Search

Fibroblast activation protein (FAP) generally shows low or undetectable expression in most normal tissues but is highly expressed in fibroblasts in almost all carcinomas. FAP is one of the potential molecules to detect activated fibroblasts and has multiple roles in tumour progression. We generated transgenic mice that specifically expressed tdTomato along with FAP promoter activity. Coculturing a mouse gastric cancer cell line and FAP-tdTomato transgenic mouse-derived fibroblasts showed that tdTomato expression was elevated in the cocultured fibroblasts. Moreover, stomach wall transplanted tumours in mice also showed FAP-tdTomato expression in fibroblasts of the stomach and each metastatic legion. These results indicated that FAP-tdTomato expression in fibroblasts was elevated by stimulation through the interaction with cancer cells. Functionally, collagen production was increased in FAP/tdTomato-positive fibroblasts cocultured with mouse cancer cells. These FAP-tdTomato transgenic mice have the potential to be used to investigate real-time FAP dynamics and the importance of FAP expression in tumour development.

Excess stroma and cancer-associated fibroblasts (CAF) enhance cancer progression and facilitate immune evasion. Insights into the mechanisms by which the stroma manipulates the immune microenvironment could help improve cancer treatment. Here, we aimed to elucidate potential approaches for stromal reprogramming and improved cancer immunotherapy. Platelet-derived growth factor C (PDGFC) and D expression were significantly associated with a poor prognosis in patients with gastric cancer, and PDGF receptor beta (PDGFRβ) was predominantly expressed in diffuse-type gastric cancer stroma. CAFs stimulated with PDGFs exhibited markedly increased expression of CXCL1, CXCL3, CXCL5, and CXCL8, which are involved in polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) recruitment. Fibrotic gastric cancer xenograft tumors exhibited increased PMN-MDSC accumulation and decreased lymphocyte infiltration, as well as resistance to anti–PD-1. Single-cell RNA sequencing and spatial transcriptomics revealed that PDGFRα/β blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRα/β blockade and anti–PD-1 treatment synergistically suppressed the growth of fibrotic tumors. These findings highlight the impact of stromal reprogramming on immune reactivation and the potential for combined immunotherapy for patients with fibrotic cancer.Significance:Stromal targeting with PDGFRα/β dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer.See related commentary by Tauriello, p. 655

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We analyzed 1256 gastric samples (1152 IMs) from 692 subjects through a prospective 10-year study. We identified 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9), largely occurring as small clonal events. Analysis of clonal dynamics between and within subjects, and also longitudinally across time, revealed that IM clones are likely transient but increase in size upon progression to dysplasia, with eventual transmission of somatic events to paired GCs. Single-cell and spatial profiling highlighted changes in tissue ecology and lineage heterogeneity in IM, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling revealed expression-based molecular subtypes of IM, including a body-resident “pseudoantralized” subtype associated with incomplete histology, antral/intestinal cell types,ARID1Amutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical- genomic models outperform clinical-only models in predicting IMs likely to progress. Our results raise opportunities for GC precision prevention and interception by highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression.

Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of β1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.Significance:This study elucidates a novel molecular mechanism through which Annexin A6 in CAF-EV activates FAK-YAP by stabilizing β1 integrin at the cell surface of gastric cancer cells and subsequently induces drug resistance.

Supplementary Figure8

Real-time imaging of AGS cells treated with CAF-CM in the ECM.

Real-time imaging of AGS cells treated with normal medium in the ECM.

Excess stroma and cancer-associated fibroblasts (CAF) enhance cancer progression and facilitate immune evasion. Insights into the mechanisms by which the stroma manipulates the immune microenvironment could help improve cancer treatment. Here, we aimed to elucidate potential approaches for stromal reprogramming and improved cancer immunotherapy. Platelet-derived growth factor C (PDGFC) and D expression were significantly associated with a poor prognosis in patients with gastric cancer, and PDGF receptor beta (PDGFRβ) was predominantly expressed in diffuse-type gastric cancer stroma. CAFs stimulated with PDGFs exhibited markedly increased expression of CXCL1, CXCL3, CXCL5, and CXCL8, which are involved in polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) recruitment. Fibrotic gastric cancer xenograft tumors exhibited increased PMN-MDSC accumulation and decreased lymphocyte infiltration, as well as resistance to anti–PD-1. Single-cell RNA sequencing and spatial transcriptomics revealed that PDGFRα/β blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRα/β blockade and anti–PD-1 treatment synergistically suppressed the growth of fibrotic tumors. These findings highlight the impact of stromal reprogramming on immune reactivation and the potential for combined immunotherapy for patients with fibrotic cancer.Significance:Stromal targeting with PDGFRα/β dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer.See related commentary by Tauriello, p. 655

Supplementary Figure 1: GC cells do not exhibit network formation or subsequent drug resistance after treatment with GC-CM in the ECM. Supplementary Figure 2: CAF-CM enhances the tubular network formation and anti-apoptotic signaling of GC cells. Supplementary Figure 3. Protocol for RNA sequencing and gene expression determination. Supplementary Figure 4. Identification of CAF-derived EVs. Supplementary Figure 5. Annexin A6 in CAF-EVs is correlated with tubular network formation. Supplementary Figure 6. CAF-EVs enhance the expression of integrins in GC cells. Supplementary Figure 7. Loss-of-function study using ITGB1 siRNA in CAFs and a GC cell line (AGS). Supplementary Figure 8. Loss-of-function study using ANXA6 siRNA in CAFs. Supplementary Figure 9. Increases in the YAP levels are correlated with increases in its nuclear localization. Supplementary Figure 10. Protocol used for evaluation of the chemoresistance of intraperitoneal mice after treatment with siCTRL- or siANXA6-transfected CAF-EVs.

Supplementary Information

Background: Appendicitis caused by a foreign body is extremely rare. We report a case of chronic appendicitis caused by a perforating fish bone. Case Report: The patient was a 50-year-old Japanese man. He felt dull lower abdominal pain for 2 months and diagnosed as appendicitis caused by a perforating fish bone. He underwent emergency laparoscopic surgery. The fish bone had perforated through the appendix wall. The fish bone was initially removed followed by laparoscopic appendectomy. Pathological investigation revealed a transmural cut line of approximately 0.5 mm that was surrounded by fibrous tissue with inflammation. Conclusion: This is the first reported case of fish bone-induced chronic appendicitis that underwent laparoscopic appendectomy. For optimum outcome, a correct diagnosis based on a detailed consultation and imaging tests, and an operation performed after careful planning are needed.

Background/aim Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor. Research using an innovative research approach is needed to identify effective biomarkers or therapeutic targets for PDAC. We aimed to identify proteins related to the peritoneal dissemination of PDAC. Materials and methods We performed proteomic analysis using ascites samples from patients with advanced PDAC and peritoneal dissemination and patients with liver cirrhosis (LC). Proteins specific to PDAC were identified in comparison to the findings for ascites from patients with LC as a control group. Results In total, 336 proteins were identified in ascites from patients with PDAC. We identified 18 specific proteins in ascites from patients with advanced PDAC. Among these proteins, CD13, lymphatic vessel endothelial hyaluronan receptor 1, ficolin-3, and V-set and immunoglobulin domain containing 4 were the most frequently detected. In addition, these 18 proteins could be classified into four categories: extracellular matrix, immunity, metabolism, and others. Conclusion The identified proteins could be informative for developing treatment strategies for patients with PDAC and peritoneal dissemination.

Remodeling the tumor microenvironment (TME) to benefit cancer cells is crucial for tumor progression. Although diffuse-type gastric cancer (DGC) preferentially interacts with the TME, the precise mechanism of the complicated network remains unknown. This study aimed to investigate the mutual activation mechanism underlying DGC progression.Mass cytometry analysis of co-cultured macrophages, noncancerous fibroblasts (NFs), and DGC cells was performed. RNA sequencing was applied to examine gene expression in fibroblasts. DGC cells were treated with cytokines to examine their effect on characteristic changes. The TCGA and Kumamoto University cohorts were used to evaluate the clinical relevance of the in vitro findings.Cohort analysis revealed that DGC patients had a poor prognosis. The fibroblasts and macrophages interacted with DGC cells to form a cell cluster in the invasive front of DGC tissue. The original 3D triple co-culture system determined the promotional effects of nonmalignant cells on DGC invasive growth. We notably identified a mixed-polarized macrophage cell type with M1/M2 cell surface markers in a triple co-culture system. IL-1β from mixed-polarized macrophages induced the conversion of NFs to cancer-associated fibroblast-like (CAF-like) cells, promoting the malignant phenotype of DGC cells by inducing the secretion of IL-6, IL-24, and leukemia inhibitory factor (LIF). Moreover, IL-6 and colony stimulating factor 2 (GM-CSF) cooperated to maintain the stable state of mixed-polarized macrophages. Finally, we found that mixed-polarized macrophages were frequently detected in DGC tissues.These findings demonstrated that mixed-polarized macrophages exist as a novel subtype through the reciprocal interaction between DGC cells and nonmalignant cells.

The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E

Background: Gastric cancer (GC) is one of the leading causes of death in the world. Evidence has shown over the past decade that cancer-associated​ fibroblasts (CAFs) play essential roles in various types of cancers, including GC, such as tumorigenesis, therapy resistance, and immunosuppression, which contribute to the progress of tumors. Although GC tumors are known to be enriched with stroma, the molecular mechanisms of how GC tumors foster the fibrotic milieu is still largely unknown. Here we analyzed a large-scale genomic and transcriptomic dataset of GC to identify GC tumor cell-intrinsic factors for developing fibroblast-rich microenvironments​. Methods: We analyzed GC patient samples with gene expression data and copy number variation profiles from the Asian Cancer Research Group (ACRG) (N = 271). The microenvironment cell populations-counter (MCP-counter) method was used for transcriptome deconvolution to estimate the population of fibroblasts and immune cells in GC tumors. Genes with q value < 0.05 and fold change > 1.5 were defined as differentially expressed genes (DEGs) and identified using the Subio Platform. The copy number amplified genes found in more than 3% of the samples were selected as amplified genes. Pathway and process enrichment analysis and protein-protein interaction analysis were performed using Metascape. Results: We analyzed MCP-counter outputs and observed a fibroblast-enriched population with few infiltrations of anti-tumor immune cells, such as CD8 T cells and cytotoxic T cells in GC patients, suggesting the immunosuppressive role of CAFs in the GC tumor. By analyzing 933 DEGs upregulated in fibroblast-high patients, we found 96 genes with frequent copy number amplification that were not listed on the curated stroma and extracellular matrix-related genes and thus potentially tumor cell-intrinsic genes correlated with the abundance of the stroma. Pathway and protein-interaction analyses revealed that G protein-coupled receptor (GPCR) signaling pathway was enriched in these genes, including HTR2A, AGTR1, FZD1, CALCRL, and NBEA with strong correlations between fibroblast score (Spearman's r > 0.55), implying that these signaling in GC tumor cells contribute to promoting fibroblast-enriched microenvironment. Conclusions: Bioinformatic analyses of a publicly available genomic and transcriptomic dataset revealed a fibroblast-rich and immune-excluded population in GC patients. Several GPCR signaling in tumor cells were strongly correlated with fibroblast abundance in tumors, and these signaling pathways have potential roles in promoting the stroma-rich GC microenvironment. Citation Format: Takashi Semba, Yiling Tong, Feng Wei, Atsuko Yonemura, Tadahito Yasuda, Tomoyuki Uchihara, Huaito Wang, Hideo Baba, Takatsugu Ishimoto. Tumor cell-intrinsic factors promoting fibrotic tumor microenvironment in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5861.

Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of β1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics. Significance: This study elucidates a novel molecular mechanism through which Annexin A6 in CAF-EV activates FAK-YAP by stabilizing β1 integrin at the cell surface of gastric cancer cells and subsequently induces drug resistance.

The accidental ingestion of foreign bodies is a common clinical issue. While most foreign bodies pass through the gastrointestinal (GI) tract without complications, a few cases unfortunately result in GI perforation. Fish bones are one of the most frequent foreign bodies found in the GI tract, and they are high-risk objects for GI perforation due to their hard and sharp-pointed ends. Here, we present a rare case of a 64-year-old man with perforation of a colorectal tumor by a fish bone. The patient received emergency Hartmann's operation with lymph node dissection. Although the patient experienced recurrence in the liver rather than peritoneal dissemination, systemic chemotherapy was considerably effective, and conversion therapy with hepatectomy was successfully performed; the patient achieved 5-year relapse-free survival after the operation. To our knowledge, this is the first report of the perforation of a GI tumor by a fish bone. This rare case suggests the significant clinical implication that proper preoperative diagnosis and prompt surgical treatment lead to better postoperative outcomes for patients with tumor perforation by a foreign body.

Summary: In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination.

The effectiveness of current chemotherapies for cancer is gradually progressing; however achieving a complete cure through chemotherapy is still difficult and has been the main goal in treatment of advanced cancer. Drug resistance is an issue in cancer therapy, therefore increasing numbers of investigations into drug resistance have focused on the characteristics of the cancer cells themselves. The interaction between the tumor microenvironment (TME) and cancer cells is also intimately involved in the development of drug resistance. Cancer‐associated fibroblasts (CAFs) are a predominant component of the TME and affect tumor progression by secreting soluble factors. This review summarizes the most up‐to‐date knowledge of CAFs and drug resistance in cancer, with a focus on factors secreted from CAFs including proteins, cytokines, extracellular vesicles, and metabolites. A perspective on the potential role of anti‐CAF therapies in overcoming CAF‐induced drug resistance is also discussed., Drug resistance is a main issue for anticancer therapies. Cancer‐associated fibroblasts (CAFS) have a huge effect in promoting drug resistance. This review summarizes the current perspectives on the role of CAFs in chemoresistance.

Advanced esophageal cancer often results in esophageal stenosis or tracheoesophageal fistula. Esophageal bypass surgery and esophageal stent insertion are palliative treatments for esophageal cancer. With improvements in metallic stents and the stent insertion technique, esophageal stent insertion appears to be performed more frequently than bypass surgery, worldwide. The aim of this study was to evaluate the outcomes of bypass surgery and stent insertion in our hospital and reevaluate which patients would benefit from bypass surgery. A total of 70 esophageal cancer patients who could not tolerate oral feeding due to esophageal stenosis or tracheoesophageal fistula underwent palliative treatment [esophageal bypass surgery (N = 34) and esophageal stent insertion (N = 36)] at Kumamoto University. We retrospectively investigated the clinicopathological factors, postoperative outcomes, and complications. Both treatments could significantly improve the amount of food intake and the dietary form (P

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Cancer stem cells (CSCs) are known to be involved in chemotherapy resistance and the development of metastases. Although CSCs harbor self-renewal and tumorigenic abilities, the immune microenvironment surrounding CSCs provides various factors and supports the maintenance of CSC properties. The current review summarizes the accumulating findings regarding the relationship between the immune microenvironment and gastric CSCs (GCSCs), which will support the possibility of developing novel therapeutic strategies for targeting GCSCs.

Anatomical esophageal position may affect the short-term outcomes after minimally invasive esophagectomy (MIE). A previous single-institutional retrospective study suggested that the presence of a left-sided esophagus (LSE) made MIE more difficult and increased the incidence of postoperative complications. The current study was a multicenter retrospective study of 303 patients with esophageal cancer who underwent MIE at six esophageal cancer high-volume centers in Kyushu, Japan, between April 2011 and August 2016. The patients were divided into the LSE (66 patients) and non-LSE groups (237 patients) based on the esophageal position on computed tomography images obtained with the patients in the supine position. Univariate analysis showed that patients with LSE were significantly older than those with non-LSE (69 ± 8 vs. 65 ± 9 years; P = 0.002), had a significantly greater incidence of cardiovascular comorbidity (65.2% vs. 47.7%; P = 0.013), and a significantly longer operating time (612 ± 112 vs. 579 ± 102 min; P = 0.025). Logistic regression analysis verified that LSE was an independent risk factor for the incidence of pneumonia (odds ratio 3.3, 95% confidence interval 1.254–8.695; P = 0.016). The presence of a LSE can increase the procedural difficulty of MIE and the incidence of morbidity after MIE. Thus, careful attention must be paid to anatomical esophageal position before performing MIE.

This study investigated the predictors associated with early recurrence (i.e. within 12 months) after curative gastrectomy for gastric cancer (GC). We evaluated the clinicopathological factors in 429 patients who underwent curative gastrectomy for GC without preoperative chemotherapy and analyzed these factors’ associations with early recurrence. Of 429 patients, 57 experienced recurrences, which were associated with gender, diameter, depth of invasion, lymph node (LN) metastasis, the LN ratio (LNr; LNs with metastasis/dissected LNs), lymphatic invasion, vascular invasion, carbohydrate antigen 19-9 (CA19-9) levels, C-reactive protein levels and the neutrophil/lymphocyte ratio. Twenty-one patients (36.8%) recurred within 12 months. Early recurrence was associated with a high LNr (P = 0.0020) and high CA19-9 levels (P = 0.0415). The other factors were not significantly associated with early recurrence. The 12-month recurrence rate was 33.9% in patients with a high LNr and 1.9% in those with a low LNr and 20.3% in patients with high CA19-9 levels and 3.5% in those with low CA19-9 levels. The 12-month recurrence rate was 62.5% in patients with a high LNr and high CA19-9 levels, 18.4% in those with a high LNr or high-CA19-9 levels, and 1.4% in those with a low LNr and low CA19-9 levels. LNr ≥ 0.15 and CA19-9 ≥ 37 U/ml were effective surrogate markers for predicting early recurrence.

Patients with gastric cancer (GC) are affected by changes in iron status. Before surgery, GC patients are likely to have iron-deficiency anemia; and after gastrectomy, patients suffer from low nutritional status and low iron. This study investigated preoperative iron status associated with prognosis after curative gastrectomy for gastric cancer. We evaluated preoperative serum hemoglobin (Hgb), Fe and total iron-binding capacity (TIBC) in 298 patients who underwent curative gastrectomy for GC without preoperative chemotherapy, and analyzed these factors’ associations with prognosis after surgery. Of the 298 patients, 129 (43.2%) had low Hgb levels, and 33 (11.1%) had low TIBC (

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15‐PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15‐PGDH suppression in PDAC. Here, we showed that interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine, downregulates 15‐PGDH expression in PDAC cells, and that IL‐1β expression was inversely correlated with 15‐PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL‐1β and reduced 15‐PGDH expression in PDAC cells. Furthermore, the number of CD163‐positive tumor‐associated macrophages was shown to be inversely correlated with 15‐PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15‐PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL‐1β derived from TAMs suppresses 15‐PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients.

The neutrophil-to-lymphocyte ratio (NLR) has been reported to predict the prognosis of various malignant tumors, including esophageal cancer. However, no previous reports have supported the use of the preoperative NLR as an independent prognostic marker focused on superficial (T1) esophageal cancer. The aim of this study was to elucidate the prognostic impact of the preoperative NLR in T1 esophageal cancer. This retrospective study recruited 245 consecutive patients with T1 esophageal cancer who underwent subtotal esophagectomy between 2005 and 2016. The relationship between the preoperative NLR and clinicopathological characteristics was analyzed. The preoperative NLR was significantly higher in male patients (p = 0.029), patients with T1b esophageal cancer (p = 0.0274), and patients with venous vessel invasion (p = 0.0082). In the Kaplan–Meier analysis, the elevated preoperative NLR was significantly associated with a poorer disease-free survival (p

The accumulation of prostaglandin E2 (PGE2) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE2, although the degradation enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all-trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of KrasLSL-G12D/+; Ptf1aCre/+ (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE2 accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh-/- KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS-driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment.

Background Primary colonic and dedifferentiated liposarcomas are both remarkably rare. This work describes a case of primary colonic well-differentiated/dedifferentiated liposarcoma and reviews the clinical characteristics and current therapies for liposarcoma tumors. Case presentation A 52-year-old woman was referred to our hospital with a submucosal tumor of the ascending colon. Clinical analysis by ultrasound colonoscopy and computed tomography revealed a partially ossified tumor with irregular edges continuous with the muscular layer. High F-18 deoxyglucose uptake was detected by positron emission tomography. Radical resection with lymph node dissection was performed, yielding a tumor specimen approximately 6.5 × 4.0 × 3.2 cm. Neoplastic spindle cell proliferation was found from submucosa to subserosa. Well-differentiated adipose tissue surrounded the tumor, but contained atypical nuclei with condensed chromosomes. Immunohistochemical staining was positive for p16, CDK4, and MDM2 expression. Based on these findings, a diagnosis of well-differentiated/dedifferentiated liposarcoma was given. Dedifferentiated liposarcomas are more aggressive than their well-differentiated, low-grade counterparts. While local recurrence can occur with both tumor types, dedifferentiated liposarcomas are more prone to developing distant metastases. The patient received no postoperative therapy, and no recurrences have been observed 12 months after surgery. Conclusions Here we report an extremely rare case of well-differentiated/dedifferentiated liposarcoma of the ascending colon. The dedifferentiated component was high-grade liposarcoma and well-differentiated liposarcoma was detected around the main tumor.

Pulmonary morbidities after esophagectomy are still common and are a major cause of surgery-related mortality. The relationship between minimally invasive esophagectomy (MIE) and pulmonary morbidities is not clear. The current study aimed to examine the incidence of pulmonary morbidities after MIE and to clarify the associated risk factors. Between May 2011 and December 2016, 184 patients underwent MIE for esophageal cancer. Clinical data were prospectively collected and analyzed. Patient- and surgery-related factors, relating to pulmonary complications, were compared between the complicated and uncomplicated cases. The incidence of any pulmonary morbidity following MIE was 17.9%. Univariate analysis showed that past heavy smoking [Brinkman index (BI) ≥ 1000], presence of neoadjuvant therapy, advanced clinical stage (stage III, IV), and intraoperative bleeding ≥ 600 g were candidates for being postoperative pulmonary morbidity risk factors. Multivariate analysis suggested that BI ≥ 1000 and advanced clinical stage were independent risk factors for causing pulmonary morbidities. Past heavy smoking and advanced stage are independent risk factors for pulmonary morbidities after MIE. When performing MIE for such cases, various preoperative precautions and careful postoperative monitoring are necessary.

Background: Cancer-associated fibroblasts (CAFs) enhance tumor progression through secretion of soluble factors. Although we demonstrated that direct-interaction between CAFs and cancer cells confer on gastric cancer (GC) cells the ability to invade extracellular matrix (ECM), the molecular mechanism underlying the drug resistance by soluble factors from CAFs has not been determined. Methods: We have established primary fibroblasts from more than 100 GC patients and collected conditioned medium (CM) of CAFs. Human GC cell lines cultured in normal medium or CAF-CM were examined the drug resistance with or without extracellular matrix (ECM). We isolated extracellular vesicles (EVs) from CAF-CM by ultracentrifugal separation. We performed RNA sequencing of GC cell lines and mass analysis of GC-EVs and CAF-EVs. Results: GC cells treated with CAF-CM or CAF-EVs did not show morphological change on normal coated plates. Notably, we found that GC cells with CAF-CM or CAF-EVs on ECM-coated plates showed unique network formation and cisplatin resistance. Given that the morphological change appeared within 1-3 hours, we predicted that the stimulation by CAF-EV had an impact on the expression pattern of membrane proteins in GC cells. Mass analysis using isolated CAF-EVs was conducted and revealed that CAF-EVs contained high amount of annexin family protein members. Moreover, we showed that annexin in CAF-EVs is critical for network formation and drug resistance of GC cells. Finally, we identified integrinβ1/FAK signaling was activated in GC cells treated with CAF-EVs during network formation. Conclusions: These findings highlight the underlying mechanism whereby CAF-EVs in tumor-microenvironment confer GC cells on drug resistance. Citation Format: Tomoyuki Uchihara, Atsuko Yonemura, Keisuke Miyake, Tadahito Yasuda, Rumi Itoyama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Hideo Baba, Takatsugu Ishimoto. Extracellular vesicles from cancer associated fibroblasts induce drug resistance via integrinβ1/FAK signaling in gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 107.

Background: Secreted factors from cancer associated fibroblast (CAFs) is likely to be implicated in cancer progression, but the precise mechanism is not fully understood. It is reported that senescent cells survive and secrete some cytokines, so called senescence-associated secretory phenotype (SASP). The purpose of current study is to identify the molecular mechanism underlying the progression of gastric cancer (GC) peritoneal dissemination by CAFs showing SASP. Methods: We examined the senescent state of CAFs activated NFkB signaling by inflammatory cytokines (iCAFs) and evaluated the expression of SASP factors. We investigated the growth ability of GC cell lines treated with iCAFs derived condition medium (CM). We transplanted GC cell lines with intraperitoneal administration to generate peritoneal metastasis mouse model and evaluated the influence of SASP factors on cancer progression. Results: We found that the growth ability of iCAFs decreased and their expression of p16 and p15, which was senescent markers increased. And the comprehensive genomic analysis revealed that iCAFs was highly enriched the senescent related genes and SASP factors related genes. Next, we also found that iCAFs derived CM significantly increased the growth ability of GC cells. Moreover, also in peritoneal metastasis mouse model, iCAFs derived CM remarkably enhanced intraperitoneal tumors. Conclusion: These findings suggest that SASP factors from senescent CAFs, which activated by inflammatory cytokines can promote peritoneal dissemination of GC cells. Citation Format: Tadahito Yasuda, Mayu Koiwa, Tomoyuki Uchihara, Atsuko Yonemura. The identification of molecular mechanism underlying the progression of gastric cancer peritoneal dissemination by senescent fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 895.

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2 (PGE2). 15-hydroxyprostaglandin dehydrogenase (15-PGDH) participates in the degradation of PGE2 and has attracted attention in recent years. Although inhibition of 15-PGDH is reported to lead to PGE2 accumulation and expand tissue stem cell fraction, the role for pancreatic tumor progression is still unknown. The aim of this study is to elucidate the regulatory mechanism and functional role of 15-PGDH for cancer stem-like cell expansion during tumor progression in pancreas. We found that 15-PGDH expression is frequently down-regulated in PDAC cells and significantly correlated with the number of infiltrating macrophages in human PDAC tissues. Moreover, direct co-culture assay revealed that macrophage derived interleukin-1 beta down-regulates 15-PGDH expression in PDAC cells. Furthermore, pharmacological blockade of 15-PGDH led to PGE2 accumulation, and promoted growth and sphere formation through the expansion of ALDH1-positive cells. We also elucidated the molecular mechanism that PGE2 accumulation by 15-PGDH inhibition increases CYP26A1 expression and subsequently depletes all-trans retinoic acid, and results in ALDH1 up-regulation. Finally, genetic ablation of 15-Pgdh promoted tumorigenesis in KrasLSL-G12D; Ptf1aCre/+ mice through the expansion of ALDH1-positive cells. Our findings highlight the role and significance of PGE2 degradation pathway for PDAC tumor progression. Note: This abstract was not presented at the meeting. Citation Format: Takatsugu Ishimoto, Kota Arima, Tomoyuki Uchihara, Keisuke Miyake, Atsuko Yonemura, Tadahito Yasuda, Rumi Itoyama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Hideo Baba. Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4677.

The cancer stem cell (CSC) paradigm suggests that tumors are organized hierarchically. Chugai previously established an LGR5+ human colorectal cancer (CRC) stem-cell-enriched cell line (colorectal CSCs) that expresses well-accepted colorectal CSC markers and that can dynamically switch between proliferative and drug-resistant noncycling states. We performed this study to elucidate the molecular mechanisms responsible for evading cell death in colorectal CSCs mediated by anticancer agents. During the cell cycle arrest caused by anticancer agents, we found that c-Myc expression was substantially decreased in colorectal CSCs. The c-Myc expression alterations were mediated by upregulation of F-box/WD repeat-containing protein 7 (FBXW7), as evidenced through FBXW7-small interfering RNA knockdown experiments that resulted in enhanced cell sensitivity to anticancer agents. Upregulation of FBXW7 following drug treatment was not evident in commercially available cancer cell lines. Colorectal CSCs were induced to differentiation by Matrigel and fetal bovine serum. Differentiated CSCs treated with anticancer agents did not show upregulation of FBXW7 and were more sensitive to irinotecan (CPT-11), highlighting the potential CSC-specific nature of our data. The FBXW7 over-expression was further validated in resected liver metastatic sites in CRC patients after chemotherapy. In conclusion, our study revealed that a CSC-specific FBXW7-regulatory mechanism is strongly associated with resistance to chemotherapeutic agents. Inhibition of FBXW7-upregulation in CSCs following chemotherapy may enhance the response to anticancer agents and represents an attractive strategy for the elimination of colorectal CSCs.

The double stapling technique (DST) is an intestinal reconstruction technique that has been widely adopted in anterior resection (AR) for rectal cancer. However, anastomotic leakage (AL) after the operation remains a major concern for colorectal surgeons. The sharp-angled corner of the remnant rectum that is often created by the ordinary DST can be a risk factor for AL. We have developed a new method of performing intentional oblique transection DST (IOT-DST). Using this technique, the anal side of the rectum is intentionally obliquely transected with linear staplers, and the area of the sharp-angled edge is totally punched out with a circular stapler. Between September 2015 and March 2016, we used the IOT-DST technique in the treatment of 15 consecutive rectal cancer patients and experienced no anastomosis-related complications, including leakage and stenosis. IOT-DST is easy to use and less stressful to perform than other techniques. IOT-DST has the potential to become the standard technique for AR in rectal cancer surgery.

Introduction: It has become clear that macrophages are important cells forming cancer microenvironment and tumor-associated macrophages (TAM) promote their proliferation in various cancer types. In particularly, M2-type macrophages have been reported to promote the production of anti-inflammatory factors and the infiltration of regulatory T cells and suppress anti-tumor immunity, and new antitumor therapies that control tumor growth by controlling TAM have been proposed. In addition, "anti-PD-1 antibody" has attracted attention also in esophageal cancer, but the relationship between TAM and PD-L1 expression has not been clarified. Methods: A retrospective study was performed on 301 patients who underwent esophagectomy for esophageal cancer between March 2005 and June 2013. We performed immunohistochemistry and evaluation of macrophage markers (CD163 and CD204) and PD-L1. In addition, we performed in vitro experiments to clarify the cellular malignancy and relationship with PD-L1 expression. Results: Out of 301 cases of esophageal cancer, 156 cases showed CD163 high expression (51.8%) while 146 cases showed CD204 high expression (48.5%). We divided into three groups of TAM status based on CD204 and CD163 expression (CD163 and CD204 both positive: TAM status high (n=100), either one positive: moderate (n=102), both negative: low (n=99)). In TAM high group, there were more advanced cancers and adenocarcinoma cases (P Conclusion: This study suggested that TAM correlated with poor prognosis in patients with esophageal cancer. In addition, TAM correlated with invasive capacity and migratory capacity. Importantly, TAM correlated PD-L1 expression in esophageal cancer cell lines. Citation Format: Taisuke Yagi, Yoshifumi Baba, Yuki Koga, Tomoyuki Uchihara, Yuki Kiyozumi, Hiroshi Sawayama, Yukiharu Hiyoshi, Masaaki Iwatsuki, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Role of tumor-associated macrophages in esophageal cancer: PD-L1 expression and prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4742.

Background: Tumor microenvironment consists of various types of cells. Although cancer associated fibroblasts (CAFs) have been reported to enhance tumor progression and anticancer drug resistance through secretion of soluble factors so far, the crucial mechanism is not fully understood. On the other hand, advanced gastric cancer (GC) is still poor prognosis due to metastasis and recurrence despite the progression of diagnosis and treatment. The aim of this study is to identify the molecular mechanism underlying anticancer drug resistance mediated by CAFs in GC. Methods: We have isolated CAFs from surgically resected GC tissues and collected conditioned medium (CM) of CAFs. Human GC cell lines with or without CAF-CM were examined the drug sensitivity and analyzed expression of specific genes using quantitative reverse transcription PCR. We isolated extracellular vesicles (EVs) from CAF-CM by ExoQuick-TC ® and ultracentrifugal separation. We observed GC cells with confocal microscopy after the solution of stained EVs treated. We performed EVs from CAF-CM and GC-CM to mass analysis. Results: GC cells with CAF-CM showed drug resistance on normal coated plates. Moreover, we found that GC cells with CAF-CM on extracellular matrix (ECM)-coated plates showed remarkable morphological change and much higher drug resistance than those without CAF-CM. In contrast, GC cells with GC cell line-CM on ECM- coated plates did not show morphological change. We also found that EVs isolated from CAF-CM caused morphological change and drug resistance of GC cells. Moreover, we identified five proteins included in CAF-EVs as possible candidates involving in GC drug resistance by mass analysis. Gene expression analysis revealed that SNAI2, which is one of the Epithelial Mesenchymal Transition (EMT)-related gene, was significantly up-regulated in GC cells cultured with CAF-CM or EVs from CAF-CM on ECM-coated plates. Conclusion and future perspective: These findings in current study suggest that EVs from CAFs cause characteristic gene expression change and enhance drug resistance along with morphological change of GC cells. We are trying to identify the critical factor in CAF-EVs for drug resistance of GC cells. Citation Format: Tomoyuki Uchihara, Keisuke Miyake, Eri Oda, Yuki Koga, Taisuke Yagi, Daisuke Kuroda, Tsugio Eto, Yuki Kiyozumi, Kota Arima, Hiroshi Sawayama, Yukiharu Hiyoshi, Masaaki Iwatsuki, Yoshifumi Baba, Yuji Miyamoto, Naoya Yoshida, Hideo Baba, Takatsugu Ishimoto. To identify the critical factors in extracellular vesicles derived from cancer-associated fibroblasts for drug resistance of gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5086.

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2 (PGE2). 15-hydroxyprostaglandin dehydrogenase (15-PGDH) participates in the degradation of PGE2 and has attracted attention in recent years. Although inhibition of 15-PGDH is reported to lead to PGE2 accumulation and expand tissue stem cell fraction, the role for pancreatic tumor progression is still unknown. The aim of this study is to elucidate the regulatory mechanism and functional role of 15-PGDH for cancer stem-like cell expansion during tumor progression in pancreas. We found that 15-PGDH expression is frequently down-regulated in PDAC cells and significantly correlated with the number of infiltrating macrophages in human PDAC tissues. Moreover, direct co-culture assay revealed that macrophage derived interleukin-1 beta down-regulates 15-PGDH expression in PDAC cells. Furthermore, pharmacological blockade of 15-PGDH led to PGE2 accumulation, and promoted growth and sphere formation through the expansion of ALDH1-positive cells. We also elucidated the molecular mechanism that PGE2 accumulation by 15-PGDH inhibition increases CYP26A1 expression and subsequently depletes all-trans retinoic acid, and results in ALDH1 up-regulation. Finally, genetic ablation of 15-Pgdh promoted tumorigenesis in KrasLSL-G12D; Ptf1aCre/+ mice through the expansion of ALDH1-positive cells. Our findings highlight the role and significance of PGE2 degradation pathway for PDAC tumor progression. Citation Format: Takatsugu Ishimoto, Kota Arima, Luke Bu, Tomoyuki Uchihara, Keisuke Miyake, Tsugio Eto, Rumi Itoyama, Hideo Baba. Expansion of pancreatic cancer stem-like cells through PGE2 accumulation in inflammatory environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1987.

A 63-year-old man diagnosed with locally advanced pancreatic ductal adenocarcinoma (PDAC; stage IIa) was treated with chemotherapy (gemcitabine, 5-fluorouracil and cisplatin) followed by radiotherapy. He had complete response by imaging and relapse-free survival for 11 years. However, he subsequently presented with local tumor recurrence and underwent pancreaticoduodenectomy followed by chemotherapy; a partial response was achieved. As in liver metastasis of colonic cancer, complete response by imaging in PDAC may not mean pathological complete response. We would propose the importance of adjuvant surgery for a patient with PDAC with complete response by imaging after chemoradiotherapy.

Purpose: Cancer cells exhibit altered glucose metabolism, termed glycolysis which is described by the increased uptake of glucose and the conversion of glucose to lactate in cancer cells under adequate oxygen tension. Alternating glucose transporters (GLUTs) expression was detected in the cancer specific metabolism to adapt to the rapid growth and tumor microenvironment in diverse malignant tumors. In this study, GLUTs profiling of ESCC patients, the relation between proliferation and GLUT1 expression using siRNA for GLUT1 were analyzed. Furthermore, the prognostic features according to GLUT1 expression was evaluated on esophageal squamous cell carcinoma (ESCC) patients. Methods: The ratio of the 11 GLUTs (GLUT1- GLUT14) expression between tumor and normal tissue (T/N) were analyzed in silico (GDS3838). GLUT1 expression was down-regulated using 3 siRNAs in vitro. Immunohistochemical staining of GLUT1 was performed using paraffin sections of tissues obtained from 145 resectable ESCC patients without preoperative treatment. Results: Expression of GLUT1 (T/N 2.44; 95% confidence interval (CI): 1.78-3.34, P Conclusions: GLUTs expression was altered in ESCC patients and GLUT1 expression was most up-regulated among the 11 GLUTs. Growth assay with siRNAs for GLUT1 revealed that GLUT1 played a curial role of ESCC cells proliferation. High expression of GLUT1 was associated with depth of invasion and poor prognosis of ESCC patients. These findings provide evidence of the significance of GLUT1 expression as a biomarker and GLUT1 may be therapeutic target in ESCC patient. Citation Format: Hiroshi Sawayama, Masaaki Iwatsuki, Naoya Yoshida, Yoshifumi Baba, Yasuo Sakamoto, Koichi Kinoshita, Kenichi Nakamura, Daisuke Kuroda, Eto Tsugio, Tasuku Toihata, Tomoyuki Uchihara, Eri Oda, Taisuke Yagi, Mayuko Ohuchi, Takatugu Ishimoto, Hideo Baba. Glucose transporter 1 is associated with proliferation and prognosis on esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4407. doi:10.1158/1538-7445.AM2017-4407

Background: Peritoneal metastasis is one of the most frequent causes of death in patients with advanced gastric carcinoma (GC). However, molecular mechanisms driving peritoneal dissemination still remain poorly understood. Here, we aimed to give new insights to the molecular mechanisms that drive the peritoneal dissemination of GC. This study identified candidates of potential regulators of peritoneal dissemination and focused on the significance of one of them in vitro experiments and clinical samples. Methods: We utilized previously reported combined expression analysis with two cell lines and samples and 200 GC patients to identify driver genes of peritoneal dissemination. The cell lines consist of HSC58, an established cell lines from scirrhous type primary GC and its progeny cell line, 58As9, with in vivo-selected highly peritoneal metastatic potential. In vitro experiments, we utilized the two gastric cancer cell lines, 58As9 and NUGC4 and evaluated the effect of SERPINE2 knockdown on proliferation, spheroid formation, invasion, and motility. As for evaluation of clinical samples, 176 primary gastric carcinomas were included, which were obtained from patients who underwent curative gastrectomy in Kumamoto university between 2005 and 2015. We evaluated expression of SERPINE2 in immunohistochemistry and divided the cohort into two groups by SERPINE2 expression and analyzed relationship with clinicopathological factors and survival. Results: Enrichment analyses of the profile of the peritoneal dissemination-associated expression signature revealed that poor prognosis and peritoneal metastasis was related with the two pathways, focal adhesion (FDR q=0.00195) and extracellular matrix (FDR q=0.00195). Among the genes related with extracellular matrix, Serine Proteinase Inhibitor, Clade E, Member 2 (SERPINE2) was found to be highly expressed in 58As9 compared with HSC58, and we focused on SERPINE2 as a candidate of potential regulators of peritoneal dissemination. In vitro experiments, the SERPINE2 knockdown was related with decrease in cell motility and invasion, but not with decrease in proliferation, spheroid formation. Immunohistochemistry analysis of the clinical samples revealed higher SERPINE2 expression was significantly related with invasion of serosa and lymphatic vessels, and lymph node matastasis, and peritoneal metastatic metastasis. Survival analysis also revealed SERPINE2 expression was related with poor peritoneal recurrence-free survival (p=0.038), and peritoneal metastasis-specific survival (p=0.036). Conclusion: We found SERPINE2 as a candidate of driving molecules of peritoneal metastasis partly because it promotes invasive potential. Further study including in vivo study is required to reveal relationship of SERPINE2 with the other molecules and pathways. Citation Format: Daisuke Kuroda, Junji Kurashige, Hiroshi Sawayama, Masaaki Iwatsuki, Tomoyuki Uchihara, Tasuku Toihata, Eri Oda, Taisuke Yagi, Tsugio Eto, Keisuke Miyake, Mayuko Ouchi, Kenichi Nakamura, Koichi Kinoshita, Kousuke Mima, Takatsugu Ishimoto, Yasuo Sakamoto, Yoshifumi Baba, Naoya Yoshida, Koshi Mimori, Hideo Baba. Significance of SERPINE2 expression in peritoneal metastasis in gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1336. doi:10.1158/1538-7445.AM2017-1336

Intestinal metastasis of angiosarcoma is extremely rare. We herein report a case of intestinal perforation due to intestinal metastasis of angiosarcoma. The patient was a 72-year-old Japanese man with multiple recurrent angiosarcomas of the scalp. He developed acute abdominal pain with guarding, and we performed an emergency exploratory laparotomy. An intestinal perforation was found 80 cm from the ligament of Treitz, and partial jejunectomy was successfully performed. Macroscopic inspection revealed no obvious injury, ulcer, or tumor at or around the perforation site. Pathological examination revealed angiosarcoma cells penetrating through all layers of the jejunum at the site of intestinal perforation. This is the first reported case of intestinal perforation caused by indistinguishable intestinal metastasis of angiosarcoma. This case emphasizes intestinal metastasis of angiosarcoma as a possible cause of small bowel perforation in patients with advanced angiosarcoma, even when no visible tumor is present during surgery.