Explore the vast range of titles available.

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.

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.

The immune checkpoint inhibitor pembrolizumab is effective for the treatment of recurrent cancer with a tumor mutation burden-high (TMB-high) status. Globally, the cutoff value of TMB-high has been set as ≥10 mut/Mb, but the optimal cutoff value of TMB for treating breast cancer (BC) with pembrolizumab has not been identified. We re-evaluated the optimal cutoff value of TMB-high status in BC by using the clinical dataset from Japan’s Center for Cancer Genomics and Advanced Therapeutics (C-CAT) profiling database. We extracted 6403 BC cases that had been enrolled from the C-CAT database of 101,231 cases of various types of cancers. Of all 6403 BC cases, 683 (10.7%) showed TMB ≥ 10 mut/Mb as TMB-high. Of the 683 TMB-high cases, 175 were administered pembrolizumab. The receiver operating characteristic curve indicated that for treating BC with pembrolizumab, a TMB ≥ 18.5 mut/Mb was an adequate cutoff regarding sensitivity and specificity. The BC patients’ overall response rate was 21.4%. The disease control rate was 42.9%. The probability of time-to-treatment failure was significantly better in the BC cases with TMB ≥ 18.5 mut/Mb versus those with TMB < 18.5 mut/Mb (p = 0.007). These findings suggested that the optimal cutoff value of the TMB for treating breast cancer with pembrolizumab might be ≥18.5 mut/Mb.

Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide, with most cases diagnosed at advanced stages. Traditional biomarkers provide only partial insights into GC’s heterogeneity. Recent advances in machine learning (ML)-driven multiomics technologies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, pathomics, and radiomics, have facilitated a deeper understanding of GC by integrating molecular and imaging data. In this review, we summarize the current landscape of ML-based multiomics integration for GC, highlighting its role in precision diagnosis, prognosis prediction, and biomarker discovery for achieving personalized medicine.

Background/Objectives: The neurotrophic tropomyosin receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 encode tyrosine kinase receptors, and their fusion genes are known as the oncogenic driver genes for cancer. This study aimed to compare the diagnostic ability of NTRK fusion among five types of multi-cancer genome profiling tests (multi-CGP tests) and determine a useful multi-CGP test for NTRK fusion, recorded in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. This study aimed to compare the diagnostic results for NTRK fusions among the five different CGP tests. Methods: A total of 88,688 tumor cases were enrolled in the C-CAT profiling database from 2019 to 2024. The detection frequency of NTRK fusion genes was compared to the results for five multi-CGP tests: NCC Oncopanel, FoundationOne CDx (F1), FoundationOne Liquid (F1L), GenMineTOP (GMT), and Guardant360. Results: NTRK fusion genes were detected in 175 (0.20%) of the 88,688 total cases. GMT, which is equipped with RNA sequencing function, frequently detected NTRK fusion genes (20 of 2926 cases; 0.68%) in comparison with the other four multi-CGP tests that do not have RNA sequencing analysis. GMT showed significantly (p < 0.05) higher diagnostic ability for NTRK fusions compared with the other four multi-CGP tests. Especially, NTRK2 fusion was significantly (p < 0.001) more highly determined by GMT than it was by the other four multi-CGP tests. The detection rates for FGFR1 and FGFR3 were significantly higher in GMT than in other multi-CGP tests. In contrast, the detection rates of the ALK and RET fusion genes were significantly higher in F1L. Conclusions: GMT, which is equipped with RNA sequencing analysis, might show a useful diagnostic ability for NTRK fusions, especially for NTRK2 fusion genes.

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: Lymph node (LN) metastasis is one of the most frequent metastatic patterns in patients with gastric cancer (GC); however, few genes predictive of LN status in GC have been identified. Aims: We aimed to identify candidate genes associated with LN metastasis by analyzing the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database and performing immunohistochemical analysis of GC cases at our hospital. Patients and Methods: A total of 2028 GCs from the C-CAT database were enrolled to identify genetic alterations. A total of 360 GC patients who underwent gastrectomy at our hospital were enrolled to examine the clinical significance of CCNE1 expression via an immunohistochemical study. Results: A total of 977 cases out of 2028 GC patients showed LN metastasis. Genetic alterations of ERBB2, CCNE1, MYC, ZNF217, and GNAS were frequent in the LN metastasis group. CCNE1-positive expression was found in 108 (30.0%) of the 360 GC samples. LN metastasis was significantly (p = 0.01) more frequent in CCNE1-positive patients. In addition, the CCNE1-positive group had a significantly (p < 0.001) poorer prognosis than the CCNE1-negative group, which was especially evident for GC patients at stage I. CCNE1 positivity was significantly (p < 0.001) correlated with postoperative recurrence. Conclusions: CCNE1 gene amplification is associated with LN metastasis of GC.

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 Tumor heterogeneity has frequently been observed in gastric cancer (GC), but the correlation between patients’ clinico-pathologic features and the tumoral heterogeneity of GC-associated molecules is unclear. We investigated the correlation between lymph node metastasis and the intra-tumoral heterogeneity of driver molecules in GC. Materials and methods We retrospectively analyzed the cases of 504 patients who underwent a gastrectomy at the Department of Gastroenterological Surgery, Osaka Metropolitan University and 389 cases drawn from The Cancer Genome Atlas (TCGA) data. We performed a clustering analysis based on eight cancer-associated molecules including HER2, c-Met, and p-Smad2 using the protein expression revealed by our immunohistochemical study of the patients’ and TCGA cases. We determined the correlations between HER2 expression and the other molecules based on the degree of lymph node metastasis. Results Immunohistochemical staining data showed that a 43 of the 504 patients with GC (8.5%) were HER2-positive. In the HER2-positive cases, the expressions of c-Met and p-Smad2 were increased in accord with the lymph-node metastatic level. The overall survival of the HER2-positive GC patients with both p-Smad2 and c-Met expression was significantly ( p  = 0.030) poorer than that of the patients with p-Smad2-negative and/or c-Met-negative expression. The results of the TCGA data analysis revealed that 58 of the 389 GC cases (14.9%) were ERBB2 -positive. MET expression was more frequent in the N1 metastasis group than the N0 group. In the high lymph-node metastasis (N2 and N3) group, SMAD2 expression was more frequent, as was ERBB2 and MET expression. Conclusion p-Smad2 and c-Met signaling might play important roles in lymph node metastasis in HER2-positive GC.