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Abstract Introduction Port-site herniation is a rare but potentially dangerous complication after laparoscopic surgery. Closure of port sites, especially those measuring 10 mm or more, has been recommended to avoid such an event. Case presentation We herein report the only case of a port site hernia among a series 52 consecutive cases of laparoscopy-assisted distal gastrectomy (LADG) carried out by our unit between July 2002 and March 2007. In this case the small bowel herniated and incarcerated through the port site on day 4 after LADG despite closure of the fascia. Initial manifestations experienced by the patient, possibly due to obstruction, and including mild abdominal pain and nausea, occurred on the third day postoperatively. The definitive diagnosis was made on day 4 based on symptoms related to leakage from the duodenal stump, which was considered to have developed after severe obstruction of the bowel. Re-operation for reduction of the incarcerated bowel and tube duodenostomy with peritoneal drainage were required to manage this complication. Conclusion We present this case report and review of literature to discuss further regarding methods of fascial closure after laparoscopic surgery.

We report a case of atrial functional tricuspid regurgitation with an atrial standstill in a 71-year-old woman with a history of chronic atrial fibrillation (AF). The ECG showed a flat baseline with no AF waves and regular, narrow QRS complexes, whereas the previous ECG demonstrated AF. Echocardiography revealed dilation of the right atrium and the tricuspid annulus with severe regurgitation, but mitral regurgitation was mild. No atrial contraction was detected. Bilateral ventricular function was preserved. Cardiac catheterization showed no pulmonary hypertension and an a-wave in atrial pressure tracings. During surgery, epicardial pacing was unable to capture both atria. The tricuspid valve was replaced and a pacemaker was implanted., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hori et al.)

Background: Calcium voltage-gated channel auxiliary subunit alpha 2/delta 1 (CACNA2D1), a gene encoding a voltage-gated calcium channel, has been reported as an oncogene in several cancers. However, its role in colon cancer (CC) remains unclear. This study aimed to investigate the function of CACNA2D1 and its effect on the microenvironment in CC., Methods: Immunohistochemistry (IHC) analysis was performed on samples collected from 200 patients with CC who underwent curative colectomy. Knockdown experiments were performed using CACNA2D1 siRNA in the human CC cell lines HCT116 and RKO, and cell proliferation, cycle, apoptosis, and migration were then analyzed. The fibroblast cell line CCD-18Co was co-cultured with CC cell lines to determine the effect of CACNA2D1 on fibroblasts and the relationship between CACNA2D1 and the cancer microenvironment. Gene expression profiles of cells were analyzed using microarray analysis., Results: IHC revealed that high CACNA2D1 expression was an independent poor prognostic factor in patients with CC and that CACNA2D1 expression and the stroma are correlated. CACNA2D1 depletion decreased cell proliferation and migration; CACNA2D1 knockdown increased the number of cells in the sub-G1 phase and induced apoptosis. CCD-18Co and HCT116 or RKO cell co-culture revealed that CACNA2D1 affects the cancer microenvironment via fibroblast regulation. Furthermore, microarray analysis showed that the p53 signaling pathway and epithelial-mesenchymal transition-associated pathways were enhanced in CACNA2D1-depleted HCT116 cells., Conclusions: CACNA2D1 plays an important role in the progression and the microenvironment of CC by regulating fibroblasts and may act as a biomarker for disease progression and a therapeutic target for CC., (© 2024. Japanese Society of Gastroenterology.)

Recent studies have identified that postoperative infectious complications (PICs) have contributed to poor prognosis in gastric cancer (GC). In this study, we investigated which complication among PICs most strongly contributes to a poor prognosis. This study included 1,653 consecutive patients who underwent curative gastrectomy for GC between 1997 and 2018. A Clavien-Dindo classification of grade II or higher was used as a cut-off for PICs. PICs occurred in 17.1% of all GC patients. Patients with a PIC had a poorer prognosis than those without [Hazard ratio (HR): 17.5, P < 0.001]. Among PICs, pancreatic fistula (PF) had the strongest effect on poor prognosis (HR: 3.16) compared to anastomotic leakage (HR: 2.41), pneumonia (HR: 2.11) and intra-abdominal abscess (HR: 1.98). Multivariate analysis on pStage II or III GC showed that PF had the strongest poor prognostic effect ( P = 0.025, HR: 2.21, 95%-CI: 1.07-3.99). Patients with PF had significantly higher C-reactive protein (CRP) levels on postoperative days 1 ( P = 0.039) and 3 ( P = 0.044), tended to experience a prolonged period of high inflammation, with CRP levels above 10 mg/dL ( P = 0.086), and had the highest incidence of recurrence compared to other PICs. Robotic gastrectomy had no incidence of PF, while open gastrectomy resulted in a 2% occurrence, and laparoscopic gastrectomy had a 1.8% occurrence. In conclusion, PF had the strongest effect on poor prognosis among PICs. Robotic gastrectomy might be the optimal approach for avoiding PF., Competing Interests: None., (AJCR Copyright © 2023.)

Background: The potential of membrane transporters activated in cancer stem cells (CSCs) as new therapeutic targets for cancer is attracting increasing interest. Therefore, the present study examined the expression profiles of ion transport-related molecules in the CSCs of esophageal adenocarcinoma (EAC)., Methods: Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from OE33 cells, a human Barrett's EAC cell line, by fluorescence-activated cell sorting. CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were examined by a microarray analysis., Results: Among OE33 cells, ALDH1A1 messenger RNA levels were higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels/transporters, such as transient receptor potential vanilloid 2 (TRPV2) and solute carrier family 12 member 2 (SLC12A2). The cytotoxicities of the TRPV2 inhibitor tranilast and the SLC12A2 inhibitor furosemide were higher at lower concentrations in CSCs than in non-CSCs, and both markedly reduced the number of tumorspheres. The cell population among OE33 cells that highly expressed ALDH1A1 also was significantly decreased by these inhibitors., Conclusions: Based on the present results, TRPV2 and SLC12A2 are involved in the maintenance of CSCs, and their specific inhibitors, tranilast and furosemide, respectively, have potential as targeted therapeutic agents for EAC., (© 2023. Society of Surgical Oncology.)

Background: Transient receptor potential vanilloid 2 (TRPV2) is a member of the TRP superfamily of non-specific cation channels with functionally diverse roles. We herein investigated the effects of TRPV2 on the expression of programmed cell death-ligand 1 (PD-L1) and its binding ability to programmed cell death-1 (PD-1) in gastric cancer (GC)., Methods: Knockdown (KD) experiments were performed on human GC cell lines using TRPV2 small-interfering RNA. The surface expression of PD-L1 and its binding ability to PD-1 were analyzed by flow cytometry. Eighty primary tissue samples were assessed by immunohistochemistry (IHC), and the relationships between IHC results, clinicopathological factors, and patient prognosis were analyzed. The molecular mechanisms underlying the effects of TRPV2 on the intracellular ion environment were also investigated., Results: TRPV2-KD decreased the expression level of PD-L1 in NUGC4 and MKN7 cells, thereby inhibiting its binding to PD-1. A survival analysis revealed that 5-year overall survival rates were significantly lower in the TRPV2 high expression and PD-L1-positive groups. In IHC multivariate analysis of GC patients, high TRPV2 expression was identified as an independent prognostic factor. Furthermore, a positive correlation was observed between the expression of TRPV2 and PD-L1. An immunofluorescence analysis showed that TRPV2-KD decreased the intracellular concentration of calcium ([Ca 2+ ] i ). Treatment with ionomycin/PMA (phorbol 12-myristate 13-acetate), which increased [Ca 2+ ] i , upregulated the protein expression of PD-L1 and promoted its binding to PD-1., Conclusions: The surface expression of PD-L1 and its binding ability to PD-1 in GC were regulated by TRPV2 through [Ca 2+ ] i , indicating the potential of TRPV2 as a biomarker and target of immune checkpoint blockage for GC., (© 2023. Society of Surgical Oncology.)

Background: Although a 3-5 cm surgical margin distance is recommended for advanced gastric cancer (GC) in Japanese guidelines, little is known about the clinical effects of the surgical margin, especially the distal resection margin (DM). This study aims to clarify the clinical significance of DM in GC., Methods: A total of 415 GC patients who underwent curative distal gastrectomy between 2008 and 2018 were analyzed retrospectively., Results: The DM significantly stratified recurrence-free survival (P = 0.002), and a DM < 30 mm was an independent factor of a poor prognosis (P = 0.023, hazard ratio: 1.91). Lymphatic recurrence occurred significantly more frequently in the DM < 30 mm group than in the DM ≥ 30 mm group (P = 0.019, 6.9% vs. 1.9%). Regarding the station No.6 lymph node metastases in advanced GC (DM < 30 mm vs. 30 mm ≤ DM ≤ 50 mm vs. DM > 50 mm), the number (P < 0.001, 1.42 ± 1.69 vs. 1.18 ± 1.80 vs. 0.18 ± 0.64), the positive rate (P < 0.001, 59.0% vs. 46.7% vs. 11.3%) and therapeutic value index (43.3 vs. 14.5 vs. 8.0) were significantly higher in the DM < 30 mm group. By subdivision using the DM distance of 30 mm, more segmented prognostic stratifications were possible (P < 0.001)., Conclusions: A DM of less than 30 mm could be a surrogate marker of poor RFS, especially increasing nodal recurrence. More intensive treatment strategies, including lymphadenectomy and chemotherapy, are needed for patients with this condition., (© 2023. The Author(s).)

Background/aim: The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for hepatocellular carcinoma (HCC). The present investigation demonstrated the expression profiles of ion channels in CSCs of HCC., Materials and Methods: Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from HepG2 cells, a human HCC cell line, by fluorescence-activated cell sorting, and CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were investigated using microarray analysis., Results: Among HepG2 cells, ALDH1A1 messenger RNA level was higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels, such as calcium voltage-gated channel auxiliary subunit gamma 4 (CACNG4). The cytotoxicity of the CACNG4 inhibitor amlodipine was higher at lower concentrations in CSCs than in non-CSCs, and markedly decreased the number of tumorspheres. The cell population among HepG2 cells that highly expressed ALDH1A1 was also significantly reduced by this inhibitor., Conclusion: CACNG4 plays a role in maintaining CSCs, and its inhibitor, amlodipine, could potentially be a targeted therapeutic agent against HCC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The tumor-stroma ratio and intratumor stromal heterogeneity have been identified as prognostic factors for several carcinomas. Recent advancements in image analysis technologies and their application to medicine have enabled detailed analysis of clinical data beyond human cognition., Objective: This study aimed to investigate the tumor-stroma ratio and intratumor stromal heterogeneity measured using a novel objective and semiautomatic method with image analysis., Design: A retrospective cohort design., Settings: Single institution., Patients: This study included patients who underwent curative colectomy for colon cancer., Main Outcome Measures: The survival analyses between tumor-stroma ratio or intratumor stromal heterogeneity high and low groups after colectomy were assessed in multivariate analyses., Results: Two hundred patients were divided into 2 groups based on the median tumor-stroma ratio and intratumor stromal heterogeneity values. The 5-year overall survival and relapse-free survival rates after colectomy significantly differed between the high and low tumor-stroma ratio or intratumor stromal heterogeneity groups. Multivariate analysis identified low tumor-stroma ratio (HR: 1.90, p = 0.03) and high intratumor stromal heterogeneity (HR: 2.44, p = 0.002) as independent poor prognostic factors for relapse-free survival. The tumor-stroma ratio and intratumor stromal heterogeneity correlated with the duration from curative surgery to recurrence. Furthermore, postoperative recurrence within 2 years was predicted with higher accuracy by using the tumor-stroma ratio or intratumor stromal heterogeneity than by using the pathological stage. In a validation cohort, interobserver agreement was assessed by 2 observers, and Cohen's κ coefficient for the tumor-stroma ratio (κ value: 0.70) and intratumor stromal heterogeneity (κ value: 0.60) revealed a substantial interobserver agreement., Limitations: This study was limited by its retrospective, single-institution design., Conclusions: Tumor-stroma ratio and intratumor stromal heterogeneity calculated using image analysis software have potential as imaging biomarkers for predicting the survival of patients with colon cancer after colectomy. See Video Abstract at http://links.lww.com/DCR/C114 ., Valor De La Proporcin De Estroma Tumoral Y La Heterogeneidad Estructural Medidos Por Una Nueva Tcnica De Anlisis De Imgenes Semiautomtica Para Predecir La Supervivencia En Pacientes Con Cncer De Colon: ANTECEDENTES:La proporción de estroma tumoral y la heterogeneidad del estroma intratumoral han sido identificados como factores pronósticos para varios tipos de carcinomas. Los avances recientes en cuanto a las tecnologías de análisis de imágenes y sus aplicaciones en la medicina, han permitido un análisis detallado de los datos clínicos más allá del conocimiento humano.OBJETIVO:Investigar la relación del estroma tumoral y la heterogeneidad del estroma intratumoral calculados mediante un nuevo método objetivo y semiautomático para el análisis de imágenes.DISEÑO:Diseño de cohorte retrospectivo.AJUSTES:Institución única.PACIENTES:Pacientes sometidos a colectomía curativa por cáncer de colon.PRINCIPALES MEDIDAS DE RESULTADO:Los análisis de supervivencia entre la relación del estroma tumoral o la heterogeneidad del estroma intratumoral entre los grupos con valores altos y bajos tras la colectomía, fueron evaluados en análisis multivariados.RESULTADOS:Fueron divididos 200 pacientes en dos grupos basados en la mediana de la proporción con respecto a los valores del estroma tumoral y la heterogeneidad del estroma intratumoral. Las tasas de supervivencia general a los 5 años y de supervivencia libre de recaídas después de la colectomía, difirieron significativamente entre los grupos con índice de estroma tumoral o heterogeneidad del estroma intratumoral altos y bajos. El análisis multivariante identificó una proporción de estroma tumoral baja (cociente de riesgos instantáneos: 1.90, p = 0.03) y una heterogeneidad estromal intratumoral alta (cociente de riesgos instantáneos: 2.44, p = 0.002) como factores independientes de mal pronóstico para la supervivencia libre de recaídas. La proporción de estroma tumoral y la heterogeneidad del estroma intratumoral se correlacionaron con la duración de la recurrencia desde la cirugía.Además, la recurrencia posoperatoria dentro de los 2 años se predijo con mayor precisión mediante el uso del índice de estroma tumoral o la heterogeneidad del estroma intratumoral que mediante el uso del estadio patológico. En una cohorte de validación, la concordancia interobservador fue evaluada por dos observadores, y el coeficiente Kappa de Cohen para la proporción de estroma tumoral y la heterogeneidad estromal intratumoral reveló una concordancia interobservador sustancial (valor Kappa: 0.70, 0.60, respectivamente).LIMITACIONES:Este estudio estuvo limitado por su diseño retrospectivo de una sola institución.CONCLUSIONES:La proporción del estroma tumoral y la heterogeneidad del estroma intratumoral calculadas mediante software de análisis de imágenes tienen potencial como biomarcadores de imagen para predecir la supervivencia de los pacientes con cáncer de colon tras la colectomía. Consulte Video Resumen en http://links.lww.com/DCR/C114 . (Traducción-Dr. Osvaldo Gauto )., (Copyright © The ASCRS 2022.)

Background: Na + /K + -ATPase α1 subunit (ATP1A1) exhibits aberrant expression in various types of cancer. Moreover, its levels in specific tissues are associated with the development of cancer. Nevertheless, the mechanism and signaling pathways underlying the effects of ATP1A1 in colon cancer (CC) have not been elucidated, and its prognostic impact remains unknown., Methods: Knockdown of ATP1A1 expression was performed in human CC cell lines HT29 and Caco2 using small interfering RNA. The roles of ATP1A1 in various biological processes of cells (i.e., proliferation, cell cycle, apoptosis, migration, and invasion) were assessed. Microarray analysis was utilized for gene expression profiling. Samples obtained from 200 patients with CC who underwent curative colectomy were analyzed through immunohistochemistry., Results: ATP1A1 knockdown suppressed cell proliferation, migration, and invasion and induced apoptosis. The results of the microarray analysis revealed that the upregulated or downregulated gene expression in ATP1A1-depleted cells was related to the extracellular signal-regulated kinase 5 (ERK5) signaling pathway [epidermal growth factor receptor (EGFR), mitogen-activated protein kinase kinase 5 (MAP2K5), mitogen-activated protein kinase 7 (MAPK7), FOS, MYC, and BCL2 associated agonist of cell death (BAD)]. Immunohistochemical analysis demonstrated a correlation between ATP1A1 expression and pathological T stage (p = 0.0054), and multivariate analysis identified high ATP1A1 expression as an independent predictor of poor recurrence-free survival in patients with CC (p = 0.0040, hazard ratio: 2.807, 95% confidence interval 1.376-6.196)., Conclusions: ATP1A1 regulates tumor progression through the ERK5 signaling pathway. High ATP1A1 expression is associated with poor long-term outcomes in patients with CC., (© 2023. Society of Surgical Oncology.)

A 39-year-old man was admitted because of cardiac arrest. Emergent coronary angiography revealed a preserved coronary blood flow; however, multiple-row detector computed tomography (MDCT) revealed that the proximal right coronary artery (RCA) was running inside the aortic wall, creating proximal stenosis without atherosclerotic changes. Surgical intervention with unroofing was performed; however, postoperative stenosis of the proximal RCA required additional coronary artery bypass grafting (CABG). Intraoperative findings during CABG did not reveal hematoma or coronary dissection. However, MDCT one year after CABG depicted improvement of the RCA and graft stenoses, suggesting that the post-unroof stenosis may have been caused by an inflammatory reaction after surgical intervention.

Recent evidence suggests that the targeting of membrane transporters specifically activated in cancer stem cells (CSCs) is an important strategy for cancer therapy. The objectives of the present study were to investigate the ion channel expression profiles in digestive CSCs. Cells strongly expressing CSC markers, such as ALDH1A1 and CD44, were separated from the human esophageal squamous cell carcinoma, gastric cancer, and pancreatic cancer cell lines using fluorescence-activated cell sorting, and CSCs were identified based on tumorsphere formation. Messenger RNA levels of CSC markers were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to anticancer agents. The microarray analysis revealed that the expression of transient receptor potential vanilloid 2 (TRPV2), voltage-gated calcium channels (VGCCs), and voltage-gated potassium channels (VGKCs) were upregulated in esophageal, gastric, and pancreatic CSCs, respectively, compared with non-CSCs. The TRPV2 inhibitor tranilast, VGCCs inhibitors amlodipine and verapamil, and VGKC inhibitor 4-aminopyridine exhibited greater cytotoxicity in CSCs compared with non-CSCs, and their inhibitory effects were also confirmed in a xenograft model in nude mice. Taking these results, phase I/II study to investigate clinical safety and efficacy of neoadjuvant combination chemotherapy of tranilast in advanced esophageal squamous cell carcinoma (TNAC study) is ongoing. These researches identified a role of ion channels in the persistence of CSCs and suggested that their inhibitors may have potential as a therapeutic agent for digestive cancers.

Background: NADPH oxidases (NOXs) are transmembrane proteins that generate reactive oxygen species. Recent studies have reported that NOXs are involved in tumor progression in various cancers. However, the expression and role of NOX2 in esophageal squamous cell carcinoma (ESCC) remain unclear. This study aimed to clarify the pathophysiologic role of NOX2 in patients with ESCC and cell lines., Methods: Two human ESCC cell lines (TE5 and KYSE170) were used for NOX2 transfection experiments, and the effects on cell proliferation, cell cycle, cell motility, and cell survival were analyzed. An mRNA microarray analysis was also performed to assess gene expression profiles. Additionally, NOX2 immunohistochemistry was performed on 130 primary ESCC tumor samples to assess the prognostic value of NOX2 in patients with ESCC., Results: NOX2 depletion significantly inhibited cell proliferation with the G 0 /G 1 arrest and resulted in apoptosis in two cell lines. Microarray analysis revealed a strong relationship between NOX2 gene expression and the signaling pathway of cell cycle regulation by the B-cell translocation gene 2 (BTG2) family, including BTG2, CCNE2, E2F1, and CDK2 genes. Immunohistochemical staining revealed that high NOX2 protein expression was significantly associated with deeper tumor invasion and selected as one of the independent prognostic factors associated with the 5-year OS rate in patients with ESCC., Conclusions: NOX2 expression in ESCC cells affects tumorigenesis, especially cell cycle progression via the BTG2-related signaling pathway, as well as the prognosis of patients with ESCC. NOX2 may be a novel biomarker and therapeutic target for ESCC., (© 2022. Society of Surgical Oncology.)

We present a case of 72-year-old man who was diagnosed with gastric cancer that occurred after coronary artery bypass grafting(CABG)with the right gastroepiploic artery(RGEA). Gastrointestinal endoscopy revealed a 0-Ⅱc lesion at the posterior wall of gastric angle, and diagnosis was cStage Ⅰ(T2N0M0). Cardiac computed-tomography showed an occlusion of the RGEA graft, suggesting that the RGEA graft could be ligated and dissected. Coronary angiography showed no severe stenosis of the right coronary artery, suggesting that coronary revascularization was not necessary. He underwent laparoscopic distal gastrectomy with D2 lymph node dissection. During the operation, the RGEA graft was dissected after clamp test for 20 minutes to confirm no cardiac event. In such cases, it is crucial to consider whether it is possible or not to dissect the RGEA graft and whether to restore the coronary flow with preoperative meticulous examination.

Background: Anoctamin 5 (ANO5)/transmembrane protein 16E belongs to the ANO/ transmembrane protein 16 anion channel family. ANOs comprise a family of plasma membrane proteins that mediate ion transport and phospholipid scrambling and regulate other membrane proteins in numerous cell types. Previous studies have elucidated the roles and mechanisms of ANO5 activation in various cancer types. However, it remains unclear whether ANO5 acts as a plasma membrane chloride channel, and its expression and functions in gastric cancer (GC) have not been investigated., Aim: To examine the role of ANO5 in the regulation of tumor progression and clinicopathological significance of its expression in GC., Methods: Knockdown experiments using ANO5 small interfering RNA were conducted in human GC cell lines, and changes in cell proliferation, cell cycle progression, apoptosis, and cellular movement were assessed. The gene expression profiles of GC cells were investigated following ANO5 silencing by microarray analysis. Immunohistochemical staining of ANO5 was performed on 195 primary tumor samples obtained from patients with GC who underwent curative gastrectomy between 2011 and 2013 at our department., Results: Reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting demonstrated high ANO5 mRNA and protein expression, respectively, in NUGC4 and MKN45 cells. In these cells, ANO5 silencing inhibited cell proliferation and induced apoptosis. In addition, the knockdown of ANO5 inhibited G 1 -S phase progression, invasion, and migration. The results of the microarray analysis revealed changes in the expression levels of several cyclin-associated genes, such as CDKN1A , CDK2/4/6 , CCNE2 , and E2F1 , in ANO5-depleted NUGC4 cells. The expression of these genes was verified using reverse transcription-quantitative PCR. Immunohistochemical staining revealed that high ANO5 expression levels were associated with a poor prognosis. Multivariate analysis identified high ANO5 expression as an independent prognostic factor for 5-year survival in patients with GC ( P = 0.0457)., Conclusion: ANO5 regulates the cell cycle progression by regulating the expression of cyclin-associated genes and affects the prognosis of patients with GC. These results may provide insights into the role of ANO5 as a key mediator in tumor progression and/or promising prognostic biomarker for GC., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Gastric wall abscess (GWA) itself is a rare clinicopathological condition, and there has been no report of primary gastric cancer complicated by GWA. Herein, we present a case of advanced gastric cancer with intramural abscess, which was successfully treated with curative gastrectomy., Case Report: A 77-year-old woman was admitted to the hospital for dull epigastric pain with inflammatory findings and diagnosed with advanced gastric cancer (cT4aN1M0 Stage III) with intramural abscess. Since an endoscopic ultrasonography-guided abscess drainage was not effective, after conservative therapy with antibiotics, she underwent distal gastrectomy with D2 lymphadenectomy and fortunately the tumor with abscess was safely and curatively removed without perforation. Microscopically, the 82×65 mm tumor invaded the subserosa and contained tubular adenocarcinoma with neuroendocrine cell carcinoma (pT3N0M0 Stage IIB), and the abscess formed from the ulcerative lesion of the cancer extended to the subserosa. The postoperative clinical course was uneventful, and she remained disease-free during the 22 months follow-up., Conclusion: Given the nature of the disease and the difficulty in endoscopic treatment, gastrectomy should be performed immediately for advanced gastric cancer with GWA to ensure control of both gastric cancer and infection., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Transient receptor potential vanilloid 2 (TRPV2) is a highly Ca 2+ -permeable ion channel that is involved in a number of cellular processes. It is expressed in various human cancers; however, the role of TRPV2 in gastric cancer (GC) remains poorly understood., Methods: TRPV2 gene expression was knocked down in GC cell lines by small-interfering RNA (siRNA), and the biological roles of TRPV2 in the proliferation, migration, and invasion of GC cells were then investigated. The gene expression profile of GC was elucidated using a microarray analysis. TRPV2 expression in tumor tissue sections was analyzed by immunohistochemistry., Results: The migration and invasion abilities of GC cells were inhibited by the knockdown of TRPV2. Moreover, the microarray assay revealed that TRPV2 was associated with the transforming growth factor (TGF)-β signaling pathway. Immunohistochemical staining showed that the strong expression of TRPV2 correlated with lymphatic invasion, venous invasion, pathological T (pT), pathological N (pN), and a poor prognosis in GC patients., Conclusions: TRPV2 appeared to promote tumor migration and invasion via the TGF-β signaling pathway, and the strong expression of TRPV2 was associated with a worse prognosis in GC patients., (© 2021. Society of Surgical Oncology.)

Background: Voltage-gated calcium channels form as a complex of several subunits, among which the function of CACNA2D1, one of the genes encoding the α2δ subunit, remains unclear. The aim of our study was to investigate the role of CACNA2D1 and evaluate the efficacy of amlodipine, a blocker of CACNA2D1, in the treatment of gastric cancer (GC)., Methods: Knockdown experiments were performed on the human GC cell lines MKN7 and HGC27 using CACNA2D1 small interfering RNA (siRNA), and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical (IHC) analysis was conducted on samples obtained from 196 GC patients who underwent curative gastrectomy. In addition, the antitumor effects of amlodipine were investigated using a xenograft model., Results: Cell proliferation, migration, and invasion were suppressed in CACNA2D1-depleted cells, and apoptosis was induced. The results of the microarray analysis showed that the apoptosis signaling pathway was enhanced via p53, BAX, and caspase 3 in CACNA2D1-depleted cells. A multivariate analysis identified high CACNA2D1 expression levels, confirmed by IHC, as an independent poor prognostic factor in GC patients. Moreover, subcutaneous tumor volumes were significantly smaller in a xenograft nude mouse model treated with a combination of amlodipine and cisplatin than in a model treated with cisplatin alone., Conclusions: The present study indicates that CACNA2D1 regulates the apoptosis signaling pathway and may have potential as a biomarker for cancer growth and as a therapeutic target for GC., (© 2022. Society of Surgical Oncology.)

Background: Malnutrition leads to accelerated tumor progression through the suppression of tumor immunity. The present study examined the significance of the preoperative prognostic nutritional index (PNI) for predicting postoperative survival outcomes in gastric cancer (GC)., Methods: A total of 447 patients who underwent curative gastrectomy for GC were included in the present study. PNI was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte counts (per mm 3 ). The prognostic impact of preoperative PNI was examined using two multivariate analysis models., Results: The optimal cutoff value of preoperative PNI for predicting overall survival (OS) was 48 based on a receiver operating characteristic curve. The 5-year OS rate was 59.5% in the PNI<48 group and 91.3% in the PNI≥48 group (p<0.001). In the first multivariate survival analysis where all explanatory variables were composed of preoperative factors alone, a PNI<48 (hazard ratio [HR] 3.33; 95% confidence interval [CI] 2.01-5.56, p<0.001), upper-third GC and cT2-T4 were identified as independent indicators of a poor OS. In the second survival analysis where explanatory variables were composed of preoperative, intraoperative, and pathological factors, a PNI<48 (HR 2.80; 95% CI 1.65-4.78, p<0.001), hypertension, open gastrectomy, intraoperative blood loss≥100g, pT2-T4, and pN+ were independent prognostic factors., Conclusion: Preoperative PNI may be a useful predictor of postoperative survival outcomes both before and immediately after surgery in GC. Appropriate perioperative interventions and the meticulous surveillance of GC relapse are necessary for patients with PNI<48., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background: In transmediastinal esophagectomy (TME) with equivalent lymphadenectomy to transthoracic procedure, an understanding of surgical anatomy in the deep mediastinum near the aortic arch or tracheal bifurcation is essential for the safe procedure. The present study aimed to evaluate the bronchial arteries (BAs) with preoperative 3D-CT in TME., Methods: Seventy-nine patients with thoracic esophageal cancer undergoing TME were examined by preoperative 3D-CT to evaluate BA variations in the number, branching pattern, and mediastinal course. For the right BAs (RBAs) crossing the esophagus, the mediastinal courses in transcervical view were classified in relation to the esophagus and tracheobronchi and compared with surgical findings., Results: A total of 107 RBAs (1.35/person) were confirmed on preoperative 3D-CT. Of these, 61 (57.0%) crossed the esophagus dorsally (type Ed), and the remaining 46 (43.0%) crossed the esophagus ventrally (type Ev). During the left transcervical procedure, all type Ed RBAs were identified and mostly preserved (57/61, 93.4%) whereas most type Ev RBAs were identified (39/46, 84.8%), but more than half were sacrificed (26/46, 56.5%) for lymphadenectomy. The blood loss during the transcervical procedure was 17.0 ± 55.8 ml. The total number of dissected mediastinal lymph nodes was 23.7 ± 9.3. There were no significant complications related to extensive lymphadenectomy., Conclusions: Preoperative 3D-CT evaluation is useful to understand the mediastinal courses of BAs specific to the transcervical approach, which may allow BAs to be handled more carefully according to the type during surgery, contributing to a safer procedure in the deep mediastinum., (© 2021. The Japan Esophageal Society.)

The patient was a 67-year-old male diagnosed with adenocarcinoma of the esophagogastric junction. The esophagus was markedly dilated due to severe stenosis, and aspiration pneumonia was observed. Therefore, he was treated with a W- ED tube for simultaneous esophageal decompression and enteral nutrition. Two weeks of W-ED tube placement improved esophageal dilatation and pneumonia while maintaining nutritional status; thus, he underwent proximal gastrectomy, lower esophagectomy and combined resection of distal pancreas, spleen and left crus of diaphragm with jejunal interposition reconstruction. His postoperative course was uneventful, and he was discharged 16 days after surgery without any postoperative infectious complications such as pneumonia, anastomotic leakage, pancreatic fistula and enterocolitis. In the preoperative management for patients with esophagogastric junction cancer with severe stenosis, simultaneous esophageal decompression and enteral nutrition using a W-ED tube is very useful because it can improve aspiration pneumonia, reduce the risk of anastomotic leakage by improving esophageal edema, and prevent disuse atrophy of small intestinal villi.

A 71-year-old man was referred to our hospital because of a gastric submucosal tumor. Gastrointestinal stromal tumor (GIST)was diagnosed in the antrum of the stomach and local resection was undergone. At this time, upper gastrointestinal endoscopy found the gastric submucosal tumor with a size of about 5 mm on the posterior wall of the fundus, but it was followed up. The lesion had grown to a size of about 10 mm by endoscopy 2 years later, and a biopsy was performed. Gastric mucosa associated lymphoid tissue(MALT)lymphoma was diagnosed by pathological examination, and Helicobacter pylori eradication therapy was performed. Endoscopy after treatment further increased the size of the lesion to about 20 mm, and ulceration was also observed. A biopsy was performed again, and a diagnosis of poorly differentiated adenocarcinoma was made, and laparoscopic proximal gastrectomy was undergone. It was the diagnosis of gastric carcinoma with lymphoid stroma(GCLS), pT3N0M0, pStage ⅡA in the postoperative pathological examination. GCLS is a rare disease with a frequency of about 1 to 4% of all gastric cancers, and preoperative diagnosis is difficult. From the morphology and histology, the differential diagnosis from submucosal tumors and lymphomas becomes problems.

Background: The Na + /K + -ATPase alpha1 subunit (ATP1A1) is a critical component of Na + /K + -ATPase (NKA), a membrane pump that maintains a low intracellular Na + /K + ratio and retains cellular volume and osmolarity. ATP1A1 was recently implicated in tumor behavior. Therefore, the present study investigated the role of ATP1A1 in patients with gastric cancer (GC)., Methods: Knockdown experiments were conducted on human GC cell lines using ATP1A1 siRNA, and its effects on proliferation, the cell cycle, apoptosis, and cellular movement were examined. Gene expression profiling was performed by a microarray analysis. Primary tumor samples from 192 GC patients who underwent gastrectomy were subjected to an immunohistochemical analysis., Results: High ATP1A1 expression levels were observed in NUGC4 and MKN74 cells. Cell proliferation was suppressed and apoptosis was induced by the siRNA-induced knockdown of ATP1A1. The microarray analysis showed that knockdown of ATP1A1 leads to the up-regulated expression of genes involved in the interferon (IFN) signaling pathway, such as STAT1, STAT2, IRF1, and IRF9. Furthermore, the depletion of ATP1A1 altered the phosphorylation of the MAPK pathway. The immunohistochemical analysis revealed that the expression of ATP1A1 was associated with the histological type, venous invasion, and the pathological T stage. Furthermore, the prognostic analysis showed a relationship between high ATP1A1 expression levels and poor postoperative survival., Conclusions: ATP1A1 appears to regulate tumor progression by altering IFN signaling, and high ATP1A1 expression levels were associated with poor postoperative survival in GC patients. The present results provide novel insights into the function of ATP1A1 as a mediator and/or biomarker of GC., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride (Cl - ) anion conducting channel, and its role in esophageal squamous cell carcinoma (ESCC) was examined in the present study., Methods: Overexpression experiments were conducted on human ESCC cell lines following the transfection of a CFTR plasmid, and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. A microarray analysis was performed to examine gene expression profiles. Fifty-three primary tumor samples collected from ESCC patients during esophagectomy were subjected to an immunohistochemical analysis., Results: Transfection of the CFTR plasmid into the ESCC KYSE 170 and KYSE 70 cell lines suppressed cell proliferation, migration, and invasion and induced apoptosis. The microarray analysis showed the up-regulated expression of genes involved in the p38 signaling pathway in CFTR plasmid-transfected KYSE 170 cells. Immunohistochemical staining revealed a relationship between the CFTR expression pattern at the invasive front and the pN category. A relationship was also observed between the weak expression of CFTR at the invasive front and a shorter postoperative survival in a prognostic analysis., Conclusions: The overexpression of CFTR in ESCC activated the p38 signaling pathway and was associated with a good patient prognosis. These results indicate the potential of CFTR as a mediator of and/or a biomarker for ESCC., (© 2021. Society of Surgical Oncology.)

The targeting of membrane proteins that are activated in cancer stem cells (CSCs) represents one of the key recent strategies in cancer therapy. The present study analyzed ion channel expression profiles and functions in pancreatic CSCs (PCSCs). Cells strongly expressing aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were isolated from the human pancreatic PK59 cell line using fluorescence‑activated cell sorting, and PCSCs were identified based on tumorsphere formation. Microarray analysis was performed to investigate the gene expression profiles in PCSCs. ALDH1A1 messenger RNA levels were higher in PCSCs compared with non‑PCSCs. PCSCs were resistant to 5‑fluorouracil and capable of redifferentiation. The results of the microarray analysis revealed that gene expression related to ion channels, including voltage‑gated potassium channels (Kv), was upregulated in PCSCs compared with non‑PCSCs. 4‑Aminopyridine (4‑AP), a potent Kv inhibitor, exhibited greater cytotoxicity in PCSCs compared with non‑PCSCs. In a xenograft model in nude mice, tumor volumes were significantly lower in mice inoculated with PK59 cells pre‑treated with 4‑AP compared with those in mice injected with non‑treated cells. The present results identified a role of Kv in the persistence of PCSCs and suggested that the Kv inhibitor 4‑AP may have potential as a therapeutic agent for pancreatic carcinoma.

Background: The deep inspiration breath hold (DIBH) technique is effective for heart dose reduction in patients with left-sided breast cancer. In deep breathing, some women breathe in thoracic respiration; and others, in abdominal respiration. This study evaluated differences in dose reduction in organs at risk (OAR) and reproducibilities of the target and OAR between thoracic DIBH (T-DIBH) and abdominal DIBH (A-DIBH)., Methods: Fourteen patients with left-sided breast cancer who had planned to receive whole-breast irradiation were included. Computed tomography (CT) was performed in free breathing (FB), T-DIBH, and A-DIBH, and the dosimetric indexes of the target and OAR for three treatment plans were compared. In T-DIBH and A-DIBH, two series CTs were taken in each breathing method and the displacements of the target and heart were calculated., Results: The averaged mean heart doses (MHDs) were 1.5 Gy and 1.6 Gy in T-DIBH and A-DIBH, respectively, significantly lower than 2.7 Gy in FB (p < 0.001 for both breathing methods). Between T-DIBH and A-DIBH, no significant difference in MHD was found (p = 0.95); however, the percentage increase in lung volume positively moderately correlated with the reduction in MHD (R = 0.68). The three-dimensional target displacements were 2.3 mm in T-DIBH and 2.0 mm in A-DIBH (p = 0.64). The three-dimensional heart displacements were 1.7 mm in T-DIBH and 1.8 mm in A-DIBH (p = 0.85)., Conclusion: The present study demonstrates that the MHD and reproducibility did not differ between T-DIBH and A-DIBH. However, the superior breathing method for increasing lung volume should be determined for each patient., (© 2021. The Japanese Breast Cancer Society.)

Background: The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for gastric cancer. The present study investigated ion channel expression profiles in gastric CSCs (GCSCs)., Methods: Cells strongly expressing CD44 were separated from MKN74 cells, a human gastric cancer cell line, by fluorescence-activated cell sorting (FACS), and GCSCs were identified based on tumorsphere formation. Gene expression profiles in GCSCs were examined by a microarray analysis., Results: Among MKN74 cells, CD44 messenger RNA levels were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to cisplatin. The microarray analysis revealed that the expression of several genes related to voltage-gated Ca 2+ channels (VGCCs), including CACNA2D1 and CACNB4, was upregulated. The cytotoxicities of the CACNA2D1 inhibitor amlodipine and the CACNB4 inhibitor verapamil were greater at lower concentrations in CSCs than in non-CSCs, and markedly reduced tumorsphere numbers. Tumor volumes were significantly smaller in a xenograft nude mouse model treated with amlodipine or verapamil in combination with cisplatin than in that treated with cisplatin alone., Conclusions: The present results indicate that VGCCs play a role in maintaining CSCs, and demonstrated the potential of their specific inhibitors, amlodipine and verapamil, as targeted therapeutic agents against gastric cancer., (© 2021. Society of Surgical Oncology.)

Background: Leucin-rich repeat containing protein A (LRRC8A), a component of the volume-regulated anion channel (VRAC), is activated by cell swelling and mediates regulatory volume decrease. We previously reported the expression of and important roles for several ion transporters in various gastrointestinal cancers, which have potential as novel targets for cancer treatment; however, the significance of LRRC8A in gastric cancer (GC) remains unclear., Materials and Methods: Knockdown experiments were performed by transfecting human GC cell lines with LRRC8A siRNA. Gene expression was then assessed using microarray analysis. Samples from 132 patients with GC were subjected to immunohistochemistry (IHC) for LRRC8A, and its relationships with clinicopathological factors and prognosis were examined., Results: The knockdown of LRRC8A suppressed the proliferation and movement of cells and enhanced apoptosis. The results of the microarray analysis showed the up- or down-regulated expression of genes related to the p53 signaling pathway (JNK, p53, p21, Bcl-2, and FAS) in LRRC8A-knockdown cells. IHC revealed a correlation between the expression of LRRC8A and the pT status (p = 0.015), and multivariate analysis identified the strong expression of LRRC8A as an independent prognostic factor for 5-year survival in GC patients (p = 0.0231)., Conclusions: The present results indicate that LRRC8A functions as a mediator of and/or biomarker for GC., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Chloride channel 2 (CLCN2) was recently shown to affect tumor behavior. The present study examined the functions of CLCN2 in the regulation of genes that play a role in tumor progression, as well as its clinicopathological significance in esophageal squamous cell carcinoma (ESCC)., Methods: Knockdown experiments were conducted using CLCN2-small-interfering RNA, and changes in proliferation, survival, and cellular movement in human ESCC cell lines were investigated. A microarray analysis of gene expression profiles in CLCN2-depleted ESCC cells was conducted. Fifty-four primary ESCC samples were examined by immunohistochemistry (IHC)., Results: The strong expression of CLCN2 was detected in TE5 and KYSE70 cells. Downregulated expression of CLCN2 enhanced proliferation and decreased apoptosis, whereas its upregulation inhibited proliferation and increased apoptosis. The effects of lubiprostone, a CLCN2 activator, were also investigated. In lubiprostone-treated cells, proliferation was inhibited and apoptosis was increased. The microarray analysis demonstrated that interferon (IFN) signaling-related genes were downregulated in CLCN2-depleted cells. IHC showed the presence of CLCN2 in the cytoplasm and cell membranes of ESCC cells. The prognostic analysis revealed a relationship between weak CLCN2 expression and shorter overall survival., Conclusions: The present results indicate that tumor progression is regulated by CLCN2 through its effects on IFN signaling. Furthermore, weak CLCN2 expression was associated with poorer outcomes in ESCC patients. The present study will contribute to a clearer understanding of the role of CLCN2 as a mediator of ESCC, as well as its use as a biomarker for this cancer., (© 2021. Society of Surgical Oncology.)

Background: Since inflammation and the immune system contribute to the development and progression of malignancies, parameters that reflect a host's immune-inflammatory status may be useful prognostic indicators of gastric cancer (GC). The present study examined the clinical significance of a preoperative systemic immune-inflammation index (SII) for predicting postoperative survival outcomes in GC., Methods: A total of 447 patients who underwent curative gastrectomy for GC were included in the present study. SII was calculated as platelet count × neutrophil count/lymphocyte count. The prognostic impact of preoperative SII was examined using univariate and multivariate analyses., Results: Preoperative SII ranged between 105 and 4455 (median 474), and the optimal cutoff value for predicting overall survival (OS) was 395 based on a receiver operating characteristic curve. The 5-year OS rate of the SII ≥ 395 group was 80.0%, which was significantly worse than that (92.7%) of the SII < 395 group (p < 0.001). The multivariate analysis identified SII ≥ 395 (hazard ratio [HR] 2.95; 95% confidence interval [CI] 1.49-6.39; p = 0.001), heart disease (HR 2.14, 95% CI 1.07-4.07), C-reactive protein ≥ 0.5 (HR 2.45, 95% CI 1.15-4.94), pT4 (HR 4.46, 95% CI 2.44-8.14), and pN+ (HR 4.02, 95% CI 2.10-7.93) as independent predictors of worse OS. Peritoneal recurrence was more frequent in the high SII group than in the low SII group (p = 0.028)., Conclusion: Preoperative SII may be a useful predictor of postoperative survival outcomes in GC. The meticulous surveillance of GC relapse, particularly peritoneal dissemination, is necessary for patients with SII ≥ 395 even after curative gastrectomy.

A recent JCOG1104, OPAS-1 trial revealed the significance of S-1 duration. However, the significance of cumulative total S-1 dose (CTSD) remains unclear. In this study, we designed to evaluate the prognostic effect of CTSD on adjuvant chemotherapy after curative gastrectomy. We retrospectively analyzed 77 consecutive pStage II and III gastric cancer (GC) patients, who underwent curative gastrectomy followed by adjuvant S-1 chemotherapy from 2008 through 2014. CTSD of 20000 mg was the upper-limit of cut-off value to stratify the prognosis (5-year relapse free survival (RFS); CTSD < 20000 mg vs. CTSD ≥ 20000 mg: 51.9% vs. 85.1%, P = 0.004). Compared patients with CTSD more than 20000 mg, those with CTSD less than 20000 mg had a significantly higher rate of preoperative anemia ( P = 0.041), low nutrition ( P = 0.008) and open gastrectomy ( P = 0.012). Multivariate Cox's proportional hazards model for RFS proved that CTSD less than 20000 mg was an independent prognostic factor [ P = 0.031, HR 3.32 (95% CI: 1.11-11.1)] although S-1 intensity and duration were not independent prognostic factors. The cumulative total S-1 dose more than 20000 mg might contribute to better prognosis., Competing Interests: None., (AJCR Copyright © 2021.)

Background/aim: This study aimed to investigate the impact of the inferior mesenteric artery (IMA) lymph node metastasis [IMALN (+)] on prognosis in left-sided colorectal cancer (LCRC)., Patients and Methods: A total of 285 patients with stage III LCRC and 118 patients with stage IV LCRC who underwent resection of primary tumor between 2005 and 2016 were included., Results: IMALN (+) patients (n=10) had worse overall survival (OS) than patients without IMA lymph node metastasis [IMALN (-); n=275] in stage III LCRC (p=0.007). Multivariate analysis revealed that IMALN (+) was a prognostic factor in stage III LCRC (OS, HR=3.09, p=0.043). Conversely, there was no difference between the OS of IMALN (+) and stage IV LCRC with distant lymph node metastasis only [stage IV LCRC (LYM); n=21; p=0.434]., Conclusion: The prognosis of IMALN (+) was worse than that of IMALN (-); it was similar to that of stage IV LCRC (LYM)., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)