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Background:FSCN1 and matrix metalloproteinase 14 (MMP14) are both invadopodia-related proteins. We herein elucidate the tumourigenicity of these proteins and identify novel therapeutic agents in esophageal squamous cell carcinoma (ESCC).Methods:FSCN1 and MMP14 were evaluated by immunohistochemistry and quantitative PCR, and microRNA (miR)-133a was also evaluated by PCR in surgical ESCC specimens. The roles of FSCN1, MMP14 and miR-133a were established in ESCC cells.Results:The expression of FSCN1 or MMP14 was an independent poor prognostic factor according to a multivariate analysis of immunohistochemistry, and their co-expression correlated with the poorest overall survival (OS) out of all the examined factors. Additionally, their mRNAs significantly correlated and both inversely correlated with miR-133a in surgical specimens. Transfection of a miR-133a mimic decreased the mRNA and protein levels of both FSCN1 and MMP14 in ESCC cells. The knockdown of FSCN1 or MMP14 and transfection of a miR-133a mimic inhibited the proliferation and invasion of ESCC cells. Patients with a lower miR-133a expression have a significantly poorer OS than those with a higher expression.Conclusion:The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC. [ABSTRACT FROM AUTHOR]

Background/aim: Identifying prognostic and molecular markers as therapeutic targets for esophageal squamous cell carcinoma (ESCC) could enhance the efficacy of multidisciplinary treatments. While tissue expression of sirtuin 1 (SIRT1) has been linked to tumor progression in ESCC, prognostic significance of serum SIRT1 levels and their correlation with tissue SIRT1 remains unexplored. This study aimed to investigate the correlation between serum and tissue SIRT1 levels in patients with ESCC., Patients and Methods: A total of 38 patients diagnosed with ESCC who were untreated preoperatively were recruited for this study. SIRT1 expression in the surgical specimens was assessed through immunostaining, while serum SIRT1 levels were measured using an enzyme-linked immunosorbent assay. We analyzed the association between tissue and serum SIRT1 levels, clinicopathological features, and patient prognosis., Results: Positive SIRT1 expression in tissue was significantly associated with deeper tumor depth (p=0.020). It was also significantly associated with poorer overall survival (OS) and relapse-free survival (RFS) (p=0.041 and p=0.012, respectively). Elevated serum SIRT1 levels were significantly correlated with increased tumor depth and weight loss (p=0.012 and p=0.030). While higher serum SIRT1 levels tended to be associated with poorer OS (p=0.069), no significant correlation was found between SIRT1 expression in tissue and its concentration in serum., Conclusion: SIRT1 tissue expression may be a valuable prognostic marker in ESCC. However, the clinical significance of serum SIRT1 levels appears to differ from that of its tissue expression. Future research is required to clarify the role of serum SIRT1 in ESCC., Competing Interests: The Authors declare no conflicts of interest in relation to this study., (©2024 The Author(s). Published by the International Institute of Anticancer Research.)

Background/aim: Although the impact of body composition on cancer treatment outcomes of patients with cancer has been increasingly reported, it is still unclear whether the radiodensity of subcutaneous adipose tissue (SAT) on computed tomography (CT) images has a prognostic impact on patients with gastric cancer. We measured muscle and SAT profiles on CT and performed an integrated analysis with clinicopathologic factors., Patients and Methods: We retrospectively analyzed 230 patients with gastric cancer who underwent gastrectomy between June 2016 and December 2020. SAT radiodensity (SAT-R), and skeletal muscle index (SMI) were measured in preoperative CT images. These were compared with clinicopathologic factors, overall survival (OS), and recurrence-free survival (RFS)., Results: High SAT-R was significantly associated with older age (p=0.003) and lower BMI, lymphocyte, hemoglobin, γ-GTP, cholinesterase, albumin, and triglyceride values (p<0.001, <0.001, 0.027, 0.032, <0.001, 0.001, and <0.001, respectively). In the univariate analysis, high SAT-R, and low SMI were significantly associated with poor OS (p=0.003 and <0.001) and poor RFS (p=0.014 and 0.011). In the multivariate analysis by Cox proportional hazard model, high SAT-R and low SMI were identified as independent prognostic factors for poor OS (p=0.037 and 0.007)., Conclusion: High SAT-R on preoperative CT was associated with poor OS in patients with gastric cancer after gastrectomy. SAT-R has a potential to be a novel prognostic marker for surgically treated patients with gastric cancer., Competing Interests: All Authors declare no conflicts of interest in relation to this study., (©2024 The Author(s). Published by the International Institute of Anticancer Research.)

Background: Proton-based, definitive chemoradiotherapy (P-CRT) for esophageal squamous cell carcinoma (ESCC) previously showed comparable survival outcomes with the surgery-based therapy, i.e., neoadjuvant chemotherapy followed by esophagectomy (NAC-S), in a single-institutional study. This study aimed to validate this message in a Japanese multicenter study., Methods: Eleven Japanese esophageal cancer specialty hospitals have participated. A total of 518 cases with clinical Stage I-IVA ESCC between 2010 and 2019, including 168 P-CRT and 350 NAC-S patients, were enrolled and long-term outcomes were evaluated. Propensity-score weighting analyses with overlap weighting for confounding adjustment were used., Results: The 3-year overall survival (OS) of the P-CRT group was equivalent to the NAC-S group (74.8% vs. 72.7%, hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.61-1.25). Although, the 3-year P-CRT group progression-free survival (PFS) was inferior to the NAC-S group (51.4% vs. 59.6%, HR 1.39, 95% CI 1.04-1.85), the progression P-CRT group cases showed better survival than the NAC-S group (HR 0.58, 95% CI 0.38-0.88), largely because of salvage surgery or endoscopic submucosal dissection for local progression. The survival advantage of P-CRT over NAC-S was more pronounced in the cT1-2 (HR 0.61, 95% CI 0.29-1.26) and cStage I-II (HR 0.50, 95% CI 0.24-1.07) subgroups, although this trend was not evident in other populations, such as cT3-4 and cStage III-IVA., Conclusions: Proton-based CRT for ESCC showed equivalent OS to surgery-based therapy. Especially for patients with cT1-2 and cStage I-II disease, proton-based CRT has the potential to serve as a first-line treatment., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Tumor cells (TC) participate in tumor progression by altering the immune responses in the tumor microenvironment. However, the clinical relevance and prognostic effect of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in esophageal squamous cell carcinoma (ESCC) are unknown. The purpose of this study was to investigate the interactions and clinical significance of PD-L1 expression and TILs in ESCC., Methods: Tissue specimens were collected from 126 patients with ESCC who underwent curative esophagectomy. Immunohistochemical analysis and multiplex immunofluorescence for CD4, CD8, CD25, FOXP3, and PD-L1 in the tumor were used to identify multiple tumor-infiltrating immune cells (TIIC), Tregs, and TC., Results: PD-L1 was expressed in tumor cells (PD-L1 TC). PD-L1 TIIC and PD-L1 TC affected the biological behavior of TC. The positive expression rate of PD-L1 TC and CD8 + TILs was 27.8% (35/126) and 31.7% (40/126), respectively. Kaplan-Meier analysis showed that overall survival (OS) was significantly associated with decreased CD8 + TILs and PD-L1 TC-positive expression, which promote ESCC progression and metastasis., Conclusion: Tumor depth, CD8, and PD-L1 TC were independent prognostic factors in ESCC, and a predictive nomogram with these three risk factors improved the accuracy of predicting OS in patients with ESCC after surgical resection. The conjoint analysis of multiple immune-related factors is beneficial for stratifying patient survival risk., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Skeletal muscle (SM) is a key factor in cancer treatment. However, it is unclear whether pretreatment SM change affects the outcome of immune checkpoint inhibitors (ICIs) therapy in gastric cancer (GC)., Methods: Advanced GCs treated with ICIs were retrospectively investigated. SM evaluated by psoas muscle area at the third lumbar vertebra was measured on CT acquired within 1 month from the start of ICIs therapy (CT-1), and on CT acquired 2.8 ± 0.84 months before CT-1. Monthly change rate of SM (MCR-SM) was defined as the change rate of SMs between those two CTs divided by the period between those CTs (month). Monthly change rate of body weight (MCR-BW) during the same period was also calculated. They were compared with disease-specific survival (DSS) and progression-free survival (PFS). MCR-SM was compared with pretreatment markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), and liver-to-spleen CT attenuation ratio (LSR) as a marker of liver lipid metabolism., Results: This study enrolled eighty-three GC patients. MCR-SM significantly correlated with DSS and PFS (P < 0.0001, 0.001, respectively), whereas MCR-BW did not. Kaplan-Meier analyses demonstrated that higher MCR-SM (MCR-SM ≥ -0.7185%) significantly associated with better DSS and PFS (P = 0.0002, 0.03, respectively). Patients with positive MCR-SM showed significantly lower NLR, MLR, and CRP than those with negative (P = 0.01, 0.006, 0.003, respectively). MCR-SM showed a significant positive correlation with LSR (P = 0.007, R = 0.30)., Conclusions: Pretreatment SM loss, associated with high systemic inflammation and hepatic fat accumulation, related to poor outcome of ICIs therapy in GC., (© 2024. The Author(s).)

Purpose: To investigate the treatment outcomes of patients with non-occlusive mesenteric ischemia (NOMI) at our institution, we focused on their post-treatment return to social activities., Methods: This study included patients with suspected NOMI who were referred to our department between 2011 and 2023. In-hospital mortality was also investigated as a prognostic factor. The Glasgow-Pittsburgh Outcome Categories (GPOC) score was used to evaluate the return to social activities. The relationship between in-hospital mortality and GPOC scores and patient background and treatment factors was examined., Results: Eighty-two patients were included in the study. Among them, 54 (65.9%) died during hospitalization. Only 9 patients (11%) returned to their social activities. In the multivariate analysis, non-surgical management was found to be the only independent factor for in-hospital mortality. Positive portal venous gas on computed tomography, no open abdomen, no pre-onset catecholamine administration, platelet count < 100,000/µL, lactate level < 5 mmol/L, APTT < 46 s, and Sequential Organ Failure Assessment score < 11 were factors significantly associated with an increased likelihood of return to social activities., Conclusion: This is the first study to assess the post-treatment return to social activities among patients with NOMI. Our findings highlight the concerning reality that survivors may face prolonged dependence on medical care., (© 2024. The Author(s).)

Esophageal squamous cell carcinoma (ESCC) is an intractable type of cancer that requires novel therapeutic modalities, since the therapeutic outcomes are often inadequate, even in response to multidisciplinary treatment. The antitumor effect of metformin, an antidiabetic drug, has been reported in esophageal cancer; however, its effects are diverse. Since various multidisciplinary therapies are used in ESCC, the antitumor effect of metformin is expected to be synergistic in some treatment strategies. The present review summarizes the antitumor effects of metformin and discusses its use in combination with existing therapies. The present study reviewed relevant studies where the molecular targets of metformin (AMPK and inflammatory system signals) were described, followed by the classification and organization of its antitumor effects, and subsequently summarized the current research on its antitumor effects, especially in ESCC. A number of studies have reported that metformin prevents the development of ESCC and exerts its antitumor effects through various pathways. In addition, metformin has been shown to inhibit tumor growth, induce apoptosis, inhibit cancer cell invasion, migration and angiogenesis into the tumor, and decrease tumor malignancy, such as metastasis. Furthermore, it may modulate host tumor immunity in a tumor-suppressive manner and is expected to improve prognosis following treatment for ESCC. Notably, metformin may be beneficial in combination with chemotherapy, such as cisplatin, and radiation. By contrast, it has been shown to potentially induce resistance to 5-fluorouracil. Finally, the effects of metformin in combination with other therapies are discussed in the present study, and perspectives on the potential benefits of metformin for future ESCC treatment are presented. In conclusion, the present review may be useful in improving the understanding of the wide range of antitumor effects of metformin. Although some concerning points remain, using metformin in ESCC treatment could be promising. Notably, more knowledge needs to be accumulated regarding the effects of metformin on ESCC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Sekino et al.)

Small bowel adenocarcinoma (SBA) is a rare tumor with a poor prognosis. Due to its rarity, the research infrastructure for SBA, including cell lines, is inadequate. The present study established a novel SBA cell line, SiCry-15X, using patient-derived xenografts of SBA. The following criteria were defined for establishment: Long-term culturability, tumorigenicity and similarity with the original tumor. The biological characteristics of the cell line, its sensitivity to anticancer drugs and its ability to produce tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were evaluated. SiCry-15X cells adhered and grew as a monolayer, with a population doubling time of 37 h. Polymerase chain reaction results confirmed the human origin of the cell line, and short tandem repeat analysis revealed that the cells were genetically identical to the original tumor. The 50% inhibitory concentrations of 5-fluorouracil, paclitaxel, irinotecan, oxaliplatin and cisplatin for SiCry-15X were 104.05, 0.24, 63.3, 146.55 and 49.29 µM, respectively. CEA and CA19-9 concentrations in the culture media were markedly elevated. In addition, CEA and CA19-9 levels in the serum of cell-derived xenograft model mice were elevated. Moreover, CEA and CA19-9 were produced by SiCry-15X cells and distributed throughout the blood. Furthermore, increases in serum CEA and CA19-9 of cell-derived xenograft model mice were consistent with the clinical course of the disease. The newly established SBA cell line, SiCry-15X, could be an effective tool for conducting further studies on SBA., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Nishioka et al.)

Despite advances in treatment and diagnosis, the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains poor. MicroRNAs (miRNAs/miRs) are associated with prognosis in esophageal cancer, indicating that they may help guide treatment decisions. The aim of the present study was to explore exosomal miR-185 as a candidate prognostic biomarker and therapeutic target in ESCC, to investigate its biological function and clinical significance, and to ascertain the applicability of circulating exosomal miR-185 for the development of targeted drugs for ESCC treatment. A GeneChip miRNA array was used to compare exosomal miRNA expression in ESCC cell lines under hypoxia with those under normoxia. Exosomal miR-185 expression was then confirmed by reverse transcription-quantitative PCR. Patient background and prognosis were compared between high and low miR-185 expression groups. Functional analyses were performed to evaluate the antitumor effects of miR-185 in ESCC cells. Global Gene Set Enrichment Analysis of The Cancer Genome Atlas data was also performed, and differentially expressed exosomal miRNAs under hypoxia were identified compared to those under normoxia. Hypoxia markedly decreased the expression of exosomal miR-185 in KYSE-960 and T.Tn cell culture media. Overexpression of miR-185 suppressed the migration, invasion and colony-forming abilities of ESCC lines, and also suppressed cell cycle progression and promoted apoptosis after cisplatin treatment. Notably, high miR-185 expression was associated with signaling pathways related to cell death, DNA damage and p53. Furthermore, circulating exosomal miR-185 levels were associated with cN and cStage, and could predict progression-free survival and disease-specific survival of patients with ESCC after initial treatment. In conclusion, miR-185 holds potential as a prognostic biomarker and therapeutic target in ESCC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Maiyulan et al.)

A 73-year-old woman was referred to our hospital with a chief complaint of black stools and abdominal distention. She was diagnosed with advanced gastric cancer with pyloric stenosis and multiple lymph node metastasis(cT4aN3M0, cStage Ⅲ)and was administered preoperative chemotherapy after laparoscopy and gastric jejunal bypass surgery. The surgical diagnosis was sT4aN3M0P0CY0. After surgery, 2 courses of DS therapy were administered. However, a new liver metastatic lesion was found, and XELOX therapy was selected as the second-line of treatment. Subsequently, enlarged hepatic hilar lymph nodes were found; microsatellite instability testing confirmed MSI-High cancer. Nivolumab was selected as the third- line therapy. After 15 courses, a new liver metastatic lesion appeared. Although Ram+nab-PTX therapy was chosen as the fourth-line therapy, the patient developed myelosuppression after 3 courses. Two years and 4 months after the initial treatment, the patient was considered to have achieved CR. Because drug-induced liver injury had occurred, the Ram therapy was discontinued. The patient has remained in CR for 1 year without receiving any anticancer drugs. This case suggests that for MSI-high patients with gastric cancer, the consideration of treatment strategy should be based on the molecular biological background.

Background: Treatment via a peripherally inserted central venous catheter is important for anticancer treatment, perioperative management, and nutrition management. In this study, we aimed to investigate the usefulness of cyanoacrylate glue (CG) in managing peripherally inserted central venous catheters in adults., Methods: This retrospective cohort study enrolled 411 adults requiring a central venous catheter for treatment in the Chiba University Esophageal-Gastro-Intestinal Surgery department between January 2021 and October 2022. The preventive effect of CG in reducing adverse events, including infection, tip migration, and thrombus formation, was evaluated by reviewing electronic medical records, chest radiographs, and contrast-enhanced computed tomography scans., Results: CG and other dressings were used in 158 (CG group) and 253 (control group) patients, respectively. The incidence of catheter infection based on the clinical course was lower in the CG group (3.2%) than in the control group (9.1%; P = 0.03). However, cases of infection confirmed by blood or catheter cultures did not differ between the CG (1.3%) and control (1.9%) groups (P = 1.0). Chest radiographs revealed that catheter tip migration (mean ± SD) was lesser in the CG group (8.2 ± 6.7 mm) than in the control group (15.0 ± 15.8 mm; P < 0.01). There were two cases of venous thrombus formation in the control group., Conclusion: In a population dominated by esophago-gastroenterological malignancy, peripherally inserted central catheter securement via CG was associated with decreased catheter removal because of suspected catheter infection. Further research on larger cohorts is needed to determine if other adverse events decrease following peripherally inserted central catheter securement via CG., (© 2024 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Introduction: Identifying accurate biomarkers for predicting response to chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC) is a critical challenge. The protein SIRT1, recognized for its implications in longevity, has been associated with tumor promotion in ESCC. However, data regarding its correlation with CRT sensitivity remain unreported. Therefore, in this study, we aimed to investigate the relationship between SIRT1 expression and CRT sensitivity and concurrently assess the effect of SIRT1 knockdown on CRT sensitivity in ESCC., Methods: This study included 73 patients who underwent radical esophagectomy after CRT. SIRT1 expression in pre-treatment endoscopic biopsies was assessed through immunostaining, followed by a comparative analysis of CRT effects on surgical specimens. Small interfering RNA was used to attenuate SIRT1 expression in TE5 and TE10 cells, which were then subjected to cisplatin treatment at varying doses and concentrations and irradiation with X-rays, respectively., Results: High SIRT1 tissue expression was significantly associated with CRT resistance. Multivariate analysis identified high SIRT1 expression as an independent biomarker for poor CRT response. In TE-5 and TE-10 cells, SIRT1 knockdown significantly decreased cell viability and increased sensitivity to cisplatin and radiation treatment compared to that of the negative control., Conclusion: Our study results demonstrate the potential of SIRT1 as a predictive biomarker for CRT response in ESCC, highlighting the heightened sensitivity to CRT upon the transcriptional inactivation of SIRT1. Targeting SIRT1 emerges as a promising strategy for enhancing the efficacy of CRT for ESCC., (© 2024 S. Karger AG, Basel.)

Background/aim: Peripheral blood inflammatory and nutritional indices are independent prognostic factors for various cancers. However, as society's longevity and the demand for surgery in the elderly increase, it remains unclear whether these indices are valuable for patients aged ≥80 years. This study aimed to assess the utility of peripheral blood indices as prognostic markers in elderly patients with gastric cancer (GC)., Patients and Methods: This study included 103 elderly patients (aged ≥80 years) who underwent radical gastrectomy at our hospital between 2008 and 2020. Preoperative systemic inflammatory and nutritional indices, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and prognostic and nutritional index (PNI), were evaluated. Prognostic evaluation was performed using Kaplan-Meier analysis and Cox regression., Results: There were no statistically significant differences in NLR, PLR, and LMR regarding overall survival (OS) and relapse-free survival (RFS). However, patients with low PNI had a markedly worse prognosis (3-year OS: 63.9% vs. 81.2%, p=0.002; 3-year RFS: 55.3% vs. 77.6%, p=0.002). Multivariate analysis revealed that male sex and low PNI were independent predictors of OS (p=0.007p=0.003, respectively) and RFS, with only PNI showing significance (p=0.023)., Conclusion: Preoperative PNI is an independent prognostic factor for survival in elderly patients with GC who undergo radical gastrectomy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Small bowel cancer is very rare, accounting for less than 5% of all gastrointestinal cancers, and small bowel adenocarcinoma accounts for approximately 40% of all small bowel cancers. Small bowel adenocarcinoma is often found in advanced stages, with only 40-65% of cases being curatively resectable. The prognosis is poor, with a 5-year survival rate of 14-33% for all patients and 40-60% for those who are curatively resectable. In Japan, practice guidelines for duodenal cancer were instituted in 2021. However, evidence-based standard treatments have not been established for jejunal and ileal cancers. In particular, chemotherapeutic options are limited, and there are only a few reports on multidisciplinary treatments, including adjuvant chemotherapy., Case Presentation: We report five cases of jejunal or ileal lesions that were treated with adjuvant chemotherapy after radical resection. Three patients were male and two were female, with a median age of 67 years. Tumor localization was observed in the jejunum in all cases. Clinical staging was as follows: stage IIIA in two cases and stage IIIB in three cases. Laparotomy was then performed in all cases, employing partial resection with lymph node dissection. Pathological staging in all cases was as follows: stage IIB in two cases, stage IIIA in one case, and stage IIIB in two cases. In all cases, the regimen for adjuvant chemotherapy was selected based on the colorectal cancer guidelines. No serious complications arose from adjuvant therapy; however, adverse events occurred in patients receiving multi-agent chemotherapy. No recurrence was observed in any of the cases, and all the patients survived, with a median survival time of 32 months. As a representative case, we present a case of adjuvant chemotherapy for jejunal adenocarcinoma staged as pT3N2M0, pStage IIIB, with no recurrence at 32 months postoperatively., Conclusions: In general, favorable outcomes were achieved with adjuvant therapy applied in accordance with the criteria for colorectal cancer. These favorable outcomes suggest that it is necessary to identify the risk factors and indications for adjuvant therapy, specifically for small bowel adenocarcinoma., (© 2023. The Author(s).)

Purpose: The gut microbiome plays an important role in cancer pathogenesis and therapy. Some studies have reported that specific bacteria in tumor tissues may contribute to the prognosis and treatment of esophageal squamous cell carcinoma (ESCC). However, there is limited evidence that the gut microbiome is associated with ESCC. This study assessed the utility of the gut microbiome as a predictive marker of the therapeutic effect in patients with ESCC undergoing chemo-radiotherapy (CRT)., Patients and Methods: Fecal samples were collected from 51 patients with ESCC who had never undergone treatment between April 2021 and May 2022 in the Department of Frontier Surgery, Chiba University. The gut microbiome was analyzed using 16S metagenomics sequencing. The association between the gut microbiome composition and stage according to the TNM classification (American Joint Committee on Cancer 7.0) and CRT response according to the RECIST criteria was evaluated., Results: The relative abundance of Fusobacteriaceae was enriched in cStage III-IVb group. Among the 27 patients who received CRT, the relative abundance of Lactobacillaceae was enriched in those with a partial and complete response. Lactobacillaceae also did not correlate with any clinical data, but the high Lactobacillales group had a higher LMR (P = 0.032) and lower PLR (P = 0.045) than in the low Lactobacillales group., Conclusions: In conclusion, we found that the relative abundance of Lactobacillaceae was enriched in patients with a partial or complete response among CRT those with ESCC, thus suggesting that the relative abundance of Lactobacillaceae can predict the effect of CRT., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background/aim: We lack reports on the clinicopathological characteristics and prognostic value of serum sirtuin 1 (SIRT1) levels and their association with SIRT1 expression in tissues of patients with gastric cancer (GC). Thus, we investigated the pathological characteristics and prognostic values of SIRT1 tissue expression and its serum concentration in GC. Moreover, we investigated the correlation between these two factors., Materials and Methods: A total of 78 patients with GC who underwent curative gastrectomy were evaluated in this study. The expression of SIRT1 in the surgical specimens was assessed using immunohistochemistry. Serum levels of SIRT1 were measured using an enzyme-linked immunosorbent assay. The association of tissue and serum SIRT1 with the clinicopathological features and prognosis were evaluated., Results: Positive SIRT1 tissue expression was significantly related to an advanced cancer stage (p=0.017). Furthermore, a significant relationship existed between a positive SIRT1 tissue expression and poorer overall survival (OS) and relapse-free survival (RFS) (p=0.033 and p=0.033, respectively). In contrast, serum SIRT1 levels showed no significant association with clinicopathological characteristics besides age. In addition, no significant correlation was observed between tissue SIRT1 expression and serum SIRT1 concentration., Conclusion: Tissue SIRT1 expression may be a valuable novel prognostic biomarker; nonetheless, further studies are required to clarify the relationship between tissue SIRT1 expression and serum SIRT1 levels in GC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Although the usefulness of the ypStage in neoadjuvant chemotherapy for advanced gastric cancer (GC) has been reported, whether or not the ypStage is applicable to all GC patients who receive preoperative chemotherapy, including conversion surgery cases, is unclear. Therefore, this retrospective study evaluated the value of the ypTNM staging system in all advanced GC patients who received chemotherapy prior to gastrectomy., Methods: A total of 66 patients who underwent chemotherapy prior to gastrectomy for advanced GC at Chiba University Hospital from January 2008 to December 2020 were enrolled in the current study. The prognostic impact of the ypStage on the overall survival (OS) and relapse-free survival (RFS) were examined via univariate and multivariate analyses., Results: The 5-year OS rates for ypStage I, II, III, and IV were 87.5%, 64.7%, 52.9%, and 28.6%, respectively, while the 5-year RFS rates were 81.3%, 57.4%, 44.4%, and 28.6%, respectively. The univariate analysis revealed that the ypStage was significantly correlated with the OS (p = 0.037) and the ypT status and ypStage showed a significant correlation with the RFS (p = 0.043 and p = 0.021, respectively). The multivariate analysis demonstrated that only the ypStage was an independent prognostic factor for the OS and RFS (p = 0.024 and p = 0.018, respectively)., Conclusion: The ypTNM stage may be a useful tool for the risk stratification of all advanced GC patients treated with chemotherapy followed by gastrectomy, including not only neoadjuvant but also conversion surgery cases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Soluble programmed death-ligand 1 (sPD-L1) levels can be used as a biomarker for gastric cancer (GC). However, comprehensive information regarding the sPD-L1 expression profiles and their association with cachexia in GC is lacking. Therefore, the present study evaluated the association between clinicopathological findings and sPD-L1 levels in patients with GC. Serum samples were collected from patients with GC during their first visit to Department of Esophageal-Gastro-Intestinal Surgery, Chiba University Hospital, Chiba, Japan (January 2012-December 2017; n=173), and sPD-L1 levels were measured using an enzyme-linked immunosorbent assay. Survival rates among 116 patients, excluding cases with preoperative chemotherapy or no radical procedures, were analyzed. sPD-L1 levels were associated with factors such as neutrophil-to-lymphocyte ratio, hemoglobin (Hb) and albumin (Alb) levels, total cholesterol and C-reactive protein (CRP) levels, and related to inflammation and nutrition in patients. Notably, the higher the number of applicable indicators related to cachexia (Hb <12 g/dl, Alb <3.2 g/dl, CRP >0.5 mg/dl and low body mass index) was, the higher the sPD-L1 value was. However, the pathological stage did not significantly differ between the groups. Clinicopathologically, there was no association with tumor depth, lymph node metastasis or vascular invasion; however, patients with the intestinal type had significantly higher sPD-L1 levels than patients with the diffuse type (P=0.032; Wilcoxon test). The overall survival did not significantly differ between the groups with low and high sPD-L1 levels; however, among patients who received radical treatment, the relapse-free survival was significantly worse in the high-sPD-L1-level group than in the low-sPD-L1-level group (P=0.025; log-rank test). Multivariate Cox regression analysis revealed that a high sPD-L1 concentration was a sign of poor prognosis, independent of pathological stage and cancer antigen CA19-9 (P=0.0029). Therefore, the present findings suggest that sPD-L1 can reflect cachexia status in patients with GC and may serve as a prognostic marker for relapse-free survival after radical GC surgery., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Matsumoto et al.)

Background: Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with a poor prognosis. Chemoradiotherapy is one of the most important strategies for patients with locally advanced unresectable ESCC; however, its therapeutic effect is unsatisfactory. Tumor-initiating cells (TICs) have been reported to be resistant to conventional chemotherapy and radiotherapy so far. Therefore, we aimed to develop a treatment strategy targeting TICs in ESCC to improve radiosensitivity., Methods: First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines using flow cytometry, Western blotting, and functional analyses. Then, we focused on disulfiram (DSF), an aldehyde dehydrogenase inhibitor, used to treat alcohol use disorder. We investigated the effect of DSF and copper (II) D-gluconate (Cu) on the radiosensitivity of ESCC in xenograft mouse models., Results: ALDH1-positive cells showed an upregulation of SOX2 and Nanog, exhibiting much stronger tumor-initiating properties than ALDH1-negative cells. Furthermore, inhibition of ALDH1 attenuated the tumor-initiating properties of ESCC cell lines. Our results also showed that ALDH1-positive cells were resistant to chemotherapy and radiotherapy, and the inhibition of ALDH1 led to the mitigation of therapeutic resistance. Our in vitro and in vivo studies revealed that the DSF/Cu complex could radiosensitize ALDH1-positive ESCC cells and downregulate the phosphoinositide 3-kinase/Akt pathway., Conclusion: ALDH1 inhibition by the DSF/Cu complex enhances the radiosensitivity of TICs in ESCC. The drug repositioning approach using disulfiram is a potential treatment option to overcome radioresistance in patients with locally advanced ESCC., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Introduction: Immune checkpoint inhibitors (ICIs) are expected to improve the prognosis of gastric cancer (GC). Also, hepatic steatosis has been reported to be associated with cancer cachexia and is expected to be a cancer biomarker. The purpose of this study was to evaluate prognostic impact of hepatic steatosis in ICI therapy for GC., Methods: Unresectable or recurrent GC treated with ICIs was investigated. Using unenhanced CT, the liver-to-spleen CT attenuation ratio (LSR) was calculated as a parameter of hepatic steatosis. LSR was compared with the presence of sarcopenia and inflammatory markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). These parameters were also compared with disease-specific survival (DSS) and progression-free survival (PFS). Associations of LSR with insulin-like growth factor 1 (IGF-1) and growth hormone were also evaluated., Results: A total of 70 patients were investigated. LSR of sarcopenia patients was significantly lower than that of non-sarcopenic ones (p = 0.02). LSR showed significant negative correlations with NLR, PLR, and MLR (p = 0.003, 0.03, 0.01, respectively). Lower LSR was significantly associated with a higher level of serum IGF-1 (p = 0.03). In univariate analysis, LSR was significantly correlated with DSS and PFS (both p < 0.0001), and multivariate analysis demonstrated that LSR was the independent prognostic factor for both DSS and PFS (both p = 0.01). ROC analysis demonstrated that LSR >1.263 was a good predictive marker for favorable DSS (>5.3 months) with an AUC of 0.80., Conclusion: Hepatic steatosis can be a promising prognostic biomarker for ICI therapy of GC, associated with sarcopenia and the elevation of inflammatory markers. Our data suggested that GC with steatohepatitis might be less responsive to ICI therapy., (© 2022 S. Karger AG, Basel.)

Background: With the aging of society and increasingly longer of life expectancy, elderly patients with esophageal cancer are more commonly encountered. This study aimed to identify the risk factors for operative mortality after esophagectomy in elderly patients., Methods: We used data from the National Clinical Database of Japan. After cleaning the data, 10,633 records obtained from 861 hospitals were analyzed. A risk model for operative mortality was developed using risk factors from the entire study population. Then, odds ratios (OR) were compared between age categories using this risk model., Results: In this study, 1959 (18.4%) patients were ≥ 75 years (defined as "elderly" in this study). Eighteen variables, including T4b, N2-N3, and M1 in the TNM classification, were included in the risk model for operative mortality. The ORs increased in age categories < 65, 65-74, and ≥ 75 years for N2-N3 (1.172, 1.200, and 1.588, respectively), and M1 (2.189, 3.164, and 4.430, respectively). Based on these results, we also focused on residual tumors, which are caused by extensive tumor development. The operative mortality in the elderly group with residual tumors increased to more than twice than that in the non-elderly groups (15.9 vs. 5.5 or 6.5%) and was much higher than that in elderly patients without residual tumors (15.9 vs. 4.6%)., Conclusion: We should carefully select the treatment for elderly patients with highly advanced tumors, which result in N2-N3 and M1, to avoid unfavorable short-term outcomes. In addition, R0 resection is important in preventing operative mortality among elderly patients., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1α (HIF-1α) and the Wnt/β-catenin pathway in oesophageal squamous cell carcinoma (ESCC)., Methods: The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry., Results: The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in T.Tn and TE1 cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, migration/invasion and epithelial-mesenchymal transition (EMT) progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth, angiogenesis, and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumour tissues compared to the corresponding non-tumour tissues. High levels of HIF-1α and TCF4/TCF7L2 expression were correlated with aggressive phenotypes and poor prognosis in ESCC patients., Conclusions: HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: In actual surgical research, case-matched studies are frequently conducted as an alternative to randomized controlled trials (RCTs). However, it is still unclear what differences there are between RCTs and case-matched studies in upper gastrointestinal surgery, and clarifying them is a very important clinical issue. Thus, the purpose of this study was to investigate estimated treatment effects between RCTs, case-matched studies, and cohort studies regarding laparoscopic distal gastrectomy (LDG) for advanced gastric cancer (AGC)., Methods: We searched the PubMed, Cochrane Central Register of Controlled Trials, and Web of Science databases for studies that compared LDG versus open distal gastrectomy for AGC published from the inception of the databases until July 2021. A meta-analysis was performed using the Review Manager version 5.3 software program from the Cochrane Collaboration, and six short-term outcomes and three long-term outcomes were assessed., Results: Twenty-three studies with 13698 patients were included. There was no difference in estimated treatment effects between RCTs and case-matched studies for all outcomes except for the number of retrieved lymph nodes and postoperative complications. In terms of intraoperative blood loss, postoperative hospital stay, number of retrieved lymph nodes, and recurrence, observational studies tended to overestimate the treatment effects., Conclusion: The estimated treatment effects of LDG for AGC in the case-matched study were almost the same as in the RCTs. However, to assess the true magnitude of the treatment effect, the design and actual implementation of the analysis must be critically evaluated., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The diagnosis of residual tumors using endoscopic ultrasound (EUS) after neoadjuvant therapy for esophageal cancer is considered challenging. However, the reasons for this difficulty are not well understood., Aim: To investigate the ultrasound imaging features of residual tumors and identify the limitations and potential of EUS., Methods: This exploratory prospective observational study enrolled 23 esophageal squamous cell carcinoma patients receiving esophagectomy after neoadjuvant therapy [15 patients after neoadjuvant chemotherapy (NAC) and 8 patients after chemoradiotherapy (CRT)] at the Department of Surgery, Chiba University Hospital, between May 2020 and October 2021. We diagnosed the T stage for specimens using ultrasound just after surgery and compared ultrasound images with the cut surface of the fixed specimens of the same level of residual tumor. The ratio of esophageal muscle layer defect measured by ultrasound was compared with clinicopathological factors. Furthermore, the rate of reduction for the muscle layer defect was evaluated using EUS images obtained before and after neoadjuvant therapy., Results: The accuracy of T stage rate was 61% ( n = 14/23), which worsened after CRT (38%, n = 3/8) than after NAC (73%, n = 11/15) because of overstaging. Moreover, pT0 could not be diagnosed in all cases. The detection rate of residual tumor for specimens using ultrasound retrospectively was 75% ( n = 15/20). There was no correlation between after-NAC (79%, n = 11/14) and after-CRT (67%, n = 4/6) detection rate. The detection of superficial and submucosal types was poor. The pathologic tumor size and pathological response were correlated. Tumor borders were irregular and echogenicity was mixed type after CRT. There was a correlation between the pT stage (pT0/1 vs pT2/3) and the length of muscle layer circumference ( P = 0.025), the length of muscle layer defect ( P < 0.001), and the ratio of muscle layer defect ( P < 0.001). There was also a correlation between the pT stage and the rate of muscle layer defect reduction measured by EUS ( P = 0.001)., Conclusion: Compared to pathological images, some tumors are undetectable by ultrasound. Focusing on the esophageal muscle layer might help diagnose the depth of the residual tumor., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Neoadjuvant chemotherapy (NAC) followed by esophagectomy can improve the prognosis of locally advanced esophageal cancer (LAEC). However, LAEC reportedly recurred in 17-21% of patients within 6 months post surgery. Thus, current treatment strategies may be inadequate for LAECs with poor prognosis. Preoperative identification of patients with poor prognosis might aid in modification of treatment strategies. This study aimed to evaluate the usefulness of the maximum standardized uptake value change rate (ΔSUV max ) in predicting treatment effects on the primary lesion, prognosis, and LAEC recurrence., Methods: This study involved 220 esophageal cancer patients who underwent esophagectomy after NAC at three facilities in Japan. The optimal cut-off point for ΔSUV max in predicting tumor regression grade (TRG) was calculated and used to assess the correlation between ΔSUV max and postoperative survival., Results: The optimal cut-off point for ΔSUV max was 0.5. The 5-year overall survival rate in patients with ΔSUV max  ≥ 0.5 was significantly higher than that in patients with ΔSUV max  < 0.5 (71.5% vs. 50.5%, P = 0.001). Multivariate analysis identified ΔSUV max (hazards ratio, 0.496; P = 0.004) as an independent prognostic factor. Among 199 patients evaluated for recurrence, 24 (12.1%) showed recurrence within 6 months post surgery. Univariate analysis revealed ΔSUV max as the only predictor for early recurrence (odds ratio, 0.222; P = 0.004)., Conclusion: ΔSUV max before and after NAC is clinically useful as it could help predict TRG, survival outcome, and early recurrence within 6 months post esophagectomy and is easily obtainable in general clinical practice. We believe that it may also help determine suitable treatment strategies for LAEC., (© 2021. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Recent progress of large-scale international studies has provided comprehensive catalogs of somatic mutations in cancers. Additionally, it has become evident that allelic imbalance in the abundance of somatic mutations between DNA and RNA were pervasive in various types of cancer. However, the allelic imbalance of the abundance of somatic mutations in esophageal squamous cell carcinoma (ESCC) has not been fully analyzed., Methods: We performed exome sequencing for 25 Japanese patients with ESCC to detect a comprehensive catalog of somatic mutations in ESCC. Additionally, we performed mRNA sequencing to evaluate the allelic imbalance of the identified somatic mutations at the transcriptional level by comparing the mutant allele frequencies between RNA and DNA., Results: The exome sequencing showed that TP53 and ZNF750 were significantly mutated genes. The expression levels of TP53 and ZNF750 were different depending on the mutation status. In almost all the tumors with missense mutations in TP53 and ZNF750, the mutant allele frequencies were higher in the RNA sequencing than those in the exome sequencing, indicating that the mutant alleles were preferentially expressed. By examining the allelic imbalances for all the identified missense mutations, we demonstrated that genes showing preferential expressions of the mutant alleles were involved in the pathways including cell cycle, cell death, and chromatin modification., Conclusions: The results of this study suggest that the allelic imbalance of the abundance of somatic mutations plays important roles in the initiation and progression of ESCC by modulating cancer-related biological pathways., (© 2021. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background/aim: Several articles have assessed the prognostic significance of the expression of sirtuin 1 (SIRT1) in esophageal squamous cell carcinoma (ESCC). However, evidence in this field is insufficient. Thus, we conducted a meta-analysis to investigate the prognostic and clinical impact of SIRT1 expression in ESCC., Materials and Methods: We searched the PubMed, Cochrane Library, and Web of Science databases for articles on the expression of SIRT1 and clinicopathological features in patients with ESCC. A meta-analysis was conducted., Results: Four studies with 429 patients were included. The meta-analysis revealed a significant relationship between the high expression of SIRT1 and higher T-stage (odds ratio=2.39. 95% confidence interval=1.12-5.13, p=0.02), more advanced TNM stage (odds ratio=2.35. 95% confidence interval=1.20-4.60, p=0.01), and a poor overall survival (hazard ratio=1.90, 95% confidence interval=1.45-2.47, p<0.00001)., Conclusion: SIRT1 expression may be a promising prognostic biomarker for patients with ESCC., Competing Interests: The Authors declare that they have no conflicts of interest., (Copyright 2022, International Institute of Anticancer Research.)

Background: Arteriovenous malformation (AVM) of the gastrointestinal (GI) tract can cause bleeding. The treatment choice for GI tract AVM is surgical resection of the involved bowel segment with complete resection of the nidus. The AVM formed in the duodenum or pancreatic head could also cause gastrointestinal bleeding, and there are several reports of pancreaticoduodenectomy as its treatment. However, if the area of AVM can be accurately identified during surgery, it may be possible to completely resect the AVM while preserving the organ. We report a case of duodenal AVM in a patient successfully treated with a subtotal stomach-preserving duodenal bulb resection using intraoperative indocyanine green (ICG) angiography technique., Case Presentation: An 18-year-old man was diagnosed with duodenal AVM after several examinations for anemia and was referred to our hospital for further treatment. Preoperative imaging studies showed that the inflow vessels of this duodenal AVM were the inferior pyloric artery and the superior duodenal artery, and the AVM was localized to the duodenal bulb. Thereafter, stomach-preserving duodenal bulb resection preceded by ligation of the inflow vessels was performed. During the surgery, ICG angiography clearly demonstrated the area, where the nidus was distributed, and a duodenal bulb resection with complete resection of the AVM was successfully performed. There was no recurrence at the 6-month follow-up., Conclusions: Intraoperative ICG angiography was a useful procedure for precise identification of the AVM of the GI tract., (© 2021. The Author(s).)

Introduction: We determined the soluble programmed cell death-1 ligand-1 (sPD-L1) concentration in patients with esophageal squamous cell carcinoma (ESCC), and confirmed the PD-L1 expression in resected specimens., Methods: Blood samples were collected from 73 patients with histologically proven ESCC. The serum levels of sPD-L1 were measured using an enzyme-linked immunosorbent assay. The correlations between the sPD-L1 concentration and the expression of PD-L1 in tumor specimens and tumor depth, lymph node metastasis, disease stage, and various laboratory data were assessed., Results: sPD-L1 levels in patients with high PD-L1 expression levels in tumor tissue were significantly higher than in patients with low PD-L1 expression levels (p = 0.042). The OS of the sPD-L1-high group was significantly worse than that of the low group (p = 0.028). Similarly, patients in whom a tissue specimen was PD-L1-positive group showed significantly poorer OS., Conclusion: The sPD-L1 concentration was correlated with the PD-L1 expression in tissues. Patients with PD-L1-positive tissue specimens showed significantly higher sPD-L1 levels in comparison to PD-L1-negative cases. Furthermore, patients with high sPD-L1 expression levels had a significantly worse prognosis than those with low sPD-L1 expression levels, and patients with a PD-L1-positive tissue specimen had a significantly worse prognosis than patients in whom the tissue specimen showed a low PD-L1 expression level., (© 2021 S. Karger AG, Basel.)

Introduction: Antidiabetic drug metformin exerts various antitumor effects on different cancers. Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer and new treatment strategy is required. In this study, we performed a comprehensive gene expression analysis of ESCC cell lines treated with metformin, which provided helpful information on the antitumor effects of metformin in ESCC. Next, we selected a promising gene among them and examined its effects on ESCC properties., Methods: We examined metformin-induced mRNA expression changes in two human ESCC cell lines by performing next-generation sequencing (NGS) and pathway analysis. Heat shock protein family A (Hsp70) member 6 (HSPA6) expression in surgical specimens obtained from 83 ESCC patients who underwent curative operations was evaluated immunohistochemically and analyzed., Results: Metformin upregulated mRNA expression of the many genes, including HSPA6, a cancer immune-related gene, and inhibited mRNA expression of the other many genes. Pathway analysis indicated major canonical pathways and upstream regulators related to metformin. The result indicated HSPA6 as a promising biomarker. HSPA6 expression correlated with disease-free survival (DFS) of the patients with all stage ESCC (p = 0.021), especially with stage I/II ESCC (p < 0.001). With stage III, low HSPA6 expression was not associated with poor DFS (p = 0.918). Multivariate analysis indicated that independent low HSPA6 expression was an independent poor prognostic factor of stage I/II ESCC (p < 0.001). However, HSPA6 expression did not correlate with the clinicopathological characteristics, including age, sex, tumor depth, lymph node metastasis, tumor stage, and tumor markers of the patients with stage I/II ESCC., Conclusions: This NGS analysis detected prospective candidate genes, including HSPA6. Our results indicate that HSPA6 is a promising biomarker of the recurrence risk of stage I/II ESCC. Further studies on HSPA6 would lead to better treatment., (© 2022 S. Karger AG, Basel.)

A 79-year-old man was detected with anemia on medical examination and underwent gastroscopy at the previous hospital. Gastroscopy revealed a 15-mm ulcerative lesion(Type 0-Ⅱc plus Ⅲ)on the greater curvature of the upper gastric body. Tumor biopsy showed well-differentiated adenocarcinoma. The patient was suspected of deep submucosal invasion due to poor stretching of the gastric wall and the ulcer depth; hence, he was transferred to our hospital for surgery. When gastroscopy was repeated, the ulcer was found to be scarred(Type 0-Ⅱc), thereby indicating the occurrence of intramucosal carcinoma; hence, endoscopic submucosal dissection was performed. The pathological finding showed 10×6 mm, tub1, pT1a, ly0, v0, pUL1, pHM0, pVM0, suggesting a curative resection. Early gastric cancer of the depressed type is known to develop a malignant cycle with repeated improvements and exacerbations of the ulcer. Diagnosing the depth of tumor invasion is particularly difficult when there is an active ulcer. For small lesions with active ulcers, repeating gastroscopy might allow for correct diagnosis and appropriate treatment.

Background: Intravoxel incoherent motion MRI (IVIM-MRI) can quantify micro-perfusion at the capillary level in the tissue. The purpose of this study is to measure tumor perfusion using IVIM-MRI, and evaluate its value as a biomarker to predict prognosis in esophageal squamous cell carcinoma (ESCC) patients., Methods: 109 ESCC patients (93 men and 16 women; median age: 72) who underwent IVIM-MRI prior to treatment between February 2018 and August 2020 were retrospectively investigated. Both mean apparent diffusion coefficient (ADC) value and mean perfusion-related parameter (PP) value of the primary tumor were measured using three b values of 0, 400, and 1000 s/mm 2 based on the IVIM model. We analyzed associations of these parameters with clinical stage and disease-specific survival (DSS)., Results: Lower ADC and PP values of the tumor were significantly associated with the higher clinical T stage (p < 0.0001, p < 0.0001, respectively). In Kaplan-Meier analyses, patients with lower PP value tumors (< 18.94, median) had significantly worse DSS (p < 0.0001), while tumor ADC value did not show a significant correlation with DSS. In a multivariate analysis, PP value of the tumor was an independent prognostic factor for DSS (p = 0.0027)., Conclusions: Quantification of tumor perfusion using IVIM-MRI can be a non-invasive prognostic biomarker of ESCC, reflecting clinical stage and survival., (© 2021. The Japan Esophageal Society.)

It has been said that "thoracoscopy suppresses the occurrence of pneumonia in comparison to thoracotomy", but does it reflect real clinical practice? To resolve this clinical question, we compared the results of randomized controlled trials (RCTs) and retrospective cohort studies from limited institutes (CLIs) in which a large number of high-volume centers were the main participants to those of retrospective cohort studies based on nationwide databases (CNDs) in which both high-volume centers and low-volume hospitals participated. A systematic review and meta-analysis were conducted to compare the short-term outcomes of thoracoscopic to open esophagectomy for esophageal cancer in the three above-mentioned research formats. In total, 43 studies with 21,057 patients, which included 1 RCT with 115 patients, 38 CLIs with 6,126 patients and 4 CNDs with 14,816 patients, were selected. Pneumonia was one of the most important complications. Although significant superiority in thoracoscopic esophagectomy was observed in RCTs (p = 0.005) and CLIs (p = 0.003), no such difference was seen in findings using nationwide databases (p = 0.69). In conclusion, unlike RCTs and CLIs, CNDs did not show the superiority of thoracoscopic surgery in terms of post-operative pneumonia. RCTs and CLIs were predominantly performed by high-volume hospitals, while CNDs were often performed by low-volume hospitals. In actual clinical practice including various types of hospitals, the superiority of thoracoscopic over open esophagectomy regarding the incidence of pneumonia may, therefore, decrease., (© 2021. The Japan Esophageal Society.)

Our laboratory previously reported the usefulness as biomarkers of exosomes in the plasma of esophageal squamous cell carcinoma (ESCC) patients. However, the influence of tumor-derived exosomes on the tumor itself and underlying mechanisms remain unclear. We here report changes in the phenotype and gene expression when cancer cells exist in an environment with tumor-derived exosomes. The exosomes were isolated from the culture medium of human ESCC cells (TE2, T.Tn) by ultracentrifugation; cell proliferation assay, wound-healing assay, and fluorescence imaging of the cell cycle were performed to clarify the phenotypic changes in the high concentration of tumor-derived exosomes. Gene expression changes were also assessed by mRNA microarray, and the data were analyzed by gene set enrichment analysis (GSEA). The data revealed that the proliferation of both TE2 and T.Tn was inhibited, and cell migration ability was upregulated in the exosome exposure group (P < .05). Fluorescence imaging using a fluorescent ubiquitination-based cell cycle indicator expressing ESCC cells revealed that the ratio of G1-phase cells was significantly increased in the exosome exposure group (P < .05). Findings of the GSEA clarified that high-density exposure of cancer-derived exosomes to their parent cancer cells downregulated the expression of genes related to cell proliferation and cell cycle, and upregulated the expression of genes related to actin filament length and extracellular structure organization. In conclusion, an environment of high-density tumor-derived exosomes induces changes in the gene expression and phenotype of tumor cells and may lead to tumor progression or malignant transformation., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Esophagostomy is important in the treatment of esophageal cancer. However, esophagectomy has a higher risk of postoperative complications. Treatment for complications is often difficult, and in some cases, oral intake is no longer possible. Recently, magnetic compression anastomosis (MCA) was developed; it is a relatively safe method of anastomosis that does not require surgery in patients with stricture, obstruction, or dehiscence of the anastomosis after surgery., Case Presentation: The patient was a 76-year-old Japanese man. He underwent esophagectomy with a three-field dissection for esophageal cancer. A cervical esophagostomy and chest drainage were performed for necrosis of the gastric tube. Following infection control, colon interposition was performed. However, after the operation, the colon necrotized and formed an abscess. Drainage controlled the infection, but the colon was completely obstructed. The patient was referred to our hospital to restore oral ingestion. Contrast studies showed that the length of the occlusion was 10 mm. The reconstruction was examined; reanastomosis by surgery was judged to be a high risk, so the strategy of anastomosis by MCA was adopted. In the operation, the anterior chest was opened to expose the colon, and a magnet was inserted directly into the blind end of the colon. The magnet was guided to the blind end of the esophagus using an oral endoscope. Two weeks after MCA, a contrast study confirmed the passage of the contrast agent from the esophagus to the colon. The patient eventually took 18 bougies after the MCA. However, since then, he has not needed a bougie. As of 1 year and 8 months after the MCA, the patient is living at home with oral intake restored., Conclusions: MCA is an effective and safe treatment for complete stenosis after esophageal cancer surgery.

A 78-year-old man was admitted to our hospital with a diagnosis of esophageal cancer and gastric cancer. Gastroscopy showed a type 2 tumor located in the cardia from the lower esophagus, and a pathological examination showed malignant melanoma. Based on the physical examination and other imaging tests, the patient was diagnosed with primary amelanotic malignant melanoma of the esophagus, but the tumor was unresectable due to extensive lymph node metastasis. According to the guideline, immune checkpoint inhibitor(nivolumab)was used for treatment, but because the tumor progressed after 2 courses and the performance status of the patient worsened, aggressive treatment was ended. Six weeks after finishing treatment, computed tomography showed that the tumor had shrunk to some extent. The patient ultimately died from aspiration pneumonia 4 months after the first consultation. The patient was thought to have had an immune-related adverse event, with the tumor showing pseudoprogression.

Background: The purpose of this study was to investigate whether histogram analysis of an apparent diffusion coefficient (ADC) can serve as a prognostic biomarker for esophageal squamous cell carcinoma (ESCC)., Methods: This retrospective study enrolled 116 patients with ESCC who received curative surgery from 2006 to 2015 (including 70 patients who received neoadjuvant chemotherapy). Diffusion-weighted magnetic resonance imaging (DWI) was performed prior to treatment. The ADC maps were generated by DWIs at b = 0 and 1000 (s/mm 2 ), and analyzed to obtain ADC histogram-derived parameters (mean ADC, kurtosis, and skewness) of the primary tumor. Associations of these parameters with pathological features were analyzed, and Cox regression and Kaplan-Meier analyses were performed to compare these parameters with recurrence-free survival (RFS) and disease-specific survival (DSS)., Results: Kurtosis was significantly higher in tumors with lymphatic invasion (p = 0.005) with respect to the associations with pathological features. In univariate Cox regression analysis, tumor depth, lymph node status, mean ADC, and kurtosis were significantly correlated with RFS (p = 0.047, p < 0.001, p = 0.037, and p < 0.001, respectively), while lymph node status and kurtosis were also correlated with DSS (p = 0.002 and p = 0.017, respectively). Furthermore, multivariate analysis demonstrated that kurtosis was the independent prognostic factor for both RFS and DSS (p < 0.001 and p = 0.015, respectively). In Kaplan-Meier analysis, patients with higher kurtosis tumors (> 3.24) showed a significantly worse RFS and DFS (p < 0.001 and p = 0.006, respectively)., Conclusions: Histogram analysis of ADC may serve as a useful biomarker for ESCC, reflecting pathological features and prognosis.

Aim: Esophageal squamous cell carcinoma (ESCC) is a refractory digestive organ cancer that requires better treatment strategies. We have recently reported that the antidiabetic drug metformin exerts antitumor effects on ESCC by inhibition of nuclear factor kappa B (NF-κB) nuclear translocation. In the present study, we focused on caspase recruitment domain family member 9 (CARD9), an essential signal adapter in NF-κB activation to examine whether it can be used as a prognostic factor in ESCC., Methods: We investigated CARD9 expression immunohistochemically in clinical samples obtained from 93 patients with ESCC who underwent curative esophagectomy. CARD9 expression was analyzed for correlation with clinicopathological characteristics and ESCC prognosis. The molecular effects were investigated by knocking down ESCC cells. Comprehensive RNA expression changes in these ESCC cells were detected by next-generation sequencing (NGS)., Results: High CARD9 expression is significantly correlated with advanced tumor depth ( P  < .001), positive lymph node metastasis ( P  = .005) and advanced stage ( P  = .001). Kaplan-Meier method and the log-rank test showed that overall survival (OS) and disease-free survival (DFS) were significantly poor in the high CARD9 expression group (OS: P  = .027, DFS: P  = .005). Univariate and multivariate analysis showed that high CARD9 expression is a significant poor prognostic factor for DFS. Cell proliferation and migration were suppressed by CARD9 knockdown. NGS detected altered the expression of some RNAs including maternally expressed 3 ( MEG3 )., Conclusion: High CARD9 expression is significantly associated with poor prognosis. Therefore, CARD9 expression may be a prospective prognostic biomarker in ESCC., Competing Interests: Conflicts of Interest: Authors declare no conflicts of interest for this article., (© 2019 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.)

Recently, the interest in cancer genomic medicine has increased, owing to the powerful and cost-effective technology of next-generation sequencing(NGS), which allows rapid identification of a large number of gene mutations. TP53 mutations are frequently found in solid cancers, especially in esophageal squamous cell carcinoma(ESCC), wherein the frequency of TP53 mutation is considered to be 90% or more. However, there is no clinical targeted therapy as yet utilizing TP53. Here, we aimed to characterize TP53 mutations associated with ESCC, in order to assess its feasibility as a therapeutic target. We extracted DNA and RNA from specimens of ESCC patients and analyzed them using NGS, which revealed different TP53 mutations. Based on previous reports, it is considered that different TP53 mutations lead to different functions of the protein, and subsequently account for varied prognosis in squamous cell carcinoma of the head and neck. We also performed cell viability assay using ESCC cell lines with different TP53 mutations and 2 kinds of p53-targeted drug and found differences in the growth inhibition of the cell lines. Although individual treatment can be determined depending on the type of TP53 mutation, it would be necessary to further examine the interaction of TP53 with other genes to determine its therapeutic efficacy as a target.

Immunocheckpoint inhibitors including anti-PD-1 antibody have shown certain therapeutic effects on various cancer types. They have also attracted great attention as novel cancer treatment options in addition to surgical resection, chemotherapy, and radiation therapy. Herein, we report a case of gastric cancer that was successfully treated with conversion surgery after nivolumab treatment. The patient was 68 years old and male. Upper gastrointestinal endoscopy revealed a type 3 tumor in the antrum, and he was referred to our department for further examination. The gastric cancer was diagnosed as cT4aN2M0, cStage ⅢA, and he was administered SOX as the first-line and nab-PTX/RAM as the second-line treatment, which was also a PD. As the third-line treatment, nivolumab showed remarkable reduction of the tumor after initiation, and after 14 courses, conversion surgery was performed. The patient remains alive without recurrence.

Introduction: Cancer patients undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remain unknown and out of concern related to the potential development of severe adverse effects. However, patients with chemosensitive cancer, such as esophageal cancer, should receive chemotherapy at a dose that is sufficient to attain a favorable therapeutic effect. We herein present an interesting case involving an esophageal cancer patient who was successfully treated with subtotal thoracic esophagectomy, and adjuvant full-dose chemotherapy with cisplatin and 5-fluorouracil while concomitantly undergoing hemodialysis. We carried out a pharmacokinetics analysis of cisplatin, and also conducted a systematic review on the dose and pharmacokinetics., Case Report: A 57-year-old male patient with esophageal cancer who was undergoing hemodialysis was referred to our hospital. He underwent subtotal thoracic esophagectomy. The pathological diagnosis was T1b, N2 (5/26), M0, ly2, v2, stage IIIA (Union for International Cancer Control, 8th edition). Because of the high degree of lymph node metastasis, adjuvant chemotherapy with cisplatin was recommended. Cisplatin (80 mg/m 2 ) was infused intravenously within 30 min on day 1, and 5-fluorouracil (800 mg/m 2 ) was infused continuously on days 1-5 of a 28-day cycle. Thrombocytopenia (grade 3) occurred on day 16, leucopenia (grade 3) occurred on day 23, and anemia (grade 3) occurred on day 30. The onset of hematologic toxicities was prolonged in comparison to patients with a normal renal function.

Background: Postoperative docetaxel plus S-1 (DS) chemotherapy is expected to be the standard therapeutic strategy for pStage III gastric cancer based on the results of the JACCRO GC-07 study. Neoadjuvant chemotherapy (NAC) is thought to have several advantages over adjuvant settings., Objective: This study aimed to compare the efficacies of NAC DS and the surgery-first strategy for advanced gastric cancer patients with D2 gastrectomy., Methods: This was a retrospective, single-institution observational study. Of 171 patients with locally advanced (cStage IIB or III) gastric cancer who underwent curative D2 gastrectomy and received NAC DS and/or S-1 adjuvant chemotherapy between 2011 and 2017, 76 (after propensity score matching for 132 patients who met the eligibility criteria) were enrolled in this study. The 3-year progression-free survival (PFS) rate was used to directly compare efficacies between NAC DS patients and surgery-first patients., Results: The 3-year PFS rates for the NAC DS group were significantly higher than those for the surgery-first group (80.0 vs. 58.7; p = 0.037), and the progression hazard ratio of the NAC DS group compared with the surgery-first group was 0.394 (95% confidence interval 0.159-0.978; p = 0.045)., Conclusions: The NAC DS group showed a high 3-year PFS compared with the surgery-first group, with standard S-1 postoperative chemotherapy or observation. NAC DS can be expected to be beneficial as the standard therapy for advanced gastric cancer and should be adopted for the test arm of a randomized controlled phase III trial.

A 67-year-old female was diagnosed with Stage Ⅳ rectal cancer with paraaortic lymph node metastasis. The patient underwent Hartmann's operation with D3 lymph node and paraaortic lymph node dissection. Postoperative chemotherapy with FOLFIRI was then administered for 1 year. However, liver metastasis developed, for which partial hepatectomy was performed. Postoperative chemotherapy with S-1(20 courses)was then administered. Three years and 11 months following the first operation, lymph node metastases developed and resection of lymph nodes(No. 12p, No. 16b1int)was performed. Postoperative chemotherapy with capecitabine(Cape)(8 courses)was then administered. Five years and 7 months following the first operation, Virchow lymph node metastasis developed. Despite chemotherapy with Cape and bevacizumab (Bmab), Virchow lymph node swelling recurred, and resection was performed. Nine years and 4 months following the first operation, lymph node metastases developed, and resection of lymph nodes(Virchow, No. 16b1int)was performed. Postoperative chemotherapy with S-1(8 courses)was then administered. At present, 11 years and 4 months after the first operation, the patient, whose chemotherapy has been discontinued, is alive without recurrence.

Aim: Application of laparoscopic approaches for the treatment of remnant gastric cancers (RGC) is still controversial. Therefore, in the present study, the safety and effectiveness of laparoscopic gastrectomy (LG) for RGC was investigated., Methods: A total of 27 patients who underwent gastrectomy for RGC from June 2008 to September 2017 were enrolled in this study. A comprehensive review of the literature on LG for RGC published before December 2017 using the PubMed database was carried out., Results: Laparoscopic gastrectomy was carried out in seven patients, and open gastrectomy (OG) was done in the remaining 20 patients. LG was associated with significantly less intraoperative blood loss (70 ± 71 vs. 1066 ± 1428 g; P  < 0.001), significantly more retrieved lymph nodes (22 ± 13 vs. 12 ± 9; P  = 0.03), a relatively lower postoperative complication rate, and a relatively shorter postoperative hospital stay than OG. A comprehensive review of the literature showed that LG for RGC was more likely to correlate with longer operative time, less blood loss, lower postoperative complication rate, shorter postoperative hospital stay, and more retrieved lymph nodes than OG., Conclusion: The clinical outcome of our patients with RGC and the literature indicated that a laparoscopic approach contributed to faster recovery after surgery than an open approach without sacrificing its radicality and was a safe and secure treatment option for RGC.

Background/aim: Gastric cancer (GC) with peritoneal metastasis remains difficult to treat. The anti-diabetic drug metformin exerts various antitumor effects via the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway and nuclear factor-kappa B (NF-ĸB). Therefore, we evaluated the antitumor effects of metformin for GC in vitro and on peritoneal metastasis., Materials and Methods: The human GC cell lines MKN1, MKN45, KATO-III and SNU-1 were used. The antiproliferative effect was evaluated in vitro with 0.5 mM or 25 mM glucose and in vivo using tumor xenograft peritoneal models of metastasis. The protein expression of AMPK, liver kinase B1 (LKB1) and NF-ĸB in tumors was examined by western blotting., Results: Metformin inhibited cell proliferation in all GC lines and sensitivity was increased under low-glucose conditions in vitro. Metformin also suppressed peritoneal metastasis. In tumors, metformin reduced the numbers of proliferating cells and NF-ĸB expression, but a similar trend was not noted for AMPK., Conclusion: Metformin may be a useful drug for the treatment of GC with peritoneal metastasis., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)