ( 2 ) 96 - 98 2017.2

Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models. International journal

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Michael Bouvet, Robert M Hoffman

Anticancer research 37 ( 1 ) 57 - 60 2017.1

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

BACKGROUND: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly-metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice. MATERIALS AND METHODS: In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly-metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room. RESULTS: After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDA-MB-231 tumors were resected. CONCLUSION: The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly-metastatic MDA-MB-231 TNBC.

WHAT ARE REAL NEEDS FOR YOUNG SURGEONS IN SURGICAL EDUCATION ? THE SURVEY OF CURRENT SURGICAL TRAINING

菊地覚次, 野間和広, 山根正修, 岸本浩行, 黒田新士, 香川俊輔, 新井禎彦, 佐野俊二, 三好新一郎, 藤原俊義

日本外科学会雑誌 = Journal of Japan Surgical Society 118 ( 5 ) 588 - 590 2017

Oncolytic virotherapy for osteosarcoma

Pharm stage 16 ( 12 ) 54 - 59 2017

HER2陽性胃癌に対する新たな治療戦略

金谷信彦, 黒田新士, 久保田哲史, 森廣俊昭, 菊地覚次, 西崎正彦, 田澤大, 香川俊輔, 藤原俊義

癌と化学療法 44 ( 10 ) 883 - 885 2017

超高齢者の進行食道癌に対し積極的に集学的治療を行い長期無再発生存中の1例

松三雄騎, 白川靖博, 田邊俊介, 河本慧, 前田直見, 二宮卓之, 野間和広, 西崎正彦, 香川俊輔, 藤原俊義

癌と化学療法 44 ( 12 ) 1784 - 1786 2017

胃癌術後再発病変に対する複数回の放射線療法が奏功し長期生存が得られた1例

堀直人, 香川俊輔, 菊地覚次, 黒田新士, 渡邉めぐみ, 坂本修一, 香川哲也, 桒田和也, 久保田哲史, 岸本浩行, 西﨑正彦, 片山敬久, 藤原俊義

癌と化学療法 44 ( 2 ) 165 - 167 2017

Language：Japanese Publisher：(株)癌と化学療法社

胃癌術後再発に対しての第一選択は化学療法であるが、胃癌術後複数箇所のリンパ節転移に対して、3回の放射線療法(radio therapy:RT)により長期の病勢制御が可能であった症例を経験したので報告する。症例は70歳、男性。胃癌に対して幽門側胃切除を行い、Stage IIICであった。S-1の補助化学療法を行ったが、3年経過後に膵頭後部リンパ節再発を来した。他に再発病巣なくRTを行い、奏効が得られた。その後、化学療法中に出現した腹部大動脈周囲リンパ節、縦隔リンパ節再発に対してもそれぞれRTを施行し、再発から4年7ヵ月間、化学療法抵抗性であった再発病巣は良好に制御されている。胃癌術後再発におけるRTは、その多くが多発病巣を呈するため適応にはなりにくく、胃周辺臓器への有害事象も考慮する必要があるが、本症例のような化学療法抵抗性の単発病変再発の局所制御には有効性を発揮することがあり、治療の選択肢として重要である。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00296&link_issn=&doc_id=20170220290014&doc_link_id=%2Fab8gtkrc%2F2017%2F004402%2F016%2F0165-0167%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2017%2F004402%2F016%2F0165-0167%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 16 ( 5 ) 406 - 414 2017

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

We previously demonstrated that quiescent cancer cells in a tumor are resistant to conventional chemotherapy as visualized with a fluorescence ubiquitination cell cycle indicator (FUCCI). We also showed that proliferating cancer cells exist in a tumor only near nascent vessels or on the tumor surface as visualized with FUCCI and green fluorescent protein (GFP)-expressing tumor vessels. In the present study, we show the relationship between cell-cycle phase and chemotherapy-induced tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and nestin-driven GFP to detect nascent blood vessels. We observed that chemotherapy-treated tumors, consisting of mostly of quiescent cancer cells after treatment, had much more and deeper tumor vessels than untreated tumors. These newly-vascularized cancer cells regrew rapidly after chemotherapy. In contrast, formerly quiescent cancer cells decoyed to S/G(2) phase by a telomerase-dependent adenovirus did not induce tumor angiogenesis. The present results further demonstrate the importance of the cancer-cell position in the cell cycle in order that chemotherapy be effective and not have the opposite effect of stimulating tumor angiogenesis and progression.

DOI： 10.1080/15384101.2016.1220461

食道がんに対する放射線併用ウイルス療法の臨床研究

藤原俊義, 田澤大, 田邊俊介, 香川俊輔, 白川靖博

日本臨床 75 ( 5 ) 746 - 751 2017

HOZOT細胞を用いた腫瘍融解ウイルス製剤のDDS

田澤大, 大西哲平, 香川俊輔, 中村修治, 藤原俊義

BIO INDUSTRY 34 ( 4 ) 16 - 23 2017

噴門側胃切除術後再建：手縫い腹腔鏡下体腔内手縫い「観音開き法」食道残胃吻合

西﨑正彦, 黒田新士, 菊地覚次, 垣内慶彦, 松村年久, 渡邉めぐみ, 香川俊輔, 藤原俊義

臨床外科 72 ( 4 ) 412 - 415 2017

観音開き法を用いた噴門機能温存

西﨑正彦, 黒田新士, 菊地覚次, 垣内慶彦, 香川俊輔, 藤原俊義

手術 71 ( 1 ) 21 - 25 2017

In Vivo Selection of Intermediately- and Highly-Malignant Variants of Triple-negative Breast Cancer in Orthotopic Nude Mouse Models

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ANTICANCER RESEARCH 36 ( 12 ) 6273 - 6277 2016.12

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

Aim: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2 (HER2), is a recalcitrant disease in need of effective therapy. We previously isolated very-highly metastatic variants of the TNBC cell line MDA-MB-231 using serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (MDA-MB-231-RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation into the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for three or seven cycles in order to isolate intermediately, or highly-metastatic variants, respectively. Results: The degree of malignancy of isolated variants of MDA-MB-231 depends on the extent of orthotopic transplantation. Serial transplantation resulted in MDA-MB-231-RFP which significantly produced larger tumors compared with the parental MDA-MB-231-RFP. Serial orthotopic implantation for three cycles resulted in intermediately-metastatic variants of MDA-MB-231-RFP. MDA-MB-231-RFP serially orthotopically transplanted seven times significantly metastasized more to lymph nodes compared with parental MDA-MB-231-RFP cells and the intermediately-metastatic variant. The highly-metastatic variant MDA-MB-231-RFP cells significantly metastasized to the lung to a greater extent compared with parental MDA-MB-231-RFP and intermediate variants of MDA-MB-231-RFP. Conclusion: These results suggest that the number of serial orthotopic transplantations of MDA-MB-231-RFP correlates positively with tumor aggressiveness, and the intermediately- and highly-metastatic variants can serve as models of metastatic progression of TNBC.

DOI： 10.21873/anticanres.11222

Tumor-targeting adenovirus OBP-401 inhibits primary and metastatic tumor growth of triple-negative breast cancer in orthotopic nude-mouse models

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 7 ( 51 ) 85273 - 85282 2016.12

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

Our laboratory previously developed a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of the human MDA-MB-231 cell line in nude mice. The isolated variant was highly-invasive in the mammary gland and lymphatic channels and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present study, the tumor-selective telomerase dependent OBP-401 adenovirus was injected intratumorally (i. t.) (1 x 10(8) PFU) when the high-metastatic MDA-MB-231 primary tumor expressing red fluorescent protein (MDA-MB-231-RFP) reached approximately 500 mm3 (diameter; 10 mm). The mockinfected orthotopic primary tumor grew rapidly. After i. t. OBP-401 injection, the growth of the orthotopic tumors was arrested. Six weeks after implantation, the fluorescent area and fluorescence intensity showed no increase from the beginning of treatment. OBP-401 was then injected into high-metastatic MDA-MB-231-RFP primary orthotopic tumor growing in mice which already had developed metastasis within lymphatic ducts. All 7 of 7 control mice subsequently developed lymph node metastasis. In contrast, none of 7 mice which received OBP-401 had lymph node metastasis. Seven of 7 control mice also had gross lung metastasis. In contrast, none of the 7 mice which received OBP-401 had gross lung metastasis. Confocal laser microscopy imaging demonstrated that all control mice had diffuse lung metastases. In contrast, all 7 mice which received OBP-401 only had a few metastatic cells in the lung. OBP-401 treatment significantly extended survival of the treated mice.

DOI： 10.18632/oncotarget.13296

[A Case of Multiple Liver Metastasis from Gastric Cancer Successfully Treated with CPT-11 as Third-Line Chemotherapy].

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

Gan to kagaku ryoho. Cancer & chemotherapy 43 ( 12 ) 2219 - 2221 2016.11

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

A 63-year-old man underwent proximal gastrectomy for early gastric cancer(pT1bN0M0, pStage I A). Twenty months after surgery, abdominal CT scans revealed multiple liver metastases. S-1 plus CDDP therapy was administered as first-line chemotherapy. After treatment, CT scans revealed tumor progression and nab-PTX was administrated. This treatment was ineffective; therefore, CPT-11 was administrated as third-line chemotherapy. Treatment with CPT-11 resulted in marked tumor reduction and improved the QOL of the patient; partial response was maintained for 8 months. After 17 courses of CPT-11 treatment, tumor regrowth was detected, and the patient was treated with S-1 plus oxaliplatin, DTX, and ramucirumab. Subsequently, the patient died of cancer 31 months after tumor recurrence. CPT-11 is potentially a key drug for the prevention of liver metastasis of gastric cancer, and using all active agents in patients with advanced gastric cancer over several lines of therapy could prolong survival.

Real-time in-vivo image-guided cell-cycle perturbation to increase tumor chemosensitivity

Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Yoshihiko Kadowaki, Nobuhiro Ishido, Takahiro Okamoto, Yasuo Urata, Kiyoto Takehara, Robert M. Hoffman, Toshiyoshi Fujiwara

MOLECULAR CANCER RESEARCH 14 2016.11

Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 7 ( 46 ) 75635 - 75647 2016.11

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

We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative highinvasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model.

DOI： 10.18632/oncotarget.12314

Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Teppei Onishi, Hiroshi Tazawa, Yuuri Hashimoto, Makoto Takeuchi, Takeshi Otani, Shuji Nakamura, Fuminori Sakurai, Hiroyuki Mizuguchi, Hiroyuki Kishimoto, Yuzo Umeda, Yasuhiro Shirakawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Scientific Reports 6 2016.11

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

"Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35-loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.

DOI： 10.1038/srep38060

高リスク神経芽腫に対するhTERT標的化膿瘍融解ウイルス療法(hTERT-targeted oncolytic virotherapy against high-risk neuroblastomas)

谷本光隆, 田澤大, 家田偉史, 納所洋, 尾山貴徳, 浦田泰生, 香川俊輔, 野田卓男, 藤原俊義

日本小児血液・がん学会雑誌 53 ( 4 ) 202 - 202 2016.11

Novel HER2-Targeted therapy combined with gold nanoparticles

Tetsushi Kubota, Shinji Kuroda, Toshiaki Morihiro, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 43 ( 10 ) 1237 - 1239 2016.10

Language：Japanese Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

Trastuzumab (Tmab) is a humanized monoclonal antibody that binds to the human epidermal growth factor receptor 2 (HER2). It is clinically used for HER2-positive breast and gastric cancers
however, the use of Tmab is restricted to tumors expressing high levels of HER2 (accounting for only 20% of tumors), and Tmab cannot be used for tumors resistant to Tmab. Although novel HER2-Targeted agents have been developed to treat Tmab-resistant tumors, none of these have shown clinical efficacy in gastric cancer patients. Recent developments in nanotechnology have had a significant impact on the field of medicine. Gold nanoparticles (AuNPs), which show characteristics such as in vivo stability and ease of surface functionali- zation, have been developed as therapeutic and contrast agents for medical applications. Previous studies show that AuNPs exert cytotoxic effects through autophagy and apoptosis
therefore, AuNPs in combination with tumor-Targeting antibodies are attractive therapeutic agents. In this study, we developed HER2-Targeted AuNPs (Tmab-AuNPs) and showed that they had a potent antitumor effect on Tmab-resistant cell lines. In addition, Tmab-AuNPs were effective against HER2-negative gastric cancer cell lines when HER2 was artificially overexpressed. Thus, our results indicate that Tmab-AuNPs may overcome the shortcomings of Tmab-based therapy.

金ナノ粒子を用いた新規HER2標的抗体療法

久保田哲史, 黒田新士, 森廣俊昭, 田澤大, 香川俊輔, 藤原俊義

癌と化学療法 43 ( 10 ) 1237 - 1239 2016.10

Language：Japanese Publisher：(株)癌と化学療法社

trastuzumab(Tmab)は、human epidermal growth factor receptor 2(HER2)に対するヒト化モノクローナル抗体で、現在乳癌や胃癌に対して臨床使用され予後を改善しているが、HER2の低発現(約20%)やTmab抵抗性の問題がある。Tmab抵抗例に対して新たなHER2標的製剤が開発されているが胃癌に対して臨床的に有効なものはまだなく、新たな治療法が望まれる。ナノ技術はその発展に伴い医療へ応用されてきている。金ナノ粒子は生体内での安定性と表面修飾の容易性などの特性があり、autophagyやoxidative stressを介したアポトーシスを誘導することも報告されている。われわれは、HER2標的金ナノ粒子製剤(Tmab-AuNPs)を作製し、Tmab抵抗性胃癌細胞株に対する抗腫瘍効果とHER2細胞外領域を強制発現させたHER2陰性株に対する抗腫瘍効果を確認しており、Tmab-AuNPsがTmab抵抗性胃癌に対する新たなHER2標的製剤になり得ると考えている。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00296&link_issn=&doc_id=20161104480020&doc_link_id=%2Fab8gtkrc%2F2016%2F004310%2F021%2F1237-1239%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2016%2F004310%2F021%2F1237-1239%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

A Phase II Clinical Trial of the Efficacy and Safety of Short-term (3 days) Enoxaparin for the Prevention of Venous Thromboembolism after Gastric Cancer Surgery

Shinji Kuroda, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Shiro Hinotsu, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 70 ( 5 ) 401 - 404 2016.10

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

Although intermittent pneumatic compression (IPC) has become common as perioperative prophylaxis for venous thromboembolism (VTE) consisting of pulmonary thromboembolism (PE) and deep vein thrombosis (DVT), the prophylactic effect against VTE, especially lethal PE, is not yet satisfactory. Therefore, pharmacologic prophylaxis, such as with enoxaparin, is desirable. While the efficacy and safety of enoxaparin have been proven in several clinical trials, concern about bleeding with long-term (at least 7 days) use have potentially decreased its widespread adoption. We have launched a phase II study to evaluate the efficacy and safety of short-term (3 days) enoxaparin, in which a total of 70 gastric cancer patients undergoing gastrectomy will be recruited, and the primary endpoint is the incidence of DVT. This study could contribute to making pharmacologic prophylaxis for VTE more common.

DOI： 10.18926/AMO/54601

Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam (R)-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

PLOS ONE 11 ( 9 ) doi: 10.1371/journal.pone.0162991 2016.9

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

Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam (R) histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam (R) grew into tumor-like structures with G(0)/G(1) cancer cells in the center and S/G(2) cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam (R) histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam (R). In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN45 cells in tumors on Gelfoam (R) to cycle from G(0)/G(1) phase to S/G(2) phase and reduced their viability. CDDP-or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam 1. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam (R) histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301.

DOI： 10.1371/journal.pone.0162991

Double-Flap Technique as an Antireflux Procedure in Esophagogastrostomy after Proximal Gastrectomy

Shinji Kuroda, Masahiko Nishizaki, Satoru Kikuchi, Kazuhiro Noma, Shunsuke Tanabe, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 223 ( 2 ) E7 - E13 2016.8

In Vivo Isolation of a Highly-aggressive Variant of Triple-negative Human Breast Cancer MDA-MB-231 Using Serial Orthotopic Transplantation

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ANTICANCER RESEARCH 36 ( 8 ) 3817 - 3820 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

Aim: We describe the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation in the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically reimplanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for two cycles and then isolated. Results: The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. Conclusion: The availability of a highly invasive variant of TNBC targeting lymph nodes will be very useful for drug discovery of TNBC, a recalcitrant cancer and for mechanistic studies of its aggressiveness.

A case of right-sided Bochdalek hernia incidentally diagnosed in a gastric cancer patient

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

BMC SURGERY 16 ( 34 ) doi: 10.1186/s12893-016-0145-2 2016.6

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

Background: Bochdalek hernia (BH) is generally congenital, presenting with respiratory distress. However, this pathology is rarely detected in adults. Some adult cases of BH present with symptoms attributed to the hernia, but incidental detection of BH is increasing among asymptomatic adults due to advances in imaging modalities. This report presents the management of incidental BH patients detected in the preoperative period of gastric cancer.
Case presentation: An asymptomatic 76-year-old woman was diagnosed with advanced gastric cancer during follow-up after radiotherapy for uterine cervical cancer. Computed tomography (CT) was performed to exclude metastatic gastric cancer, incidentally detecting right-sided BH. We planned distal gastrectomy with lymph node dissection for gastric cancer and simultaneous repair of BH using a laparoscopic approach. We performed laparoscopic gastrectomy for gastric cancer and investigated the right-sided BH to assess whether repair during surgery was warranted. Herniation of the liver into the right hemithorax was observed, but was followed-up without surgical repair because the right hepatic lobe was adherent to the remnant right anterior hemidiaphragm and covered the huge defect in the right hemidiaphragm. No intra-or postoperative pneumothorax was observed during pneumoperitoneum.
Conclusion: Regardless of symptoms, repair of adult BH is generally recommended to prevent visceral incarceration. However, BH in asymptomatic adults appears to be more common than previously reported in the literature. Surgeons need to consider the management of incidental BH encountered during thoracic or abdominal surgery.

DOI： 10.1186/s12893-016-0145-2

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

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

Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas

Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

SCIENTIFIC REPORTS 6 ( 28953 ) doi: 10.1038/srep28953 2016.6

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

Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.

DOI： 10.1038/srep28953

Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Yasuhiro Shirakawa, Hiroshi Tazawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

MOLECULAR CANCER THERAPEUTICS 15 ( 3 ) 402 - 411 2016.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than HER2 has hampered the development of treatments for peritoneal dissemination of gastric cancer. Wehypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective antitumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)-mediated PIT induced selective cell death of HER2-ECD-transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700-mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer. (C) 2016 AACR.

DOI： 10.1158/1535-7163.MCT-15-0644

【新薬認可で治療革命の幕開けがんのウイルス療法がん細胞だけを破壊する組換えウイルスその作用機序と開発動向】テロメラーゼ標的化がん治療・診断用アデノウイルス

田澤大, 香川俊輔, 重安邦俊, 藤原俊義

実験医学 34 ( 1 ) 13 - 18 2016.1

Language：Japanese Publisher：(株)羊土社

アデノウイルスは本来ヒトの細胞に感染・増殖し、最終的に感染した細胞をさまざまな機序により破壊する。近年の遺伝子工学技術の進歩により、アデノウイルスの増殖能にがん選択性をもたせることで新たながん治療薬としての臨床開発が進められている。本稿では、われわれが独自に開発したテロメラーゼ活性選択的に制限増殖するアデノウイルス製剤を用いたがん治療法・診断法に関する研究成果や臨床応用について概説する。がん細胞の無制限な増殖能に関連するテロメラーゼを標的とすることで多くのがん患者に対する治療・診断技術の開発が期待される。(著者抄録)

p53 Replacement Therapy for Cancer. Reviewed

Tazawa H, Kagawa S, Fujiwara T

Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 209 1 - 15 2016

Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models

Yano S, Takehara K, Tazawa H, Kishimoto H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

Journal of Cellular Biochemistry doi: 10.1002/jcb.25735 2016

Adenoviral targeting of malignant melanoma for fluorescenceguided surgery prevents recurrence in orthotopic nude-mouse models

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

Oncotarget 7 ( 14 ) 18558 - 18572 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：Impact Journals LLC

Malignant melanoma requires precise resection in order to avoid metastatic recurrence. We report here that the telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401 could label malignant melanoma with GFP in situ in orthotopic mouse models. OBP-401-based fluorescence-guided surgery (FGS) resulted in the complete resection of malignant melanoma in the orthotopic models, where conventional bright-light surgery (BLS) could not. High-dose administration of OBP-401 enabled FGS without residual cancer cells or recurrence, due to its dual effect of cancer-cell labeling with GFP and killing.

DOI： 10.18632/oncotarget.6670

Iron depletion enhances the effect of sorafenib in hepatocarcinoma

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 - 656 2016

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

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 (R)) and/or deferasirox (EXJADE (R)) 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

Therapeutic efficacy in vivo of a telomerase-dependent adenovirus in an orthotopic model of chemotherapy-resistant human stomach carcinomatosis peritonitis visualized with cell cycle color coding FUCCI imaging

Yano S, Takehara K, Tazawa H, Kishimoto H, Urata Y, Kagawa S, Fujiwara T, Hoffman RM

Journal of Cellular Biochemistry doi: 10.1002/jcb.25593 2016

胃癌術後肝転移再発に対してThird-LineのCPT-11が奏効し長期生存を得た1 例

菊地覚次, 西﨑正彦, 黒田新士, 香川俊輔, 藤原俊義

癌と化学療法 43 ( 12 ) 2219 - 2221 2016

Language：Japanese Publisher：(株)癌と化学療法社

症例は63歳、男性。早期胃癌(pT1bN0M0、pStage IA)術後20ヵ月のCTにて多発肝転移再発を認め、first-lineとしてS-1+CDDP療法2コース施行後、腫瘍は増大し、second-lineとしてnab-PTX6コース施行するも腫瘍増大、肝酵素上昇、体重減少と全身状態の悪化を認めた。しかし、third-lineのCPT-11が奏効し、肝酵素も正常化、体重も増加し全身状態、ADLの改善も認め、8ヵ月PRを維持した。CPT-11合計17コース施行後に腫瘍が増大し、その後S-1+oxaliplatin療法、DTX、再度CPT-11、ramucirumab投与を行い、再発後31ヵ月原病死された。胃癌肝転移に対してCPT-11はkey drugになる可能性があり、また予後延長には胃癌に有効なkey drugをすべて使い切るマネージメントが重要と考えられた。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00296&link_issn=&doc_id=20161222480266&doc_link_id=%2Fab8gtkrc%2F2016%2F004312%2F266%2F2219-2221%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2016%2F004312%2F266%2F2219-2221%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model. International journal

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Yukihiko Hiroshima, Takashi Murakami, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M Hoffman

PloS one 11 ( 2 ) e0148760 2016

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

Fluorescence-guided surgery (FGS) of cancer is an area of intense development. In the present report, we demonstrate that the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 could label colon-cancer liver metastasis in situ in an orthotopic mouse model enabling successful FGS. OBP-401-GFP-labeled liver metastasis resulted in complete resection with FGS, in contrast, conventional bright-light surgery (BLS) did not result in complete resection of the metastasis. OBP-401-FGS reduced the recurrence rate and prolonged over-all survival compared with BLS. In conclusion, adenovirus OBP-401 is a powerful tool to label liver metastasis in situ with GFP which enables its complete resection, not possible with conventional BLS.

DOI： 10.1371/journal.pone.0148760

[Therapeutic Potential of Targeting Cancer-Associated Fibroblasts in Esophageal Cancer]. Reviewed

Kazuhiro Noma, Hajime Kashima, Takayuki Ninomiya, Ryoichi Katsube, Shinichiro Watanabe, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 42 ( 10 ) 1228 - 30 2015.10

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

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.

胃疾患に対する内視鏡外科手術手技腹腔鏡下噴門側胃切除術におけるリンパ節郭清手技の定型化

西崎正彦, 黒田新士, 菊地覚次, 坂本修一, 田邊俊介, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

日本臨床外科学会雑誌 76 ( 増刊 ) 389 - 389 2015.10

手術手技腹腔鏡下噴門側胃切除後の「観音開き法」による完全体腔内食道残胃吻合

黒田新士, 西崎正彦, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

手術 69 ( 10 ) 1487 - 1492 2015.9

胃癌合併Bochdalek孔ヘルニアに対する用手補助腹腔鏡下手術による一期的根治手術の1例

堀直人, 香川俊輔, 黒田新士, 岸本浩行, 西崎正彦, 藤原俊義

日本内視鏡外科学会雑誌 20 ( 5 ) 473 - 479 2015.9

Language：Japanese Publisher：(一社)日本内視鏡外科学会

患者は65歳,男性.腹痛・嘔吐を主訴に前医を受診し,上部消化管内視鏡検査で早期胃癌を,CTで左横隔膜にBochdalek孔ヘルニアを指摘された.胃癌に対する内視鏡的切除が非治癒切除となり,追加切除目的に当院紹介となった.胃癌のリンパ節郭清と今後のヘルニア嵌頓のリスクを考慮し,同時手術にて腹腔鏡補助下に胃切除およびヘルニア修復術を行った.気腹による胸腔内圧上昇に胸腔トロッカーを要し,ヘルニア門修復での視野確保には用手補助を追加したが,腹腔鏡下に幽門側胃切除とヘルニア根治術を完遂した.これまでに横隔膜ヘルニアと悪性腫瘍とを同時に手術した報告はなく,若干の文献的考察を加えて報告する.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J03270&link_issn=&doc_id=20150925140005&doc_link_id=10.11477%2Fmf.4426200166&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.4426200166&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery

S. Yano, Y. Hiroshima, A. Maawy, H. Kishimoto, A. Suetsugu, S. Miwa, M. Toneri, M. Yamamoto, M. H. G. Katz, J. B. Fleming, Y. Urata, H. Tazawa, S. Kagawa, M. Bouvet, T. Fujiwara, R. M. Hoffman

CANCER GENE THERAPY 22 ( 7 ) 344 - 350 2015.7

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

Precise fluorescence-guided surgery (FGS) for pancreatic canter has the potential to greatly improve the outcome in this recalcitrant disease. To achieve this goal, we have used genetic reporters to-color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 was used to label the cancer cells of a pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic Mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX Model enabled FGS to to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence; which bright-light surgery or single-color FGS could not. FGS, with color-coded canter and stroma cells has important potential for improving the outcome of recalcitrant-cancer surgery.

DOI： 10.1038/cgt.2015.26

Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability

Keisuke Toda, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Takashi Kawai, Tomokazu Fuji, Fumitaka Taniguchi, Kazuya Yasui, Nobuhito Kubota, Yuko Takehara, Hiroshi Tazawa, Shunsuke Kagawa, Dong-Sheng Sun, Naoshi Nishida, Ajay Goel, Toshiyoshi Fujiwara

CLINICAL EPIGENETICS 7 doi:10.1186/s13148-015-0096-y 2015.7

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

Background: The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis.
Results: In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers.
Conclusions: Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.

DOI： 10.1186/s13148-015-0096-y

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.

Pathological complete response in a case of advanced gastric cancer after neoadjuvant chemotherapy Reviewed

Satoru Kikuchi, Shunsuke Kagawa, Tetsushi Kubota, Kazuya Kuwada, Shinji Kuroda, Masahiko Nishizaki, Takehiro Tanaka, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 41 ( 12 ) 2282 - 2284 2014.11

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

A 62-year-old man with advanced gastric cancer was referred to our hospital. A gastroscopy revealed a type 3 tumor invading the esophagus in the lesser curvature of the stomach cardia. We diagnosed the tumor as cStage IIIB (T4BN1M0) gastric cancer. For the best chance of a pathological complete response, we selected neoadjuvant chemotherapy (NAC) with S-1 + CDDP (SP therapy). A total gastrectomy with lymph node dissection was performed after 2 courses of SP therapy-Pathological evaluation of the resected stomach and lymph nodes indicated an absence of cancerous cells, confirming a pathological complete response (pCR). The patient has been followed up for 4 months without evidence of recurrence.

MECHANISM OF RESISTANCE TO TRASTUZUMAB AND MOLECULAR SENSITIZATION VIA ADCC ACTIVATION BY EXOGENOUS EXPRESSION OF HER2 EXTRACELLULAR DOMAIN

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 16 ( 7-8 ) 277 - 278 2014.7

MiCRORNA-7 INHIBITS THE STEM-LIKE PROPERTIES OF CD133(+) HUMAN GASTRIC CANCER CELLS

Teppei Onishi, Hiroshi Tazawa, Shuya Yano, Yuuri Hashimoto, Ryosuke Yoshida, Shunsuke Kagawa, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 16 ( 7-8 ) 266 - 266 2014.7

ONCOLYTIC ADENOVIRUS INHIBITS TRANSFORMING GROWTH FACTOR-beta-INDUCED EPITHELIAL-MESENCHYMAL TRANSITION IN HUMAN CANCER CELLS

Yuuri Hashimoto, Hiroshi Tazawa, Ryosuke Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 16 ( 7-8 ) 244 - 245 2014.7

消化器癌に対する個別化治療 Genetic/epigenetic変異を基盤とした大腸癌個別化治療の構築

永坂岳司, 母里淑子, 稲田涼, 岸本浩行, 近藤喜太, 浅野博昭, 佃和憲, 西崎正彦, 香川俊輔, 藤原俊義

日本消化器外科学会総会 69回 SY - 8 2014.7

HER2陽性胃癌に対するtrastuzumabを含む化学療法施行症例の解析

香川俊輔, 黒田新士, 菊地覚次, 西崎正彦, 渡辺めぐみ, 石田道拡, 堀直人, 岸本浩行, 藤原俊義

日本癌治療学会誌 49 ( 3 ) 2376 - 2376 2014.6

化学療法後切除により組織学的完全奏効が得られた高度進行胃癌の3例

菊地覚次, 香川俊輔, 久保田哲史, 黒田新士, 西崎正彦, 藤原俊義

日本癌治療学会誌 49 ( 3 ) 1977 - 1977 2014.6

Molecular surgery using a novel biological agent, OBP-301, for lymph node micrometastasis in human colorectal cancer.

Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

JOURNAL OF CLINICAL ONCOLOGY 32 ( 15 ) 2014.5

OP-134-1 大学-関連施設連携強化による外科医育成のための研修プログラムの質保証向上の試み(OP-134 臨床研修,一般演題,第114回日本外科学会定期学術集会)

山根正修, 香川俊輔, 佃和憲, 新井禎彦, 藤原俊義, 三好新一郎, 佐野俊二

日本外科学会雑誌 115 ( 2 ) 550 - 550 2014.3

がん関連線維芽細胞(Cancer Associated Fibroblasts)を標的とした新規癌治療法の開発 Reviewed

野間和広, 白川靖博, 二宮卓之, 勝部亮一, 前田直見, 田辺俊介, 大原利章, 田澤大, 香川俊輔, 藤原俊義

日本外科学会雑誌 115 ( 臨増2 ) 678 - 678 2014.3

テロメラーゼ依存性増殖型アデノウイルス製剤を用いた早期大腸癌に対する低侵襲治療の開発

菊地覚次, 岸本浩行, 田澤大, 西崎正彦, 香川俊輔, 浦田泰生, Hoffman Robert, 藤原俊義

日本外科学会雑誌 115 ( 臨増2 ) 401 - 401 2014.3

ハイリスク患者に対する腹腔鏡下胃切除の意義高リスク症例に対する腹腔鏡下胃切除術と開腹胃切除の短期成績に関する比較検討

黒田新士, 香川俊輔, 堀直人, 岸本浩行, 西崎正彦, 藤原俊義

日本胃癌学会総会記事 86回 166 - 166 2014.3

胃腫瘍に対する腹腔鏡内視鏡合同手術の可能性当院におけるLECSの工夫 Closed LECSの可能性

西崎正彦, 黒田新士, 堀直人, 岸本浩行, 香川俊輔, 岡田裕之, 藤原俊義

日本胃癌学会総会記事 86回 170 - 170 2014.3

食道癌・胃癌におけるロボット支援手術の有用性ロボット支援下噴門側胃切除術後のロボットによる体腔内手縫い食道残胃吻合

西崎正彦, 黒田新士, 岸本浩行, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

日本外科学会雑誌 115 ( 臨増2 ) 189 - 189 2014.3

HER2陽性進行再発胃癌に対するTrastuzumabの使用経験とその有効性について

黒田新士, 香川俊輔, 渡邊めぐみ, 堀直人, 石田道拡, 岸本浩行, 西崎正彦, 藤原俊義

日本外科学会雑誌 115 ( 臨増2 ) 692 - 692 2014.3

ESD/EMR非治癒切除後の外科切除症例の検討

堀直人, 香川俊輔, 黒田新士, 岸本浩行, 西崎正彦, 藤原俊義

日本胃癌学会総会記事 86回 224 - 224 2014.3

HER2陰性胃癌におけるウイルスベクターを用いたHER2標識化とそれに対する分子標的光免疫療法

石田道拡, 香川俊輔, 田澤大, 下山京子, 竹原清人, 黒田新士, 野間和広, 岸本浩行, 西崎正彦, 小林久隆, 藤原俊義

日本胃癌学会総会記事 86回 316 - 316 2014.3

イマチニブで長期病勢コントロール中の再発消化管間質腫瘍に胃癌を発症した1例

宇野太, 岸本浩行, 香川俊輔, 藤原俊義

日本外科系連合学会誌 39 ( 1 ) 45 - 51 2014.2

Language：Japanese Publisher：日本外科系連合学会

症例は81歳女性で,当院で同時性肝転移を伴う胃の消化管間質腫瘍(gastrointestinal stromal tumor:GIST)に対し,胃局所切除と肝切除が施行されていた.その後術後8ヵ月で肝転移再発し,イマチニブ投与され4年間病勢コントロールされていたが,胃癌を発症し胃全摘術施行した.病理結果では高分化型腺癌とともに局所再発と思われるGISTも併存していた.胃全摘1ヵ月後からイマチニブ投与を再開し,現在外来通院にて経過観察中である.当院での胃癌切除症例の685例のうち切除胃に同時性GISTを指摘した症例が11例(1.6%)あったが,胃GIST術後再発加療中に胃癌を発症した例は初めて経験した.しかし切除不能再発GISTもイマチニブなどの分子標的薬出現により長期の生存が期待されることを考えると,再発GIST症例においても2次癌を念頭においた慎重な経過観察が重要であると思われる.(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J01066&link_issn=&doc_id=20140306110009&doc_link_id=10.4030%2Fjjcs.39.45&url=https%3A%2F%2Fdoi.org%2F10.4030%2Fjjcs.39.45&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Telomerase-specific oncolytic virotherapy for human cancer

13 ( 6 ) 817 - 823 2014

噴門側胃切除後の逆流防止機構を伴った食道残胃吻合法

西崎正彦, 黒田新士, 菊地覚次, 久保田哲史, 香川俊輔, 藤原俊義

胃癌perspective 7 ( 1 ) 20 - 26 2014

術前補助化学療法によりpCRが得られた高度進行胃癌の1例

菊地覚次, 香川俊輔, 久保田哲史, 桒田和也, 黒田新士, 西﨑正彦, 田中健大, 藤原俊義

癌と化学療法 41 ( 12 ) 2282 - 2284 2014

Biological Ablation of Sentinel Lymph Node Metastasis in Submucosally Invaded Early Gastrointestinal Cancer

Kikuchi Satoru, Kishimoto Hiroyuki, Tazawa Hiroshi, Hashimoto Yuuri, Kuroda Shinji, Nishizaki Masahiko, Nagasaka Takeshi, Shirakawa Yasuhiro, Kagawa Shunsuke, Urata Yasuo, Robert M Hoffman, Fujiwara Toshiyoshi

Molecular Therapy doi: 10.1038/mt.2014.244 2014

縮小手術のコツとピットフォール① 噴門側胃切除術（観音開き法）

西﨑正彦, 黒田新士, 松村年久, 高嶌寛年, 加藤大, 菊池覚次, 桒田和也, 香川俊輔, 藤原俊義

臨床外科 69 ( 13 ) 1464 - 1471 2014

化学療法後に切除しpCRを得たStageⅣ胃癌の２例

久保田哲史, 香川俊輔, 菊地覚次, 黒田新士, 西﨑正彦, 藤原俊義

癌と化学療法 41 ( 12 ) 2308 - 2310 2014

ロボット支援下噴門側胃切除術後のロボットによる体腔内手縫い吻合

西﨑正彦, 黒田新士, 岸本浩行, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

癌の臨床 60 ( 3 ) 311 - 317 2014

Language：Japanese Publisher：(株)篠原出版新社

胃上部に限局する内視鏡的粘膜下層剥離術適応外のcStage IA早期胃癌2例に対し、ロボット支援下噴門側胃切除術(RAPG)後に完全体腔内ロボット手縫い吻合による[観音開き法]食道残胃吻合による再建を行った。RAPG後の体腔内手縫い吻合は、腹腔鏡補助下噴門側胃切除術(LAPG)より平均手術時間や体腔内吻合時間が大幅に延長したが、平均出血量は少量で、開腹手縫いと同等に安全で正確な吻合を行うことができた。RAPG後の体腔内ロボット手縫い吻合は、低侵襲手技として機能温存を試みる際に再評価される可能性があると思われた。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00297&link_issn=&doc_id=20140730100010&doc_link_id=%2Fad7gnrsc%2F2014%2F006003%2F010%2F0311-0317%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fad7gnrsc%2F2014%2F006003%2F010%2F0311-0317%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

A Case of Gastric Cancer with Stable Disease Controlled Recurrence of Gastrointestinal Stromal Tumor with Imatinib

Uno Futoshi, Kishimoto Hiroyuki, Kagawa Shunsuke, Fujiwara Toshiyoshi

Nihon Gekakei Rengo Gakkaishi (Journal of Japanese College of Surgeons) 39 ( 1 ) 45 - 51 2014

Language：Japanese Publisher：Japanese College of Surgeons

A case was 81-year-old woman with gastrointestinal stromal tumor (GIST) of stomach accompanied by liver metastases, who underwent partial gastrectomy and hepatectomy. Multiple liver metastases were diagnosed 8 months after R0 surgery. While metastases disease was well controlled with administration of imatinib for 4 years, gastric cancer in remnant stomach was diagnosed. Total gastrectomy was undergone, pathological findings were that well differentiated tubular adenocarcinoma cells were localized in mucosa and no lymph node metastases was found but local recurrence of GIST was pointed out. One month after total gastrectomy, she resumed administration of imatinib and she has no sign of progression with neither gastric cancer nor GIST. Only 11 synchronous GIST cases of 685 gastric cancer cases were found and it is first case for our institution that gastric cancer was occurred during imatinib therapy for recurrence GIST. But secondary cancer should be concern because of long survival time for unresectable metastases GIST patients with imatinib.

DOI： 10.4030/jjcs.39.45

DOI： 10.3919/jjsa.81.2225_references_DOI_HvAPNRy8vi3arMN5Gv9eBAuRYyx

Oncolytic Adenovirus-Induced Autophagy: Tumor-Suppressive Effect and Molecular Basis

Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 67 ( 6 ) 333 - 342 2013.12

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Autophagy is a catabolic process that produces energy through lysosomal degradation of intracellular organelles. Autophagy functions as a cytoprotective factor under physiological conditions such as nutrient deprivation, hypoxia, and interruption of growth factors. On the other hand, infection with pathogenic viruses and bacteria also induces autophagy in infected cells. Oncolytic virotherapy with replication-competent viruses is thus a promising strategy to induce tumor-specific cell death. Oncolytic adenoviruses induce autophagy and subsequently contribute to cell death rather than cell survival in tumor cells. We previously developed a telomerase-specific replication-competent oncolytic adenovirus, OBP-301, which induces cell lysis in tumor cells with telomerase activities. OBP-301-mediated cytopathic activity is significantly associated with induction of autophagy biomarkers. In this review, we focus on the tumor-suppressive role and molecular basis of autophagic machinery induced by oncolytic adenoviruses. Addition of tumor-specific promoters and modification of the fiber knob of adenoviruses supports the oncolytic adenovirus-mediated autophagic cell death. Autophagy is cooperatively regulated by the El-dependent activation pathway, E4-dependent inhibitory pathway, and microRNA-dependent fine-tuning. Thus, future exploration of the functional role and molecular mechanisms underlying oncolytic adenovirus-induced autophagy would provide novel insights and improve the therapeutic potential of oncolytic adenoviruses.

DOI： 10.18926/AMO/52006

A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem-like Cells in S/G(2)/M Phases

Shuya Yano, Hiroshi Tazawa, Yuuri Hashimoto, Yasuhiro Shirakawa, Shinji Kuroda, Masahiko Nishizaki, Hiroyuki Kishimoto, Futoshi Uno, Takeshi Nagasaka, Yasuo Urata, Shunsuke Kagawa, Robert M. Hoffman, Toshiyoshi Fujiwara

CLINICAL CANCER RESEARCH 19 ( 23 ) 6495 - 6505 2013.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem-like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem-like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem-like cells.
Experimental Design: We established CD133(+) cancer stem-like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem-like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem-like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI).
Results: CD133(+) gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133(+) cancer stem-like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G(0)-G(1) to S/G(2)/M phases and subsequent cell death in quiescent CD133(+) cancer stem-like cells by mobilizing cell-cycle-related proteins. FUCCI enabled visualization of quiescent CD133(+) cancer stem-like cells and proliferating CD133(-) non-cancer stem-like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133(+) cancer stem-like cells maintained stemness by remaining in G(0)-G(1) phase. We showed that OBP-301 mobilized quiescent cancer stem-like cells in tumor spheres and xenografts into S/G(2)/M phases where they lost viability and cancer stem-like cell properties and became chemosensitive.
Conclusion: Oncolytic adenoviralinfection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem-like cells. Clin Cancer Res; 19(23); 6495-505. (C) 2013 AACR.

DOI： 10.1158/1078-0432.CCR-13-0742

Genetically engineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis

125 ( 3 ) 195 - 199 2013.12

当科における進行食道癌における合理的胸腔鏡下手術の試み Reviewed

野間和広, 白川靖博, 前田直見, 二宮卓之, 大原利章, 田辺俊介, 櫻間教文, 西崎正彦, 香川俊輔, 藤原俊義

日本内視鏡外科学会雑誌 18 ( 7 ) 549 - 549 2013.11

胃癌切除 #8〜#13の郭清法(開腹術と同等に行えるか) 神経解剖を軸とした膵上縁郭清の工夫と実際

黒田新士, 西崎正彦, 堀直人, 岸本浩行, 香川俊輔, 藤原俊義

日本内視鏡外科学会雑誌 18 ( 7 ) 371 - 371 2013.11

Closed LECSの開発と臨床応用

西崎正彦, 加藤大, 黒田新士, 田邊俊介, 堀直人, 岸本浩行, 香川俊輔, 白川靖博, 藤原俊義

日本内視鏡外科学会雑誌 18 ( 7 ) 499 - 499 2013.11

Advances in adenovirus-mediated p53 cancer gene therapy

Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

Expert Opinion on Biological Therapy 13 ( 11 ) 1569 - 1583 2013.11

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

Introduction: The tumor suppressor p53 gene regulates diverse cellular processes, such as cell-cycle arrest, senescence, apoptosis and autophagy, and it is frequently inactivated by genetic alterations in ∼ 50% of all types of human cancers. To restore wild-type p53 function in p53-inactivated tumors, adenovirus-mediated p53 gene therapy has been developed as a promising antitumor strategy in preclinical experiments and clinical studies. Areas covered: This review focuses on the clinical relevance of replication-deficient adenovirus vectors that carry the wild-type p53 gene (Ad-p53
Advexin, Gendicine and SCH-58500) in clinical studies of patients with various cancers and the future perspectives regarding conditionally replicating adenovirus vectors expressing the wild-type p53 gene (CRAd-p53
AdDelta24-p53, SG600-p53, OBP-702) in preclinical experiments. Moreover, the recent advances in our understanding of the molecular basis for the p53-mediated tumor suppression network induced by Ad-p53 and CRAd-p53 vectors and the combination therapies for promoting the therapeutic potential of adenovirus-mediated p53 gene therapy are discussed. Expert opinion: Exploration of the molecular mechanism underlying the p53-mediated tumor suppression network and the effective strategy for enhancing the p53-mediated cell death signaling pathway would provide novel insights into the improvement of clinical outcome in p53-based cancer gene therapy. © 2013 Informa UK, Ltd.

DOI： 10.1517/14712598.2013.845662

腹腔鏡下有茎直腸による腟形成術の3例

永坂岳司, 宇野太, 稲田涼, 杉本盛人, 母里淑子, 近藤喜太, 黒田新二, 浅野博昭, 岸本浩行, 西崎正彦, 佃和憲, 香川俊輔, 長谷川健二郎, 難波祐三郎, 藤原俊義

日本内視鏡外科学会雑誌 18 ( 7 ) 757 - 757 2013.11

成人Bochdalek孔ヘルニアを合併した胃癌に対し腹腔鏡手術にて一期的に根治手術し得た1例

堀直人, 香川俊輔, 黒田信士, 岸本浩行, 西崎正彦, 藤原俊義

日本内視鏡外科学会雑誌 18 ( 7 ) 639 - 639 2013.11

胃癌患者の腹腔洗浄液における蛍光発現ウイルス試薬による新たな生物学的診断(Biological assessment of peritoneal lavage cytology of gastric cancer by fluorescence-expressing virus TelomeScan)

香川俊輔, 石田道拡, 渡邉めぐみ, 田澤大, 黒田新士, 岸本浩行, 橋本悠里, 西崎正彦, 藤原俊義

日本癌学会総会記事 72回 187 - 187 2013.10

早期大腸癌のリンパ節転移制御に向けた新規治療(Novel strategy for eradicating lymph node metastasis of earlystage colorectal cancers)

菊地覚次, 岸本浩行, 田澤大, 橋本悠里, 宇野太, 西崎正彦, 香川俊輔, 浦田泰生, ロバート・ホフマン, 藤原俊義

日本癌学会総会記事 72回 178 - 178 2013.10

進行胃癌に対する手術進行胃癌に対し自律神経解剖を郭清範囲決定に応用したD2郭清

西崎正彦, 黒田新士, 堀直人, 岸本浩行, 香川俊輔, 藤原俊義

日本臨床外科学会雑誌 74 ( 増刊 ) 461 - 461 2013.10

HER2遺伝子導入技術を用いたHER2陰性癌細胞に対する分子標的光免疫療法(Neotargeting HER2 negative cancer cells with photoimmunotherapy by virally transduction of HER2- extracellular domain)

石田道拡, 香川俊輔, 下山京子, 竹原清人, 野間和広, 田澤大, 黒田新士, 岸本浩行, 田邊俊介, 松岡順治, 小林久隆, 篠原俊義

日本癌学会総会記事 72回 495 - 495 2013.10

蛍光標識による血中遊離癌細胞のLiquid Biopsy技術のバイオマーカー解析への応用 Reviewed

重安邦俊, 橋本悠里, 竹原清人, 宇野太, 永坂岳司, 田澤大, 香川俊輔, 浦田泰生, 藤原俊義

日本癌治療学会誌 48 ( 3 ) 2759 - 2759 2013.9

がん選択的生物製剤を用いた早期大腸癌の低侵襲治療の開発

菊地覚次, 岸本浩行, 田澤大, 西崎正彦, 香川俊輔, 浦田泰生, Hoffman Robert M., 藤原俊義

日本癌治療学会誌 48 ( 3 ) 1918 - 1918 2013.9

Selectively Replicating Oncolytic Adenoviruses Combined with Chemotherapy, Radiotherapy, or Molecular Targeted Therapy for Treatment of Human Cancers Reviewed

Shinji Kuroda, Shunsuke Kagawa, Toshiyoshi Fujiwara

Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation: Third Edition 171 - 183 2013.8

Language：English Publishing type：Part of collection (book) Publisher：Elsevier Inc.

Oncolytic adenovirotherapy presents a novel approach for cancer therapy. Oncolytic adenoviruses are modified to replicate and induce oncolytic cell death in cancer cells but not in normal somatic cells. The first oncolytic adenovirus to be developed was ONYX-015, an E1B-55. kDa gene-deleted oncolytic adenovirus
after which many inventive oncolytic adenoviruses have followed. H101, an oncolytic adenovirus with very similar gene constructs as ONYX-015, was approved in China as the world's first adenovirus cancer treatment in humans in 2005. Many clinical trials have revealed that oncolytic adenoviruses produce synergistic antitumor effects in combination with conventional chemotherapeutic agents, radiation, and some molecular targeted agents, although monotherapy with oncolytic adenoviruses shows limited effects. In this chapter, we discuss the developments of oncolytic adenoviruses, focusing on their synergistic effects when combined with other treatment modalities. Then we discuss the problems that must be overcome for adenoviruses to become more attractive as cancer treatment agents and to expand their clinical applications. © 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/B978-0-12-394295-1.00012-3

LADG、D2における神経解剖を軸とした膵上縁リンパ節郭清

黒田新士, 西崎正彦, 渡邊めぐみ, 石田道拡, 岸本浩行, 宇野太, 香川俊輔, 藤原俊義

日本消化器外科学会総会 68回 RV - 2 2013.7

腹腔鏡補助下噴門側胃切除術における郭清手技と「観音開き法」食道残胃吻合

西崎正彦, 黒田新士, 野間和広, 渡邉めぐみ, 岸本浩行, 香川俊輔, 白川靖博, 藤原俊義

日本消化器外科学会総会 68回 O - 6 2013.7

HER2陽性胃癌の臨床病理学的特徴と当院におけるtrastuzumabの使用経験

渡辺めぐみ, 香川俊輔, 石田道拡, 黒田新士, 岸本浩行, 宇野太, 西崎正彦, 藤原俊義

日本消化器外科学会総会 68回 RS - 2 2013.7

テロメラーゼ依存性増殖型アデノウイルス製剤を用いた早期大腸癌の低侵襲治療の開発

菊地覚次, 岸本浩行, 田澤大, 橋本悠里, 宇野太, 西崎正彦, 香川俊輔, 浦田泰生, ロバート・ホフマン, 藤原俊義

日本消化器外科学会総会 68回 RS - 2 2013.7

A novel synergistic effect of iron depletion on antiangiogenic cancer therapy

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 - 2713 2013.6

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

Roux stasis syndromeの長期保存的加療に経胃瘻的空腸カテーテルを用いた1例

大岩雅彦, 香川俊輔, 重安邦俊, 金谷信彦, 宇野太, 岸本浩行, 西崎正彦, 藤原俊義

Gastroenterological Endoscopy 55 ( 5 ) 1650 - 1654 2013.5

Language：Japanese Publisher：(一社)日本消化器内視鏡学会

74歳男性。胃癌に対する幽門側胃切除、Roux-en-Y再建術後、胃空腸吻合部通過障害を生じた。再吻合を施行したが、通過障害は遷延し、Roux stasis syndrome(RSS)と診断した。胃減圧と長期栄養管理のため、経皮内視鏡的胃瘻造設術、percutaneous endoscopic gastrostomy(PEG)を施行し、経胃瘻的に空腸カテーテル(PEG-J)を留置した。134日後に食事摂取可能になりカテーテルを抜去した。PEG-Jにより中心静脈カテーテルや経鼻胃管の長期留置を回避できることからRSSに対する長期保存治療の1選択肢になりうると考えられた。(著者抄録)

DOI： 10.11280/gee.55.1650

Application of percutaneous endoscopic gastrostomy with jejunal extension in a case of post-gastrectomy Roux Stasis syndrome

Masahiko Oiwa, Shunsuke Kagawa, Kunitoshi Shigeyasu, Nobuhiko Kanaya, Futoshi Uno, Hiroyuki Kishimoto, Masahiko Nishizaki, Toshiyoshi Fujiwara

Gastroenterological Endoscopy 55 ( 5 ) 1650 - 1654 2013.5

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

We present herein on a 74-years-old man, who underwent distal gastrectomy and Roux-en-Y reconstruction for stomach cancer, and developed gastro-jejunostomy obstruction. Re-anastomosis, however, did not relieve the symptoms. Delayed gastric emptying without mechanical obstruction lead to a diagnosis of Roux stasis syndrome (RSS). To achieve both gastric decompression and nutritional therapy, a percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) was performed in two steps. Firstly, a gastrostomy was placed endoscopically and then a jejunal catheter was inserted through the gastrostomy tube. This system can feed nutritional solution through the jejunal catheter while gastric juice is drained from the gastrostomy tube. The patient was spared an uncomfortable nasal gastric tube and long-term central-venous hyperalimentation, and his RSS was completely cleared 134 days later. This experience suggested that PEG-J can be one of the options in the conservative treatment of RSS.

Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination

Kunitoshi Shigeyasu, Shunsuke Kagawa, Futoshi Uno, Masahiko Nishizaki, Hiroyuki Kishimoto, Akira Gochi, Toshikazu Kimura, Takaomi Takahata, Yasuyuki Nonaka, Motoki Ninomiya, Toshiyoshi Fujiwara

Cancer Chemotherapy and Pharmacology 71 ( 4 ) 937 - 943 2013.4

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

Purpose: Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination. Methods: Nineteen patients with histologically confirmed unresectable or recurrent gastric cancer with peritoneal dissemination were enrolled. Oral S-1 at 80 mg/m2/day was administered twice daily for 2 weeks, followed by 1 drug-free week. Docetaxel infusion at 40 mg/m2 was performed on day 1, simultaneous with S-1 administration. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary endpoints were the response rates and safety status. Results: Patients received a median of 4 cycles of the S-1 and docetaxel regimen (range 1-43). The disease control rate was 73.7 % (14/19). Median overall survival was 459 days (15.3 months), while median time to progression was 212 days (7.1 months). Neutropenia was the most common type of toxicity (n = 7, 36.8 %). Conclusions: Combination chemotherapy with S-1 and docetaxel is a tolerable and effective treatment for advanced or recurrent gastric cancer patients with peritoneal dissemination. © 2013 Springer-Verlag Berlin Heidelberg.

DOI： 10.1007/s00280-013-2086-0

癌微小リンパ節転移を標的とするテロメラーゼ特異的制限増殖型ウイルス製剤の開発

児島亨, 渡邉雄一, 橋本悠里, 黒田新士, 山崎泰源, 矢野修也, 田澤大, 宇野太, 香川俊輔, 田中紀章, 浦田泰生, 藤原俊義

岡山医学会雑誌 125 ( 1 ) 9 - 12 2013.4

Gene therapy for cancer treatment Reviewed

Shunsuke Kagawa, Toshiyoshi Fujiwara

Gene Therapy: Technologies and Applications 70 - 83 2013.3

高リスクGIST症例の検討無作為化比較試験SSGXVIII/AIOの報告をうけて Reviewed

宇野太, 永坂岳司, 香川俊輔, 西崎正彦, 岸本浩行, 黒田新士, 石田道拡, 青山克幸, 稲田涼, 前田直見, 大原利章, 近藤喜太, 田辺俊介, 野間和広, 白川靖博, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 891 - 891 2013.3

胃癌腹膜播種に関する新たな知見と治療への応用胃癌における蛍光発現ウイルスによる腹腔洗浄液診断:生物学的悪性度指標としての可能性 Reviewed

香川俊輔, 岸本浩行, 宇野太, 黒田新士, 石田道拡, 橋本悠里, 重安邦俊, 西崎正彦, 白川靖博, 永坂岳司, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 144 - 144 2013.3

消化器癌における血中遊離癌細胞の検出と臨床応用テロメラーゼ活性を指標とする血中遊離癌細胞の高感度検出法の開発と遺伝子解析技術への応用 Reviewed

重安邦俊, 橋本悠里, 宇野太, 永坂岳司, 田澤大, 香川俊輔, 水口裕之, 浦田泰生, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 338 - 338 2013.3

超高齢者に対する外科治療の問題点消化管外科、術式の選択当科における80歳以上の超高齢者食道癌症例に対する外科治療の変遷 Reviewed

田辺俊介, 白川靖博, 青山克幸, 前田直見, 大原利章, 櫻間教文, 野間和広, 西崎正彦, 香川俊輔, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 317 - 317 2013.3

腹臥位胸腔鏡下食道亜全摘術においてEndoCAMeleonがもたらした新たな視野展開 Reviewed

野間和広, 白川靖博, 青山克幸, 前田直見, 大原利章, 田辺俊介, 櫻間教文, 西崎正彦, 香川俊輔, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 451 - 451 2013.3

テロメラーゼ依存性増殖型アデノウイルス製剤を用いた早期大腸癌の低侵襲治療の開発

菊地覚次, 岸本浩行, 田澤大, 橋本悠里, 宇野太, 西崎正彦, 香川俊輔, 浦田泰生, Robert Hoffman, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 612 - 612 2013.3

ロボット支援下幽門側胃切除術におけるリンパ節郭清手技

西崎正彦, 香川俊輔, 石田道拡, 黒田新士, 近藤喜太, 野間和広, 岸本浩行, 宇野太, 永坂岳司, 白川靖博, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 438 - 438 2013.3

腹腔細胞診陽性胃癌症例に対する外科的切除の検討

香川俊輔, 岸本浩行, 宇野太, 西崎正彦, 黒田新士, 石田道拡, 藤原俊義

日本胃癌学会総会記事 85回 283 - 283 2013.2

腹腔鏡下胃切除術におけるリンパ節郭清のコツ da Vinci手術からLADGへのfeedback 幽門下リンパ節郭清

西崎正彦, 香川俊輔, 宇野太, 石田道拡, 黒田新士, 岸本浩行, 白川靖博, 藤原俊義

日本胃癌学会総会記事 85回 202 - 202 2013.2

A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus.

Sasaki T, Tazawa H, Hasei J, Osaki S, Kunisada T, Yoshida A, Hashimoto Y, Yano S, Yoshida R, Kagawa S, Uno F, Urata Y, Ozaki T, Fujiwara T

Gene Ther 2013

我々の目指すチーム内視鏡外科当科における腹臥位胸腔鏡下食道亜全摘における術者助手のコラボレーション Reviewed

野間和広, 白川靖博, 青山克幸, 前田直見, 大原利章, 田辺俊介, 香川俊輔, 藤原俊義

日本内視鏡外科学会雑誌 17 ( 7 ) 604 - 604 2012.12

Robotic Surgeryによる胃切除 Double bipolar techniqueによる術野展開の工夫と郭清手技

西崎正彦, 石田道拡, 黒田新士, 岸本浩行, 宇野太, 香川俊輔, 藤原俊義

日本内視鏡外科学会雑誌 17 ( 7 ) 296 - 296 2012.12

Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Shuya Yano, Teppei Onishi, Tsuyoshi Sasaki, Yasuhiro Shirakawa, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER IMMUNOLOGY IMMUNOTHERAPY 61 ( 11 ) 1905 - 1916 2012.11

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

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1007/s00262-012-1249-x

[A case of transverse myelopathy due to spinal bone metastasis of gastric cancer].

Aiko Kono, Shunsuke Kagawa, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Masahiko Oiwa, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 39 ( 12 ) 2357 - 9 2012.11

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

We report a case of gastric cancer that presented as transverse myelopathy due to spinal bone metastasis. A 45-year- old man with advanced gastric cancer underwent distal gastrectomy and lymph node dissection for curative intent. However, pathological examination of the specimen revealed positive cytological findings in the peritoneal lavage fluid in addition to serosal invasion and lymph node metastasis(pT4aN3bCY1, stage IV). Three months after the operation, during the second course of chemotherapy with S-1, he began to complain of back pain, and positron emission tomography-computed tomography revealed spinal bone metastasis. Despite immediate radiotherapy for the bone metastasis, he soon suffered from paraplegia in the lower extremities followed by disturbances of bladder and bowel function. We created a sigmoid colostomy, which enabled self-care for defecation, and resumed radiotherapy and chemotherapy. Bone metastasis of gastric cancer is rare but the prognosis is very poor. Because of a rapidly deteriorating clinical course, early diagnosis and multidisciplinary approaches are important for gastric cancer patients with spinal metastasis.

[Stent placement using a double-balloon endoscope for malignant duodenal obstruction with Roux-en-Y Anastomosis-a case report].

Masahiko Oiwa, Shunsuke Kagawa, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Aiko Kono, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 39 ( 12 ) 2372 - 4 2012.11

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

A 79-year-old man who had previously undergone partial resection of the remnant stomach and Roux-en-Y reconstruction was diagnosed as having peritoneal recurrence near the ligament of Treitz. In the course of chemotherapy for recurrent gastric cancer, he complained of colic pain. CT examination revealed a marked dilation of the duodenum suggesting the presence of a distal duodenal stricture resulting from the known recurrent tumor. To palliate this intestinal obstruction, we successfully placed an expandable metal stent(EMS) using a double-balloon enteroscope(DBE), which achieved immediate relief of the obstruction and enabled the resumption of oral intake and chemotherapy. While the endoscopic placement of an EMS is available for malignant gastro-intestinal obstruction, it is considerably more difficult to approach the duodenum with Roux-en-Y anastomosis. A DBE has made it possible to place an EMS deep in the small intestine. In the present case, this minimally invasive procedure avoided the need for surgery and greatly contributed to palliation. Thus, EMS placement using a DBE is a possible palliative treatment for malignant small bowel obstruction.

当科における食道胃接合部癌に対する再建法の工夫胸腔内観音開き法吻合の経験 Reviewed

野間和広, 白川靖博, 青山克幸, 前田直見, 大原利章, 田辺俊介, 西崎正彦, 香川俊輔, 藤原俊義

日本臨床外科学会雑誌 73 ( 増刊 ) 525 - 525 2012.10

出血性ショックをきたした回腸静脈瘤破裂に対しバルーン下逆行性経静脈的塞栓術(BRTO)が奏功した1例

濱田侑紀, 竹原裕子, 竹原清人, 大原利章, 近藤喜太, 永坂岳司, 香川俊輔, 藤原俊義

日本臨床外科学会雑誌 73 ( 増刊 ) 1084 - 1084 2012.10

腹腔鏡下胃全摘術・噴門切除術とその再建術式腹腔鏡補助下噴門側胃切除術のための「観音開き法」食道残胃吻合の工夫

西崎正彦, 石田道拡, 黒田新士, 岸本浩行, 香川俊輔, 藤原俊義

日本臨床外科学会雑誌 73 ( 増刊 ) 372 - 372 2012.10

コンポジットメッシュと非吸収性タックを用い腹腔鏡下にて修復した腹壁瘢痕ヘルニアの一例

石田道拡, 香川俊輔, 岸本浩行, 黒田新士, 西崎正彦, 藤原俊義

日本臨床外科学会雑誌 73 ( 増刊 ) 947 - 947 2012.10

A novel apoptotic mechanism of genetically engineered adenovirus-mediated tumour-specific p53 overexpression through E1A-dependent p21 and MDM2 suppression

Yasumoto Yamasaki, Hiroshi Tazawa, Yuuri Hashimoto, Toru Kojima, Shinji Kuroda, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Hiroyuki Mizuguchi, Akira Ohtsuru, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

EUROPEAN JOURNAL OF CANCER 48 ( 14 ) 2282 - 2291 2012.9

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

Oncolytic viruses engineered to replicate in tumour cells but not in normal cells could be used as tumour-specific vectors carrying the therapeutic genes. We previously developed a telomerase-specific oncolytic adenovirus, OBP-301, that causes cell death in human cancer cells with telomerase activities. Here, we further modified OBP-301 to express the wild-type p53 tumour suppressor gene (OBP-702), and investigated whether OBP-702 induces stronger antitumour activity than OBP-301. The antitumour effect of OBP-702 was compared to that of OBP-301 on OBP-301-sensitive (H358 and H460) and OBP-301-resistant (T.Tn and HSC4) human cancer cells. OBP-702 suppressed the viability of both OBP-301-sensitive and OBP-301-resistant cancer cells more efficiently than OBP-301. OBP-702 caused increased apoptosis compared to OBP-301 or a replication-deficient adenovirus expressing the p53 gene (Ad-p53) in H358 and T.Tn cells. Adenovirus E1A-mediated p21 and MDM2 downregulation was involved in the apoptosis caused by OBP-702. Moreover, OBP-702 significantly suppressed tumour growth in subcutaneous tumour xenograft models compared to monotherapy with OBP-301 or Ad-p53. Our data demonstrated that OBP-702 infection expressed adenovirus E1A and then inhibited p21 and MDM2 expression, which in turn efficiently induced apoptotic cell death. This novel apoptotic mechanism suggests that the p53-expressing OBP-702 is a promising antitumour reagent for human cancer and could improve the clinical outcome. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ejca.2011.12.020

腫瘍特異的制限増殖型アデノウイルスを用いた血液循環腫瘍細胞の遺伝子解析技術の開発(Development of genetic analysis of circulating tumor cells using a telomerase-specific replication-competent adenovirus) Reviewed

重安邦俊, 橋本悠里, 宇野太, 永坂岳司, 田澤大, 香川俊輔, 水口裕之, 浦田泰生, 藤原俊義

日本癌学会総会記事 71回 50 - 50 2012.8

テロメラーゼ依存性増殖型アデノウイルス製剤を用いた早期大腸癌の低侵襲治療の開発(Less invasive therapeutic intervention for early colorectal cancers using telomerase-dependent replicating adenovirus)

菊地覚次, 岸本浩行, 田澤大, 橋本悠里, 宇野太, 西崎正彦, 香川俊輔, 浦田泰生, ロバート・ホフマン, 藤原俊義

日本癌学会総会記事 71回 202 - 202 2012.8

耐術能を有する超高齢者は胃癌に対する手術の意義が示唆される Reviewed

香川俊輔, 宇野太, 岸本浩行, 西崎正彦, 白川靖博, 永坂岳司, 野間和広, 田辺俊介, 近藤喜太, 大原利章

日本消化器外科学会総会 67回 3 - 3 2012.7

がん特異的増殖アデノウイルス製剤OBP-401を用いた生体内癌組織蛍光イメージング

岸本浩行, 菊地覚次, 橋本悠里, 宇野太, 田澤大, 西崎正彦, 香川俊輔, 藤原俊義

日本消化器外科学会総会 67回 1 - 1 2012.7

ロボット支援下胃切除術の術野展開と郭清手技

西崎正彦, 香川俊輔, 宇野太, 岸本浩行, 藤原俊義

日本消化器外科学会総会 67回 1 - 1 2012.7

The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment

Yuuri Hashimoto, Hiroshi Tazawa, Fuminori Teraishi, Toru Kojima, Yuichi Watanabe, Futoshi Uno, Shuya Yano, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

PLOS ONE 7 ( 6 ) 2012.6

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

Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1 alpha and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.

DOI： 10.1371/journal.pone.0039292

ロボット支援下幽門側胃切除術の安全な導入 Reviewed

西崎正彦, 香川俊輔, 宇野太, 岸本浩行, 近藤喜太, 田邊俊介, 大原利章, 野間和広, 永坂岳志, 白川靖博, 藤原俊義

日本外科学会雑誌 113 ( 臨増2 ) 490 - 490 2012.3

消化管間質腫瘍における血中浮遊腫瘍細胞検出の試み Reviewed

宇野太, 重安邦俊, 永坂岳司, 香川俊輔, 西崎正彦, 岸本浩行, 藤原俊義

日本外科学会雑誌 113 ( 臨増2 ) 369 - 369 2012.3

遺伝子変異情報を基盤とした大腸癌個別化治療〜治療前分類の重要性

永坂岳司, 杉原正大, 母里淑子, 森川達也, 久保田暢人, 近藤喜太, 楳田祐三, 西崎正彦, 香川俊輔, 白川靖博, 貞森裕, 八木孝仁, 三嶋秀行, 藤原俊儀

日本外科学会雑誌 113 ( 臨増2 ) 408 - 408 2012.3

胃管癌の治療当科において経験した食道癌術後胃管癌18例の検討 Reviewed

白川靖博, 前田直見, 田辺俊介, 大原利章, 野間和広, 岸本浩行, 宇野太, 西崎正彦, 香川俊輔, 藤原俊義

日本胃癌学会総会記事 84回 175 - 175 2012.2

胃癌術後再発症例に対する放射線療法の経験

香川俊輔, 宇野太, 岸本浩行, 西崎まさひこ, 白川靖博, 永坂岳司, 野間和広, 藤原俊義

日本胃癌学会総会記事 84回 334 - 334 2012.2

当院における胃GISTに対するイマチニブ投与の位置づけ

宇野太, 香川俊輔, 西崎正彦, 岸本浩行, 藤原俊義

日本胃癌学会総会記事 84回 359 - 359 2012.2

A telomerase-specific oncolytic virotherapy for gastric cancer stem cells

KAGAWA Shunsuke, YANO Shuya, FUJIWARA Toshiyoshi

Cytometry Research 22 ( 2 ) 21 - 25 2012

Language：Japanese Publisher：Japan Cytometry Society

<p>Since cancer stem cells show their resistance to chemo- and radiotherapy, they are thought to be correlated with the treatment resistance of many cancers, and thus help explain recurrence and advanced disease. Here, we examined the therapeutic effect of a genetically engineered telomerase specific oncolytic adenovirus, Telomelysin, (OBP-301) against cancer stem cells. OBP-301 killed CD133+ human gastric cancer, which have a stem cell-like phenotype, more efficiently than conventional therapies. Visualization of cell-cycle behavior in living cells by Fucci showed that tumor spheres of CD133+ cells maintained a G0/G1 state, and that OBP-301 then killed them through virus-induced S phase transition. Mobilization of quiescent CSCs may sensitize them to cell death signals.</p>

DOI： 10.18947/cytometryresearch.22.2_21

Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas

124 ( 2 ) 105 - 110 2012

大学病院におけるrobotic surgery導入の経験.

香川俊輔, 西崎正彦, 宇野太, 岸本浩行, 藤原俊義

外科 74 ( 8 ) 809 - 812 2012

腹部食道癌に対して左開胸開腹連続切開および観音開き法食道残胃吻合を行った1症例

野間和広, 白川靖博, 青山克幸, 前田直見, 大原利章, 田辺俊介, 西崎正彦, 香川俊輔, 藤原俊義

General Thoracic and Cardiovascular Surgery 60 ( Supplement ) 2012

胃癌術後腹膜播種による十二指腸閉塞に対して内視鏡的ステント留置術が奏効した1例

大岩雅彦, 香川俊輔, 岸本浩行, 宇野太, 西崎正彦, 河野藍子, 藤原俊義

癌と化学療法 39 ( 12 ) 2372 - 2374 2012

Language：Japanese Publisher：(株)癌と化学療法社

症例は79歳、男性。十二指腸潰瘍の手術既往による残胃の吻合部に残胃癌を指摘され、残胃部分切除・Roux-en-Y再建を行った。術後Treitz靱帯近傍に再発腫瘍を指摘され、化学療法を施行中に腸閉塞症状が出現した。CTで十二指腸の著明な拡張を認め、既知の再発腫瘍によるY脚部の通過障害と診断した。閉塞部位が一ヶ所であったことから、ダブルバルーン小腸内視鏡を用い狭窄部にステントを留置した。ステント留置後腸閉塞は解除され、経口摂取と化学療法の再開が可能となった。近年普及してきたダブルバルーン内視鏡により従来困難であったRoux-en-Y再建後の十二指腸側Y脚へのアプローチが可能となった。本症例では狭窄部へのステント留置により手術を回避し得たことから、緩和治療として悪性腸閉塞症治療の1選択肢になり得ると考え報告する。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00296&link_issn=&doc_id=20121206360205&doc_link_id=%2Fab8gtkrc%2F2012%2F003912%2F205%2F2372-2374%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2012%2F003912%2F205%2F2372-2374%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

胃癌術後脊椎転移による横断性脊髄障害を呈した1例

河野藍子, 香川俊輔, 岸本浩行, 宇野太, 西崎正彦, 大岩雅彦, 藤原俊義

癌と化学療法 39 ( 12 ) 2357 - 2359 2012

Language：Japanese Publisher：(株)癌と化学療法社

症例は45歳、男性。心窩部痛・体重減少を主訴に発見された進行胃癌に対して幽門側胃切除術、D2、Roux-en Y再建を行い、術後診断はpT4aN3bCY1、stage IVであった。術後S-1による化学療法を施行中、術後3ヵ月に背部痛が出現した。PET-CTではTh4-6の骨転移を指摘された。直ちに骨転移に対し放射線療法を開始したが、第5治療日より脊髄横断症状を呈し座位保持も不能となった。その後、癒着性の小腸イレウスが発症し小腸部分切除術を施行することとなり、同時に直腸肛門機能低下による排便困難に対しS状結腸ストーマ造設を併施した。その結果、排便の自己管理が可能になり、さらに放射線治療の完遂ならびに、その後の化学療法と緩和治療が在宅で可能であった。胃癌の骨転移はまれであるが、その予後は極めて不良である。胃癌の骨転移の特徴・対策を知り、早期診断と集学的治療は重要であり、本症例の経験に文献的考察を加え報告する。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00296&link_issn=&doc_id=20121206360200&doc_link_id=%2Fab8gtkrc%2F2012%2F003912%2F200%2F2357-2359%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2012%2F003912%2F200%2F2357-2359%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Ileal perforation induced by acute radiation injury under gefitinib treatment

Takayuki Muraoka, Kazunori Tsukuda, Shinichi Toyooka, Shunsuke Kagawa, Yoshio Naomoto, Mitsuhiro Takemoto, Kuniaki Katsui, Susumu Kanazawa, Yuho Maki, Hiroko Masuda, Masaaki Harada, Hiroaki Asano, Minoru Naito, Shinichiro Miyoshi

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 16 ( 6 ) 774 - 777 2011.12

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

Enteritis is one of the side effects of radiotherapy to the abdominal cavity. Radiation enteritis involves damage to mucous membranes in the acute phase and to stromal tissues in the late phase. Perforation of the intestine tends to occur in the late phase, and rarely in the acute phase. However, we describe here a case of intestinal perforation occurring in the acute phase after irradiation in a patient who received gefitinib treatment. Gefitinib, one of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), is widely used to treat non-small cell lung cancer (NSCLC) patients, but is simultaneously known to inhibit wound healing. We suspect that gefitinib may affect regeneration of the small intestinal mucosa injured by irradiation. A 76-year-old woman had NSCLC with metastases to the 5th lumbar, sacral, and right iliac bones. To control the pain from bone metastasis, anterior-posterior opposing portal irradiation (total 35 Gy) was started, and was completed over 22 days. On day 25 after starting radiotherapy, the patient began to take gefitinib. On day 35, she presented with acute peritonitis, and an emergency laparotomy was performed. The terminal ileum was affected by radiation enteritis and there were two pin-hole perforations. In the surgical specimen, no cancerous lesions were detected, and immunohistochemical staining of phosphorylated EGFR (pEGFR) was negative. pEGFR has an important role in mucous membrane repair after irradiation. Intestinal perforation in the acute phase of radiation enteritis may be associated with impaired mucosal repair mechanisms due to the use of an EGFR-TKI such as gefitinib, as evidenced by the absence of pEGFR.

DOI： 10.1007/s10147-011-0249-8

各領域におけるロボット手術現状と今後の展望(消化器) ロボット支援下幽門側胃切除術の安全な導入を目指して導入初期3例の検討

西崎正彦, 香川俊輔, 宇野太, 岸本浩行, 近藤喜太, 田邊俊介, 野間和広, 永坂岳司, 白川靖博, 藤原俊義

日本内視鏡外科学会雑誌 16 ( 7 ) 247 - 247 2011.12

Prolonged complete response obtained by radiation and chemotherapy with paclitaxel in a case of recurrent gastric cancer in the rectovesical pouch.

Gan To Kagaku Ryoho 38 ( 12 ) 2100 - 2102 2011.11

消化器外科手術アトラス腹腔鏡補助下噴門側胃切除術観音開き法食道残胃吻合

西崎正彦, 香川俊輔, 宇野太, 岸本浩行, 白川靖博, 藤原俊義

消化器外科 34 ( 12 ) 1687 - 1697 2011.11

当科における胃管再建作成および吻合における工夫 Reviewed

野間和広, 白川康博, 前田直見, 大原利章, 田辺俊介, 永坂岳司, 香川俊輔, 藤原俊義

日本臨床外科学会雑誌 72 ( 増刊 ) 517 - 517 2011.10

胃癌に対するRobot Assisted Gastrectomyの導入経験

西崎正彦, 近藤喜太, 田邊俊介, 野間和広, 岸本浩行, 宇野太, 永坂岳司, 香川俊輔, 白川靖弘, 藤原俊義

日本消化器外科学会雑誌 44 ( Suppl.2 ) 185 - 185 2011.10

鉄欠乏状態は食道がんにおいてNカドヘリンを低下させることでEMTを抑制する(Iron deficiency suppress EMT through downregulation of N-cadherin in esophageal cancer) Reviewed

西谷正史, 野間和広, 大原利章, 長谷井嬢, 佐々木剛, 渡邊伸一郎, 大西哲平, 吉田亮介, 橋本悠里, 田澤大, 宇野太, 香川俊輔, 藤原俊義

日本癌学会総会記事 70回 467 - 468 2011.9

BRAF変異大腸癌根治切除後の分子生物学的/臨床的特徴

永坂岳司, 近藤喜太, 母里淑子, 森川達也, 楳田祐三, 田辺俊介, 野間和広, 岸本浩行, 宇野太, 西崎正彦, 香川俊輔, 白川靖博, 貞森裕, 八木孝仁, 藤原俊義

日本癌治療学会誌 46 ( 2 ) 398 - 398 2011.9

HER2陰性胃癌細胞におけるHER2細胞外ドメイン発現によるトラスツズマブへの感受性誘導

吉田亮介, 田澤大, 橋本悠里, 大西哲平, 岸本浩行, 宇野太, 西崎正彦, 香川俊輔, 藤原俊義

日本癌治療学会誌 46 ( 2 ) 655 - 655 2011.9

胃癌幹細胞に対するテロメラーゼ特異的腫瘍融解ウイルス治療

香川俊輔, 矢野修也, 田澤大, 橋本悠里, 宇野太, 岸本浩行, 西崎正彦, 浦田泰生, 藤原俊義

日本癌治療学会誌 46 ( 2 ) 395 - 395 2011.9

悪性リンパ腫合併胸部食道癌症例の治療経験

横道直佑, 白川靖博, 野間和広, 田辺俊介, 森川達也, 近藤喜太, 櫻間教文, 岸本浩行, 宇野太, 永坂岳司, 西崎正彦, 香川俊輔, 藤原俊義

岡山医学会雑誌 123 ( 2 ) 166 - 166 2011.8

頭頸部癌・食道癌におけるPEGを用いた栄養管理の有用性の検討

田辺俊介, 白川靖博, 野間和広, 横道直佑, 森川達也, 近藤喜太, 櫻間教文, 岸本浩行, 宇野太, 永坂岳司, 西崎正彦, 香川俊輔, 藤原俊義

岡山医学会雑誌 123 ( 2 ) 166 - 166 2011.8

岡山大学病院における胃癌に対するダビンチS(da Vinci S surgical system)によるロボット支援腹腔鏡下手術の導入

香川俊輔, 西崎正彦, 宇野太, 岸本浩行, 白川靖博, 永坂岳司, 野間和広, 田辺俊介, 近藤喜太, 横道直佑, 森川達也, 佃和憲, 浅野博昭, 内藤稔, 藤原俊義

岡山医学会雑誌 123 ( 2 ) 167 - 167 2011.8

同時多発性胃癌術後の残胃癌に関する検討

香川俊輔, 宇野太, 岸本浩行, 西崎正彦, 白川靖博, 永坂岳司, 野間和広, 近藤喜太, 田辺俊介, 藤原俊義

日本消化器外科学会総会 66回 297 - 297 2011.7

岡山大学外科研修マネージメントセンター医局を超えた外科研修教育の取り組み

菊地覚次, 香川俊輔, 篠浦先, 野間和広, 松岡順治, 土井原博義, 八木孝仁, 佐野俊二, 三好新一郎, 藤原俊義

日本消化器外科学会総会 66回 185 - 185 2011.7

胃癌に対する腹腔鏡下手術の新たな考え方と工夫肝十二指腸間膜左側アプローチによるNo.12a郭清

西崎正彦, 香川俊輔, 宇野太, 岸本浩行, 合地明, 藤原俊義

日本消化器外科学会総会 66回 276 - 276 2011.7

食道GISTの切除例2例の経験

井筒将斗, 白川靖博, 田辺俊介, 近藤喜太, 野間和広, 櫻間教文, 宇野太, 永坂岳司, 香川俊輔, 繁光薫, 山辻知樹, 羽井佐実, 松岡順治, 猶本良夫, 藤原俊義

岡山医学会雑誌 123 ( 1 ) 74 - 74 2011.4

Stage IVa食道癌の治療方針の検討

田辺俊介, 白川靖博, 井筒将斗, 近藤喜太, 野間和広, 櫻間教文, 宇野太, 永坂岳司, 香川俊輔, 繁光薫, 山辻知樹, 羽井佐実, 松岡順治, 猶本良夫, 藤原俊義

岡山医学会雑誌 123 ( 1 ) 74 - 74 2011.4

MicroRNAs as potential target gene in cancer gene therapy of gastrointestinal tumors Reviewed

Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

EXPERT OPINION ON BIOLOGICAL THERAPY 11 ( 2 ) 145 - 155 2011.2

Language：English Publisher：INFORMA HEALTHCARE

Introduction: MicroRNA (miRNA) is a small non-coding RNA, which negatively regulates the expression of many target genes, thereby contributing to the modulation of diverse cell fates. Recent advances in molecular biology have revealed the potential role of miRNAs in tumor initiation, progression and metastasis. Aberrant regulation of miRNAs has been frequently reported in a variety of cancers, including gastrointestinal tumors, suggesting that cancer-related miRNAs are promising as novel biomarkers for tumor diagnosis and are potential target genes for cancer gene therapy against gastrointestinal tumors.
Areas covered: The review focuses on the role of specific miRNAs (miR-192/194/215 and miR-7) in the differentiation of gastrointestinal epithelium and on the role of tumor-suppressive (miR-34, miR-143, miR-145) and oncogenic miRNAs (miR-21, miR-17-92 cluster) in gastrointestinal tumors. Furthermore, the potential role of miRNAs as novel biomarkers and target genes for cancer gene therapy against gastrointestinal tumors are discussed. We will also outline the potential clinical application of miRNAs for tumor diagnosis and cancer gene therapy against gastrointestinal tumors.
Expert opinion: Exploration of tumor-related miRNAs would provide important opportunities for the development of novel cancer gene therapies aimed at normalizing the critical miRNAs that are deregulated in gastrointestinal tumors.

DOI： 10.1517/14712598.2011.542749

Telomerase-specific oncolytic virotherapy for human gastrointestinal cancer.

Fujiwara T, Shirakawa Y, Kagawa S

Expert Rev Anticancer Ther 2011

Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas. International journal

Tsuyoshi Sasaki, Hiroshi Tazawa, Jo Hasei, Toshiyuki Kunisada, Aki Yoshida, Yuuri Hashimoto, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Shunsuke Kagawa, Yuki Morimoto, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

Clinical cancer research : an official journal of the American Association for Cancer Research 17 ( 7 ) 1828 - 38 2011

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

PURPOSE: Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells. EXPERIMENTAL DESIGN: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301-resistant sarcomas. RESULTS: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells. CONCLUSIONS: A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas.

DOI： 10.1158/1078-0432.CCR-10-2066

Radiosensitization by telomerase-dependent oncolytic adenovirus

Kuroda Shinji, Noma Kazuhiro, Urata Yasuo, Kagawa Shunsuke, Fujiwara Toshiyoshi, Fujiwara Toshiya, Shirakawa Yasuhiro, Yamasaki Yasumoto, Yano Syuya, Uno Futoshi, Tazawa Hiroshi, Hashimoto Yuuri, Watanabe Yuichi

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 123 ( 2 ) 103 - 109 2011

Language：Japanese Publisher：Okayama Medical Association

DNA修復機能阻害は放射線感受性を増強させるため，DNA修復に関与する因子の阻害剤は放射線増感剤となり得る．我々の開発したテロメラーゼ依存的腫瘍融解アデノウイルス製剤OBP-301（テロメライシン）は，アデノウイルスE1B55kDaタンパクを介して細胞のDNA修復に重要な役割を果たすMRN複合体（Mre11，Rad50，NBS1）を分解する機能を有する．このMRN複合体の分解によりATM（ataxia-telangiectasia mutated）の活性化が抑制され結果的にDNA修復機構が阻害される．我々はOBP-301と放射線との併用が強力な相乗効果を生み出すことをマウスの皮下腫瘍モデルおよび食道癌同所性モデルにおいて証明した．これらの結果はOBP-301が将来有望な放射線増感剤となり得ることだけでなく，E1B55kDaタンパクを産生する腫瘍融解アデノウイルス製剤と放射線との併用が悪性腫瘍に対する有力な治療戦略となり得ることを示す．

DOI： 10.4044/joma.123.103

Synergistic Interaction of Telomerase-Specific Oncolytic Virotherapy and Chemotherapeutic Agents for Human Cancer.

Fujiwara T, Kagawa S, Tazawa H

Curr Pharm Biotechnol 2011

胃がん (新しい手術のモダリティ) -- (最新の外科治療総論 : アプローチを中心に)

西﨑正彦, 香川俊輔, 藤原俊義

がん治療レクチャー : チーム医療のための 2 ( 4 ) 788 - 792 2011

TELOMERASE-SPECIFIC ONCOLYTIC ADENOVIRUS ARMED WITH WILD-TYPE P53 GENE (CGCT-04) EFFICIENTLY INDUCES APOPTOSIS IN HUMAN CANCER CELLS

Yasumoto Yamasaki, Hideki Onimatsu, Yuuri Hashimoto, Toru Kojima, Hiroshi Tazawa, Shunsuke Kagawa, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 12 ( 12 ) 1035 - 1035 2010.12

Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery. Reviewed International journal

Kuroda S, Fujiwara T, Shirakawa Y, Yamasaki Y, Yano S, Uno F, Tazawa H, Hashimoto Y, Watanabe Y, Noma K, Urata Y, Kagawa S, Fujiwara T

Cancer research 70 ( 22 ) 9339 - 9348 2010.11

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

The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer.

DOI： 10.1158/0008-5472.CAN-10-2333

Portal/splenic Vein Thrombosis Following Splenectomy in Gastric Cancer Surgery Reviewed

Shunsuke Kagawa, Futoshi Uno, Akira Gochi, Yoshio Naomoto, Toshiyoshi Fujiwara

ASIAN JOURNAL OF SURGERY 33 ( 4 ) 208 - 211 2010.10

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

Although splenectomy is often performed along with en bloc node dissection in gastric cancer surgery, portal/splenic vein thrombosis (PSVT) has been rarely reported. We recently encountered a case of PSVT after a splenectomy was performed during gastric cancer surgery. A 53-year-old woman underwent total gastrectomy, splenectomy, and en bloc regional lymph node dissection for gastric cancer. An uneventful postoperative course ended with abrupt development of a fever and general fatigue. Laboratory tests showed elevated levels of liver transaminases and fibrinogen degenerative products. Contrast-enhanced computed tomography revealed splenic vein thrombosis and partial liver infarction. Immediate anticoagulant treatment resulted in clinical improvement and partial thrombolysis in 2 months. PSVT after splenectomy in haematological disorders has been recognized as a possibly lethal complication. However, it has been underappreciated in cases of splenectomy for gastric cancer. The present case demonstrates the importance of considering PSVT as a possible complication of splenectomy in gastric cancer surgery. [Asian J Surg 2010;33(4):208-11]

腹腔鏡下胃切除術における穿刺法による肝外側域の挙上 Reviewed

香川俊輔, 宇野太, 重安邦俊, 合地明, 藤原俊義

日本内視鏡外科学会雑誌 15 ( 7 ) 456 - 456 2010.10

当科における食道憩室手術症例の報告

田辺俊介, 藤原裕子, 近藤喜太, 藤原康宏, 野間和広, 櫻間教文, 宇野太, 永坂岳司, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 羽井佐実, 松岡順治, 猶本良夫

岡山医学会雑誌 122 ( 2 ) 180 - 180 2010.8

Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer Reviewed

Ryo Sakai, Shunsuke Kagawa, Yasumoto Yamasaki, Toru Kojima, Futoshi Uno, Yuuri Hashimoto, Yuichi Watanabe, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

MOLECULAR CANCER THERAPEUTICS 9 ( 6 ) 1884 - 1893 2010.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Multimodal approaches combining drugs that differentially function is the most popular regimen for treating human cancer. Understanding the molecular mechanisms underlying the synergistic, potentiative, and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations. We previously showed that telomerase-specific replication-competent adenovirus (Telomelysin, OBP-301), in which the human telomerase reverse transcriptase promoter controls the adenoviral E1 gene expression, induces a selective antitumor effect in human cancer cells. Here, using E1-deleted replication-deficient adenovirus expressing the p53 tumor suppressor gene (Advexin, Ad-p53) and OBP-301, we investigate how these adenoviruses that kill tumor cells with different mechanisms could work in combination on human cancer. We found that E1-deficient Ad-p53 could kill cancer cells more efficiently in the presence of OBP-301 than Ad-p53 alone or OBP-301 alone, because Ad-p53 could become replication-competent by being supplied adenoviral E1 from coinfected OBP-301 in trans. Ad-p53 plus OBP-301 induced high levels of p53 protein expression without p21 induction, resulting in apoptotic cell death documented by active caspase-3 expression with a cytometric bead array and an increased subdiploid apoptotic fraction of the cell cycle. For in vivo evaluation, nude mice xenografted with human lung tumors received intratumoral injection of OBP-301 and/or Ad-p53. Analysis of the growth of implanted tumors showed an enhanced antitumor effect in combination therapy. Our data show that Ad-p53 in combination with OBP-301 induces not only oncolytic but also apoptotic cancer cell death and enhances antitumor activity in vitro and in vivo, providing potential merits as a multimodal treatment for human cancer. Mol Cancer Ther; 9(6); 1884-93. (C)2010 AACR.

DOI： 10.1158/1535-7163.MCT-10-0205

In Vivo Biological Purging for Lymph Node Metastasis of Human Colorectal Cancer by Telomerase-Specific Oncolytic Virotherapy

Toru Kojima, Yuichi Watanabe, Yuuri Hashimoto, Shinji Kuroda, Yasumoto Yamasaki, Shuya Yano, Masaaki Ouchi, Hiroshi Tazawa, Futoshi Uno, Shunsuke Kagawa, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

ANNALS OF SURGERY 251 ( 6 ) 1079 - 1086 2010.6

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background/Objective: The aim of this study was to develop a less invasive way of targeting lymph node metastasis for the treatment of human gastrointestinal cancer. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with malignancies.
Methods: Human telomerase reverse transcription (hTERT) is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. OBP-301 (Telomelysin) is an attenuated adenovirus with oncolytic potency that contains the hTERT promoter element to regulate viral replication. We examined whether OBP-301 injected into the primary tumor might be useful for purging micrometastasis from regional lymph nodes in an orthotopic colorectal cancer model.
Results: OBP-301 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice. By using a highly sensitive quantitative PCR analysis that targets the human-specific Alu sequence, we showed that OBP-301 caused viral spread into the regional lymphatic area and selectively replicated in neoplastic lesions, resulting in tumor-cell-specific death in metastatic lymph nodes. Moreover, although the surgical removal of primary tumors increased the tendency of lymph node metastasis, preoperative intratumoral injection of virus significantly reduced lymph node metastasis.
Conclusions: Our results indicate that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human cancer, especially gastrointestinal malignancies.

DOI： 10.1097/SLA.0b013e3181deb69d

A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy

Y. Watanabe, T. Kojima, S. Kagawa, F. Uno, Y. Hashimoto, S. Kyo, H. Mizuguchi, N. Tanaka, H. Kawamura, D. Ichimaru, Y. Urata, T. Fujiwara

ONCOGENE 29 ( 8 ) 1145 - 1154 2010.2

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

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that is related to asbestos exposure. MPM is characterized by rapid and diffuse local growth in the thoracic cavity, and it has a poor prognosis because it is often refractory to conventional therapy. Although MPM is an extraordinarily challenging disease to treat, locoregional virotherapy may be useful against this aggressive disease because of the accessibility by intrapleural virus delivery. In this study, we show that telomerase-specific, replication-selective adenovirus OBP-301 can efficiently infect and kill human mesothelioma cells by viral replication. Intrathoracic administration of virus significantly reduced the number and size of human mesothelioma tumors intrathoracically implanted into nu/nu mice. A high-definition, fluorescence optical imaging system with an ultra-thin, flexible fibered microprobe clearly detected intracellular replication of green fluorescent protein-expressing oncolytic virus in intrathoracically established mesothelioma tumors. As the extracellular matrix (ECM) may contribute to the physiological resistance of a solid tumor by preventing the penetration of therapeutic agents (including oncolytic viruses), we also examined whether the co-expression of heparanase, an endoglucuronidase capable of specifically degrading heparan sulfate, that influences the physiological barrier to macromolecule penetration, can modify the permeability of the ECM, resulting in profound therapeutic efficacy. Co-injection of OBP-301 and a replication-defective adenovirus (Ad-S/hep)-expressing heparanase resulted in more profound antitumor effects without apparent toxicity in an orthotopic pleural dissemination model. Our results suggest that intrathoracic dual virotherapy with telomerase-specific oncolytic adenovirus in combination with heparanase-expressing adenovirus may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma. Oncogene (2010) 29, 1145-1154; doi: 10.1038/onc.2009.415; published online 23 November 2009

DOI： 10.1038/onc.2009.415

当院における内視鏡的胃瘻造設の現況

田辺俊介, 白川靖博, 近藤喜太, 藤原康宏, 野間和広, 宇野太, 永坂岳司, 香川俊輔, 山辻知樹, 小林直哉, 藤原俊義, 内藤稔, 猶本良夫

岡山医学会雑誌 121 ( 3 ) 230 - 231 2009.12

腹腔鏡補助下胃切除術における術野展開の工夫

香川俊輔, 宇野太, 合地明, 小林直哉, 山辻知樹, 白川靖博, 永坂岳司, 野間和広, 藤原康宏, 田辺俊介, 近藤喜太, 猶本良夫, 藤原俊義

日本内視鏡外科学会雑誌 14 ( 7 ) 562 - 562 2009.12

A simple biological imaging system for detecting viable human circulating tumor cells

Toru Kojima, Yuuri Hashimoto, Yuichi Watanabe, Shunsuke Kagawa, Futoshi Uno, Shinji Kuroda, Hiroshi Tazawa, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

JOURNAL OF CLINICAL INVESTIGATION 119 ( 10 ) 3172 - 3181 2009.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL INVESTIGATION INC

The presence of circulating tumor cells (CTCs) in the peripheral blood is associated with short survival, making the detection of CTCs clinically useful as a prognostic factor of disease outcome and/or a surrogate marker of treatment response. Recent technical advances in immunocytometric analysis and quantitative real-time PCR have made it possible to detect a few CTCs in the blood; however, there is no sensitive assay to specifically detect viable CTCs. Here, we report what we believe to be a new approach to visually detect live human CTCs among millions of peripheral blood leukocytes, using a telomerase-specific replication-selective adenovirus expressing GFP. First, we constructed a GFP-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401; TelomeScan). We then used OBP-401 to establish a simple ex vivo method that was able to detect viable human CTCs in the peripheral blood. The detection method involved a 3-step procedure, including the lysis of rbc, the subsequent addition of OBP-401 to the cell pellets, and an automated scan using fluorescence microscopy. OBP-401 infection increased the signal-to-background ratio as a tumor-specific probe, because the fluorescent signal was amplified only in viable, infected human tumor cells, by viral replication. This GFP-expressing virus-based method is remarkably simple and allows precise enumeration of CTCs.

DOI： 10.1172/JCI38609

進行再発大腸癌に対するセツキシマブの治療経験

藤原康宏, 猶本良夫, 近藤喜太, 田辺俊介, 桜間一史, 野間和広, 高岡宗徳, 宇野太, 永坂岳司, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松岡順治, 田中紀章, 羽井佐実

岡山医学会雑誌 121 ( 2 ) 133 - 133 2009.8

テロメラーゼ依存的制限増殖型GFP発現アデノウイルスによる末梢血中ヒト循環がん細胞の検出(A simple biological imaging method for detection of viable human circulating tumor cells in the blood)

橋本悠里, 児島亨, 宇野太, 香川俊輔, 渡邉雄一, 黒田新士, 浦田泰生, 田中紀章, 藤原俊義

日本癌学会総会記事 68回 244 - 244 2009.8

当科におけるバレット食道癌症例の検討

野間和広, 猶本良夫, 田辺俊介, 近藤喜太, 藤原康宏, 櫻間一史, 高岡宗徳, 宇野太, 永坂岳司, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松岡順治, 田中紀章, 羽井佐実

岡山医学会雑誌 121 ( 2 ) 133 - 133 2009.8

食道原発小細胞癌の一治療例の報告

田辺俊介, 猶本良夫, 近藤喜太, 藤原康宏, 野間和広, 櫻間一史, 高岡宗徳, 宇野太, 永坂岳司, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松岡順治, 田中紀章, 羽井佐実

岡山医学会雑誌 121 ( 2 ) 132 - 132 2009.8

ゲノム研究が切り開く肺がんの新たな予防・治療戦略肺癌に対する遺伝子およびベクターを用いた分子治療(Novel therapeutic and preventive strategies blazed by genome research on lung cancer Gene and Vector-based Molecular Therapy for Lung Cancer)

香川俊輔, 黒田新士, 宇野太, 田澤大, 浦田泰生, 藤原俊義

日本癌学会総会記事 68回 56 - 56 2009.8

分子標的薬治療中のOncologic emergencyに対する対応

山辻知樹, 猶本良夫, 西谷正史, 田辺俊介, 近藤喜太, 藤原康宏, 野間和広, 櫻間一史, 高岡宗徳, 宇野太, 香川俊輔, 白川靖博, 小林直哉, 藤原俊義, 松原長秀, 松岡順治, 田中紀章

岡山医学会雑誌 121 ( 1 ) 65 - 65 2009.4

イマチニブ抵抗性GISTに対するスニチニブの使用経験

藤原康宏, 田辺俊介, 猶本良夫, 西谷正史, 近藤喜太, 野間和広, 櫻間一史, 高岡宗徳, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 松岡順治, 田中紀章

岡山医学会雑誌 121 ( 1 ) 64 - 64 2009.4

当科における胃機能温存食道切除再建術の工夫

野間和広, 藤原康宏, 田辺俊介, 猶本良夫, 西谷正史, 近藤喜太, 櫻間一史, 高岡宗徳, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 羽井佐実, 松岡順治, 田中紀章

岡山医学会雑誌 121 ( 1 ) 66 - 66 2009.4

オーバーチューブによる頸部食道穿孔に対して手術を施行した2症例の検討

田辺俊介, 猶本良夫, 西谷正史, 近藤喜太, 藤原康宏, 野間和広, 櫻間一史, 高岡宗徳, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 羽井佐実, 松岡順治, 田中紀章

岡山医学会雑誌 121 ( 1 ) 65 - 66 2009.4

A Novel Antiangiogenic Effect for Telomerase-Specific Virotherapy through Host Immune System Reviewed

Yoshihiro Ikeda, Toru Kojima, Shinji Kuroda, Yoshikatsu Endo, Ryo Sakai, Masayoshi Hioki, Hiroyuki Kishimoto, Futoshi Uno, Shunsuke Kagawa, Yuichi Watanabe, Yuuri Hashimoto, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

JOURNAL OF IMMUNOLOGY 182 ( 3 ) 1763 - 1769 2009.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC IMMUNOLOGISTS

Soluble factors in the tumor microenvironment may influence the process of angiogenesis; a process essential for the growth and progression of malignant tumors. In this study, we describe a novel antiangiogenic effect of conditional replication-selective adenovirus through the stimulation of host immune reaction. An attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of El genes, could replicate in and cause selective lysis of cancer cells. Mixed lymphocyte-tumor cell culture demonstrated that OBP-301-infected cancer cells stimulated PBMC to produce IFN-gamma into the supernatants. When the supernatants were subjected to the assay of in vitro angiogenesis, the tube formation of HUVECs was inhibited more efficiently than recombinant IFN-gamma. Moreover, in vivo angiogenic assay using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice showed that tumor cell-induced neovascularization was markedly reduced when the chambers contained the mixed lymphocyte-tumor cell culture supernatants. The growth of s.c. murine colon tumors in syngenic mice was significantly inhibited due to the reduced vascularity by intratumoral injection of OBP-301. The antitumor as well as antiangiogenic effects, however, were less apparent in SCID mice due to the lack of host immune responses. Our data suggest that OBP-301 seems to have antiangiogenic properties through the stimulation of host immune cells to produce endogenous antiangiogenic factors such as IFN-gamma. The Journal of Immunology, 2009, 182: 1763-1769.

早期胃癌に対する腹腔鏡補助下胃切除術―導入初期18例の検討

香川俊輔, 宇野太, 合地明, 藤原康宏, 田辺俊介, 近藤喜太, 楳田祐三, 小林直哉, 猶本良夫, 田中紀章

日本外科系連合学会雑誌 34 ( 2 ) 151 - 156 2009

Language：Japanese Publisher：日本外科系連合学会

目的:2006年より導入した腹腔鏡補助下胃切除術(laparoscope-assisted gastrectomy:LAG)と開腹下胃切除術(open gastrectomy:OG)との比較により,われわれのLAGの妥当性を検討した.方法:胃中下部の早期胃癌を適応とし,2006年3月より2008年8月まで18例に対して腹腔鏡補助下に幽門保存胃切除術(pylorus preserving gastrectomy:PPG),幽門側胃切除術(distal gastrectomy:DG),分節胃切除術(segmental gastrectomy:SEG)を行ったが,これらの術後成績をOG 50例と比較した.結果:LADGを7例,LAPPGを10例,LASEGを1例に行い,OG症例より手術時間はLAGで80分長く,出血量は約200ml少なかった.排ガス,および解熱までの日数は約1日早かった.経口摂取時期,在院日数に有意差はなかった.結語:LAGは安全に施行でき,今後推進していくに足るものと考えられる.(著者抄録)

DOI： 10.4030/jjcs.34.151

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J01066&link_issn=&doc_id=20090609200004&doc_link_id=10.4030%2Fjjcs.34.151&url=https%3A%2F%2Fdoi.org%2F10.4030%2Fjjcs.34.151&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

腹腔鏡補助下手術を施行した大腸内視鏡検査で発見された回腸カルチノイド腫瘍の一例

小林直哉, 香川俊輔, 近藤喜太, 楳田祐三, 西谷正史, 山辻知樹, 白川靖博, 田辺俊介, 藤原康宏, 宇野太, 猶本良夫, 田中紀章, 堀井城一朗, 川野誠司, 浦岡俊夫, 平岡佐規子, 加藤順, 岡田裕之, 山本和秀, 大原信哉, 市村浩一, 大森昌子, 森谷行利

外科治療 100 ( 2 ) 212 - 215 2009

Language：Japanese Publisher：(株)永井書店

症例は61歳男性で検診にて便潜血反応を指摘され、精検の大腸内視鏡では大腸に特記すべき所見は認めなかったが、回腸終末部(バウヒン弁から3cm口側)に10mm大の粘膜下腫瘍様突起を認め、生検所見から回腸カルチノイド腫瘍と診断された。入院時、血液・生化学試験は正常範囲で、腹部CTでは造影にて回腸末端部位に造影効果を有する10mm大の腫瘍像を認め、小腸内視鏡では多発病変は認めなかった。治療は腹腔鏡補助下に第2群リンパ節郭清D2+回盲部切除術を施行、切除標本は10×10mm大で漿膜への露出は認めず、術後経過良好で10日目に退院となった。病理組織学的所見では腫瘍は粘膜下層を主座に増生し、表層は一部粘膜内、深部は固有筋層から一部漿膜下層への浸潤を認め、深達度SSで第1群リンパ節転移陽性、脈管侵襲陽性(ly1・v1)であった。主体は異型を伴うカルチノイド腫瘍像で、最近の分類では高分化神経内分泌癌(well differentiated neuroendocrine carcinoma、G2、T3、N1、Stage IIIBに相当した。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J00396&link_issn=&doc_id=20090206220018&doc_link_id=%2Faf2gktye%2F2009%2F010002%2F018%2F0212-0215%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faf2gktye%2F2009%2F010002%2F018%2F0212-0215%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

テロメラーゼ依存性腫瘍融解アデノウイルスによる放射線感受性増強 E1B55kDaによるATMリン酸化阻害(Radiosensitization by telomerase-specific oncolytic adenovirus via E1B 55kDa-mediated inhibition of ATM phosphorylation)

黒田新士, 藤原俊哉, 矢野修也, 山崎泰源, 児島亨, 宇野太, 香川俊輔, 田澤大, 橋本悠里, 大内正明, 浦田泰生, 田中紀章, 藤原俊義

日本癌学会総会記事 67回 90 - 90 2008.9

胃癌幹細胞に対する新規治療テロメラーゼ特異的腫瘍融解ウイルス治療(A Novel Telomerase-Specific Oncolytic Virotherapy Targeting Human Gastric Cancer Stem Cells)

矢野修也, 橋本悠里, 山崎泰源, 黒田新士, 児島亨, 田澤大, 宇野太, 香川俊輔, 大内正明, 浦田泰生, 田中紀章, 藤原俊義

日本癌学会総会記事 67回 73 - 74 2008.9

当院における早期胃癌に対する腹腔鏡補助下胃切除術と開腹胃切除術との比較検討

香川俊輔, 宇野太, 合地明, 松原長秀, 小林直哉, 山辻知樹, 白川靖博, 藤原康宏, 近藤喜太, 田辺俊介, 猶本良夫, 藤原俊義, 田中紀章

日本内視鏡外科学会雑誌 13 ( 7 ) 232 - 232 2008.9

テロメアーゼ特異的制限増殖型アデノウイルスによる末梢血中ヒトがん細胞検出方法の開発(A three-step simple imaging method to detect viable human circulating tumor cells in the peripheral blood)

橋本悠里, 児島亨, 渡邉雄一, 黒田新士, 宇野太, 香川俊輔, 水口裕之, 浦田泰生, 田中紀章, 藤原俊義

日本癌学会総会記事 67回 486 - 486 2008.9

食道癌化学療法中にウェルニッケ脳症を発症した1例

藤原康宏, 猶本良夫, 田辺俊介, 近藤喜太, 河本洋伸, 元木崇之, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 松岡順治, 田中紀章

岡山医学会雑誌 120 ( 2 ) 241 - 241 2008.8

EUS-FNA後の出血により緊急手術を行った胃GISTの1例

藤智和, 猶本良夫, 田邊俊介, 近藤喜太, 藤原康宏, 吉田亮介, 野間和広, 櫻間一史, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 松岡順治, 田中紀章

岡山医学会雑誌 120 ( 2 ) 249 - 250 2008.8

当科における食道類基底細胞癌切除症例の検討

田辺俊介, 猶本良夫, 近藤喜太, 河本洋伸, 藤原康宏, 櫻間一史, 宇野太, 高岡宗徳, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 羽井佐実, 松岡順治, 田中紀章

岡山医学会雑誌 120 ( 2 ) 241 - 241 2008.8

Combination of oncolytic adenovirotherapy and Bax gene therapy in human cancer xenografted models. Potential merits and hurdles for combination therapy

Masayoshi Hioki, Shunsuke Kagawa, Toshiya Fujiwara, Ryo Sakai, Turn Kojima, Yuichi Watanabe, Yuuri Hashimoto, Futoshi Uno, Norialki Tanaka, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 122 ( 11 ) 2628 - 2633 2008.6

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

Cancer gene therapy and oncolytic virotherapy have been studied extensively. However, their clinical application is hampered by their weak anticancer activity. We previously constructed a replicating adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of the adenoviral El genes, and causes selective lysis of human cancer cells. We hypothesized that combination adenoviral therapy containing OBP-301 and a nonreplicating adenovirus expressing the proapoptotic Bax gene could overcome the weakness and augment the anticancer efficacy of each modality. Combination treatment resulted in marked Bax protein expression and enhanced efficacy in in vitro cell viability assay, when compared with either single treatment. However, combination treatment was not as effective in suppressing both subcutaneous and pleural disseminated tumors compared with OBP-301 treatment alone. Further investigation revealed that combination treatment resulted in suppressed EIA protein expression associated with reduced viral replication. Our results suggest that Bax gene therapy in combination with oncolytic adenovirotherapy potentially augments their antitumor activity, but further improvements may be required to maximize the combinatorial effect in vivo, for the Bax gene expression to avoid interference with production of the oncolytic virus. (c) 2008 Wiley-Liss, Inc.

DOI： 10.1002/ijc.23438

Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation

Y. Endo, R. Sakai, M. Ouchi, H. Onimatsu, M. Hioki, S. Kagawa, F. Uno, Y. Watanabe, Y. Urata, N. Tanaka, T. Fujiwara

ONCOGENE 27 ( 17 ) 2375 - 2381 2008.4

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

Dendritic cells ( DCs) are the most potent antigen-presenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell- to- cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP- 301 ( Telomelysin) is a telomerase-specific replication- competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP- 301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-gamma ( IFN-gamma) and interleukin 12 ( IL- 12). Subsequently, IFN-gamma release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T- lymphocytes. Our data suggest that virus- mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.

DOI： 10.1038/sj.onc.1210884

Establishment of biological and pharmacokinetic assays of telomerase-specific replication-selective adenovirus

Yuuri Hashimoto, Yuichi Watanabe, Yoshiko Shirakiya, Futoshi Uno, Shunsuke Kagawa, Hitoshi Kawamura, Katsuyuki Nagai, Noriaki Tanaka, Horomi Kumon, Yasuo Urata, Toshiyoshi Fujiwara

CANCER SCIENCE 99 ( 2 ) 385 - 390 2008.2

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

The use of replication-selective tumor-specific viruses represents a novel approach for the treatment of neoplastic disease. We constructed an attenuated adenovirus, telomerase-specific replication-selective adenovirus (TRAD), in which the human telomerase reverse transcriptase promoter element drives the expression of the E1A and E1B genes linked with an internal ribosome entry site (IRES). Forty-eight hours after TRAD infection at a multiplicity of infection of 1.0, the cell viability of H1299 human lung cancer cells was consistently less than 50% and therefore this procedure could be used as a potency assay to assess the biological activity of TRAD. We also established a quantitative real-time polymerase chain reaction (PCR) analysis with consensus primers for either the adenovirus E1A or IRES sequence. The linear ranges of quantitation with E1A and IRES primers were 10(3)-10(8) and 10(2)-10(8) plaque-forming units/mL in the plasma, respectively. The PCR analysis demonstrated that the levels of E1A in normal tissues were more than 10(3) lower than in the tumors of A549 human lung tumor xenografts in nu/n mu mice at 28 days after intratumoral injection. Our results suggest that the cell-killing assay against H1299 cells and real-time PCR can be used to assess the biological activity and biodistribution of TRAD in clinical trials.

DOI： 10.1111/j.1349-7006.2007.00665.x

In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus

KISHIMOTO Hiroyuki, KOJIMA Toru, WATANABE Yuichi, KAGAWA Shunsuke, FUJIWARA Toshiya, UNO Futoshi, TERAISHI Fuminori, KYO Satoru, MIZUGUCHI Hiroyuki, HASHIMOTO Yuuri, URATA Yasuo, TANAKA Noriaki, FUJIWARA Toshiyoshi

120 ( 1 ) 13 - 21 2008

腫瘍融解ウイルスによる細胞死であるオンコライシスは細胞内にdanger signalを発生させ、プロテアソームアクチベーター（PA28）発現を増強することで細胞障害性Tリンパ球による免疫応答を活性化する.

遠藤芳克, 酒井亮, 大内正明, 鬼松秀樹, 日置勝義, 香川俊輔, 宇野太, 渡邉雄一, 浦田泰生, 田中紀章, 藤原俊義

岡山医学会雑誌 120 ( 3 ) 259 - 264 2008

Adenomyoma of the stomach presenting as localized peritonitis

Shunsuke Kagawa, Toshiyoshi Fujiwara, Masahiko Nishizaki, Yoshio Naomoto, Isozaki Hiroshi, Noriaki Tanaka

DIGESTIVE DISEASES AND SCIENCES 52 ( 11 ) 3184 - 3187 2007.11

リンパ節微小転移を標的としたテロメラーゼ依存性腫瘍融解ウイルス療法(Telomerase-specific virotherapy targeting lymph node micrometastasis of human cancer)

児島亨, 渡辺雄一, 橋本悠里, 黒田新士, 宇野太, 香川俊輔, 浦田泰生, 田中紀章, 藤原俊義

日本癌学会総会記事 66回 91 - 91 2007.8

テロメラーゼ依存性腫瘍融解ウイルス療法と放射線療法の相互増感作用(Mutual sensitization with telomerase-specific oncolytic virotherapy and ionizing radiation in antitumor activity)

黒田新士, 藤原俊哉, 児島亨, 渡邊雄一, 橋本悠里, 宇野太, 香川俊輔, 浦田泰生, 田中紀章, 藤原俊義

日本癌学会総会記事 66回 385 - 385 2007.8

Advanced gastric adenocarcinoma mimicking a submucosal tumor

F. Teraishi, F. Uno, S. Kagawa, T. Fujiwara, A. Gouchi, N. Tanaka

ENDOSCOPY 39 ( Suppl 1 ) E191 - E192 2007.2

Cisplatin/Docetaxel+同時性放射線照射が奏効し根治手術を施行し得たstage IIIA非小細胞肺癌の1例

寺石文則, 香川俊輔, 宇野太, 武田洋正, 瀧川奈義夫, 藤原俊義, 田中紀章

癌と化学療法 34 ( 9 ) 1493 - 1495 2007

A case of nodular silicosis mimicking metastatic lung tumors

62 ( 9 ) 1269 - 1271 2007

Telomerase-specific replication-selective virotherapy for prostate cancer Reviewed

Kaku Haruki, Nasu Yasutomo, Huang Peng, Saika Takashi, Kagawa Shunsuke, Fujiwara Toshiyoshi, Kumon Hiromi, Urata Yasuo

JOURNAL OF GENE MEDICINE 8 ( 12 ) 1454 2006.12

JNK2 deficient cells acquire high adenoviral infectivity and adenovirus-mediated transgene expression

Fuminori Teraishi, Shunsuke Kagawa, Toshiyoshi Fujiwara, Noriaki Tanaka

JOURNAL OF GENE MEDICINE 8 ( 12 ) 1466 - 1466 2006.12

In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus

Hiroyuki Kishimoto, Toru Kojima, Yuichi Watanabe, Shunsuke Kagawa, Toshiya Fujiwara, Futoshi Uno, Fuminori Teraishi, Satoru Kyo, Hiroyuki Mizuguchi, Yuuri Hashimoto, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

NATURE MEDICINE 12 ( 10 ) 1213 - 1219 2006.10

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

Currently available methods for detection of tumors in vivo such as computed tomography and magnetic resonance imaging are not specific for tumors. Here we describe a new approach for visualizing tumors whose fluorescence can be detected using telomerase-specific replication-competent adenovirus expressing green fluorescent protein (GFP) (OBP-401). OBP-401 contains the replication cassette, in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of E1 genes, and the GFP gene for monitoring viral replication. When OBP-401 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that OBP-401 causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This technology is adaptable to detect lymph node metastasis in vivo as a preclinical model of surgical navigation.

DOI： 10.1038/nm1404

テロメラーゼ特異的GFP発現ナノバイオ・ウイルス製剤(OBP-401)を用いた微小癌組織のin vivoイメージング・システム

児島亨, 藤原俊義, 岸本浩行, 橋本悠里, 香川俊輔, 宇野太, 浦田泰生, 田中紀章

日本癌学会総会記事 65回 258 - 258 2006.9

Enhanced antitumor efficacy of telomerase-selective oncolytic adenoviral agent OBP-401 with docetaxel: Preclinical evaluation of chemovirotherapy

Toshiya Fujiwara, Shunsuke Kagawa, Hiroyuki Kishimoto, Yoshikatsu Endo, Masayoshi Hioki, Yoshihiro Ikeda, Ryo Sakai, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 119 ( 2 ) 432 - 440 2006.7

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

Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemotherapeutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.21846

Histone deacetylase inhibitor FR901228 enhances the antitumor effect of telomerase-specific replication-selective adenoviral agent OBP-301 in human lung cancer cells

T Watanabe, M Hioki, T Fujiwara, M Nishizaki, S Kagawa, M Taki, H Kishimoto, Y Endo, Y Urata, N Tanaka, T Fujiwara

EXPERIMENTAL CELL RESEARCH 312 ( 3 ) 256 - 265 2006.2

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

Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus OBP-301 (Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of EIA and El B genes linked with an internal ribosome entry site, could replicate in and causes selective lysis, of human cancer cells. Infection efficiency in target cancer cells is the most important factor that predicts the antitumor effects of OBP-301. The ob objectives of this study are to examine the effects of the histone deacetylase inhibitor FR901228 on the level of coxsackie and adenovirus receptor (CAR) expression and OBP-301-mediated oncolysis in human non-small cell lung cancer cell lines. Flow cytometric analysis revealed up-regulated CAR expression in A549 and H460 cells following treatment with 1 ng/ml of FR901228. which was associated with increased infection efficiency as confirmed by replication-deficient beta-galactosidase-expressing adenovirus vector. In contrast. neither CAR expression nor infection efficiency was affected by FR901228 in H1299 cells. To visualize and quantify viral replication in the presence of FR901228, we used 01311-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region. Fluorescence microscopy and flow cytometry showed that FR901228 increased GFP expression in A549 and 11460 cells following OBP-401 infection in a dose-dependent manner, but this effect did not occur in H1299 cells. In addition. OBP-301 and FR901228 demonstrated a synergistic antitumor effect in A549 cells in vitro, as confirmed by isobologram analysis. Our data indicate that FR901228 preferentially increases adenovirus infectivity via up-regulation of CAR expression, leading to a profound oncolytic effect, which may have a significant impact on the outcome of adenovirus-based oncolytic virotherapy. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexcr.2005.10.026

テロメラーゼ特異的に増幅するGFP蛋白を用いたマウスの固形腫瘍の胸膜播種の可視化

梅岡達生, 川嶋健, 香川俊輔, 寺石文則, 滝正樹, 京哲, 永井勝幸, 浦田泰生, 田中紀章, 藤原俊義

岡山医学会雑誌 118 ( 1 ) 9 - 15 2006

症例報告多発肝転移を伴う進行性胃癌に対するイリノテカンと低用量シスプラチン化学療法に併用したゲノシタビンに対する顕著な反応

寺石文則, 宇野太, 香川俊輔, 合地明, 藤原俊義, 田中紀章

癌と化学療法 2006

CPT-11+Low-Dose5-FU+CDDP療法が著効した多発肝転移を有する噴門部胃癌の1例

香川俊輔, 藤原俊義, 徳永尚之, 西崎正彦, 宇野太, 寺石文則, 合地明, 松岡順治, 田中紀章

癌と化学療法 2006

胃癌術後縦隔リンパ節再発による気管狭窄にステント+放射線治療が奏効した1例

香川俊輔, 藤原俊義, 西崎正彦, 徳永尚之, 合地明, 田中紀章

癌と化学療法 2006

A case report--The marked response to gemcitabine combined with irinotecan and low-dose cisplatin chemotherapy for advanced gastric cancer with multiple liver metastases.

Fuminori Teraishi, Futoshi Uno, Shunsuke Kagawa, Akira Gochi, Toshiyoshi Fujiwara, Noriaki Tanaka

Gan to kagaku ryoho. Cancer & chemotherapy 33 ( 12 ) 1885 - 1887 2006

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

A 69-year-old man with no sign of symptoms was admitted to our hospital for further examination and treatment of gastric cancer. Endoscopy revealed a Borrmann 3-type tumor in the cardia of the stomach. CT of the abdomen demonstrated a marked thickening of the stomach wall near the esophago-gastric junction, multiple liver metastases in bilateral liver lobes, and regional lymph node swelling around the cardia of the stomach. He consented and received systemic chemotherapy consisting of 0.5 h infusion of cisplatin (25 mg/body) followed by 0.5 h infusion of gemcitabine (800 mg/body) and 2.5 h infusion of irinotecan (60 mg/body) every 14 days as described below. Only the initial 1 course was administered with 5-FU (500 mg/body) as an inpatient, and further courses were performed as an outpatient with no severe adverse events. His tumors responded immediately to the chemotherapy, and restaging abdominal CT after 4-cycles of chemotherapy showed almost complete regression of liver metastases, and partial response to lymphadenopathy. The patient currently undergoes regular chemotherapy and remains in remission more than 6 months after the diagnosis of unresectable gastric cancer with liver metastases. It may be possible that the current chemotherapy will be neoadjuvant chemotherapy, and curative surgical resection can be performed.

A case of advanced gastric cancer with liver metastasis completely responding to CPT-11+low-dose 5-FU+CDDP chemotherapy

Shunsuke Kagawa, Toshiyoshi Fujiwara, Naoyuki Tokunaga, Masahiko Nishizaki, Futoshi Uno, Fuminori Teraishi, Akira Gouchi, Junji Matsuoka, Noriaki Tanaka

Gan to kagaku ryoho. Cancer & chemotherapy 33 ( 9 ) 1317 - 1320 2006

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

The case was a 54-year-old man with type-3 gastric cancer in the cardia accompanied by multiple liver metastasis. He received combination chemotherapy consisting of CPT-11 (60 mg/body, day 1 and 8)+low-dose 5-FU and CDDP (5-FU 500 mg/body/day and CDDP 5 mg/body/day, day 1-5 and 8-12, continuous infusion) every 3 weeks. The initial 2 courses were administered on an inpatient basis,and further courses as an outpatient. After 7 courses of therapy without severe adverse events, not only primary lesion but also hepatic metastasis disappeared. He has been free from disease for 4 months, and chemotherapy was further continued with TS-1 (100 mg/body, day 1-14)+CPT-11 60 mg/body, day 1, 8), every 3 weeks. CPT-11 in combination with low-dose 5-FU+CDDP can be one of the most effective regimens for unresectable advanced gastric cancer.

Stenting and radiotherapy for malignant tracheal stenosis due to mediastinal lymph node recurrence from gastric cancer--a case report

Shunsuke Kagawa, Toshiyoshi Fujiwara, Masahiko Nishizaki, Naoyuki Tokunaga, Akira Gochi, Noriaki Tanaka

Gan to kagaku ryoho. Cancer & chemotherapy 33 ( 1 ) 91 - 93 2006

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

The case is a 74-year-old woman,who underwent curative resection six years earlier for stomach cancer in the cardia extending to the esophagus (Stage IIIA). She noticed hoarseness and cough in September 2004, and CT revealed lymph node metastasis of the cancer in the upper mediastinum. The tumor pressured the SVC, the esophagus,and especially the trachea that narrowed up to a diameter of 5 mm.To secure the air way, first, a self-expandable metallic stent was placed in the narrowed trachea under general anesthesia. Irradiation to the upper mediastinal tumor was further applied for a total of 46 Gy from October to November, 2004.Symptom relief was obtained over the course by a marked reduction in the size of the metastatic tumor, and the disease remained stable for 5 months. In general,a stomach cancer that is mostly adenocarcinoma has been recognized to have low receptivity for radiotherapy. Nevertheless,this case suggests that radiotherapy can play an important role in local control and symptom relief for symptomatic stomach cancer patients.

テロメラーゼ依存性GFP蛍光発現ウイルス製剤OBP-401を用いた微小癌組織ナビゲーション・システムの開発

藤原俊義, 岸本浩行, 香川俊輔, 宇野太, 田中紀章, 河村仁, 浦田泰生

日本癌治療学会誌 40 ( 2 ) 350 - 350 2005.9

テロメラーゼ特異的腫瘍融解アデノウイルス(Telomelysin:OBP301)新たな抗腫瘍分子機構腫瘍免疫系への影響の解析

遠藤芳克, 徳永尚之, 池田義博, 酒井亮, 日置勝義, 岸本浩行, 藤原俊哉, 香川俊輔, 浦田泰生, 田中紀章, 藤原俊義

日本癌学会総会記事 64回 484 - 484 2005.9

がん特異的増殖可能アデノウイルス製剤OBP-401を用いた生体内癌組織診断がん特異的GFP蛍光イメージング技術の開発

岸本浩行, 香川俊輔, 藤原俊哉, 遠藤芳克, 池田義博, 日置義勝, 酒井亮, 浦田泰生, 田中紀章, 藤原俊義

日本癌学会総会記事 64回 447 - 448 2005.9

抗癌剤耐性細胞におけるテロメラーゼ特異的制限増殖型アデノウイルスTelomelysin(OBP-301)の抗腫瘍効果の検討

藤原俊哉, 藤原俊義, 香川俊輔, 岸本浩行, 遠藤芳克, 酒井亮, 日置勝義, 池田義博, 浦田泰生, 田中紀章

日本癌学会総会記事 64回 434 - 434 2005.9

ZD1839 (Gefitinib, 'Iressa'), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma

F Teralshi, S Kagawa, T Watanabe, Y Tango, T Kawashima, T Umeoka, M Nisizaki, N Tanaka, T Fujiwara

FEBS LETTERS 579 ( 19 ) 4069 - 4075 2005.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Getitinib, 'Iressa') blocks the cell signaling pathways involved in cell proliferation, survival, and angiogenesis in various cancer cells. TNF-related death apoptosis inducing ligand (TRAIL) acts as an anticancer agent. We investigated the antitumor effects of ZD-1839 alone or in combination with TRAIL against human esophageal squamous cell cancer (ESCC) lines. Although all ESCC cells expressed EGF receptor at a protein level, the effect of ZD1839 on cell growth did not correlate with the level of EGFR expression and phosphorylation of EGF receptor protein in ESCC lines. ZD1839 caused a dose-dependent growth arrest at GO-G, phase associated with increased p27 expression. As TE8 cells are resistant to TRAIL, we tested whether ZD1839 combined with TRAIL induced apoptosis of TE8 cells via the inhibition of EGF receptor signaling by ZD1839. ZD1839 inhibited the phosphorylation of Akt, and enhanced TRAIL-induced apoptosis via activation of caspase-3 and caspase-9, and inactivation of Bcl-xL. Our results indicated that ZD1839 has anti-cancer properties against human esophageal cancer cells. ZD1839 also augmented the anti-cancer activity of TRAIL, even in TRAIL-resistant tumors. These results suggest that treatment with ZD1839 and TRAIL may have potential in the treatment of ESCC patients. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.febslet.2005.06.031

Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 ('Telomelysin-RGD)

M Taki, S Kagawa, M Nishizaki, H Mizuguchi, T Hayakawa, S Kyo, K Nagai, Y Urata, N Tanaka, T Fujiwara

ONCOGENE 24 ( 19 ) 3130 - 3140 2005.4

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

Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus (OBP-301, 'Telomelysin'), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES, could replicate in cancer cells, and causes selective lysis of cancer cells. We further constructed OBP-405 ('Telomelysin-RGD') that contains an RGD motif in the HI loop of the fiber knob. We examined whether OBP-405 could be effective in overcoming the limitations of OBP-301, specifically their inefficient infection into cells lacking the primary receptor, the coxsackievirus and adenovirus receptor ( CAR). By flow cytometric analysis, H1299 ( lung) and SW620 ( colorectal) tumor cells showed high levels of CAR expression, whereas LN444 ( glioblastoma), LNZ308 ( glioblastoma), and H1299-R5 ( lung) tumor cells were negative for CAR expression. A quantitative realtime PCR analysis demonstrated that fiber-modified OBP-405 infected more efficiently than OBP-301, although the intracellular replication rate of both viruses was consistent. The comparative antitumor effect of fiber-modified OBP-405 and unmodified OBP-301 for human cancer cells was evaluated in vitro by XTT assay as well as in vivo by using athymic mice carrying xenografts. OBP-405 had a profound oncolytic effect on human cancer cell lines compared to OBP-301, in particular on cells with low CAR expression. Intratumoral injection of 107 plaque-forming units of OBP-405 into CAR-negative H1299-R5 lung tumor xenografts in nu/nu mice resulted in a significant inhibition of tumor growth and long-term survival in all treated mice. Moreover, selective replication of OBP-405 in the distant, uninjected H1299-R5 tumors was demonstrated. Our results suggest that fiber-modified replication-competent adenovirus OBP-405 exhibits a broad target range by increasing infection efficiency, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1038/sj.onc.1208460

Human monocyte-derived dendritic cells pulsed with wild-type p53 protein efficiently induce CTLs against p53 overexpressing human cancer cells

N Tokunaga, T Murakami, Y Endo, M Nishizaki, S Kagawa, N Tanaka, T Fujiwara

CLINICAL CANCER RESEARCH 11 ( 3 ) 1312 - 1318 2005.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Dendritic cells are the most potent antigenpresenting cells for initiating cellular immune responses. Dendritic cells are attractive immunoregulatory cells for cancer immunotherapy, and their efficacy has been investigated in clinical trials. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and p53-based immunization is an attractive approach to cancer immunotherapy because of the accumulation of p53 protein in malignant but not in normal cells. It has been shown that dendritic cells transduced with an adenoviral wild-type p53 (wt-p53) construct mediate the antitumor immune responses against p53-overexpressing tumor cells. We examined whether monocyte-derived human dendritic cells pulsed with the purified full-length wt-p53 protein were also capable of inducing the specific antitumor responses against p53-overexpressing tumors in vitro.
Experimental Design: Immature dendritic cells generated in the presence of interleukin4 and granulocyte/macrophage colony-stimulating factor from monocytes of HLA-A2- or HLA-A24-positive healthy individuals were pulsed with the purified p53 protein. Uptake of p53 protein by human dendritic cells was assessed by Western blotting and immunohistochemical staining using anti-p53 antibody. Induction of p53-specific CTL response was also evaluated by the cytotoxic assay against p53-overexpressing human tumor cells.
Results: Both Western blot and immunohistochemical analysis showed the accumulation of p53 protein in human immature dendritic cells. T cells obtained from HLA-A2- or HLA-A24-positive healthy donors were stimulated twice with p53 protein-pulsed dendritic cells and then applied to the cytotoxicity assay against p53-overexpressing target cells. The CTL activity was specific for p53-overexpressing tumor cells and MHC class I restricted. Moreover, the CTL activity generated by p53 protein-pulsed dendritic cells was nearly identical with that induced by adenoviral wt-p53-transduced dendritic cells.
Conclusions: Our results indicate that monocyte-derived human dendritic cells pulsed with the wt-p53 protein could induce the specific antitumor effect against p53-overexpressing tumors and that this in vitro model offers a new and more simple approach to the development of p53-based immunotherapy.

Gene therapy for lung cancer

Toshiyoshi Fujiwara, Shunsuke Kagawa, Noriaki Tanaka

Nippon rinsho. Japanese journal of clinical medicine 63 507 - 511 2005

癌に対する遺伝子治療：肺癌

藤原俊義, 香川俊輔, 田中紀章

遺伝子診療学（日本臨床増刊号） 63,507-511 2005

Visualization of intrathoracically disseminated solid tumors in mice with optical imaging by telomerase-specific amplification of a transferred green fluorescent protein gene

T Umeoka, T Kawashima, S Kagawa, F Teraishi, M Taki, M Nishizaki, S Kyo, K Nagai, Y Urata, N Tanaka, T Fujiwara

CANCER RESEARCH 64 ( 17 ) 6259 - 6265 2004.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Currently available methods for detection of tumors in vivo such as X-ray, computed tomography, and ultrasonography are noninvasive and have been well studied; the images, however, are not specific for tumors. Direct optical imaging of tumor cells in vivo that can clearly distinguish them from surrounding normal tissues may be clinically useful. Here, we describe a new approach to visualizing tumors whose fluorescence can be detected using tumor-specific replication-competent adenovirus (OBP-301, Telomelysin) in combination with Ad-GFP, a replication-deficient adenovirus expressing green fluorescent protein (GFP). Human telomerase reverse transcriptase is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. We constructed an adenovirus 5 vector in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site and showed that OBP-301 replicated efficiently in human cancer cells, but not in normal cells such as human fibroblasts. When the human lung and colon cancer cell lines were infected with Ad-GFP at a low multiplicity of infection, GFP expression could not be detected under a fluorescence microscope; in the presence of OBP-301, however, Ad-GFP replicated in these tumor cells and showed strong green signals. In contrast, coinfection with OBP-301 and Ad-GFP did not show any signals in normal cells such as fibroblasts and vascular endothelial cells. We also found that established subcutaneous tumors could be visualized after intraturnoral injection of OBP-301 and Ad-GFP. A549 human lung tumors and SW620 human colon tumors transplanted into BALB/c nu/nu mice were intraturnorally injected with 8 X 10(5) plaque-forming units of Ad-GFP in combination with 8 X 106 plaque-forming units of OBP-301. Within 3 days of treatment, the fluorescence of the expressed GFP became visible by a three-chip color cooled charged-coupled device camera in these tumors, whereas intraturnoral injection of Ad-GFP alone could not induce GFP fluorescence. Moreover, intrathoracic administration of Ad-GFP and OBP-301 could visualize disseminated A549 tumor nodules in mice after intrathoracic implantation. Our results indicate that intratumoral or intrathoracic injection of Ad-GFP in combination with OBP-301 might be a useful diagnostic method that provides a foundation for future clinical application.

DOI： 10.1158/0008-5472.CAN-04-1335

GFP発現テロメラーゼ特異的制限増殖型ウイルスTelomelysin-GFPを用いた腫瘍組織ナビゲーション・システム

岸本浩行, 香川俊輔, 滝正樹, 藤原俊哉, 渡辺貴紀, 遠藤芳克, 京哲, 水口裕之, 田中紀章, 藤原俊義

日本癌学会総会記事 63回 454 - 454 2004.9

テロメラーゼ特異的制限増殖型アデノウイルスTelomelysinと微小管作用型抗癌剤の併用効果の検討

藤原俊哉, 藤原俊義, 香川俊輔, 滝正樹, 岸本浩行, 渡邉貴紀, 遠藤芳克, 京哲, 水口裕之, 田中紀章

日本癌学会総会記事 63回 510 - 510 2004.9

HDAC阻害剤FR901228によるテロメラーゼ特異的制限増殖型アデノウイルスTelomelysinの選択的抗腫瘍効果の増強

渡邉貴紀, 西崎正彦, 香川俊輔, 滝正樹, 岸本浩行, 藤原俊哉, 遠藤芳克, 京哲, 水口裕之, 田中紀章, 藤原俊義

日本癌学会総会記事 63回 499 - 499 2004.9

テロメラーゼ活性を標的とした治療 (特集分子・細胞標的治療--基礎と臨床) -- (基礎)

藤原俊義, 香川俊輔, 田中紀章

現代医療 36 ( 7 ) 1366 - 1372 2004.7

Antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene

T Murakami, N Tokunaga, T Waku, S Gomi, S Kagawa, N Tanaka, T Fujiwara

CLINICAL CANCER RESEARCH 10 ( 11 ) 3871 - 3880 2004.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Dendritic cells (130) are attractive effectors for cancer immunotherapy because of their potential to function as professional antigen-presenting cells for initiating cellular immune responses. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and similar to50% of human malignancies exhibit mutation and aberrant expression of p53. We investigated the antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene.
Experimental Design: We examined whether intratumoral administration of DCs infected with recombinant adenovirus expressing murine wild-type p53 (Ad-mp53) could induce systemic antitumor responses against mutant p53-expressing tumors, highly immunogenic MethA, or weakly immunogenic MCA-207 implanted in syngeneic mice.
Results: Accumulation of wild-type p53 protein in bone marrow-derived murine DCs could be successfully achieved by Ad-mp53 infection. Treatment with intratumoral injection of Ad-mp53-transduced DCs caused a marked reduction in the in vivo growth of established MethA and MCA-207 tumors with massive cellular infiltrates. Administration of p53-expressing DCs suppressed the growth of both injected MCA-207 tumors and untreated distant MCA-207 tumors, but not unrelated Lewis lung carcinoma tumors, suggesting the augmentation of systemic immunogenicity against MCA-207 tumor cells. Moreover, intratumoral injection of p53-expressing DCs had a greater antitumor effect than did s.c. immunization.
Conclusions: Our results indicate that intratumoral administration of DCs expressing murine wild-type p53 leads to significant systemic immune responses and potent antitumor effects in mutant p53-expressing murine cancer models. These findings raise the possibility of using this strategy of intratumoral injection of p53-expressing DCs for human cancer treatment.

DOI： 10.1158/1078-0432.CCR-03-0599

Thoracic tumors treated with CT-guided radiofrequency ablation: Initial experience

K Yasui, S Kanazawa, Y Sano, T Fujiwara, S Kagawa, H Mimura, S Dendo, T Mukai, H Fujiwara, T Iguchi, T Hyodo, N Shimizu, N Tanaka, Y Hiraki

RADIOLOGY 231 ( 3 ) 850 - 857 2004.6

Language：English Publishing type：Research paper (scientific journal) Publisher：RADIOLOGICAL SOC NORTH AMERICA

PURPOSE: To determine the effectiveness of computed tomography (CT)-guided radiofrequency (RF) ablation of malignant thoracic tumors.
MATERIALS AND METHODS: CT-guided RF ablations of 99 malignant thoracic tumors (3-80 mm in largest diameter; mean, 19.5 mm) were performed in 35 patients in 54 sessions. Ablation was performed with an RF generator by using a single internally cooled electrode. Tumors were both primary (three lesions) and, secondary (pulmonary or pleural metastases, 96 lesions). Follow-up was 1-17 months (mean, 7.1 months). Follow-up CT and histopathologic examinations were evaluated. Univariate analysis was performed with the Fisher exact test and Welch, t test was used to evaluate differences between group means. P < .05 represented a significant difference. The maximal diameter of each residual tumor or local recurrence or the proportion of primary lesions of pulmonary metastatic tumors with recurrence after RF ablation were analyzed. Complications, management, and outcomes of the complications were recorded.
RESULTS: The appearance of each ablation zone, including the target tumor and surrounding normal lung parenchyma, showed involution at follow-up CT. Local recurrence was demonstrated histopathologically or radiologically in nine tumors. The other 90 tumors showed no growth progression at follow-up CT. Probable complete coagulation necrosis obtained with initial RF ablation was achieved in 91% (90 of 99) of the tumors. The mean maximal diameter of the nine tumors (19.6 mm +/- 7.7 [SD]) was not significantly different (P = .994) from that of the other 90 tumors (19.5 mm +/- 13.0). Primary lesions of those nine metastatic tumors varied and did not demonstrate a specific tendency. Complications included pneumothorax, fever higher than 37.5&DEG;C, hemoptysis, cough, pleural effusion, abscess formation, and hemothorax. The overall complication rate was 76% (41 of 54 sessions).
CONCLUSION: RF ablation seems to be a promising treatment for malignant (C) RSNA, 2004.

DOI： 10.1148/radiol.2313030347

Late resistance to adenoviral p53-mediated apoptosis caused by decreased expression of Coxsackie-adenovirus receptors in human lung cancer cells

Y Tango, M Taki, Y Shirakiya, S Ohtani, N Tokunaga, Y Tsunemitsu, S Kagawa, T Tani, N Tanaka, T Fujiwara

CANCER SCIENCE 95 ( 5 ) 459 - 463 2004.5

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE CANCER ASSOC

Adenovirus-mediated wild-type p53 gene transfer induces apoptosis in a variety of human cancer cells. Although clinical trials have demonstrated that a replication-deficient recombinant adenovirus expressing the wild-type p53 gene (Ad-p53) is effective in suppressing growth of non-small cell lung cancer (NSCLC), we often experienced late resistance to this treatment. To elucidate the mechanism of late resistance to Ad-p53 in human lung cancer cells, we generated 5 different resistant variants from p53-susceptible H1299 NSCLC cells by repeated infections with Ad-p53. We first examined the transduction efficiency of adenoviral vector by Ad-LacZ transduction followed by X-gal staining in parental and 5 resistant H1299 cell lines. Their sensitivity to viral infection decreased in correlation with the magnitude of resistance, and Ad-p53-mediated tumor suppression could be restored by dose escalation of Ad-p53 in the resistant variants. The expression of Coxsackie and adenovirus receptor (CAR) and alphaV integrins, which are cellular receptors for attachment and internalization of the virus, respectively, was next investigated in these cell lines. Flow cytometry revealed that alphaVbeta3 and alphaVbeta5 integrin expression was consistent, while p53-resistant cell lines showed that diminished CAR expression correlated with the magnitude of the resistance. Our results demonstrated that decreased CAR expression could be one of the mechanisms of late resistance to Ad-p53, which may have a significant impact on the outcome of adenovirus-based cancer gene therapy.

DOI： 10.1111/j.1349-7006.2004.tb03232.x

Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer

Y Tsunemitsu, S Kagawa, N Tokunaga, S Otani, T Umeoka, JA Roth, B Fang, N Tanaka, T Fujiwara

GUT 53 ( 4 ) 554 - 560 2004.4

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

Background: Gene therapy is an innovative therapeutic approach for cancer. An adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently under clinical evaluation for various cancers. We recently developed a binary adenoviral vector system that can express the strong proapoptotic gene Bax (Ad/ PGK-GV16+ Ad/ GT-Bax: Ad/Bax).
Aims: To evaluate the potential of Bax gene therapy for gastric cancer, we assessed its antitumour effect in comparison with that of p53.
Methods: The human gastric cancer cell lines MKN-1, MKN-7, MKN-28, and MKN-45 were treated with Ad/ Bax or Ad/ p53, and cell viability, transgene expression, and caspase activation were assessed in vitro. To compare the antitumour effects of Ad/ Bax and Ad/ p53 treatment in vivo, subcutaneous tumours and peritoneal dissemination of MKN-45 cells were generated in nude mice. Each mouse underwent intratumoral or intraperitoneal administration of viruses and the growth of implanted tumours was observed after treatment.
Results: Treatment with Ad/ Bax and Ad/ p53 resulted in marked Bax and p53 protein expression and effective apoptosis induction in MKN-1, MKN-7, and MKN-28 cells in vitro. In contrast, MKN-45 cells showed resistance to Ad/ p53 and only treatment with Ad/ Bax resulted in activation of caspase 3 expression and massive apoptosis. Ad/ Bax treatment was more effective in suppressing both subcutaneous and peritoneally disseminated MKN-45 tumours compared with Ad/ p53 treatment.
Conclusion: Ad/ Bax treatment significantly inhibited the growth of even p53 resistant gastric cancer in vitro and in vivo. Therefore, adenovirus mediated Bax gene transfer may be useful in gene therapy for gastric cancers.

DOI： 10.1136/gut.2003.021683

Telomerase-specific replication-selective virotherapy for human cancer

T Kawashima, S Kagawa, N Kobayashi, Y Shirakiya, T Umeoka, F Teraishi, S Kyo, M Taki, N Tanaka, T Fujiwara

CLINICAL CANCER RESEARCH 10 ( 1 ) 285 - 292 2004.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on human cancer cells.
Experimental Design: We constructed an adenovirus 5 vector [tumor- or telomerase-specific replication-competent adenovirus (TRAD)], in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, and we examined the selective replication and antitumor effect in human cancer cells in vitro and in vivo.
Results: TRAD induced selective E1A and E1B expression in human cancer cells, but not in normal cells such as human fibroblasts. TRAD replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human fibroblasts lacking telomerase activity. In nu/nu mice carrying s.c. human lung tumor xenografts, intratumoral injection of TRAD resulted in a significant inhibition of tumor growth. No evidence of TRAD was identified in tissues outside of the tumors, despite the presence of TRAD in the circulation. Moreover, TRAD replication in the distant, noninjected tumors was demonstrated.
Conclusions: Our results suggest that the hTERT promoter confers competence for selective replication of TRAD in human cancer cells, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1158/1078-0432.CCR-1075-3

Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo

S Ohtani, S Kagawa, Y Tango, T Umeoka, N Tokunaga, Y Tsunemitsu, JA Roth, Y Taya, N Tanaka, T Fujiwara

MOLECULAR CANCER THERAPEUTICS 3 ( 1 ) 93 - 100 2004.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

To analyze the mechanism of the antitumor effect of an adenoviral vector expressing the p53 tumor suppressor (Ad-p53) in vivo, we quantitatively assessed p53-targeted gene expression and visualized transcriptional activity of p53 in tumors in nude mice treated with Ad-p53. Human lung cancer (H1299) xenografts- established in nude mice were treated by intratumoral administration of Ad-p53. The levels of expression of exogenous p53 and p53-targeted genes p21, MDM2, Noxa, and p53AIP1 were quantified by real-time reverse transcription-PCR (RT-PCR) and induction of apoptosis was observed histochemically on days 1-3, 7, and 14 after treatment. Expression of mRNA of exogenous p53 and p53-targeted genes (except p53AIP1) was at its maximum 1 day after Ad-p53 treatment and then decreased rapidly; apoptosis was evident in situ 2-3 days after treatment. We developed a noninvasive and simple method for monitoring the transcriptional activity of exogenous p53 following intratumoral administration of Ad-p53 in nude mice. We established H1299 cells that express the green fluorescent protein (GFP) reporter gene under the control of p53-responsive p21 promoter (i.e., the p53R-GFP reporter system). Xenografts of these cells in nude mice were treated by intratumoral administration of Ad-p53, and the transcriptional activity of exogenous p53 could be visualized as intratumoral GFP expression in real time by 3-CCD camera. Expression of GFP was maximal 3 days after treatment and decreased remarkably by 7 days after treatment. We demonstrated that Ad-p53 treatment rapidly induced p53-targeted genes and apoptosis in tumors and succeeded in visualizing p53 transcriptional activity in vivo. We also found that Ad-p53 infection induced phosphorylation of p53 at Ser(46) in p53-sensitive H1299 cells in vitro but not in p53-resistant H226Br cells, suggesting that phosphorylation of Ser(46) is involved in p53dependent apoptosis. Our data indicate that quantitative analysis of p53-targeted gene expression by real-time quantitative RT-PCR and visualization of p53 transcriptional activity in fresh xenografts by using the p53R-GFP reporter system may be useful in assessing the mechanisms of the antitumor effects of Ad-p53 and novel therapeutic approaches.

進行非小細胞肺癌に対してp53遺伝子治療を施行し奏効が得られた1例

香川俊輔, 藤原俊義, 大谷彰一郎, 田中紀章, 岡山大病院, 遺伝子, 細胞治療センタ

癌と化学療法 31,11,1788-1790 2004

A case of advanced non-small lung cancer responding to tumor suppressor p53 gene therapy

Shunsuke Kagawa, Shoichiro Ohtani, Noriaki Tanaka, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 31 ( 11 ) 1788 - 1790 2004

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

The phase I study of the tumor suppressor p53 gene therapy for advanced lung cancer was performed. A 57-year-old man with locally advanced squamous cell carcinoma at the tracheal bifurcation, clinical stage IIIB, had previously been treated by radiotherapy and chemotherapy. Because of the local recurrence, he was enrolled to the study. He was treated by a local injection of ADVEXIN once every 4 weeks for 14 times without marked adverse events, which resulted in tumor regression and relief of his symptom for a year. In conclusion, gene therapy with ADVEXIN may be an effective treatment for locally advanced non-small lung cancer.

RGDファイバー変異を挿入した腫瘍特異的増殖可能アデノウイルス(TRAD)の抗腫瘍効果の増強

滝正樹, 藤原俊義, 川嶋健, 岸本浩行, 藤原俊哉, 水口裕之, 京哲, 香川俊輔, 西崎正彦, 田中紀章

日本癌学会総会記事 62回 161 - 161 2003.8

Ectopic p21(sdi1) gene transfer induces retinoic acid receptor beta expression and sensitizes human cancer cells to retinoid treatment

F Teraishi, Y Kadowaki, Y Tango, T Kawashima, T Umeoka, S Kagawa, N Tanaka, T Fujiwara

INTERNATIONAL JOURNAL OF CANCER 103 ( 6 ) 833 - 839 2003.3

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

The biological effects of retinoic acid (RA) are mediated by nuclear retinoic acid receptors (RARs) that function as ligand-activated transcriptional factors. The response of human cancer cells to RA is known to be associated with the expression of RARbeta. Recent studies have demonstrated that the loss of RARbeta expression is involved in the development of a variety of human malignancies. We show that recombinant adenovirus-mediated p21(sdi1) gene transfer enhances RARbeta mRNA expression as well as protein expression and induces the sensitivity to all-trans RA (ATRA) in human cancer cells. Semi-quantitative reverse transcription-polymerase chain reaction analysis demonstrated that infection with adenovirus carrying human p21(sdi1) gene (AdSCMV-p21), which encodes a cyclin-dependent kinase inhibitor, induced RARbeta mRNA and protein expression in H1299 human non-small cell lung cancer cells and DLD-1 human colorectal cancer cells. We also found that exogenous introduction of the p21(sdil) gene transcriptionally activated the upstream promoter function of the RARbeta gene. Treatment with I muM of ATRA showed no significant inhibitory effects on the growth of H 1299 and DLD-1 cells; after Ad5CMV-p21 infection, however, cells underwent apoptosis with ATRA treatment at the same concentration, suggesting that p21(sdil) gene transfer sensitized H1299 and DLD-1 cells, presumably, through RARbeta upregulation. We also demonstrated the efficacy of intratumoral injection of AdSCMV-p21 in combination with systemic administration of ATRA in a nude mice xenograft model. Our results indicate that recombinant adenovirus-mediated p21(sdil) gene transfer could be potentially useful for the local induction of RA sensitivity in human premalignant and malignant lesions lacking appropriate RARbeta expression. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/ijc.10892

Clinical study of adenoviral mediated p53 gene therapy for non-small cell lung cancer in Japan

Shunsuke Kagawa, Toshiyoshi Fujiwara, Noriaki Tanaka

Gan to kagaku ryoho. Cancer & chemotherapy 30 ( 2 ) 193 - 197 2003

Language：Japanese

The prognosis in case of non-small cell lung cancer (NSCLC) remains poor, and novel treatment modalities are urgently needed for advanced NSCLC. Backed by advances in the understanding of cancer biology, gene therapy has been developed in recent years. The p53 gene is altered in over 50% of cancers and has been extensively studied as a tumor suppressor gene. Adenoviral-mediated p53 gene transfer is currently under clinical evaluation worldwide for the treatment of cancer. We are now conducting a phase I study of Ad-p53 for advanced NSCLC patients in Japan. As an interim report, we provide a brief summary of the current status of this study, highlighting the safety and clinical efficacy of Ad-p53. As of September 2002, 13 patients were enrolled to this study, and safety and antitumor effects have been noted.

肺癌の遺伝子治療

香川俊輔, 藤原俊義, 田中紀章

病理と臨床 21,519-522 2003

遺伝子治療の実際

香川俊輔, 藤原俊義, 田中紀章

癌と化学療法 30,193-197 2003

制限増殖型アデノウイルスによる非増殖型p53遺伝子発現アデノウイルスベクター(Ad5CMV-p53)の腫瘍選択的増殖

谷本光隆, 藤原俊義, 高田佳子, 大谷彰一郎, 川嶋健, 香川俊輔, 西崎正彦, 田中紀章

日本癌学会総会記事 61回 187 - 187 2002.10

A recombinant adenovirus expressing wild-type Bax induces apoptosis in prostate cancer cells independently

T Honda, S Kagawa, KB Spurgers, BT Gjertsen, JA Roth, BL Fang, SL Lowe, JS Norris, RE Meyn, TJ McDonnell

CANCER BIOLOGY & THERAPY 1 ( 2 ) 163 - 167 2002.3

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

Using a binary co-transfection strategy of Ad/GT Box and Ad/PGK-GV16, we have succeeded in inducing overexpression of Box protein in three prostate cell lines (androgen-insensitive DU145 and PC3, and androgen-sensitive LNCaP). The expression of Box protein by this system was sufficient to induce all three prostate lines to undergo apoptosis. The fact that DU145 cells which have a p53 mutation and are deficient in Box, responded to this treatment, suggests that this effect is independent of these pathways. Initiation of the cleavage of Caspase-3 (CPP32/Yama/apopain) and PARP (poly (ADP-ribose) polymerase) by the introduction of Box were confirmed by western blot analysis. Bcl-2 expression is relevant in the progression of prostate cancer and contributes to an androgen, apoptotic-resistant phenotype in the advanced stages. We examined stable Bcl-2 overexpressing DU145, PC3 and LNCaP cell lines as models of advanced prostate cancer. The adenoviral co-transfection system induced Box protein expression and apoptosis even in these Bcl-2 transfected cell lines. Taken together, our results suggest that this Box expression system might represent a useful gene therapy strategy when applied to the treatment of prostate cancer and its efficacy would be independent of the Bcl-2 status and androgen sensitivity of these cancers.

肺癌に対する遺伝子治療：p53発現アデノウイルスベクターによる肺癌遺伝子治療臨床試験の現況.

香川俊輔, 藤原俊義, 田中紀章

医学のあゆみ 203,5,302-306 2002

肺癌非手術療法の新しい試み 7.遺伝子治療.

片岡正文, 藤原俊義, 香川俊輔, 田中紀章

日本外科学会雑誌 103,2,244-249 2002

p53を用いた肺癌遺伝子治療.

香川俊輔, 藤原俊義, 田中紀章

日本臨床 60,Suppl 5, 630-634 2002

腹壁原発末梢型神経外胚葉性腫瘍(PNET)の1切除例

渡辺信之, 片岡正文, 斎藤信也, 常光洋輔, 香川俊輔, 田中紀章, 難波康男, 漆畑貴行, 久山彰一, 田端雅弘

岡山医学会雑誌 113 ( 3 ) 317 - 317 2001.12

Use of the probasin promoter ARR(2)PB to express Bax in androgen receptor-positive prostate cancer cells

F Andriani, B Nan, J Yu, XY Li, NL Weigel, MJ McPhaul, S Kasper, S Kagawa, BL Fang, RJ Matusik, L Denner, M Marcelli

JOURNAL OF THE NATIONAL CANCER INSTITUTE 93 ( 17 ) 1314 - 1324 2001.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL CANCER INSTITUTE

Background: Adenovirus-mediated overexpression of the apoptosis-inducing protein Bax can induce apoptosis in prostate cancer cell lines. Constitutive overexpression of Bax could result in unwanted apoptosis in every site of accidental Bax accumulation in vivo. Therefore, we developed an adenoviral construct (Av-ARR(2)PB-Bax) in which the probasin promoter, modified to contain two androgen response elements, drives Bax expression. This promoter would be expected to limit expression of Bax to cells expressing the androgen receptor. Methods: A variety of androgen receptor (AR)-positive and -negative cell lines of prostatic or nonprostatic origin were infected with Av-ARR2PB-Bax or a control virus, Av-ARR(2)PB-CAT, in which the same promoter drives expression of the chloramphenicol acetyl transferase-reporter gene. Bax expression and apoptosis in vitro were assessed by western blot analysis. Tumor size and apoptosis in vivo were assessed after four weekly injections of Av-ARR(2)PB-Bax or Av-ARR(2)PB-CAT into subcutaneous LNCaP xenografts growing in uncastrated male mice. All statistical tests were two-sided. Results: Bax was overexpressed in an androgen-dependent way in AR-positive cell lines of prostatic origin but not in AR-positive cells of nonprostatic origin or in AR-negative cell lines of either prostatic or nonprostatic origin. The androgen dihydrotestosterone activated apoptosis in LNCaP cells infected with Av-ARR2PB-Bax but not in those infected with Av-ARR(2)-PB-CAT. Av-ARR(2)PB-Bax-injected LNCaP xenograft tumors decreased in tumor size from 34.1 mm(3) (95% confidence interval [CI] = 25.1 mm(3) to 43.1 mm(3)) to 24.6 mm(3) (95% CI = -2.5 mm(3) to 51.7 mm(3)), but the difference was not statistically significant (P = .5). Tumors injected with Av-ARR(2)PB-CAT increased in size, from 28.9 mm(3) (95% CI = 12.7 mm(3) to 45.1 mm(3)) to 206 mm(3) (95% CI = 122 mm(3) to 290 mm(3)) (P = .002) and contained statistically significant more apoptotic cells (23.3% [95% CI = 21.1% to 25.6%] versus 9.5% [95% CI = 8.0% to 11.1]) (P < .001). Conclusions: Av-ARR2PB-Bax induces androgen-dependent therapeutic apoptosis in vitro and in vivo by activating apoptosis in AR-positive cells derived specifically from prostatic epithelium and does not affect nonprostatic cells.

Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells

T Fukazawa, T Fujiwara, F Uno, F Teraishi, Y Kadowaki, T Itoshima, Y Takata, S Kagawa, JA Roth, J Tschopp, N Tanaka

ONCOGENE 20 ( 37 ) 5225 - 5231 2001.8

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

Apoptosis is a morphologically distinct form of programmed cell death that plays a major role in cancer treatments. This cellular suicide program is known to be regulated by many different signals from both intracellular and extracellular stimuli. Here we report that p53 suppressed expression of the cellular FLICE-inhibitory protein (FLIP) that potentially blocks apoptotic signaling in human colon cancer cell lines expressing mutated and wild-type p53. In contrast, the expression of the death receptor KILLER/DR5 (TRAIL-R2) had no effect on FLIP expression, although exogenous p53 is known to induce KILLER/DR5 expression. In line with these observations, FLIP-negative cancer cells were sensitive to both p53- and KILLER/DR5-mediated apoptosis, whereas cells containing high levels of FLIP underwent apoptotic cell death when triggered by ectopic p53 expression but not by KILLER/DR5 expression. Treating the cells with a specific inhibitor of the proteasome inhibited the decrease of FLIP by p53, suggesting that p53 enhances the degradation of FLIP via a ubiquitin-proteasome pathway. Thus, the data indicate that p53-mediated downregulation of FLIP may explain the potent sensitization of human cancer cells to the apoptotic suicide program induced by wild-type p53 gene transfer.

DOI： 10.1038/sj.onc.1204673

Deficiency of caspase-3 in MCF7 cells blocks bax-mediated nuclear fragmentation but not cell death

S Kagawa, J Go, T Honda, TJ McDonnell, SG Swisher, JA Roth, BL Fang

CLINICAL CANCER RESEARCH 7 ( 5 ) 1474 - 1480 2001.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Caspase-3 plays a critical role in a proteolytic cascade within the apoptosis signal pathway; this enzyme is commonly activated by numerous death signals and cleaves a variety of important cellular proteins, Using caspase-3-deficient MCF7 cells and clones stably transfected with the caspase-3 gene (MCF7/Casp3), we evaluated the role of caspase-3 in Bax-induced apoptosis, Bax overexpression induced cell death in both parental MCF7 cells and MCF7/Casp3 cells, The introduction of the caspase-3 gene did not change the rate of cell death. Caspase-3-deficient parental MCF7 cells, however, failed to undergo morphological nuclear and DNA fragmentation, whereas MCF7/casp3 cells displayed intact nuclear dismantling and DNA fragmentation. Caspase-3 deficiency, however, did not affect Bax-induced levels of poly(ADP-ribose) polymerase cleavage, caspase-6 activation, and lamin B cleavage, Together, these results suggest that a deficit in caspase-3 is not sufficient to block Bax-induced cell death.

Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene

S Kagawa, C He, J Gu, P Koch, SJ Rha, JA Roth, SA Curley, LC Stephens, BL Fang

CANCER RESEARCH 61 ( 8 ) 3330 - 3338 2001.4

Augmenting transgene expression from carcinoembryonic antigen (CEA) promoter via a GAL4 gene regulatory system

PE Koch, ZS Guo, S Kagawa, J Gu, JA Roth, B Fang

MOLECULAR THERAPY 3 ( 3 ) 278 - 283 2001.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC

Though extensively studied, the use of tissue- or cell-type-specific promoters to target transgene expression is hampered by their weak activity. We hypothesized that this problem could be addressed by using a GAL4 gene regulatory system, wherein a weak, tissue-specific promoter would drive expression of the GAL4/VP16 fusion protein (GV16), which in turn would transactivate a minimal synthetic promoter, GAL4/TATA (GT), upstream of a transgene. To test this hypothesis, we constructed adenoviral vectors expressing a IacZ or GV16 gene driven by a carcinoembryonic antigen (CEA) promoter (Ad/CEA-LacZ or Ad/CEA-GV16) and evaluated levels of transgene expression they produced in cultured cells and in subcutaneous tumors after intratumoral administration. In CEA-positive cells, treatment with Ad/CEA-GV16 + Ad/GT-LacZ versus Ad/CEA-LacZ increased transgene expression 20- to 100-fold. In CEA-negative cells, treatment with Ad/CEA-GV16 + Ad/GT-LacZ increased transgene expression to a much lower degree (6- to 8-fold). In addition, analysis of Bax gene-mediated cell death revealed that this system can be used to avoid Bax's toxic effects on CEA-negative cells without compromising its ability to kill CEA-positive cells in vitro and in vivo. Thus, the combination of a tissue-specific promoter with the GAL4 gene regulatory system could be useful for targeting transgene expression.

DOI： 10.1006/mthe.2001.0273

特集肺癌の診断治療法における最近の進歩 4.化学療法の進歩肺癌の遺伝子治療.

片岡正文, 香川俊輔, 藤原俊義, 田中紀章

肺癌の臨床 4,2,221-230 2001

p53遺伝子を用いた肺癌の遺伝子治療.

香川俊輔, 藤原俊義, 片岡正文, 田中紀章

Lung Cancer Today 1 ,12-16 2001

呼吸器疾患に対する遺伝子治療.

香川俊輔, 藤原俊義, 片岡正文, 田中紀章

外科 63, 1740-1747 2001

Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers Reviewed

J Gu, S Kagawa, M Takakura, S Kyo, M Inoue, JA Roth, BL Fang

CANCER RESEARCH 60 ( 19 ) 5359 - 5364 2000.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly active in immortalized cells and >85% of human cancers but is quiescent in most normal somatic cells. To test the feasibility of using the hTERT promoter to induce tumor-specific transgene expression in cancer gene therapy, we constructed an adenoviral vector expressing a LacZ reporter gene driven by the hTERT core promoter and evaluated its activity in vitro and in vivo. The hTERT promoter could drive high-level expression of LacZ in tumor cells but not in normal cells and normal mouse tissues. Using a binary adenoviral system that can induce Bax gene expression, we showed that induction of the Bax gene expression via the hTERT promoter elicited tumor-specific apoptosis in vitro, suppressed tumor growth in nude mice, and prevented the toxicity of the Bax gene in vitro and in vivo. Thus, the hTERT promoter is apparently a strong and tumor-selective promoter with potential application in targeted cancer gene therapy.

Antitumor effect of adenovirus-mediated Bax gene transfer on p53-sensitive and p53-resistant cancer lines

S Kagawa, J Gu, SG Swisher, L Ji, JA Roth, D Lai, LC Stephens, BL Fang

CANCER RESEARCH 60 ( 5 ) 1157 - 1161 2000.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Antitumor effects of the proapoptotic Bax gene have been evaluated in vitro and in vivo by a binary adenovirus system expressing the human Bax gene. Overexpression of the Bax gene in cultured cell fines from human lung carcinoma results in caspase activation, apoptosis induction, and cell growth suppression. Intratumoral injection of adenovirus vector expressing the Bax gene suppressed growth of human lung cancer xenografts established in nude mice. Histological examination of tumors from mice treated with the Bax gene demonstrated high levels of Bax expression and extensive apoptosis in tumors. In comparison with the treatment by an adenoviral vector expressing human p53, the Bax gene can effectively suppress tumor growth in both p53-sensitive and p53-resistant human lung carcinoma cell lines. Toxicity was not detected in liver and other systems in animals treated intralesionally with the Bax gene. Therefore, our results suggest that the Bax gene may be useful in cancer treatment.

Adenoviral Bak overexpression mediates caspase-dependent tumor killing

A Pataer, BL Fang, R Yu, S Kagawa, KK Hunt, TJ McDonnell, JA Roth, SG Swisher

CANCER RESEARCH 60 ( 4 ) 788 - 792 2000.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

One of the most promising strategies in cancer gene therapy is adenoviral transfer of proapoptotic genes. We therefore evaluated the novel strategy of adenovirally overexpressing the proapoptotic Bak gene. Our results showed marked apoptosis in cancer cells in vivo and in vitro after Bak gene transfer via a binary adenoviral vector system. This effect was not seen in a caspase 3-defective cell Line (MCF-7) and was abrogated in Bah-sensitive tumors after administration of the caspase inhibitor z-DEVD-fmk. Our results suggest that adenoviral-mediated overexpression of Bak provides a novel therapeutic strategy for cancer therapy, but this process appears to be caspase dependent.

A binary adenoviral vector system for expressing high levels of the proapoptotic gene bax

S Kagawa, SA Pearson, L Ji, K Xu, TJ McDonnell, SG Swisher, JA Roth, B Fang

GENE THERAPY 7 ( 1 ) 75 - 79 2000.1

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

The bax gene plays a critical role in signaling apoptosis and expression through gene transfer may be valuable in the treatment of a variety of apoptosis-related diseases such as cancer. However, constructing an adenoviral vector expressing a bax gene driven by a constitutive promoter has been difficult, presumably because of the gene's high proapoptotic activity. Here we report a system that induces the expression of the bax gene safely by adenovirus-mediated gene cotransfer. Briefly, the system involves an adenoviral vector containing a human bax cDNA driven by a synthetic promoter consisting of five GAL4-binding sites and a TATA box (GT). This vector expresses a minimal background level of bax protein in cultured mammalian cells thus preventing apoptosis of packaging cells. However, expression of the bax gene can be induced substantially in vitro and in vivo by transferring it into target cells along with an adenoviral vector expressing the transactivator, fusion protein GAL4/VP16. Extensive apoptosis was observed after induction of the bax gene both in cultured human lung carcinoma cells and in the livers of Balb/c mice. Our results suggest that this GAL4 gene regulatory system provides an alternative approach to constructing viral vectors that express potentially toxic genes.

Induction of differentiation-dependent apoptosis in human esophageal squamous cell carcinoma by adenovirus-mediated p21sdi1 gene transfer.

Kadowaki Y, Fujiwara T, Fukazawa T, Shao J, Yasuda T, Itoshima T, Kagawa S, Hudson LG, Roth JA, Tanaka N

Clin Cancer Res. 2000

Overexpression of the p21(sdi1) gene induces senescence-like state in human cancer cells: implication for senescence-directed molecular therapy for cancer

S Kagawa, T Fujiwara, Y Kadowaki, T Fukazawa, R Sok-Joo, JA Roth, N Tanaka

CELL DEATH AND DIFFERENTIATION 6 ( 8 ) 765 - 772 1999.8

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

Normal cells in a culture enter a nondividing state after a finite number of population doubling, which is termed replicative senescence, whereas cancer cells have unlimited proliferative potential and are thought to exhibit an immortal phenotype by escaping from senescence. The p21 gene (also known as sdi1), which encodes the cyclin-dependent kinase inhibitor, is expressed at high levels in senescent cells and contributes to the growth arrest. To examine if the p21(sdi1) gene transfer could induce senescence in human cancer cells, we utilized an adenoviral vector-based expression system and four human cancer cell lines differing in their p53 status. Transient overexpression of p21(sdi1) on cancer cells induced quiescence by arresting the cell cycle at the G(1) phase and exhibited morphological changes, such as enlarged nuclei as well as a flattened cellular shape, specific to the senescence phenotype. We also showed that p21(sid1)-transduced cancer cells expressed beta-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Moreover, the polymerase chain reaction-based assay demonstrated that levels of telomerase activity were significantly lower in p21(sdi1)-expressing cells compared to parental cancer cells. These observations provide the evidence that p21(sdi1) overexpression could induce a senescence-like state and reduce telomerase activity in human cancer cells, suggesting that these novel p21(sdi1) functions may have important implications for anticancer therapy.

Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer

Miyake Hideaki, Hanada Norihisa, Nakamura Hideo, Kagawa Shunsuke, Fujiwara Toshiyoshi, Hara Isao, Eto Hiroshi, Gohji Kazuo, Arakawa Soichi, Kamidono Sadao, Saya Hideyuki

Oncogene 16 ( 7 ) 933 - 943 1998.2

Language：English

<p>To investigate the effects of the expression of Bcl-2 protein in bladder cancer on the apoptosis induced by cisplatin or adenoviral-mediated p53 gene (Ad5CMV-p53) transfer, we transfected the bcl-2 gene into KoTCC-1, a human bladder cancer cell line that does not express the Bcl-2 protein. The Bcl-2-transfected KoTCC-1 (KoTCC-1/B) exhibited significantly higher resistance to both cisplatin and Ad5CMV-p53 transfer than did either the parental KoTCC-1 (KoTCC-1/P) or the vector-only transfected cell line (KoTCC-1/C). The flow cytometric analysis of the propidium iodide-stained nuclei and DNA fragmentation analysis after cisplatin or Ad5CMV-p53 treatment revealed DNA degradation in both KoTCC-1/P and KoTCC-1/C, whereas KoTCC1/B showed a marked inhibition of DNA degradation. Following the treatment with cisplatin or Ad5CMV-p53, the accumulation of p53 protein was highly detectable for a long period in KoTCC-1/B compared to that in KoTTC-1/P and KoTCC-1/C. Furthermore, the cisplatin and Ad5CMV-p53 treatments each reduced the volume of the subcutaneous tumors established in nude mice formed by KoTCC-1/P or KoTCC-1/C; in contrast, their reductive effects on the tumors formed by KoTCC-1/

p53遺伝子導入によるがん治療の可能性 (特集p53の生理作用--その多様性の源に迫る)

藤原俊義, 香川俊輔, 西崎正彦

細胞工学 16 ( 4 ) 556 - 563 1997.4

Novel combination therapy for human colon cancer with adenovirus- mediated wild-type p53 gene transfer and DNA-damaging chemotherapeutic agent Reviewed

Nobuyuki Ogawa, Toshiyoshi Fujiwara, Shunsuke Kagawa, Masahiko Nishizaki, Yoshinori Morimoto, Tohru Tanida, Akio Hizuta, Tutsuji Yasuda, Jack A. Roth, Noriaki Tanaka

International Journal of Cancer 73 ( 3 ) 367 - 370 1997

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

Alteration of the wild-type (wt) p53 gene by mutation, deletion or re- arrangement is a major factor in the development of human colon cancer. Recent studies have demonstrated that p53 might be an essential component of the apoptotic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We examined the anti-tumor effects of adenovirus-mediated wt-p53 gene transfer in combination with a chemotherapeutic drug on the human colon cancer cell line WiDr, which is homozygous for a mutation in the p53 gene. Treatment with the chemotherapeutic drug cisplatin following infection with a replication- deficient, recombinant adenoviral vector expressing wt-p53 (termed AdCMVp53) significantly suppressed the growth of WiDr cells compared to single treatments alone. To evaluate the in vivo efficacy of AdCMYp53 and cisplatin given sequentially, WiDr cells were inoculated s.c. in nu/nu mice. After 3 days, AdCMVp53 was injected s.c. into the area where tumor cells were implanted, followed by i.p. administration of cisplatin. Analysis of initial growth inhibition at 21 days demonstrated a profound therapeutic cooperativity, though administration of either AdCMVp53 or cisplatin alone was followed only by a slowing of growth. Our results suggest that gene therapy using wt-p53-expressing adenovirus in combination with a chemotherapeutic DNA-damaging drug could be a useful strategy for treating human colon cancer.

DOI： 10.1002/(SICI)1097-0215(19971104)73:3<367::AID-IJC11>3.0.CO;2-A

p53 expression overcomes p21WAF1/CIP1-mediated G1 arrest and induces apoptosis in human cancer cells Reviewed

Shunsuke Kagawa, Toshiyoshi Fujiwara, Akio Hizuta, Tatsuji Yasuda, Wei-Wei Zhang, Jack A. Roth, Noriaki Tanaka

Oncogene 15 ( 16 ) 1903 - 1909 1997

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

The p21WAF1/CIP1 gene, which encodes a cyclin-dependent kinase inhibitor, may be critical for tumor suppressor gene p53-induced cell cycle arrest. The p53 gene is known to regulate G1 checkpoint, which can either induce G1 arrest or initiate apoptosis. To directly examine the role of p21WAF1/CIP1 in the control of p53 function, we have introduced human p21WAF1/CIP1 gene into a p53-deficient human non-small cell lung cancer cell line H1299 using a p21WAF1/CIP1-expressing adenoviral vector (AdCMVp21). Infection with AdCMVp21 resulted in high levels of p21WAF1/CIP1 expression and significantly suppressed the growth of H1299 cells through the G1 arrest of the cell cycle. In contrast, transient expression of the wild-type p53 gene by a recombinant adenoviral vector (AdCMVp53) in H1299 cells induced apoptotic cell death and resulted in a rapid loss of cell viability. We then examined the effects of combined infection with AdCMVp21 and AdCMVp53 on H1299 cells to explore the dominant function of these molecules. Interestingly, introduction of exogenous p53 overcame p21WAF1/CIP1-mediated cell cycle arrest at G1 and induced apoptosis, although viral-transduced p21WAF1/CIP1 expression level was unaffected. These observations suggest that p53 expression converts a p21WAF1/CIP1-mediated growth arrest into apoptosis. The result was repeated with two additional human colon adenocarcinoma cell lines with the different p53 status, mutant p53-expressing DLD-1 and wild-type p53-expressing LoVo, suggesting that this phemonenon is a general event among human cancer cells. Thus, p53-mediated apoptotic pathway is dominant over the growth arrest pathway, indicating that p53 may be an essential upstream mediator of p21WAF1/CIP1 in the regulation of a cell process leading either to growth arrest or to apoptotic suicide. © 1997 Stockton Press All rights reserved.

DOI： 10.1038/sj.onc.1201362

The changing pattern of platelet count after gastrointestinal surgery according to the healing stage

Hitoshi Takeuchi, Eiji Konaga, Masahiko Kuinose, Masahiko Nishizaki, Takayoshi Murakami, Shunsuke Kagawa, Takashi Yoshioka, Yuhji Kanaoka, Kohji Tanakaya, Yoshimasa Yasui, Kazuo Tanemoto, Masaaki Kashitani, Genso Kobayashi

Japanese Journal of National Medical Services 48 ( 7 ) 483 - 487 1994

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

In order to speculate the role of platelet in the wound healing, we examined platelet count in 27 patients who showed anastomotic leakage after gastrointestinal surgery. Thirty-nine patients who did not show leakage were served as control. Results were as follows: (1) The maximal values of platelet after surgery correlated with the surgical invasion. (2) Platelet count showed biphasic pattern after surgery. At first platelet count decreased. Then the count increased and reached its maximal values in the 2nd week in the control group. However, the maximal values were obtained in the 3rd week in the case of the patients with leakage. After that, platelet count decreased to normal level in healing stage. This tendency was more prominent in early leakage group than delayed leakage group. (3) The changing pattern of platelet count after surgery did not coincide with that of white cell count. White cell count was normal in 10 out of 27 (37%) in leakage cases. However, the platelet count in these cases increased in 9 out of 10 (90%). Therefore, it is concluded that the maximum of platelet after surgery reflects surgical invasion well. The changing pattern of platelet count after surgery is useful in speculating healing stage and detecting anastomotic leakage early. © 1994, Japanese Society of National Medical Services. All rights reserved.

DOI： 10.11261/iryo1946.48.483

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