Faculty Profiles - KAGAWA Shunsuke

Papers - KAGAWA Shunsuke

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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

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