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The prognosis for patients with cancers known for a highly activated stromal reaction, including diffuse‐type (scirrhous) gastric cancer, consensus molecular subtype 4 (CMS4) colorectal cancer, and pancreatic ductal adenocarcinoma, is extremely poor. To explore the resistance of conventional therapy for those refractory cancers, detailed classification and investigation of the different subsets of cancer‐associated fibroblasts (CAFs) involved are needed. Recent studies with a single‐cell transcriptomics strategy (single‐cell RNA‐seq) have demonstrated that CAF subpopulations contain different origins and marker proteins with the capacity to either promote or suppress cancer progression. Through multiple signaling pathways, CAFs can promote tumor growth, metastasis, and angiogenesis with extracellular matrix (ECM) remodeling; they can also interact with tumor‐infiltrating immune cells and modulate the antitumor immunological state in the tumor microenvironment (TME). Here, we review the recent literature on the various subpopulations of CAFs to improve our understanding of the cell‐cell interactions in the TME and highlight future avenues for CAF‐targeted therapy.

Our group revealed that the combination of intra-operative stamp cytology and peritoneal lavage cytology (CY) improved the identification of individuals with high risk of peritoneal metastasis. In this exploratory Phase II study, we aimed to evaluate the effect on relapse-free survival (RFS) of extensive intraoperative peritoneal lavage (EIPL) for gastric cancer with positive peritoneal cytology (CY1) and/or stamp cytology positive (stamp+). This study was a single arm, multi-institutional, exploratory phase 2 trial to assess the effects of EIPL after open gastrectomy for gastric cancer with CY1 and/ or stamp+. The primary endpoint was RFS. Secondary endpoints were overall survival (OS), postoperative recurrence site and incidence of postoperative adverse events. Between 2017 and 2021, 13 patients from 2 institutions were enrolled in this study. Because of the recent decline in open abdominal surgery, the number of cases did not increase and the trial was closed due to lack of applicants at 13 cases. Median 3-year RFS was 14.5 months (95% CI 5.4-NA), median 3-year OS was not reached (95% CI 14.5-NA) and median3-year peritoneal RFS was 16.0 months (95% CI 5.4-NA). Median 3-year peritoneal RFS rate was 83% in CY0 and stamp+ cases (n=6), and 0% in CY1 and stamp+/- cases (n=7). (Log-rank p=0.015). Because of the slow accrual pace and early stop of the trial, we were not able to evaluate the prespecified endpoints thoroughly. However, EIPL might be effective to prevent perineal recurrence, especially in CY0 and stamp+ case.

Complete mesocolic excision (CME) with central vascular ligation (CVL) in laparoscopic surgery for right-sided colon cancer (RSCC) requires a precise understanding of the vascular anatomy. The efficacy of intraoperative ultrasound (IUS) in the identification of blood vessels for RSCC surgery was not evaluated. The aim of this study was to compare the intraoperative and short-term outcomes of CME with CVL with or without IUS by laparoscopic surgery for RSCC. We performed IUS on 26 patients of RSCC and compared with a total of 124 patients who underwent the surgery for RSCC at our institution. Propensity score matching (PSM) was performed to reduce the confounding effects to imbalances in the use of IUS. The IUS identified the main feeding artery and the accompanying vein in all 26 cases. After PSM, the amount of intraoperative blood loss in the IUS group was significantly lower than that in the conventional group (5 ml vs. 30 ml, p = 0.035) and no significant difference of the postoperative complications was observed. The IUS reduced the risk of bleeding in the surgery for RSCC. The IUS is a safe and feasible technique that help the surgeons for anatomical understandings under real-time condition in the laparoscopic surgery of RSCC.

We reported that chemokine C-X-C motif receptor 2 (CXCR2) signaling appears to play an important role in the pathogenic signaling of gastric cancer (GC), and although CXCR2 may have a role in other solid cancers, the significance of CXCR2 in cholangiocarcinoma (CCA) has not been evaluated. Herein, we determined the clinicopathologic significance of CXCL1-CXCR2 signaling in CCA. Two human CCA cell lines, OCUG-1 and HuCCT1, were used. CXCR2 expression was examined by western blotting. We investigated the effects of CXCL1 on the proliferation (by MTT assay) and migration activity (by a wound-healing assay) of each cell line. Our immunohistochemical study of the cases of 178 CCA patients examined the expression levels of CXCR2 and CXCL1, and we analyzed the relationship between these expression levels and the patients' clinicopathologic features. CXCR2 was expressed on both CCA cell lines. CXCL1 significantly inhibited both the proliferative activity and migratory activity of both cell lines. CXCL1 and CXCR2 were immunohistochemically expressed in 73% and 18% of the CCA cases, respectively. The CXCL1-positive group was significantly associated with negative lymph node metastasis (p = 0.043). The CXCR2-positive group showed significantly better survival (p = 0.042, Kaplan-Meier). A multivariate logistic regression analysis revealed that CXCR2 expression (p = 0.031) and lymph node metastasis (p = 0.004) were significantly correlated with the CCA patients' overall survival. CXCR2 signaling might exert a tumor-suppressive effect on CCA cells. CXCR2 might be a useful independent prognostic marker for CCA patients after surgical resection.

Gastric cancer (GC) patients frequently develop peritoneal metastasis. Recently, it has been reported that peritoneal mesothelial cells (PMCs) activated by GC cells acquire a migratory capacity and promote GC cell invasion. The invasiveness of PMCs reportedly depends on the activity of Tks5, an adaptor protein required for invadopodia formation. However, the relationship between clinicopathologic features and Tks5 expression in PMCs has been poorly documented. In this study, we evaluated the clinicopathologic significance of the Tks5 expression of PMCs in GC patients. A total of 110 GC patients who underwent gastrectomy were enrolled in this study. Tks5 expressions in PMCs from the greater omentum, lesser omentum and retroperitoneum were evaluated by immunohistochemistry. We analyzed the correlation between Tks5 expressions in PMCs and the patients' clinicopathologic features. Tks5 expression was found in 71 (64.5%) of the 110 patients, while 39 (35.5%) were Tks5-negative. Tks5 positivity was significantly (p = 0.038) associated with a greater tumor depth (i.e., T3/4 compared with T1/T2). Peritoneal recurrence was found in 12 of 98 cases within 3 years of surgery. The 3-year peritoneal recurrence-free survival (PRFS) rate in Tks5-positive cases was significantly poorer than that in Tks5-negative cases (80.1% vs 97.4%, p = 0.024). Multivariate analysis revealed that Tks5 positivity and lymph node metastasis were independent factors for PRFS. Tks5 is frequently expressed in PMCs in advanced-stage gastric cancer. Tks5 might be a useful predictor for peritoneal recurrence in GC patients.

Background This study aimed to evaluate the clinical utility and prognostic significance of sarcopenia classification based on the psoas major muscle volume index (PVI) in elderly patients with rectal cancer. Methods We retrospectively analyzed 428 patients aged ≥ 65 years who underwent laparoscopic or robot‐assisted radical rectal cancer resection between 2014 and 2018. PVI was calculated by dividing the semi‐automatically measured psoas major muscle volume on three‐dimensional computed tomography (CT) by the cube of height (m3). Sex‐specific PVI cutoff values for 5‐year overall survival (OS) were determined using time‐dependent receiver operating characteristic analysis. Associations between PVI, nutritional and inflammatory markers, conventional sarcopenia indices, and long‐term outcomes were investigated. Results PVI cut‐off values were ≤ 58.9 cm3/m3 for males and ≤ 39.9 cm3/m3 for females. Patients with low PVI had significantly worse nutritional and inflammatory profiles. The 5‐year OS (86.6% vs. 94.6%, p = 0.001), cancer‐specific survival (93.5% vs. 97.4%, p = 0.003), and relapse‐free survival (76.2% vs. 85.4%, p = 0.021) were significantly lower in the low PVI group than in the normal‐high PVI group. Multivariate analysis identified low PVI (hazard ratio: 2.55; p = 0.012) and Prognostic Nutritional Index < 40 as independent predictors of poor OS. Conclusion PVI‐based sarcopenia classification reflects nutritional and inflammatory status and enables effective prognostic stratification in elderly patients with rectal cancer. It may serve as a simple and objective tool for preoperative risk assessment, offering improved prognostic stratification compared with conventional CT‐based indices. This study investigates the prognostic utility of a novel volumetric indicator—psoas volume index (PVI)—for assessing sarcopenia in elderly rectal cancer patients. Sarcopenia classified by our proposed PVI cut‐off values was associated with poor nutritional and inflammatory status, and patients with low PVI showed significantly worse long‐term outcomes. Compared with conventional indices, PVI more sensitively captured systemic vulnerability and independently predicted overall survival.

Background/Aim The effectiveness of a transanal drainage tube (TAT) for the prevention of anastomotic leakage after double stapling technique (DST) anastomosis in colorectal cancer has been reported. Previously, TATs had been placed and connected to drainage bags. It was considered that a higher decompression effect could be expected by inserting an open-type TAT, without connection to a drainage bag. In this study, the relation between anastomotic leakage and the application of this type of TAT in left-sided colorectal cancer surgery was investigated, using propensity score matching (PSM). Materials and methods From January 2016 to July 2023, 233 consecutive patients underwent radical surgery for sigmoid colon and rectal cancers and reconstruction using DST at Osaka Metropolitan University Hospital. Patients were divided into two groups: those who had a closed TAT inserted (CLOSED group), and those who had an open TAT inserted (OPEN group). Results Overall, open TATs were inserted in 43 patients, and closed TATs were inserted in 190 patients. PSM was performed between the OPEN and CLOSED groups on the basis of the following 13 factors: age, sex, BMI, diabetes mellitus (DM), smoking history, modified Glasgow prognostic score (mGPS), ASA-PS, location of distal tumor edge, operative procedure, surgical approach, operative time, intraoperative blood loss, and pathological stage. The multivariate analysis of significant factors identified a BMI of 25 or more, a location of distal edge on middle to lower rectum, and a closed TAT, as independent risk factors for anastomotic leakage (HR: 8.72; p  = 0.038, HR: 10.06; p  = 0.034 and HR: 17.43; p  = 0.033). Conclusion An open TAT may be effective in preventing anastomotic leakage in left-sided colorectal cancer surgery.

Background Cancer‐associated fibroblasts (CAFs) have been reported to be tumor‐specific cells. We have recently reported that thrombospondin‐4 (THBS4) expression is exclusive to CAFs. This study aimed to clarify whether the identification of circulating CAFs (cir‐CAFs) by THBS4 is detectable in the blood of gastric cancer (GC) patients, and whether cir‐CAFs are useful for the screening test of GC. Materials and Methods CAFs and normal fibroblasts (NFs) were respectively established from 17 GC specimens. A total of 24 healthy volunteers and 77 GC patients were enrolled. Flow cytometric analysis was performed using anti‐THBS4 antibody. The sensitivity and specificity of THBS4‐positive cir‐CAFs for detection of GC were calculated. Results THBS4+ cells showed ovoid‐like cells and expressed THBS4. THBS4+ expression was significantly (p = 0.014) higher on CAFs than NFs. GC patients had a significantly (p = 0.0323) higher average number of THBS4‐positive cir‐CAFs than healthy volunteers: 212 cells versus 6.4 cells. The ROC curve indicated that 27 THBS4‐positive cells per 10,000 blood cells was an adequate cutoff for GC diagnosis. The sensitivity and specificity of cir‐CAFs were 76.6% and 100%, respectively. In contrast, the sensitivities of CEA and CA19‐9 were only 22.1% and 9.1%, respectively. The sensitivity of cir‐CAFs was high even for Stage I GC, at 73.5%, while the sensitivity of CEA and CA19‐9 was low at 14.7% and 0%, respectively. Conclusion THBS4‐positive cir‐CAFs are detectable in the blood of GC patients. The cir‐CAFs might be a useful tumor marker in a GC screening test, especially for early‐stage GC.

Gastric cancer (GC) with microsatellite instability (MSI) has been reported to be sensitive to immunotherapy, however some of GC cases with MSI remain resistant to immunotherapy. Cancer cell lines showing MSI might be useful for the analysis of mechanisms of immunotherapy, while only a few GC cell lines with MSI are available so far. In this study, we established a unique GC cell line with MSI, OCUM‐13, from a primary GC with abundant tumor‐infiltrating lymphocytes. MSI assay indicated that OCUM‐13 cells as well as the primary tumor showed a band shift in more than 3 of 5 microsatellite loci, suggesting that OCUM‐13 did have high MSI. The subcutaneous inoculation of OCUM‐13 cells into mice performed tumor formation. Insulin‐like growth factor 1 receptor inhibitor decreased the growth of OCUM‐13 cells. The newly established cell line with MSI, OCUM‐13, might be useful for the analysis of cancer therapy for GC with MSI.

Background Recently, the concepts of progression due to pre-existing lesions (PPL) and progression due to new metastasis (PNM) have been proposed to differentiate the progression types of treatment-resistant cancers. Previously, the differences between these two progression types did not affect the determination of treatment strategies since both PPL and PNM are classified as progressive disease based on the response evaluation criteria in solid tumors (RECIST) diagnostic criteria. On the other hand, tumor infiltrating lymphocytes (TILs) are effective when used as indicators for monitoring the immune tumor microenvironment (iTME) in the cancer host, and TILs play an important role as biomarkers in predicting prognosis and therapeutic effects. This study focused on the progression types of cancer in patients undergoing eribulin chemotherapy. In addition, the iTME in individuals with PPL and PNM was evaluated using TILs as a marker. Methods Of the 52 patients with locally advanced or metastatic breast cancer who underwent chemotherapy with eribulin, 40 remained in the study, and 12 patients were dropout cases. The antitumor effect was evaluated based on the RECIST criteria using version 1.1. TILs were defined as the infiltrating lymphocytes within tumor stroma and were expressed in proportion to the field investigated. In PPL cases, the high-TIL group was considered as type I and the low-TIL group was classified as type II. In PNM cases, the high-TIL group was considered as type III and the low-TIL group was classified as type IV. Results In 19 cases, individuals with type I progression had significantly longer progression free survival and overall survival (OS) compared to those with type III progression (p = 0.040, p < 0.001, log-rank). Individuals with type I progression had significantly prolonged survival post progression compared to those with type II progression (p = 0.048, log-rank). A multivariate analysis that validate the effect of OS showed that these were independent factors of good prognosis (p = 0.003; hazard ratio [HR] = 0.065) (p = 0.006; HR = 0.105). Conclusions The effects of eribulin chemotherapy suggested that patients with progressive-type breast cancer that proliferates in a good iTME may have a good prognosis.