WileyActa Medica Okayama2045-76341552026Multi-Transcriptomic Analysis Reveals That EREG-Driven TME Crosstalk Defines Anti-EGFR Response in Colorectal Cancere71853ENAtsukiTaniguchiDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShunsukeKagawaDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShoheiNogiDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTomohikoYagiDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNobuhikoKanayaDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShinjiKurodaDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySatoruKikuchiDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroshiTazawaDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySidedness influences colorectal cancer (CRC) prognosis and treatment response, yet the mechanism dictating differential EGFR inhibitor (EGFRI) sensitivity is unclear. This study investigated the tumor microenvironment (TME) in relation to EGFRI eligibility―clinically defined by factors such as tumor sidedness (e.g., left-sided), RAS/BRAF wild-type status, and microsatellite stability (MSS)―using integrated single-cell RNA sequencing (scRNA-seq), with bulk RNA-seq and spatial transcriptomics validation. We found cancer cell features reflected EGFRI eligibility more strongly than sidedness. EGFRI eligible tumors exhibited high Epiregulin (EREG) expression by cancer cells. Cell interaction analysis revealed a specific “EREG/EGFR/CSF axis” in EGFRI eligible CRC: EREG derived from cancer cell stimulates EGFR-expressing non-myCAF subtypes of cancer-associated fibroblasts (CAFs), which signal via CSF to M1/M2-like Tumor-Associated Macrophages/Monocytes (TAM/TAMo), potentially promoting M2 polarization. Spatial analysis confirmed the proximity of these interacting cell populations and localized EGFR pathway activation near cancer cells specifically in eligible tumors. This study provides a TME-centric view of EGFRI eligibility, identifying a key intercellular communication network driving differential responses. These findings suggest TME features could offer more precise patient stratification than sidedness alone, potentially improving CRC therapeutic strategies.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama2950-32993422026Mitochondrial inhibition enhances the sensitivity of pancreatic ductal adenocarcinoma cells to oncolytic adenovirus201180ENRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakeyoshiNishiyamaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinoriKajiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMotohikoYamadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoNagaiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroakiInoueDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaoyukiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesThe metabolism of cancer cells is associated with resistance to anticancer therapies. Pancreatic ductal adenocarcinoma (PDAC) cells exhibit glycolytic and non-glycolytic subtypes. Although oncolytic virotherapy is a novel antitumor modality, the relationship between metabolism and virus sensitivity remains unclear. We demonstrated the cytopathic activity of telomerase-specific, replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 against PDAC cells. Here, we show the role of metabolism in the virus sensitivity of PDAC cells. The virus sensitivity of human PDAC cells of glycolytic (MIA PaCa-2, PK-45H) and non-glycolytic (PK-59, Capan-2) subtypes was assessed by evaluating replication, glycolysis, and glutamine metabolism through exposure to hypoxia and glucose deprivation or treatment with the mitochondrial metabolism inhibitor CPI-613. Glycolytic PDAC cells were sensitive, and non-glycolytic cells were resistant to oncolytic adenoviruses, which was improved by hypoxia and glucose deprivation or CPI-613 treatment to induce glycolytic activation. OBP-702-mediated p53 activation modulated glutamine metabolism to promote virus sensitivity. In vivo experiments demonstrated the antitumor efficacy of combination therapy with CPI-613 and OBP-702, and the utility of positron emission tomography/computed tomography metabolic parameters for assessing glycolytic activity. Our results suggest that non-glycolytic PDAC cells are refractory to oncolytic adenoviruses. CPI-613 is a promising reagent for overcoming virotherapy resistance in PDAC tumors.No potential conflict of interest relevant to this article was reported.International Institute of Anticancer ResearchActa Medica Okayama0250-70054642026P53-armed Oncolytic Adenovirus Enhances the Efficacy of PD-1 Blockade in Neuroblastoma by Inducing Immunogenic Cell Death17691784ENMORIMICHITANIDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHIROSHITAZAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTERUTAKATANIMOTODepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHIROSHINOUSODepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHINAKOWATANABEDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTAKANORIOYAMADepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYASUOURATAOncolys BioPharma, Inc.SHUNSUKEKAGAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTAKUONODADepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHINJIKURODADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIYOSHIFUJIWARADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground/Aim: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. Although immunotherapy with immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) has emerged as novel antitumor therapy, high-risk NB tumors are refractory to ICI therapy. Oncolytic virotherapy is expected to potentiate the antitumor immune response by inducing immunogenic cell death (ICD). In the present study, we assessed the therapeutic potential of OBP-301 and OBP-702, telomerase-specific oncolytic adenoviruses, for the induction of ICD and combined effect with PD-1 blockade against NB cells.<br>
Materials and Methods: The cytopathic activity of OBP-301 and OBP-702 was assessed using three human MYCN-amplified NB cell lines (IMR-32, LA-N-5, and NB-1) and a murine non-MYCN-amplified NB cell line (Neuro-2a). Virus-mediated antitumor effect was assessed by analyzing cell viability, secretion of extracellular adenosine triphosphate (ATP) and high-mobility group box protein B1 (HMGB1), apoptosis, autophagy, and PD-L1 levels. A subcutaneous Neuro-2a tumor model was used to evaluate the in vivo antitumor effect of combination therapy with OBP-702 and anti-PD-1 antibody.<br>
Results: OBP-702 exhibited stronger cytopathic activity, inducing ICD with secretion of ATP and HMGB1, compared to OBP-301 in human and murine NB cells. OBP-301 and OBP-702 increased apoptosis, autophagy, and PD-L1 expression in murine NB cells. Moreover, OBP-702 significantly prolonged the survival of tumor-bearing mice compared to monotherapy with PD-1 blockade.<br>
Conclusion: OBP-702 is a promising antitumor strategy to promote the antitumor effect of ICIs by inducing ICD against NB tumors.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1341-96252026Turning pancreatic cancer from cold to hot: the promise of a p53-expressing oncolytic adenovirus (OBP-702)ENShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaCenter for Innovative Clinical Medicine, Okayama University HospitalMasashiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma IncToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and poor responsiveness to immune checkpoint inhibitors (ICIs). This resistance is largely attributed to its profoundly immunosuppressive and desmoplastic tumor microenvironment (TME), characterized by low tumor mutational burden, dense stroma, and abundant immunosuppressive cell populations. Therefore, strategies capable of enhancing tumor immunogenicity and overcoming immune evasion are urgently needed. Oncolytic virotherapy is a promising approach, offering not only tumor-selective cytotoxicity, but also potent immunomodulatory effects. Of these agents, Telomelysin (OBP-301, Suratadenoturev), a telomerase-specific oncolytic adenovirus, demonstrated clinical safety but limited efficacy in refractory tumors. To address this challenge, we developed OBP-702, a next-generation, p53-armed, oncolytic adenovirus designed to augment antitumor activity. Preclinical studies have shown that OBP-702 exerts robust cytotoxicity through multiple mechanisms, including p53-mediated apoptosis and autophagy, E1A–E2F1-mediated p21 suppression, and inhibition of oncogenic KRAS pathways. Importantly, OBP-702 induces strong immunogenic cell death, activates dendritic cells, and promotes tumor-specific T-cell responses, effectively converting immunologically “cold” pancreatic tumors into “hot” tumors. OBP-702 also remodels the immunosuppressive TME by reducing granulocyte–macrophage colony-stimulating factor (GM-CSF) secretion, suppressing myeloid-derived suppressor cells (MDSCs), and targeting stromal components, such as cancer-associated fibroblasts (CAFs). These effects contribute to enhanced responses to ICIs and standard chemotherapies. Given its multifaceted antitumor functions and ability to overcome key barriers in pancreatic cancer, OBP-702 represents a highly promising therapeutic candidate. A first-in-human clinical trial evaluating endoscopic ultrasonography-guided intratumoral injection of OBP-702 is currently in preparation, expected to advance clinical translation of this novel virotherapeutic strategy.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama2950-32993342025Collagen depletion by pirfenidone enhances antitumor effect of oncolytic adenovirus against peritoneal metastases of gastric cancer201045ENTomohiroOkuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuMikaneDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesEmaMitsuiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYutaUneDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunkoOhtsukaLaboratory of Fundamental Oncology, National Cancer Center Research InstituteRiekoOhkiLaboratory of Fundamental Oncology, National Cancer Center Research InstituteShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrata Oncolys BioPharma, Inc.ToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCancer-associated fibroblasts (CAFs) play a crucial role in collagen accumulation, which develops and promotes peritoneal metastasis (PM) in gastric cancer (GC). In addition, the abundant stromal collagens in the tumor microenvironment function as a physical barrier against penetration of antitumor drugs and oncolytic viruses. This study investigated whether collagen depletion by pirfenidone (PFD), an antifibrotic drug, enhances the antitumor effects of oncolytic adenoviruses. Analysis of the clinical samples revealed a significant association of high expression of collagen 1 and α-smooth muscle actin (α-SMA) with PM development and poor prognosis of advanced GC. Human and murine GC cells enhanced collagen production by fibroblasts, which was suppressed by PFD. Abundant fibroblasts and collagen inhibited the penetration of OBP-702, which reduced the antitumor effects of OBP-702 in the spheroid model. Intraperitoneal co-injection of GC cells and fibroblasts promoted the development of collagen-rich PM and reduced the antitumor effects of OBP-702 in vivo model. PFD suppressed collagen production in PM and improved viral penetration into the tumors, which enhanced the antitumor effects of OBP-702 against PM of GC. Collagen depletion by PFD enhances the penetration of OBP-702 into PM of GC, in turn enhancing the antitumor effects of OBP-702 against PM of GC.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1432-08517512025Gut microbial metabolite butyrate boosts p53-expressing telomerase-specific oncolytic adenovirus efficacy by enhancing infectivity and activating MHC-I/cGAS-STING10ENMasakiSakamotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsuyaKatayamaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuMikaneDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunyaHanzawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDaisukeKadowakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiHamadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyomaSugimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChiakiYagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesThe gut microbiota plays an essential role in regulating host immunity, and its metabolites such as butyrate exert immunomodulatory effects by acting as histone deacetylase inhibitors. Oncolytic virotherapy has emerged as a promising approach for cancer treatment, and we have developed OBP-702, a telomerase-specific oncolytic adenovirus that expresses p53 and elicits strong systemic antitumor responses. In this study, the potential synergy between butyrate and OBP-702 was investigated in colorectal cancer models. Using human and murine colorectal carcinoma cell lines, butyrate was found to directly enhance the infectivity of OBP-702 by upregulating CAR and integrins, thereby promoting apoptosis and autophagy in tumor cells. In addition, butyrate indirectly boosted systemic antitumor immunity by upregulating MHC-I expression through activation of the cGAS-STING pathway and enhancing CD8 + T cell recruitment via CXCL10 secretion. These findings were supported by in vivo experiments using CT26 subcutaneous, bilateral, and orthotopic tumor models, in which the combination of oral butyrate and intratumoral OBP-702 administration produced synergistic antitumor effects. These results highlight the therapeutic potential of integrating gut microbial metabolites with oncolytic virotherapy as a novel immunotherapeutic strategy for colorectal cancer.No potential conflict of interest relevant to this article was reported.International Institute of Anticancer ResearchActa Medica Okayama0250-70054612025P53-Armed Oncolytic Virotherapy Promotes the Efficacy of PD1 Blockade in Murine Osteosarcoma Tumors6984ENMIHOKUREDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHIROSHITAZAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKOJIDEMIYADepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHIROYAKONDODepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYUSUKEMOCHIZUKIDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTADASHIKOMATSUBARADepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAKIYOSHIDADepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKOJIUOTANIDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJOEHASEIDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOMOHIROFUJIWARADepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIYUKIKUNISADADepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYASUOURATADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHUNSUKEKAGAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIFUMIOZAKIDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIYOSHIFUJIWARADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground/Aim: Osteosarcoma (OS) is refractory to immune checkpoint inhibitors targeting programmed cell death 1 (PD1)/PD ligand 1 (PD-L1) due to poor immune response. We previously developed telomerase-specific, replication-competent oncolytic adenoviruses non-armed OBP-301 and P53-armed OBP-702 that exert antitumor efficacy against human OS cells. Recently, we demonstrated that P53-armed OBP-702 induces more profound immunogenic cell death and antitumor immune response against human and murine OS cells than does non-armed OBP-301. In the present study, we assessed the combined efficacy of PD1 blockade and P53-armed OBP-702 against murine OS cells.<br>
Materials and Methods: Three murine OS cell lines (K7M2, NHOS, NHOS-LM4) were used to assess the cytopathic effect of non-armed OBP-301 and P53-armed OBP-702 by XTT assay. Virus-induced immunogenic cell death was assessed by analyzing the levels of extracellular adenosine triphosphate and high-mobility group box protein B1. The expression of PD-L1 and PD-L2 was analyzed by flow cytometry. The malignant potential of NHOS-LM4 cells was analyzed by a migration and invasion assay. An orthotopic NHOS-LM4 tumor model was used to evaluate the antitumor efficacy of combination therapy with P53-armed OBP-702 and anti-PD1.<br>
Results: P53-armed OBP-702 exhibited antitumor potential for the induction of immunogenic cell death, apoptosis, autophagy, and PD-L1/2 upregulation in K7M2 and NHOS cells. NHOS-LM4 cells showed increased migratory and invasive ability compared to NHOS cells. P53-armed OBP-702 significantly suppressed the malignant potential of NHOS-LM4 cells. Combination dosing showed that P53-armed OBP-702 significantly promoted the antitumor effect of PD1 blockade against NHOS-LM4 tumors.<br>
Conclusion: Our results suggest that P53-armed OBP-702 is a promising agent for improving the antitumor effect of PD1 blockade in treating invasive OS.No potential conflict of interest relevant to this article was reported.International Institute of Anticancer ResearchActa Medica Okayama0250-70054612025Near-infrared Photoimmunotherapy Targeting High-risk Human Neuroblastoma Cells Expressing GD22538ENHIROSHINOUSODepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHIROSHITAZAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTERUTAKATANIMOTODepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMORIMICHITANIDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHINAKOWATANABEDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTAKANORIOYAMADepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKAZUHIRONOMADepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHUNSUKEKAGAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHISATAKAKOBAYASHIMolecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of HealthTAKUONODADepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHINJIKURODADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIYOSHIFUJIWARADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground/Aim: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system in infancy. Despite advances in treatment, the prognosis remains poor for high-risk NB patients. Although immunotherapy using anti-GD2 antibodies is available for high-risk NB, the therapeutic efficacy is insufficient. Near-infrared photoimmunotherapy (NIR-PIT) is an antitumor strategy that induces tumor-specific cytotoxicity by combining an antibody-photoabsorber conjugate (APC) with NIR light irradiation. In this study, we investigated the therapeutic efficacy of GD2-targeted NIR-PIT against human NB cells.<br>
Materials and Methods: GD2 expression was analyzed on the surface of high-risk human NB cells (CHP-134, LA-N-5, IMR-32) and non-high-risk human NB cells (SK-N-SH) by flow cytometry. The APC was synthesized by incubating anti-GD2 antibody and IR700. The cytotoxic effect of GD2-targeted NIR-PIT was evaluated using the XTT assay. The distribution of dead cells within tumor spheres was evaluated using a live/dead assay. The in vivo antitumor effect of GD2-targeted NIR-PIT was assessed using a subcutaneous human NB xenograft tumor model.<br>
Results: GD2 protein was expressed on the surface of CHP-134, LA-N-5, and IMR-32 cells but not SK-N-SH cells. GD2-targeted NIR-PIT significantly suppressed the viability of GD2-positive NB cells but not GD2-negative NB cells, compared to the control and monotherapy groups. GD2-targeted NIR-PIT significantly reduced the volume of GD2-positive CHP-134 tumor spheres by inducing the accumulation of dead cells. Subcutaneous CHP-134 xenograft tumor models demonstrated that GD2-targeted NIR-PIT significantly inhibited tumor growth compared with the control and monotherapy groups.<br>
Conclusion: GD2-targeted NIR-PIT is a promising antitumor strategy for treating high-risk NB tumors expressing GD2.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama2468-2942452025Neoadjuvant FOLFOXIRI for locally advanced rectal cancer: A retrospective analysis focusing on long-term anal preservation101049ENRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiMatsumiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshikoMoriDepartment of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical UniversityShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTo investigate the safety and efficacy of FOLFOXIRI as neoadjuvant chemotherapy (NAC) for locally advanced rectal cancer (LARC). The outcomes of preoperative and perioperative treatments, as well as long-term outcomes, were retrospectively compared between 26 patients who underwent FOLFOXIRI as NAC for LARC with cT3–4 and/or N+ at our institute between 2015 and 2022, and 31 patients with LARC who underwent neoadjuvant chemoradiotherapy (CAPOX-RT) at our institute between 2011 and 2022. Grade 3 or higher adverse events due to neoadjuvant treatment were significantly more common in the FOLFOXIRI group (11 cases, 42.3 %) than in the CAPOX-RT group (3 cases, 9.7 %), and most of these were neutropenia. Based on the postoperative pathological findings, the complete response rate was significantly lower in the FOLFOXIRI group (1 case, 3.8 %) than in the CAPOX-RT group (7 cases, 22.6 %), but there were no significant differences in the R0 resection rate, survival rate, or relapse-free survival rate. In the CAPOX-RT group, 17 patients (54.8 %) had anal preservation, and during the observation period, 4 patients required stoma construction due to loss of anal function in the late stage. In contrast, in the FOLFOXIRI group, there were no cases of loss of anal function among the 20 patients (76.9 %) who had anal preservation. FOLFOXIRI as NAC requires caution regarding hematological toxicity, but it can be an effective treatment option for patients with LARC who wish to preserve their anus.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0929-19032025p53-armed oncolytic adenovirus induces apoptosis in pancreatic cancer-associated stellate cells via macropinocytosisENTakeyoshiNishiyamaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoNagaiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinoriKajiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaoyukiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYosukeTakahashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyoshi Y.TanakaDepartment of Pharmaceutical Biomedicine, Okayama University Graduate School of Interdisciplinary Science and Engineering in Health SystemsMitsunobu R.KanoDepartment of Pharmaceutical Biomedicine, Okayama University Graduate School of Interdisciplinary Science and Engineering in Health SystemsAtsushiMasamuneDivision of Gastroenterology, Tohoku University Graduate School of MedicineYasuoUrataOncolys BioPharma, Inc.ShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPancreatic ductal adenocarcinoma (PDAC)-associated pancreatic stellate cells (PSCs) promote PDAC tumor progression. Notably, PDAC tumors display enhanced macropinocytosis, resulting in enhanced uptake of extracellular particles, including nutrients and viruses. We previously demonstrated the therapeutic potential of telomerase-specific oncolytic adenoviruses OBP-301 and p53-armed OBP-702 against human PDAC cells. However, it remains unclear whether macropinocytosis promotes the virus sensitivity of PDAC-associated PSCs. Here, we show that PSCs activated by human PDAC cells (Panc-1 and BxPC-3) exhibit enhanced sensitivity to wild-type and oncolytic adenoviruses via enhanced macropinocytosis. The virus sensitivity of PSCs was analyzed for the infectivity, replication, and cytopathic activity of wild-type and oncolytic adenoviruses. PDAC-associated PSCs were more sensitive to wild-type and oncolytic adenoviruses than were control PSCs; this sensitivity was mediated by activation of macropinocytosis. In three-dimensional (3D) culture models, p53-armed OBP-702 decreased the viability of PDAC-associated PSCs more strongly than did non-armed OBP-301, reflecting induction of p53-mediated apoptosis. Co-inoculation of PSCs enhanced the growth of PDAC tumors, an effect that was attenuated by OBP-702-mediated p53 activation in the tumor stroma. Our results suggest that p53-armed oncolytic adenovirus OBP-702 eliminates PDAC-associated PSCs via enhancement of macropinocytosis-mediated virus entry and induction of p53-mediated apoptosis.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1436-32912862025Gallbladder edema as a clue to zolbetuximab-associated protein-losing enteropathy in gastric cancer: a case report12971301ENYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShinjiKurodaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunyaHanzawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineNobuhikoKanayaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineHajimeKashimaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineSatoruKikuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYoshiyasuKonoDepartment of Gastroenterology and Hepatology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunsukeKagawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineWe report a rare case of protein-losing enteropathy (PLE) during zolbetuximab treatment in a 73-year-old woman with Stage IVB gastric cancer. After chemo-immunotherapy and curative surgery, 3rd-line treatment with capecitabine, oxaliplatin, and zolbetuximab was initiated due to recurrence. The patient developed persistent right upper abdominal pain; imaging revealed gallbladder wall edema, followed by mild gastric wall edema, despite unremarkable laboratory findings. Protein-losing scintigraphy demonstrated abnormal gastric protein leakage, leading to a diagnosis of PLE. While gastrointestinal toxicity is known with zolbetuximab, this is, to our knowledge, the first clinically diagnosed case of PLE in which gallbladder edema served as a diagnostic clue. As treatment strategies for advanced gastric cancer grow increasingly complex, achieving maximum therapeutic benefit requires not only optimal drug selection but also timely recognition and management of adverse events. With the broader use of zolbetuximab, clinicians should be mindful of this rare but potentially significant complication.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1471-230X2512025Neoadjuvant chemotherapy strategies for optimizing safety and efficacy in elderly patients with locally advanced gastric cancer670ENYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShinjiKurodaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunyaHanzawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineNobuhikoKanayaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineHajimeKashimaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineSatoruKikuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunsukeKagawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineBackground The completion rate of adjuvant chemotherapy for gastric cancer (GC) is suboptimal, particularly in elderly patients. While neoadjuvant chemotherapy (NAC) for locally advanced GC has shown promise, data on elderly patients remain limited. Given the considerable physical burden of NAC, optimizing its administration is crucial. This study evaluates the safety and efficacy of a modified approach for elderly patients.<br>
Methods A retrospective analysis was conducted on 38 patients with cStage II/III GC who received NAC between November 2015 and December 2023. Additionally, 25 patients aged ≥ 75 years with cStage III who underwent upfront surgery during the same period were analyzed.<br>
Results The NAC group was divided into non-elderly (< 75 years, n = 27) and elderly (≥ 75 years, n = 11) groups. The elderly group had poorer ECOG-PS (p = 0.016). While all non-elderly patients completed ≤ 3 cycles, more elderly patients underwent 4 cycles (p = 0.0047). However, per-cycles of S-1 (p = 0.0003) and oxaliplatin (p = 0.0018) were lower in the elderly group. Importantly, adverse events and treatment efficacy were comparable between groups. Among patients aged ≥ 75 years, the upfront surgery group had poorer ECOG-PS (p = 0.017) and underwent more frequent distal gastrectomy (p = 0.014).<br>
Conclusions NAC can be safely administered to elderly patients by increasing cycles while reducing per-cycle dosage. It may also serve as a viable alternative to upfront surgery.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2045-23221512025Serum extracellular vesicles containing adenoviral E1A-DNA as a predictive biomarker for liquid biopsy in oncolytic adenovirus therapy38590ENChiakiYagiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShinjiKurodaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunyaHanzawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineDaisukeKadowakiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYusukeYoshidaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineMasakiSakamotoDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYukiHamadaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineRyomaSugimotoDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineTomokoOhtaniDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKentoKumonDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineMasashiHashimotoDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineNobuhikoKanayaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineSatoruKikuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunsukeKagawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineHiroshiTazawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYasuoUrataOncolys BioPharma, Inc.ToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineOncolytic adenoviruses replicate selectively in tumor cells and induce immunogenic cell death, but predictive biomarkers for early therapeutic response are lacking. This study evaluated extracellular vesicle-encapsulated adenoviral E1A-DNA (EV-E1A-DNA) as a minimally invasive biomarker for monitoring responses to telomerase-specific oncolytic adenoviruses OBP-301 and OBP-502. EVs were isolated from human and murine cancer cell lines and from the serum of treated mice using ultracentrifugation. EV-associated E1A-DNA levels were measured by quantitative polymerase chain reaction and found to correlate with cytotoxicity in vitro and tumor regression in vivo. In xenograft models, serum EV-E1A-DNA levels at 2 days post-treatment showed strong correlations with final tumor volume and survival, supporting their utility as an early predictive biomarker. In immunocompetent mice pre-immunized with wild-type adenovirus, free viral DNA was undetectable in serum due to neutralizing antibodies, whereas EV-E1A-DNA remained detectable. This “stealth effect” indicates that EVs protect viral components from immune clearance. These results demonstrate that EV-E1A-DNA is a sensitive and virus-specific biomarker that enables early assessment of therapeutic efficacy, even in the presence of antiviral immunity. This strategy offers a promising liquid biopsy approach for personalized monitoring of oncolytic virotherapy and may be applicable to other virus-based therapies.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0007-09202025Gemcitabine-induced neutrophil extracellular traps via interleukin-8-CXCR1/2 pathway promote chemoresistance in pancreatic cancerENShoheiNogiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtsukiTaniguchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohikoYagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaYasuiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokazuFujiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshiyasuKonoDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKoseiTakagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, and chemoresistance poses a significant challenge in its treatment. Neutrophil extracellular traps (NETs) have emerged as key players in the tumour microenvironment, but their role in chemoresistance remains unclear.<br>
Methods: We investigated the involvement of NETs in PDAC chemoresistance using patient tumour samples, in vitro assays with gemcitabine (GEM)-treated PDAC cells, and in vivo mouse models. We evaluated cytokine production, NET formation and tumour response to GEM, with or without the CXCR1/2 inhibitor navarixin.<br>
Results: NETs are significantly accumulated in the tumours of PDAC patients exhibiting poor response to chemotherapy. GEM-treated PDAC cells secrete pro-inflammatory cytokines such as interleukin-8 (IL-8). IL-8 promote the formation of chemotherapy-induced NETs (chemoNETosis) through activation of CXCR 1/2 on neutrophils. Importantly, treatment with navarixin significantly suppressed chemoNETosis, restored sensitivity to GEM, and significantly reduced tumour growth in vivo.<br>
Conclusions: Our findings reveal that NETs contribute to chemoresistance in PDAC and that IL-8–mediated chemoNETosis plays a pivotal role in this process. Inhibition of CXCR1/2-mediated NET formation enhances the efficacy of GEM. This approach may represent a promising therapeutic strategy for overcoming chemoresistance in PDAC. These results support further clinical investigation of anti-NETs therapies.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1865-72572025A case of retrograde colonic intussusception by tubulovillous adenomaENMichikoIkiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIntroduction Retrograde colonic intussusception is a rare condition in adults, often caused by organic lesions such as tumors. Autonomic dysfunction in disorders like multiple system atrophy (MSA) might contribute to its occurrence.<br>
Case presentation An 81-year-old bedridden woman with a history of MSA presented with severe abdominal pain and abdominal distension lasting 4 days. She had chronic severe constipation managed with laxatives and manual disimpaction. CT imaging revealed retrograde intussusception of the rectum into the sigmoid colon. Endoscopic reduction was attempted but was unsuccessful due to scope impassability. Emergency laparotomy identified a 4–5 cm tumor at the lead point, and manual reduction resulted in bowel perforation. Hartmann’s procedure with D2 lymphadenectomy was performed. The tumor was histopathologically diagnosed as a tubulovillous adenoma with no malignant features. The patient’s postoperative recovery was uneventful except for a urinary tract infection (Clavien–Dindo Grade II), and she was transferred to a rehabilitation facility on postoperative day 24.<br>
Conclusion Failure of reduction by air enema should raise suspicion for retrograde intussusception, warranting prompt surgery if an organic lead point is suspected.No potential conflict of interest relevant to this article was reported.Japan Surgical SocietyActa Medica Okayama2198-77931112025Obese Patient with Gastric Diverticulum Undergoing Laparoscopic Sleeve Gastrectomy Guided by Preoperative Endoscopic Measurement: A Case Report and Literature Reviewcr.25-0141ENKensukeHirosunaCenter for Graduate Medical Education, Okayama University HospitalHajimeKashimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYukiMatsumiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesINTRODUCTION: Gastric diverticulum is a rare condition, often asymptomatic and incidentally detected. Laparoscopic sleeve gastrectomy (LSG) is a widely performed bariatric procedure, but a gastric diverticulum complicates surgical planning. In this case, careful preoperative assessment allowed safe execution of LSG despite the diverticulum’s proximity to the esophagogastric junction.<br>
CASE PRESENTATION: A 45-year-old woman (BMI: 46.8 kg/m2) with hypertension, dyslipidemia, and glucose intolerance was referred for bariatric surgery after unsuccessful weight loss with conservative management. Preoperative endoscopy revealed an 18 × 14 mm gastric diverticulum on the posterior wall of the gastric fundus, 40 mm from the esophagogastric junction. LSG was performed using a surgical stapler, ensuring complete diverticulum resection while preserving gastric tube integrity. The surgery was uneventful, with minimal blood loss and a duration of 2 hours and 52 minutes. The patient had an uneventful postoperative course and was discharged on day 9. Her BMI decreased to 39.3 kg/m2 at the 1-year follow-up, with improved metabolic parameters.<br>
CONCLUSIONS: This case highlights the importance of thorough preoperative evaluation when performing LSG in patients with gastric diverticulum. Accurate endoscopic measurement of the diverticulum’s location aids in determining the optimal resection line, ensuring surgical safety and efficacy. Surgeons should remain vigilant when encountering such anatomical variations to optimize outcomes in bariatric surgery.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1435-245141012024An effective surgical educational system in the era of robotic surgery: “Double-Surgeon Technique” in robotic gastrectomy for minimally invasive surgery20ENYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHajimeKashimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPurpose 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.<br>
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).<br>
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.<br>
Conclusion Surgical education using the DST could be effective in the current context of the need for RG and LG.No potential conflict of interest relevant to this article was reported.Japan Surgical SocietyActa Medica Okayama2198-77931112025A Case of Omental Bleeding as a Result of Segmental Arterial Mediolysis Treated Successfully by Laparoscopic Partial Omentectomycr.25-0262ENYudaiMimataDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHitoshiMinagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesINTRODUCTION: Segmental arterial mediolysis (SAM) is a rare, non-atherosclerotic, non-inflammatory arteriopathy characterized by lysis of the arterial media, leading to aneurysm formation and possible rupture. Although visceral arteries are typically involved, SAM-induced omental bleeding is extremely uncommon. While transcatheter arterial embolization (TAE) has been reported, surgical resection offers both definitive hemostasis and histopathological confirmation.<br>
CASE PRESENTATION: A 56-year-old man presented with upper abdominal pain without a history of trauma. Contrast-enhanced CT revealed a hematoma and fusiform dilation of an omental artery, suggesting omental hemorrhage. As he was hemodynamically stable, initial conservative management was chosen. However, a follow-up CT on day 7 demonstrated aneurysm enlargement, prompting laparoscopic partial omentectomy. Intraoperative findings included a 5-cm hematoma in the central omentum. Histopathological examination showed vacuolization of the tunica media and loss of the internal elastic lamina, confirming the diagnosis of SAM. The patient had an uneventful postoperative course and was discharged on the 3rd postoperative day.<br>
CONCLUSIONS: This rare case of SAM-related omental bleeding was successfully treated with laparoscopic partial omentectomy. Tailored treatment strategies including laparoscopic surgery are essential for optimal outcomes in SAM.<br>No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1435-245140912024Subjective global assessment for nutritional screening and its impact on surgical outcomes: A prospective study in older patients with colorectal cancer356ENFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiMatsumiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRieTamuraPerioperative Management Center, Okayama University HospitalYoshikazuMatsuokaPerioperative Management Center, Okayama University HospitalHiroshiMorimatsuPerioperative Management Center, Okayama University HospitalToshiharuMitsuhashiCenter for Innovative Clinical Medicine, Okayama University HospitalToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPurpose 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.<br>
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.<br>
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).<br>
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.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2045-23221512025ADAR1 as a prognostic marker for patients with colorectal cancer and synchronous liver metastasis and a predictor of chemotherapy efficacy26752ENKaoriNittaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHibikiUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshiakiTakahashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaMoriwakeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuhiroYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShoTakedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYukiMatsumiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroyukiKishimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTomokazuFujiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaYasuiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKoseiTakagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasashiKayanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeNakamuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroyukiMichiueNeutron Therapy Research Center, Okayama UniversityHidekiYamamotoDepartment of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYuheiKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesEikiMiyakeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYusukeYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesRNA editing by adenosine deaminase acting on RNA (ADAR) enzymes plays a role in cancer progression. However, its clinical significance in metastatic colorectal cancer (CRC) remains unclear. This study aimed to evaluate whether ADAR1 expression predicts prognosis and treatment response in colorectal cancer (CRC) with synchronous liver metastasis. This study included 40 patients with stage IV CRC and synchronous liver metastases. ADAR1 expression in tumor tissues was evaluated using immunohistochemistry. Expression levels were quantified using the immunoreactive score, and associations with clinicopathological features, overall survival (OS), and chemotherapy response were examined. High ADAR1 expression was significantly associated with multiple liver metastases (P = 0.0206), lymph node metastasis (P = 0.0241), and reduced response to chemotherapy (P = 0.0224). Significantly shorter OS was observed in patients with high ADAR1 expression in the nucleus (P = 0.0458). ADAR1 expression was an independent prognostic factor comparable to the presence of extrahepatic metastases. Low ADAR1 expression was correlated with a higher likelihood of achieving a response to chemotherapy. ADAR1 expression can reflect tumor aggressiveness and chemotherapy resistance in patients with CRC and synchronous liver metastasis. ADAR1 has considerable potential as a dual-purpose biomarker for stratifying patients based on prognosis and optimizing treatment intensity.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2059-01051012025Oncolytic virus-mediated p53 activation boosts the antitumor immunity of a p53-transduced dendritic cell vaccine158ENMotohikoYamadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKantoSuemoriDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaohiroOkadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinoriKajiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoNagaiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroakiInoueDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaoyukiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiMichiueNeutron Therapy Research Center, Okayama University HospitalYasuoUrataOncolys BioPharma, IncShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDendritic cells (DCs) transduced with replication-deficient, wild-type human p53-expressing adenovirus Ad-p53 (Ad-p53 DCs) induce p53-targeting cytotoxic T lymphocytes (CTLs). However, the antitumor efficacy of Ad-p53 DCs is diminished by weak p53 immunogenicity in tumor cells and poor immune responses. We developed a p53-armed oncolytic adenovirus, OBP-702, to induce tumor-specific p53 expression and antitumor immune response, suggesting a role for OBP-702 in enhancing the antitumor efficacy of Ad-p53 DCs. The combined effect of Ad-p53 DCs and OBP-702 was investigated using murine colon cancer (CC) tumor models. Ad-p53 DCs were obtained by stimulating bone marrow-derived cells with granulocyte-macrophage colony-stimulating factor, interleukin-4, and Ad-p53. Subcutaneous tumor models of CT26 (p53 wild-type) and MC38 (p53 mutant-type) murine CC cell lines were used to evaluate the therapeutic potential of combination therapy in the terms of tumor growth, abscopal effect, antitumor immune response, and presentation of p53 peptides in tumor cells. Combination therapy with Ad-p53 DCs and OBP-702 significantly suppressed the growth of p53-intact CT26 tumors at treated and untreated sites by inducing tumor-infiltration of CD8+ CTLs and CD11c+ DCs. OBP-702-infected tumor cells presented human p53 epitopes in the context of major histocompatibility complex molecules, which were recognized by CTLs induced by Ad-p53 DCs. Combination therapy significantly suppressed the growth of p53-mutant MC38 tumors by activating the antitumor immune response. Our results suggest that OBP-702-mediated presentation of p53 epitopes on tumor cells enhances the antitumor efficacy of Ad-p53 DCs against murine CC tumors by attracting p53-targeting CTLs.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama0340-70047472025Osteosarcoma cell-derived CCL2 facilitates lung metastasis via accumulation of tumor-associated macrophages193ENHiroyaKondoDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohiroFujiwaraDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkiYoshidaDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMihoKureDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKojiDemiyaDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiHataDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKojiUotaniDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJoeHaseiDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyukiKunisadaDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeYoshiokaDepartment of Molecular and Cellular Medicine, Tokyo Medical UniversityToshifumiOzakiDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOsteosarcoma (OS) is the most common malignant tumor of bone in children and adolescents. Although lung metastasis is a major obstacle to improving the prognosis of OS patients, the underlying mechanism of lung metastasis of OS is poorly understood. Tumor-associated macrophages (TAMs) with M2-like characteristics are reportedly associated with lung metastasis and poor prognosis in OS patients. In this study, we investigated the metastasis-associated tumor microenvironment (TME) in orthotopic OS tumor models with non-metastatic and metastatic OS cells. Non-metastatic and metastatic tumor cells derived from mouse OS (Dunn and LM8) and human OS (HOS and 143B) were used to analyze the TME associated with lung metastasis in orthotopic OS tumor models. OS cell-derived secretion factors were identified by cytokine array and enzyme-linked immunosorbent assay (ELISA). Orthotopic tumor models with metastatic LM8 and 143B cells were analyzed to evaluate the therapeutic potential of a neutralizing antibody in the development of primary and metastatic tumors. Metastatic OS cells developed metastatic tumors with infiltration of M2-like TAMs in the lungs. Cytokine array and ELISA demonstrated that metastatic mouse and human OS cells commonly secreted CCL2, which was partially encapsulated in extracellular vesicles. In vivo experiments demonstrated that while primary tumor growth was unaffected, administration of CCL2-neutralizing antibody led to a significant suppression of lung metastasis and infiltration of M2-like TAMs in the lung tissue. Our results suggest that CCL2 plays a crucial role in promoting the lung metastasis of OS cells via accumulation of M2-like TAMs.No potential conflict of interest relevant to this article was reported.BMCActa Medica Okayama1476-45982412025ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer116ENHibikiUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshiakiTakahashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaMoriwakeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuhiroYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShoTakedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYukiMatsumiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroyukiKishimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTomokazuFujiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaYasuiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHidekiYamamotoDepartment of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKoseiTakagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasashiKayanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroyukiMichiueNeutron Therapy Research Center, Okayama UniversityKeiichiroNakamuraDepartment of Obstetrics and Gynecology, Okayama University Gradu�ate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshikoMoriDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesAjayGoelDepartment of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute, City of Hope Comprehensive Cancer CenterToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesBackground 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.<br>
Methods The effects of RNA-editing on phenotypes in macrophages were analyzed using clinical samples and in vitro and in vivo models.<br>
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 NF kappa B 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.<br>
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.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2049-41732025Novel Therapeutic Algorism in Patients With Anterior Cutaneous Nerve Entrapment SyndromeENYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAmiKobayashiDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical SchoolKyosukeArakawaDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of MedicineYoshikazuMatsuokaDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of MedicineYudaiMimataDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground: Anterior cutaneous nerve entrapment syndrome (ACNES) is often overlooked as a cause of chronic abdominal pain. Trigger point injections (TPIs) serve as both a diagnostic and therapeutic tool. Although neurectomy is frequently chosen for patients with severe ACNES, its surgical outcomes remain unclear.<br>
Aim: This study aims to evaluate both the short- and long-term outcomes for neurectomy and propose a novel therapeutic algorithm.<br>
Methods: A cohort of postoperative patients presenting with ACNES between 2016 and 2023 was retrospectively evaluated. Patients received a single diagnostic TPI. When the pain subsided, an anterior neurectomy was performed using either an anterior or laparoscopic approach. Pain scores were assessed using the numeric rating scale (NRS).<br>
Results: Among 37 patients (60% females, mean age 33.8 ± 3.4 years), 29 patients (78.4%) experienced pain recurrence following initial neurectomy. Of these, 22 patients underwent repeat neurectomies, resulting in complete remission in 15 patients and no benefit in 7 patients. Long-term outcomes showed that 62.2% achieved clinical remission (NRS = 0), whereas 8.1% reported reduced but persistent pain (NRS 1–2). Preoperative TPI effectiveness was a strong predictor of surgical success, with patients achieving post-TPI NRS (0–1) significantly more likely to attain remission (p = 0.0074). Older age was also associated with higher remission rates (p = 0.0476).<br>
Conclusion: TPI is critical for predicting neurectomy success. These findings support the integration of preoperative TPI evaluation and tailored surgical strategies to optimize outcomes for patients with ACNES.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0941-43553342025Cancer-related alopecia and wig acquisition: how age, sex, and treatment affect patient choices283ENHidekiKatayamaDepartment of Palliative and Supportive Care, Okayama University HospitalEikiIchiharaCenter for Clinical Oncology, Okayama University HospitalAyakoMoritaDepartment of Allergy and Respiratory Medicine , Okayama University HospitalGoMakimotoDepartment of Allergy and Respiratory Medicine , Okayama University HospitalShunsukeKagawaCenter for Clinical Oncology, Okayama University HospitalAyanoIshiiIntegrated Support Center for Patients and Self-Learning , Okayama University HospitalMasahiroTabataDepartment of Palliative and Supportive Care, Okayama University HospitalYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalPurpose This study aimed to explore the prevalence and cost of wig purchases among patients with cancer in Okayama Prefecture, Japan, and examine the relationship between wig purchases and various demographic, social, and clinical factors. The findings aim to provide insights into appearance care and support systems for patients with cancer, particularly wig subsidies.<br>
Methods A survey was conducted between July and August 2023 among 3000 patients with cancer at 13 designated cancer care hospitals in Okayama Prefecture. Data on demographics, cancer treatment status, and wig purchase details were collected. Statistical analyses, including the Mann–Whitney U test, chi-square test, and logistic regression, were performed to identify factors significantly associated with wig purchases.<br>
Results Among the 863 respondents, 31.4% (271 patients) reported purchasing wigs. Factors significantly associated with wig purchase included young age (odds ratio [OR] = 1.04), female sex (OR = 1.61), and current cancer treatment (OR = 1.16). No significant correlation was found between wig purchase and household income, although higher-income patients tended to purchase more expensive wigs.<br>
Conclusion The findings suggest that younger female patients with cancer and those undergoing treatment were more likely to purchase wigs, highlighting the importance of appearance care and the need for enhanced financial support for low-income patients.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama0340-70047432025Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone96ENTomohikoYagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShoheiNogiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtsukiTaniguchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiYoshimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKantoSuemoriDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoNagaiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShutoFujitaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKoseiTakagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartments of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground 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.<br>
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.<br>
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.<br>
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.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2045-23221512025Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer3267ENEmaMitsuiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohiroOkuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYutaUneDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNoriyukiNishiwakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunkoOhtsukaLaboratory of Fundamental Oncology, National Cancer Center Research InstituteRiekoOhkiLaboratory of Fundamental Oncology, National Cancer Center Research InstituteToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCancer-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 alpha-smooth muscle (alpha-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 alpha-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 alpha-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.No potential conflict of interest relevant to this article was reported.Anticancer Research USA Inc.Acta Medica Okayama0258-851X3912024Effect of Oral Nutritional Supplements Composed of High Protein on Body Weight Loss After Gastrectomy426432ENSATORUKIKUCHIDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNOBUOTAKATADepartment of Gastroenterological Surgery, Kochi Health Sciences CenterYOSHIHIKOKAKIUCHIDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHINJIKURODADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHAJIMEKASHIMADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHUNSUKETANABEDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKAZUHIRONOMADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAYAKOTAKAHASHIDepartment of Clinical Nutrition, Okayama University HospitalSHUNSUKEKAGAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIYOSHIFUJIWARADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground/Aim: Body weight loss (BWL) after gastrectomy for gastric cancer (GC) decreases postoperative quality of life and survival in patients with GC. This study aimed to evaluate the effect of oral nutritional supplements composed of high protein on BWL in the early period following gastrectomy. Patients and Methods: Pre- and postoperative body weight and skeletal muscle mass were measured using bioelectrical impedance analysis in patients undergoing radical gastrectomy for GC and analyzed retrospectively. Patients received either a regular diet (control group, n=43) or 250 ml (320 kcal) per day of a high-protein oral nutritional supplement (ONS) (22 g protein) in addition to their regular diet (ONS group, n=40) for four weeks after gastrectomy. The actual daily intake of ONS was recorded by patients themselves. The BWL and skeletal muscle loss (SML) at one month after surgery were compared between the two groups. Results: BWL and SML at one month after surgery were similar between the two groups. In the ONS group, patients were divided into two subgroups (ONS-H and ONS-L) according to whether their ONS intake amount was above or below the average value of 216 kcal. The ONS-H group (ONS intake ≥216 kcal) showed significantly lower BWL compared to the control group (−4.6±2.6% vs. −6.2±2.5%; p=0.03). Moreover, the ONS group showed significantly lower BWL at one month after surgery than the control group in cases of total or proximal gastrectomy (−5.9±3.0% vs. −7.8±1.9%; p=0.04), although no significant difference was observed between the two groups in distal gastrectomy. The hematological nutritional parameters were similar between the two groups. Conclusion: The administration of ONS composed of high protein for four weeks after gastrectomy did not improve BWL at one month after gastrectomy. However, adequate amount of ONS intake and ONS intake after total or proximal gastrectomy might improve BWL.No potential conflict of interest relevant to this article was reported.Japan Society of Plastic and Reconstructive SurgeryActa Medica Okayama2436-259X232023A Case of a Transwoman with Colorectal Cancer after Flap Vaginoplasty98101ENShihoWatanabeDepartment of Plastic and Reconstructive Surgery, Okayama University HospitalFuminoriTeraishiDepartment of Minimally Invasive Therapy Center, Okayama University HospitalSariFujimotoDepartment of Plastic and Reconstructive Surgery, Okayama University HospitalToshiyukiWatanabeDepartment of Plastic and Reconstructive Surgery, Okayama University HospitalShoTakedaDepartment of Gastroenterological Surgery, Okayama University HospitalShuheiNaritaDepartment of Gastroenterological Surgery, Okayama University HospitalKoyaYamashitaDepartment of Gastroenterological Surgery, Okayama University HospitalKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University HospitalShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University HospitalYuzaburoNambaDepartment of Gender Center, Okayama University HospitalYoshihiroKimataDepartment of Plastic and Reconstructive Surgery, Okayama University HospitalVaginoplasty is a gender-affirming surgery (GAS) for transwomen that laid its foundation in the 1950s and continues to be widely practiced worldwide. We present here a case of a 70-year-old transwoman who underwent lower anterior resection for rectal cancer 12 years after vaginoplasty. The preoperative diagnosis was rectal cancer (Rb-Ra, type 2, cT2N0M0, stage 1). All imaging studies showed a cord-like structure between the prostate and the anterior wall of the rectum, which was thought to be the neovagina. Careful dissection of the anterior rectal wall was required because the distance between the neovagina and the rectum was only 1.5 mm. The role of hormonal therapy and GAS in cancer development in transwomen is unclear. It is important to have regular check-ups for malignancies in patients who have undergone GAS, and if surgical procedures are needed, they should be treated by physicians who are familiar with the procedure.No potential conflict of interest relevant to this article was reported.BMCActa Medica Okayama1471-24072512025Predictive marker for response to trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer patients1ENToshiakiTakahashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShoTakedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHibikiUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaMoriwakeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasashiKayanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYuyaSakuraiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeNakamuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasafumiTakahashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKaoriNittaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuhiroYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYukiMatsumiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroyukiMichiueNeutron Therapy Research Center, Okayama UniversityHidekiYamamotoDepartment of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroyukiKishimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHajimeKashimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesObjective 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).<br>
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.<br>
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).<br>
ConclusionLow 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.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0941-12912024Optimization of workflow processes for sustainable paternal involvement: case study of an academic “daddy surgeon” in JapanENNobuhikoKanayaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShinjiKurodaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYoshitakaKondoDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYukoTakeharaDepartment of Surgery, Okayama Saiseikai General HospitalYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineHitoshiMinagiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineMasakiSakamotoDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunsukeKagawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineHitomiKataokaIntegrated Clinical Education Center, Kyoto University HospitalToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineWork–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).No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1432-08517412024Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity12ENTomokoOhtaniDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKentoKumonDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChiakiYagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyomaSugimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, IncToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDendritic 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.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama2198-77931012024Primary ileal myeloid sarcoma presenting with bowel obstruction: a case report229ENHitoshiMinagiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineNobuhikoKanayaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYoshitakaKondoDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShinjiKurodaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineRyoheiShojiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineHajimeKashimaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYukiMatsumiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineSatoruKikuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineFuminoriTeraishiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunsukeKagawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineBackground 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.<br>
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.<br>
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.No potential conflict of interest relevant to this article was reported.International Institute of Anticancer ResearchActa Medica Okayama0250-70054462024Senescent Fibroblasts Potentiate Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells via IL-8–mediated Crosstalk24972509ENYUNCHENGLIDepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHIROSHITAZAWADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYASUONAGAIDepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHUTOFUJITADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOMOHIROOKURADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRYOHEISHOJIDepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMOTOHIKOYAMADADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSATORUKIKUCHIDepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHINJIKURODADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIAKIOHARADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKAZUHIRONOMADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMASAHIKONISHIZAKIDepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHUNSUKEKAGAWADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIYOSHIFUJIWARADepartments of Gastroenterological Surgery and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground/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.No potential conflict of interest relevant to this article was reported.Informa UK LimitedActa Medica Okayama0163-55817662024Perioperative and Postoperative Continuous Nutritional Counseling Improves Quality of Life of Gastric Cancer Patient Undergoing Gastrectomy476485ENShunyaHanzawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHajimeKashimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiMatsumiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAyakoTakahashiClinical Nutrition, Okayama University HospitalYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKoseiTakagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeTanabeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKenichiShikataClinical Nutrition, Okayama University HospitalToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPost-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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7822024p53-Armed Oncolytic Virotherapy Improves Radiosensitivity in Soft-Tissue Sarcoma by Suppressing BCL-xL Expression151161ENTadashiKomatsubaraDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJoeHaseiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshinoriOmoriDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhisaSugiuDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeMochizukiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKojiDemiyaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkiYoshidaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohiroFujiwaraDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyukiKunisadaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshifumiOzakiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOriginal Article10.18926/AMO/66924Soft-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.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2475-0328832024A multi-center, prospective, clinical study to evaluate the anti-reflux efficacy of laparoscopic double-flap technique (lD-FLAP Study)374382ENShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMichihiroIshidaDepartment of Surgery, Hiroshima City Hiroshima Citizens Hospital, HiroshimaYasuhiroChodaDepartment of Surgery, Hiroshima City Hiroshima Citizens Hospital, HiroshimaAtsushiMuraokaDepartment of Surgery, Kagawa Rosai HospitalShinjiHatoDepartment of Surgery, Shikoku Cancer CenterTetsuyaKagawaDepartment of Surgery, Shikoku Cancer CenterNorimitsuTanakaDepartment of Surgery, Kagawa Prefectural Central HospitalToshiharuMitsuhashiCenter for Innovative Clinical Medicine, Okayama University HospitalYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Surgery, Tsuyama Chuo HospitalShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground: 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.<br>
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%.<br>
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).<br>
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.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0007-092013072024Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic adenovirus11871195ENMasashiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDaisukeKadowakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasakiSakamotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiHamadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyomaSugimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChiakiYagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokoOhtaniDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKentoKumonDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaYasuiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakahitoYagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground: 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).<br>
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).<br>
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.<br>
Conclusion: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.No potential conflict of interest relevant to this article was reported.Public Library of ScienceActa Medica Okayama1932-620318112023p53-armed oncolytic adenovirus induces autophagy and apoptosis in KRAS and BRAF-mutant colorectal cancer cellse0294491ENShutaTamuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaotoHoriDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYunchengLiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMotohikoYamadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesColorectal 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.No potential conflict of interest relevant to this article was reported.AME Publishing CompanyActa Medica Okayama2078-68911352022Prognostic risk factors for postoperative long-term outcomes in elderly stage IA gastric cancer patients21782185ENYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground: The number of gastric cancer (GC) patients with other diseases is increasing due to the aging of the population. In particular, in stage IA GC patients who have multiple diseases, surgical indications should be considered after identifying prognostic factors. We therefore investigated prognostic factors for stage IA GC in the elderly.<br>
Methods: Patient characteristics were collected and analyzed retrospectively for elderly patients with stage IA GC who underwent curative surgical treatment at Okayama University Hospital between 2010 and 2015, and an elderly group (EG; 75–79 years old) and very elderly group (VEG; ≥80 years old) were compared.<br>
Results: Fifty-three patient in the EG and 31 patients in the VEG were compared. No factors associated with clinicopathological characteristics or surgical or postoperative short-term outcomes differed significantly between groups. Although no factors in the EG appeared significantly associated with poor overall survival (OS), severe comorbidity [Charlson Comorbidity Index (CCI) ≥2; P=0.019], open gastrectomy (P=0.012), high volume of blood loss (≥300 mL; P=0.013) and long postoperative hospital stay (≥14 days; P=0.041) were significantly associated with poor OS. Furthermore, only CCI ≥2 [hazard ratio (HR) =9.2; 95% confidence interval (CI): 1.2–68.9; P=0.032] was an independent prognostic factor associated with poor OS. Five-year OS was 88.9% for CCI 0/1 patients and 62.3% for CCI ≥2 patients, representing very impressive results.<br>
Conclusions: CCI ≥2 is an important prognostic factor in clinical decisions in stage IA GC patients ≥2, so careful determination of surgical indications is desirable.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama2168-81841552023Collagenous Colitis in a Patient With Gastric Cancer Who Underwent Chemotherapye39466ENMasayaIwamuroDepartment of Gastroenterology and Hepatology, Okayama University HospitalTakehiroTanakaDepartment of Pathology, Okayama University HospitalShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShokoInooDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMotoyukiOtsukaDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHerein, 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.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0304-38355672023Dual antiplatelet therapy inhibits neutrophil extracellular traps to reduce liver micrometastases of intrahepatic cholangiocarcinoma216260ENMasashiYoshimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHirokiKajiokaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtsukiTaniguchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohikoYagiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShoheiNogiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesThe 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7722023Locally Advanced Rectal Cancer Invading the Gluteus Maximus Muscle Completely Responded to Total Neoadjuvant Therapy209213ENMasakiSakamotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCase Report10.18926/AMO/65152A 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7712023A Case Report of Non-typical Annular Pancreas Diagnosed during Laparoscopic Gastric Surgery9195ENToshiakiTakahashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShoTakedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCase Report10.18926/AMO/64368An 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.No potential conflict of interest relevant to this article was reported.BMCActa Medica Okayama1477-78192012022Involvement in the tumor-infiltrating CD8(+) T cell expression by the initial disease of remnant gastric cancer374ENYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground 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.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2045-23221212022Dual-targeted near-infrared photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in the tumor microenvironment20152ENHiroakiSatoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKentoKawasakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasaakiAkaiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTerukiKobayashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNoriyukiNishiwakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToruNarusakaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoshiKomotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHajimeKashimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiKatsuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakuyaKatoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroShirakawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHisatakaKobayashiMolecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, BethesdaToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCancer-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.No potential conflict of interest relevant to this article was reported.Cell PressActa Medica Okayama2372-7705272022Oncolytic virus-mediated p53 overexpression promotes immunogenic cell death and efficacy of PD-1 blockade in pancreatic cancer313ENHiroyukiArakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinoriKajiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMotohikoYamadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesImmune checkpoint inhibitors, including anti-programmed cell death 1 (PD-1) antibody, provide improved clinical outcome in certain cancers. However, pancreatic ductal adeno-carcinoma (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 telo-merase-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 extracel-lular adenosine triphosphate and high-mobility group box pro-tein 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 overexpres-sion 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.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2045-23221212022RNA editing facilitates the enhanced production of neoantigens during the simultaneous administration of oxaliplatin and radiotherapy in colorectal cancer13540ENYasuhiroKomatsuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShoTakedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazutakaTakahashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNanakoHataDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHibikiUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuhiroYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshikoMoriDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaYasuiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroyukiKishimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroyukiMichiueNeutron Therapy Research Center, Okayama UniversityHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesAjayGoelDepartment of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute, City of Hope Biomedical Research CenterToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMost 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 CAPDX (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.No potential conflict of interest relevant to this article was reported.Oxford University PressActa Medica Okayama2042-8812202252022Anorectal leiomyoma with GLUT1 overexpression mimicking malignancy on FDG-PET/CTrjac101ENFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesA 43-year-old female underwent pelvic magnetic resonance imaging for uterine myoma that incidentally revealed a 4.6 x 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 x 3.5 x 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 alpha SMA 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.No potential conflict of interest relevant to this article was reported.Cell PressActa Medica Okayama2372-7705252022Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of cancer249261ENToshihiroOgawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMotoyasuTabuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesEmaMitsuiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYutaUneDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharmaToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCancer-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.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1347-90322022Tumor-targeted fluorescence labeling systems for cancer diagnosis and treatmentENHiroshiTazawaKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFuminoriSakuraiLaboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka UniversityHiroyukiMizuguchiLaboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka UniversityHisatakaKobayashiMolecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of HealthTakeshiImamuraDepartment of Molecular Medicine for Pathogenesis, Ehime University Graduate School of MedicineToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesConventional 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7622022Overexpression of Adenovirus E1A Reverses Transforming Growth Factor-β-induced Epithelial-mesenchymal Transition in Human Esophageal Cancer Cells203215ENTomoyaMasudaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuuriHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakeshiIedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma Inc.ShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOriginal Article10.18926/AMO/63425The 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.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1435-244340722022Surgical technique of suprapancreatic D2 lymphadenectomy focusing on the posterior hepatic plexus for advanced gastric cancer871877ENNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShoTakedaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineSatoruKikuchiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKazuhiroNomaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineRyuichiYoshidaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYuzoUmedaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineFuminoriTeraishiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineMasahikoNishizakiDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunsukeKagawaDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicinePurpose<br>
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.<br>
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Methods<br>
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.<br>
<br>
Results<br>
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.<br>
<br>
Conclusion<br>
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.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2050-0904992021Longitudinal observation of insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes mellitus: A report of two casese04574ENNorikoFujiwaraDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineMayuWatanabeDepartment of Primary Care and Medical Education, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineAkihiroKatayamaDiabetes Center, Okayama University HospitalYoheiNodaDepartment of Otolaryngology-Head and Neck Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineJunEguchiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineHitomiKataokaDepartment of Primary Care and Medical Education, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineShunsukeKagawaMinimally Invasive Therapy Center, Okayama University HospitalJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineImmune checkpoint inhibitor-induced diabetes mellitus is a rare immune-related adverse event. This report illustrates clinical data and insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes.No potential conflict of interest relevant to this article was reported.The American Society of Gene and Cell TherapyActa Medica Okayama1525001629102021Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles29202930ENYoshihikoKakiuchi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKuroda Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanaya Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKentoKumon Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokoTsumura Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiHashimoto Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChiakiYagi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyomaSugimoto Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiHamada Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizaki Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, IncToshiyoshiFujiwara Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesExtracellular 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. In this study, 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 they 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.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0959-80491532021Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments98108ENYasuhiroShirakawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeTanabeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakeshiKoujimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHajimeKashimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakuyaKatoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKuniakiKatsuiDepartment of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSusumuKanazawaDepartment of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPurpose: 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.<br>
<br>
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.<br>
<br>
Results: Of the 13 patients, 7, 3 and 3 patients were treated with 10(10), 10(11) and 10(12) 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 thorn cells and increased PD-L1 expression.<br>
<br>
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. (C) 2021 Elsevier Ltd. All rights reserved.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0344-57048832021Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression513524ENKazuhisaSugiuDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJoeHaseiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuakiYamakawaGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToshinoriOmoriDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadashiKomatsubaraDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeMochizukiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyaKondoDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuheiOsakiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohiroFujiwaraCenter for Innovative Clinical Medicine, Okayama University HospitalAkiYoshidaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyukiKunisadaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKojiUedaProject for Personalized Cancer Medicine, Cancer Precision Medicine Center, Japanese Foundation for Cancer ResearchYasuoUrataOncolys BioPharma, IncShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshifumiOzakiDepartment of Orthopaedic Surgery, Okayama University HospitalToshiyoshiFujiwaraDepartment of Gastroenterological Surgery Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground <br>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.<br><br>
Materials and methods <br>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.<br><br>
Results <br>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.<br><br>
Conclusion <br>Our results suggest that MDR1 is 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.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama1743-9191892021Efficacy and safety of short-term (3 days) enoxaparin in preventing venous thromboembolism after gastric cancer surgery: A single-center, prospective cohort study105946ENShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiOkayama University HospitalYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMegumiWatanabeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaKuwadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokoTsumuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShiroHinotsuDepartment of Biostatistics and Data Management, Sapporo Medical University School of MedicineToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground: 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.<br>
Methods: Gastric cancer patients who underwent gastrectomy received enoxaparin for 3 days from postoperative day (POD) 1 to 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.<br>
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).<br>
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.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0941-1291512021Accreditation as a qualified surgeon improves surgical outcomes in laparoscopic distal gastrectomy19781984ENSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsuyaKagawaDepartment of Gastroenterological Surgery, Shikoku Cancer CenterShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuoTakataDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaKuwadaDepartment of Surgery, Okayama Red Cross HospitalRyoheiShojiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiharuMitsuhashiCenter for Innovative Clinical Medicine, Okayama University HospitalYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPurpose: 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.<br>
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).<br>
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).<br>
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.No potential conflict of interest relevant to this article was reported.Public Library ScienceActa Medica Okayama1932-62031642021Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expressione0250643ENToshinoriOmoriDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuakiYamakawaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuheiOsakiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJoeHaseiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhisaSugiuDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadashiKomatsubaraDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohiroFujiwaraDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkiYoshidaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyukiKunisadaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshifumiOzakiDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSoft 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.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama2198-7793712021Long-term survival without recurrence after surgery for gastric yolk sac tumor-like carcinoma: a case report111ENHibikiUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakehiroTanakaDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesBackground 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7522021Long-term Survival with a Rare Advanced Primary Gastrointestinal Malignant Melanoma Treated with Laparoscopic Surgery/Immune Checkpoint Inhibitor231238ENMotochikaEndoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroakiAsanoDepartment of Surgery, Mitoyo general HospitalShoTakedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiHamadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshitakaKondoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakehiroTanakaDepartment of Pathology, Okayama University HospitalFuminoriTeraishiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCase Report10.18926/AMO/61906Targeted 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.No potential conflict of interest relevant to this article was reported.BMCActa Medica Okayama1471-24072112021Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation102ENAteneItoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuichiSakamotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaKuwadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHirokiKajiokaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiYoshimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground</br>
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.</br>
Methods</br>
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.</br>
Results</br>
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.</br>
Conclusion</br>
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.No potential conflict of interest relevant to this article was reported.Nature ResearchActa Medica Okayama2045-23221112021Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer1693ENRyoichiKatsubeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToshiakiOharaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNoriyukiNishiwakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTerukiKobayashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSatoshiKomotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroakiSatoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHajimeKashimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakuyaKatoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYasuhiroShirakawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHisatakaKobayashiMolecular Imaging Program, Center for Cancer Research, National Cancer Institute, US National Institutes of HealthToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesCancer-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.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama1422-00672222021Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment879ENShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiKishimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRobert M.HoffmanAntiCancer, Inc.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.No potential conflict of interest relevant to this article was reported.ElsevierActa Medica Okayama0304-38354972021Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis13ENHirokiKajiokaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAteneItoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiYoshimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuichiSakamotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuzoUmedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSurgery is the only curative treatment option for pancreatic cancer, but patients often develop postoperative recurrence. Surgical invasiveness might be involved in the mechanism of recurrence. The associations among inflammation caused by surgery, neutrophils, and cancer metastasis were investigated. At first, neutrophil extracellular traps (NETs) were examined in clinical specimens, and NETs were observed around metastatic tumors. To explore how NETs were induced, neutrophils were cultured with pancreatic cancer or in cancer-conditioned medium. Neutrophils formed NETs when they were cultured with pancreatic cancer or even its conditioned medium. The effects of NETs on cancer cells were further investigated in vitro and in vivo. NETs induced the epithelial to mesenchymal transition in cancer cells and thereby promoted their migration and invasion. HMGB1 derived from NETs appeared to potentiate the malignancy of cancer cells. In a mouse model of liver metastasis with inflammation, NETs participated in the metastatic process by enhancing extravasation. Interestingly, thrombomodulin degraded HMGB1 and consequently inhibited the induction of NETs, thereby preventing pancreatic cancer metastasis to the liver. In conclusion, NETs interact reciprocally with pancreatic cancer cells, which play a pivotal role in inflammation-associated metastasis. Targeting NETs with thrombomodulin can be a novel strategy to improve the surgical outcome of pancreatic cancer patients.No potential conflict of interest relevant to this article was reported.Public Library of ScienceActa Medica Okayama1932-620315112020Short-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 cancere0242223ENTomokoTsumuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuoTakataDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAteneItoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMegumiWatanabeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaKuwadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground</br>
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).</br>
Methods</br>
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.</br>
Results</br>
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).</br>
Conclusions</br>
LAPG with DFT was superior to LATG in postoperative nutritional maintenance, and can be the first option for early proximal gastric cancer.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama0340-7004702020Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma14051417ENYusukeMochizukiDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaGastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKojiDemiyaDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMihoKureDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyaKondoDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadashiKomatsubaraDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhisaSugiuDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJoeHaseiSports Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineAkiYoshidaDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyukiKunisadaMedical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of MedicineYasuoUrataOncolys BioPharma, Inc,ShunsukeKagawaGastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshifumiOzakiDepartments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraGastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesImmune 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.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1758-59022021142020Intracorporeal semi‐hand‐sewn Billroth I reconstruction in total laparoscopic distal gastrectomy640643ENSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaKuwadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuoTakataDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences YoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNoma Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIntroduction</br>
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.</br>
Materials and surgical technique</br>
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.</br>
Discussion</br>
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.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2072-66941292020FUCCI Real-Time Cell-Cycle Imaging as a Guide for Designing Improved Cancer Therapy: A Review of Innovative Strategies to Target Quiescent Chemo-Resistant Cancer Cells2655ENShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRobert M.HoffmanAntiCancer, Inc.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.No potential conflict of interest relevant to this article was reported.Cell PressActa Medica Okayama2372-7705182020Elimination of MYCN-Amplified Neuroblastoma Cells by Telomerase-Targeted Oncolytic Virus via MYCN Suppression1423ENTerutakaTanimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakeshiIedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiNousoDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMorimichiTaniDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakanoriOyamaDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakuoNodaDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNeuroblastoma (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.No potential conflict of interest relevant to this article was reported.Cell PressActa Medica Okayama2372-7705182020Boosting Replication and Penetration of Oncolytic Adenovirus by Paclitaxel Eradicate Peritoneal Metastasis of Gastric Cancer262271ENWataruIshikawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshihiroOgawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMotoyasuTabuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoUrataOncolys BioPharma, Inc.ToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPeritoneal 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.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2072-66941222020Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic VirotherapyENHiroshiTazawaCenter for Innovative Clinical Medicine, Okayama University HospitalJoeHaseiDepartment of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshifumiOzakiDepartment of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAdenovirus 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.No potential conflict of interest relevant to this article was reported.Cell PressActa Medica Okayama152500162832020Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody794804ENNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKentoKumonDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokoTsumuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiHashimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiMorihiroDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsushiKubotaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiAoyamaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiMizuguchiLaboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka UniversityYasuoUrataOncolys BioPharmaToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesThe 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.No potential conflict of interest relevant to this article was reported.Nature Publishing GroupActa Medica Okayama2045-232292019Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network 16378ENTakeshiIedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHirokiOkabayashiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuyaYanoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKunitoshiShigeyasuDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiKishimotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroShirakawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakashiSaitouDepartment of Molecular Medicine for Pathogenesis, Ehime University Graduate School of MedicineTakeshiImamuraDepartment of Molecular Medicine for Pathogenesis, Ehime University Graduate School of MedicineToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesEpithelial-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-alpha, IL-1 beta, 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.No potential conflict of interest relevant to this article was reported.Nature Publishing GroupActa Medica Okayama2045-232292019PD-L1 expression combined with microsatellite instability/CD8+tumor infiltrating lymphocytes as a useful prognostic biomarker in gastric cancer4633ENToshiakiMorihiroDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuhikoKanayaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsushiKubotaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyukiAoyamaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakehiroTanakaDepartment of Pathology, Okayama UniversitySatoruKikuch Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakeshiNagasakaDepartment of Clinical Oncology, Kawasaki Medical SchoolMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesWhile 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 No potential conflict of interest relevant to this article was reported.WoleyActa Medica Okayama2475-0328312018Multicenter retrospective study to evaluate the efficacy and safety of the double-flap technique as antireflux esophagogastrostomy after proximal gastrectomy (rD-FLAP Study)96103ENShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroChodaDepartment of Surgery, Hiroshima City Hiroshima Citizens HospitalShinyaOtsukaDepartment of Surgery, Fukuyama Medical CenterSatoshiUeyamaDepartment of Surgery, Mihara Red Cross HospitalNorimitsuTanakaDepartment of Surgery, Kagawa Prefectural Center HospitalAtsushiMuraokaDepartment of Surgery, Kagawa Rosai HospitalShinjiHatoDepartment of Surgery, Shikoku Cancer CenterToshikazuKimuraDepartment of Surgery, Okayama Saiseikai General Hospital,KohjiTanakayaDepartment of Surgery, Iwakuni Clinical CenterSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeTanabeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroShirakawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuakiKamikawaDepartment of Surgery, Matsuda HospitalToshiyoshiFujiwaraDepartment of Gastroenterological Surgery Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAIM:
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.<br/>
METHODS:<br/>
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.<br/>
RESULTS:<br/>
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).<br/>
CONCLUSION:<br/>
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.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2072-66941122019A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness177ENYukiKatsuraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartment of Pathology and Experimental MedicineOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakayukiNinomiyaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHajimeKashimaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakuyaKatoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroakiSatoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoshiKomotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToruNarusakaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasukoTomono Shigei Medical Research InstituteBoyiXingDepartment of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuehuaChenDepartment of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroShirakawa Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomonariKasai School of Bioscience and Biotechnology, Tokyo University of TechnologyMasaharuSeno Laboratory of Nano-Biotechnology, Okayama University Graduate School of Interdisciplinary Science and Engineering in Health SystemsAkihiroMatsukawa Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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.No potential conflict of interest relevant to this article was reported.TAYLOR & FRANCISActa Medica Okayama2162402X8122019Intraperitoneal cancer-immune microenvironment promotes peritoneal dissemination of gastric cancere1671760ENShuichiSakamotoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaKuwadaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAteneItoDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHirokiKajiokaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihikoKakiuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMegumiWatanabeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsuyaKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyuichiYoshidaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiTazawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7122017Outcome of Radiation Monotherapy for High-risk Patients with Stage I Esophageal Cancer127133ENYasuhiroShirakawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroNomaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaoakiMaedaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeTanabeDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical SciencesShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical SciencesKuniakiKatsuiDepartment of Proton Beam Therapy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNorihisaKatayamaDepartment of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSusumuKanazawaDepartment of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOriginal Article10.18926/AMO/54981Currently, 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7052016A Phase II Clinical Trial of the Efficacy and Safety of Short-term (3 days) Enoxaparin for the Prevention of Venous Thromboembolism after Gastric Cancer Surgery401404ENShinjiKurodaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruKikuchiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShiroHinotsuCenter for Innovative Clinical Medicine, Okayama University HospitalToshiyoshiFujiwaraDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesClinical Study Protocols10.18926/AMO/54601Although 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 longterm (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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7032016Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion213216ENSatoruKikuchiDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunsukeKagawaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiakiOharaDepartments of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsushiKubotaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaKuwadaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsuyaKagawaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinjiKurodaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroShirakawaDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoNishizakiDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyoshiFujiwaraDepartments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCase Report10.18926/AMO/54421A 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6932015Prone-Position Thoracoscopic Ligation of the Thoracic Duct for Chyle Leak Following Radical Neck Dissection in a Patient with a Right Aortic Arch173176ENYasuhiroShirakawaKazuhiroNomaToshiakiOharaHajimeKashimaNaoakiMaedaShunsukeTanabeShunsukeKagawaToshiyoshiFujiwaraCase Report10.18926/AMO/53524A chyle leak can occur as a complication after neck or chest surgery. Such a leak prolongs the hospital stay and is sometimes life-threatening. The treatment options are conservative management, interventional radiologic embolization, and surgery. Thoracoscopic ligation of the thoracic duct has emerged as a promising and definitive treatment. The case of a 65-year-old Japanese male patient with a rare congenital right aortic arch (typeⅢB1 of Edwardʼs 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.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1525-00162014Biological Ablation of Sentinel Lymph Node Metastasis in Submucosally Invaded Early Gastrointestinal CancerENSatoruKikuchiHiroyukiKishimotoHiroshiTazawaYuuriHashimotoShinjiKurodaMasahikoNishizakiTakeshiNagasakaYasuhiroShirakawaShunsukeKagawaYasuoUrataRobert M HoffmanToshiyoshiFujiwaraCurrently, early gastrointestinal cancers are treated endoscopically, as long as there are no lymph node metastases. However, once a gastrointestinal cancer invades the submucosal layer, the lymph node metastatic rate rises to higher than 10%. Therefore, surgery is still the gold standard to remove regional lymph nodes containing possible metastases. Here, to avoid prophylactic surgery, we propose a less-invasive biological ablation of lymph node metastasis in submucosally invaded gastrointestinal cancer patients. We have established an orthotopic early rectal cancer xenograft model with spontaneous lymph node metastasis by implantation of green fluorescent protein (GFP)-labeled human colon cancer cells into the submucosal layer of the murine rectum. A solution containing telomerase-specific oncolytic adenovirus was injected into the peritumoral submucosal space, followed by excision of the primary rectal tumors mimicking the endoscopic submucosal dissection (ESD) technique. Seven days after treatment, GFP signals had completely disappeared indicating that sentinel lymph node metastasis was selectively eradicated. Moreover, biologically treated mice were confirmed to be relapse-free even 4 weeks after treatment. These results indicate that virus-mediated biological ablation selectively targets lymph node metastasis and provides a potential alternative to surgery for submucosal invasive gastrointestinal cancer patients.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama2014Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnosticsENKunitoshiShigeyasuHiroshiTazawaYuuriHashimotoYoshikoMoriMasahikoNishizakiHiroyukiKishimotoTakeshiNagasakaShinjiKurodaYasuoUrataAjayGoelShunsukeKagawaToshiyoshiFujiwaraBackground 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.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1078-043219232013A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem-like Cells in S/G(2)/M Phases64956505ENShuyaYanoHiroshiTazawaYuuriHashimotoYasuhiroShirakawaShinjiKurodaMasahikoNishizakiHiroyukiKishimotoFutoshiUnoTakeshiNagasakaYasuoUrataShunsukeKagawaRobert M.HoffmanToshiyoshiFujiwaraPurpose: 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6762013Oncolytic Adenovirus-Induced Autophagy: Tumor-Suppressive Effect and Molecular Basis333342ENHiroshiTazawaShunsukeKagawaToshiyoshiFujiwaraReview10.18926/AMO/52006Autophagy 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 E1-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.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812532013腫瘍融解アデノウイルスによるE2F1-マイクロRNA-7-EGFR経路を介したオートファジー細胞死の誘導分子機構195199ENHiroshiTazawaSyuyaYanoRyosukeYoshidaYasumotoYamasakiTsuyoshiSasakiYuuriHashimotoShinjiKurodaMasaakiOuchiTeppeiOnishiFutoshiUnoSyunsukeKagawaYasuoUrataToshiyoshiFujiwaraNo potential conflict of interest relevant to this article was reported.Amer Assoc Cancer ResearchActa Medica Okayama1535-71631232013Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells314325ENJoeHaseiTsuyoshiSasakiHiroshiTazawaShuheiOsakiYasuakiYamakawaToshiyukiKunisadaAkiYoshidaYuuriHashimotoTeppeiOnishiFutoshiUnoShunsukeKagawaYasuoUrataToshifumiOzakiToshiyoshiFujiwaraTumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Ad-p53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells. Mol Cancer Ther; 12(3); 314-25.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1932-6203762012The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic MicroenvironmentENYuuriHashimotoHiroshiTazawaFuminoriTeraishiToruKojimaYuichiWatanabeFutoshiUnoShuyaYanoYasuoUrataShunsukeKagawaToshiyoshiFujiwaraHypoxia 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.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0340-700461112012Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells19051916ENRyosukeYoshidaHiroshiTazawaYuuriHashimotoShuyaYanoTeppeiOnishiTsuyoshiSasakiYasuhiroShirakawaHiroyukiKishimotoFutoshiUnoMasahikoNishizakiShunsukeKagawaToshiyoshiFujiwaraTrastuzumab, 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.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812512013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912ENToruKojimaYuichiWatanabeYuuriHashimotoShinjiKurodaYasumotoYamasakiShuyaYanoHiroshiTazawaFutoshiUnoShunsukeKagawaNoriakiTanakaYasuoUrataToshiyoshiFujiwaraNo potential conflict of interest relevant to this article was reported.American Society for Clinical InvestigationActa Medica Okayama0021-9738119102009A simple biological imaging system for detecting viable human circulating tumor cells31723181ENToruKojimaYuuriHashimotoYuichiWatanabeShunsukeKagawaFutoshiUnoShinjiKurodaHiroshiTazawaSatoruKyoHiroyukiMizuguchiYasuoUrataNoriakiTanakaToshiyoshiFujiwaraThe 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.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812422012テロメラーゼ依存性腫瘍融解ウイルス療法の骨・軟部肉腫に対する前臨床的検討105110ENTsuyoshiSasakiHiroshiTazawaJoHaseiToshiyukiKunisadaAkiYoshidaYuuriHashimotoShuyaYanoRyosukeYoshidaFutoshiUnoShunsukeKagawaYukiMorimotoYasuoUrataToshiyoshiFujiwaraToshifumiOzaki骨・軟部肉腫は, 一部に治療抵抗性で予後の悪い症例が存在するため, 新たな治療法の確立が重要な課題である. 我々は, 5型アデノウイルスを基本骨格として, テロメラーゼ活性に依存して増殖する腫瘍融解ウイルス（OBP-301）や, coxsackie and adenovirus receptor（CAR）陰性の腫瘍細胞に感染するファイバー改変型ウイルス（OBP-405）を用い, 骨・軟部肉腫細胞に対する抗腫瘍効果を検討した.
14種類の骨・軟部肉腫細胞株に対してOBP-301の細胞障害活性を検討し, 12種類の細胞株でOBP-301に感受性を認めた. また, OBP-301の細胞障害活性はCARの発現と相関していた. さらに, テロメラーゼ活性の低い細胞に対しても, 5型アデノウイルスの複製に必須のE1Aによりテロメラーゼ活性の増強効果がおこり, 強い抗腫瘍活性を示すことを明らかにした. 次に, 骨肉腫脛骨同所性移植動物モデルを作成しOBP-301を投与したところ, OBP-301投与群では対象群と比べて有意に腫瘍増殖を抑制した. 最後に, OBP-301に感受性を認めなかったCAR陰性細胞株に対してOBP-405を用いて検討し, OBP-405が有効に作用することを確認した.
OBP-301やOBP-405を用いたウイルス療法は, 骨・軟部肉腫に対する新たな治療法となる可能性がある. No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812322011テロメラーゼ依存的腫瘍融解アデノウイルス製剤による 放射線感受性増強作用103109ENShinjiKurodaToshiyaFujiwaraYasuhiroShirakawaYasumotoYamasakiSyuyaYanoFutoshiUnoHiroshiTazawaYuuriHashimotoYuichiWatanabeKazuhiroNomaYasuoUrataShunsukeKagawaToshiyoshiFujiwaraDNA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．No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812232010制限増殖型アデノウイルス製剤を用いた新たな微小がん病変の検出法の開発と治療への応用203208ENToruKojimaYuuriHashimotoShunsukeKagawaNoriakiTanakaYasuoUrataToshiyoshiFujiwaraNo potential conflict of interest relevant to this article was reported.Elsevier B.V.Acta Medica Okayama0014-5793579192005ZD1839 (Gefitinib, 'Iressa'), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma40694075ENFuminoriTeraishiShunsukeKagawaTakanoriWatanabeYasuhisaTangoTakeshiKawashimaTatsuoUmeokaMasahikoNisizakiNoriakiTanakaToshiyoshiFujiwaraThe EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Gefitinib, '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 ZD1839 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 G0–G1 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.No potential conflict of interest relevant to this article was reported.American Association for Cancer ResearchActa Medica Okayama0008-547264172004Visualization of intrathoracically disseminated solid tumors in mice with optical imaging by telomerase-specific amplification of a transferred green fluorescent protein gene62596265ENTatsuoUmeokaTakeshiKawashimaShunsukeKagawaFuminoriTeraishiMasakiTakiMasahikoNishizakiSatoruKyoKatsuyukiNagaiYasuoUrataNoriakiTanakaToshiyoshiFujiwaraCurrently 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.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-1558995-61987ヒト胃粘膜ガラクトース転移酵素の研究 第二編 胃潰瘍症例における検討667672ENShunsukeKagawaBiopsied specimens of gastric mucosa of normal subjects and patients with gastric ulcer were obtained under routine gastrofiberscopy. UDP-galactosyltransferase activity was measured with the use of ovomucoid as a substrate. In endoscopically normal subjects, UDP-galactosyltransferase activity of the fundic gland area was significantly (p<0.01) higher than that of the pyloric gland area. In ulcer patients without anti-ulcer treatment, UDP-galactosyltransferase activity was elevated in the mucosa surrounding the ulcer at the healing stage and red scarring stage as compared with the corresponding area of non-ulcer individuals. However, under administration of an H(2)-blocker, the change in UDP-galactosyltransferase activity was not observed. These observations may suggest that (1) increased glycoprotein synthses may be a physiological response of the gastric mucosa to the ulcer and may promote ulcer healing, and that (2) the process of the H(2)-blocker induced ulcer healing may not be associated with the apparent increase in glycoprotein synthesis.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-1558995-61987ヒト胃粘膜ガラクトース転移酵素活性の研究 第一編 オボムコイドを基質とした測定法の基礎的検討657665ENShunsukeKagawaThe conditions assaying for UDP-galactosyltransferase in human gastric mucosa was studied. Ovomucoid without any pretreatment was employed as a substrate. The optimal pH was 6.8. Manganese, 2-mercaptoethanol and Triton X-100 were required for maximum enzyme activity. In the standard assay; 20 μl of enzyme solution was added to 30 μl of 50 mM MES buffer containing 5 mM 2-mercaptoethanol, 15 mM MnCl(2), 9.9mg protein/ml ovomucoid, 0.3 mM UDP-galactose, 1.7 μCi/ml UDP-[(3)H]-galactose and 1.5 mg/ml Triton X-100, and incubation was carried out at 37℃ for 20 min. [(3)H]-labelled ovomucoid was the only radioreactive reaction product detected. All galactose residue incorporated was liberated by β-galactosidase but not by α-galactosidase.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812032008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259264ENYoshikatsuEndoRyoSakaiMasaakiOuchiHidekiOnimatsuMasayoshiHiokiShunsukeKagawaFutoshiUnoYuichiWatanabeYasuoUrataNoriakiTanakaToshiyoshiFujiwaraNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155811812006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915ENNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030155812012008テロメラーゼ特異的制限増殖型アデノウイルスを用いた転移リンパ節の生体内イメージング1321ENHiroyukiKishimotoToruKojimaYuichiWatanabeShunsukeKagawaToshiyaFujiwaraFutoshiUnoFuminoriTeraishiSatoruKyoHiroyukiMizuguchiYuuriHashimotoYasuoUrataNoriakiTanakaToshiyoshiFujiwaraNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama1997p53 expression overcomes WAF1/CIP1 p'21 - mediated G arre induces apoptosis in human cancerst and cellsENNo potential conflict of interest relevant to this article was reported.