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Although gastric neuroendocrine tumors (NETs) are uncommon compared with gastric carcinomas, the incidence of NETs has been recently increasing. Gastric NETs are classified into three subgroups, and among these, gastrin-independent sporadic type 3 gastric NETs have a poor prognosis because of frequent lymph node or distant metastasis. We experienced a case of an early-stage type 3 gastric NET associated with lymphovascular and submucosal invasion. In a 54 year-old woman, esophagogastroduodenoscopy performed during a health screening identified an elevated lesion of the upper body of the stomach. The results of immunohistochemical analyses of endoscopic biopsy specimens obtained from the lesion were positive for chromogranin A and synaptophysin, indicating an NET. Because the patient's serum gastrin level was normal and she had no predisposing conditions for NET development, the tumor was diagnosed as a type 3 gastric NET. The patient underwent local resection of the tumor and regional lymph node dissection. The resected specimen indicated a diagnosis of type 3 gastric NET with invasion into the submucosa and lymphatic duct. This is an extremely rare case of an early-stage type 3 gastric NET. Our discussion provides insight into the pathogenesis and development of these tumors and the appropriate therapeutic strategy., (© 2024. Japanese Society of Gastroenterology.)

Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody-drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours., (© 2024. Springer Nature Limited.)

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Although heterotopic pancreas usually occurs in the stomach and rarely presents as a submucosal tumor, an accurate preoperative diagnosis is often difficult because of the variety of clinical symptoms and findings depending on the size and location of the lesion. We experienced a case of gastric type III heterotopic pancreas presenting as a gastric adenomyoma in the antrum of the stomach. A 62-year-old woman visited a local hospital for epigastric discomfort. An esophagogastroduodenoscopy study indicated a submucosal tumor in the greater curvature of the gastric antrum. The patient underwent surgical resection of the tumor because it was enlarged. The histological sections of the resected specimen showed that the tumor was composed of ductular structures lined by tall columnar epithelia and a prominent smooth muscle stroma with no atypical cells. The tumor was compatible with Heinrich's type III heterotopic pancreas, which presented as an adenomyoma of the stomach. These findings provide useful histological features and some insight into a better understanding of the embryonic origin and development of adenomyoma and heterotopic pancreas in the antrum of the stomach., (© 2023. Japanese Society of Gastroenterology.)

Background: Trifluridine/tipiracil plus VEGF inhibition with ramucirumab (RAM) for advanced gastric cancer (AGC) demonstrated clinical activity with an acceptable toxicity profile in previous phase II trial. However, little is known about its efficacy and safety in clinical practice in comparison with trifluridine/tipiracil monotherapy., Methods: We retrospectively investigated efficacy and safety of trifluridine/tipiracil plus RAM and trifluridine/tipiracil monotherapy as third or later line treatment for AGC patients., Results: Forty-one patients receiving trifluridine/tipiracil plus RAM and 60 patients receiving trifluridine/tipiracil monotherapy were analyzed. The objective response rate (ORR) and the disease control rate (DCR) were 13.5% and 64.9% in the trifluridine/tipiracil plus RAM group, and 3.8% and 42.3% in the trifluridine/tipiracil monotherapy group, respectively (ORR; P = 0.122, DCR; P = 0.052). The median progression-free survival (PFS) and the median overall survival (OS) were 3.0 months and 7.2 months in the trifluridine/tipiracil plus RAM group, and 1.8 months and 3.8 months in the trifluridine/tipiracil monotherapy group, respectively (HR for PFS = 0.66; P = 0.059, HR for OS = 0.50; P = 0.007). Multivariate analysis showed significantly longer PFS (HR = 0.52; P = 0.011) and OS (HR = 0.51; P = 0.031) in the trifluridine/tipiracil plus RAM group compared to the trifluridine/tipiracil monotherapy group. No unexpected adverse events were observed in both groups., Conclusions: Trifluridine/tipiracil plus RAM might show favorable anti-tumor activity with an acceptable toxicity profile in comparison with trifluridine/tipiracil monotherapy, suggesting one treatment option for AGC patients in salvage line. The combination needs further evaluation in ongoing randomized trials., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Although nivolumab has a high efficacy, reliable biomarkers are needed to predict the efficacy. We evaluated the nivolumab efficacy according to the TP53 mutation in advanced gastric cancer patients enrolled in the GI-SCREEN project., Methods: Sequence data of tumour specimens and clinicopathological information of 913 patients with advanced gastric cancer who were enrolled between April 2015 and March 2017 were obtained from the GI-SCREEN database. The follow-up information of 266 patients treated with nivolumab was also provided., Results: Among 266 patients treated with nivolumab, the objective response rate (ORR) of TP53 wild type (wt) patients (24.6%) was higher than that of TP53 mutant patients (14.8%). Among TP53 mutant patients, the ORR of the frameshift type tended to be higher than the transition and transversion type (23.1%, 13.6%, and 13.0%, respectively). The median progression-free survival (PFS) was statistically longer in TP53 wt patients than in mutant patients (3.3 vs 2.1 months, HR 1.4, 95% CI 1.1-1.9). Among TP53 mutant patients, PFS was statistically longer in the frameshift type than in the transversion type., Conclusion: Nivolumab showed better efficacy in TP53 wt patients than in mutant patients. Among TP53 mutant patients, the frameshift type may have efficacy from nivolumab treatment., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The lipid scavenger receptor cluster of differentiation 36 (CD36) has been shown to have a pro-metastatic function in several cancers. Adipose tissue, a favorable site for peritoneal metastasis (PM) from gastric cancer (GC), promotes this process by providing free fatty acids (FFAs); however, the role of CD36 in PM progression from GC remains to be elucidated., Materials and Methods: We evaluated CD36 expression in the GC cells under various conditions. CD36 overexpressing (CD36OE) MKN45 cells were prepared and their migration and invasive properties were assessed. A PM mouse model was used to investigate the biological effects of palmitic acid (PA) and CD36. Furthermore, we examined the clinical role of CD36 expression in 82 human PM samples by immunohistochemical staining., Results: Hypoxia markedly increased CD36 expression in GC cells. In normoxia, only CD36OE MKN45 cells treated with PA showed an increase in migration and invasion abilities. An increased expression of active Rac1 and Cdc42 was observed, which decreased following etomoxir treatment. Conversely, hypoxia increased those capacities of both vector and CD36OE MKN45 cells. In a mouse model transplanted with CD36OE MKN45 cells, more peritoneal tumors were observed in the high-fat diet group than those in the normal diet group. In clinical samples, 80% of PM lesions expressed CD36, consistent with hypoxic regions, indicating a significant association with prognosis., Conclusion: Our findings indicate that a hypoxia in the peritoneal cavity induces CD36 expression in GC cells, which contributes to PM through the uptake of FFAs., (© 2022. The Author(s).)

Background: We conducted comprehensive clinical and molecular characterization of claudin 18.2 expression (CLDN18.2) in advanced gastric or gastroesophageal junction cancer (GC/GEJC)., Patients and Methods: Patients with advanced GC/GEJC who received systemic chemotherapy from October 2015 to December 2019 with available tumor specimens were analyzed. We evaluated clinicopathological features of CLDN18.2 expression with four molecular subtypes: mismatch repair deficient, Epstein-Barr virus-positive, human epidermal growth factor receptor 2-positive, and others. In addition, programmed death-ligand 1 (PD-L1) combined positive score (CPS), genomic alterations, and the expression of immune cell markers were assessed. Clinical outcomes of standard first- or second-line chemotherapy and subsequent anti-programmed cell death protein 1 (anti-PD-1) therapy were also investigated according to CLDN18.2 expression., Results: Among 408 patients, CLDN18.2-positive (moderate-to-strong expression in ≥75%) was identified in 98 patients (24.0%) with almost equal distribution in the four molecular subtypes or CPS subgroups. CLDN18.2-positive was associated with Borrmann type 4, KRAS amplification, low CD16, and high CD68 expression. Overall survival with first-line chemotherapy was not significantly different between CLDN18.2-positive and -negative groups [median 18.4 versus 20.1 months; hazard ratio 1.26 (95% confidence interval 0.89-1.78); P = 0.191] regardless of stratification by PD-L1 CPS ≥5. Progression-free survival and objective response rates of first- and second-line chemotherapy, and anti-PD-1 therapy also showed no significant differences according to CLDN18.2 status., Conclusions: CLDN18.2 expression in advanced GC/GEJC was associated with some clinical and molecular features but had no impact on treatment outcomes with chemotherapy or checkpoint inhibition. CLDN18.2-positive also had no impact on overall survival. This information could be useful to interpret the results from currently ongoing clinical trials of CLDN18.2-targeted therapies for advanced GC/GEJC and to consider a treatment strategy for CLDN18.2-positive GC/GEJC., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Gene amplification and protein overexpression of human epidermal growth factor receptor type 2 (HER2) are specific targets for HER2-targeting drugs in breast, gastric, salivary gland, and colorectal cancers. The histopathological determination of HER2 status is crucial for treatment, highlighting the importance of improving HER2 detection accuracy in clinical practice. We prepared tissue microarray (TMA) slides for use as control slides for the standardization of gastric HER2 testing. Four human gastric cancer cell lines with HER2 scores of 3+, 2+, 1+, and 0 were xenografted in NOG mice. The TMA slides were constructed using samples from three different areas in these tumors. Staining properties were determined using six clinical kits for HER2. In TMA, HER2-positive tumors with HER2 scores of 3+ and 2+ showed good staining with all diagnostic kits, and the tissue images were similar to those of clinical samples. Xenograft tumor slides could potentially be used as external controls to standardize staining conditions for a variety of kits and may improve the accuracy of HER2 detection in clinical practice., (© 2022 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Collision tumors composed of adenocarcinoma and gastrointestinal stromal tumor (GIST) of the stomach are extremely uncommon, and only a few cases have been reported in the English literature. In the present case, a 67-year-old woman visited a local hospital for vomiting and hematemesis. An esophagogastroduodenoscopy study indicated an elevated lesion with ulceration. Histology of the endoscopic biopsy specimen indicated gastric adenocarcinoma. The patient underwent laparoscopic distal gastrectomy with D2 lymph node dissection. The resected specimen showed that the primary tumor consisted of a GIST and that early-stage gastric carcinoma coexisted in the mucosa surrounding the central ulceration of the GIST. Although close contact of the adenocarcinoma and GIST was observed on the mucosal surface, no intermixing of tumor cells was observed in the primary tumor. This case is an extremely rare case of a collision tumor composed of early-stage gastric adenocarcinoma and GIST occurring in the stomach, which provides some insight into a better understanding of the pathogenesis of collision tumors., (© 2022. Japanese Society of Gastroenterology.)

Elucidation of spatial interactions between cancer and host cells is important for the development of new therapies against disseminated cancers. The aim of this study is to establish easy and useful method for elucidating spatial interactions. In this study, we developed a practical spatial analysis method using a gel-based embedding system and applied it to a murine model of cancer dissemination. After euthanization, every abdominal organ enclosed in the peritoneum was extracted en bloc. We injected agarose gel into the peritoneal cavities to preserve the spatial locations of the organs, including their metastatic niches, and then produced specimens when the gel had solidified. Preservation of the original spatial localization was confirmed by correlating magnetic resonance imaging results with the sectioned specimens. We examined the effects of spatial localization on cancer hypoxia using immunohistochemical hypoxia markers. Finally, we identified the mRNA expression of the specimens and demonstrated the applicability of spatial genetic analysis. In conclusion, we established a practical method for the in vivo investigation of spatial location-specific biological mechanisms in disseminated cancers. Our method can elucidate dissemination mechanisms, find therapeutic targets, and evaluate cancer therapeutic effects., (© 2022. The Author(s).)

A 66-year-old man was diagnosed with inoperable advanced gastric cancer with liver and peritoneal metastases. The patient underwent SOX therapy as primary chemotherapy; subsequently, liver and peritoneal metastases disappeared. However, lung metastasis was detected later, and weekly paclitaxel(PTX)combined with ramucirumab(RAM)chemotherapy was initiated; subsequently, lung metastasis and advanced gastric cancer disappeared. During remission, lung metastasis was detected again. Although weekly PTX combined with RAM chemotherapy was reinitiated, a progressive disease status was achieved. As tertiary chemotherapy, nivolumab therapy(240 mg/body, every 2 weeks)was initiated for 20 courses over 11 months. This therapy was significantly effective, which aid the patient to achieve a complete response. The patient survived and is healthy for 5 years due to chemotherapy administration alone.

Background: Although several randomized trials (RCTs) showed survival benefits of immune checkpoint inhibitor (ICI) plus first-line chemotherapy for advanced gastric or gastroesophageal cancer (AGC), these trials could enroll patients who fulfilled the strict eligibility criteria or waited for certain screening period for central assessment of PD-L1 status., Methods: We retrospectively compared characteristics and clinical outcomes of the patients with AGC who received first-line chemotherapy in control arm of RCTs with ICIs (control group) or clinical practice (practice group) at our institution from February 2016 to April 2019., Results: The control group had a better baseline Eastern Cooperative Oncology Group performance status (PS0, 81.2% vs. 51.4%, p < 0.001) and a longer interval from first visit to first-line chemotherapy initiation (19 days vs. 9 days, p < 0.001) than the practice group. Median overall survival (OS) was 20.3 months in control group and 15.7 months in practice group, with a trend of longer OS in control group than that in practice group (hazard ratio, 0.71; p = 0.062). More patients in control group were treated with subsequent chemotherapy including ICIs., Conclusion: Patients with AGC in RCTs of ICIs had a better PS or a higher chance to receive subsequent chemotherapy, resulting in a better prognosis than those treated in clinical practice. This information should be considered when interpreting RCT results and applying new treatments into clinical practice., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Purpose: We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy., Patients and Methods: Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC., Results: In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors., Conclusions: Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: Subset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR- amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR- amplified GEA to date., Patients and Methods: A total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB)., Results: Sixty patients with EGFR -amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR -amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR -amplified GEA received EGFRi., Conclusion: Patients with EGFR- amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

Background: The role of tumor-stroma interactions in tumor immune microenvironment (TME) is attracting attention. We have previously reported that cancer-associated fibroblasts (CAFs) contribute to the progression of peritoneal metastasis (PM) in gastric cancer (GC), and M2 macrophages and mast cells also contribute to TME of PM. To elucidate the role of CAFs in TME, we established an immunocompetent mouse PM model with fibrosis, which reflects clinical features of TME. However, the involvement of CAFs in the immunosuppressive microenvironment remains unclear. In this study, we investigated the efficacy of Tranilast at modifying this immune tolerance by suppressing CAFs., Methods: The interaction between mouse myofibroblast cell line LmcMF and mouse GC cell line YTN16 on M2 macrophage migration was investigated, and the inhibitory effect of Tranilast was examined in vitro. Using C57BL/6J mouse PM model established using YTN16 with co-inoculation of LmcMF, TME of resected PM treated with or without Tranilast was analyzed by immunohistochemistry., Results: The addition of YTN16 cell-conditioned medium to LmcMF cells enhanced CXCL12 expression and stimulated M2 macrophage migration, whereas Tranilast inhibited the migration ability of M2 macrophages by suppressing CXCL12 secretion from LmcMF. In PM model, Tranilast inhibited tumor growth and fibrosis, M2 macrophage, and mast cell infiltration and significantly promoted CD8 + lymphocyte infiltration into the tumor, leading to apoptosis of cancer cells by an immune response., Conclusion: Tranilast improved the immunosuppressive microenvironment by inhibiting CAF function in a mouse PM model. Tranilast is thus a promising candidate for the treatment of PM., (© 2022. The Author(s).)

In past reports, the incidence of gastric perforation accounts for 0.08 to 3.6% of all gastric cancers, and the proportion of perforated gastric cancer(PGC)in gastric perforations is 26 to 32%. In the treatment of PGC, critical care for peritonitis, diagnosis of gastric cancer and curability for gastric cancer are required simultaneously, so it is not easy to decide the treatment strategies. Therefore, for the purpose to consider treatment strategies for PGC, we conducted a clinicopathological study on PGC in our hospital for the past 12 years. There were 22 cases of PGC, and we analyzed clinicopathologically 19 cases excluding perforation during endoscopic resection and perforation during chemotherapy. The R0 surgery group tended to have a good prognosis even in PGC cases, and there was surgery-related death in the one-stage gastrectomy group. So it was considered desirable to perform radical surgery after the general condition was stable by the treatment of peritonitis was given priority in the PGC.

Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer., Experimental Design: We assessed genomic characteristics of FGFR2 -amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2 -amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors., Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%-4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number., Conclusions: ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2 -amplified advanced gastric cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions., (© 2021. Springer Nature Limited.)

Gastric cancer is a major global health burden, especially when patients are diagnosed with recurrent or metastatic gastric cancer. Despite recent advances in treatment options with palliative chemotherapy, the median overall survival of patients with gastric cancer remains within 1 or 2 years after the diagnosis of metastatic disease. Gastric cancer is significantly more prevalent in eastern Asia (e.g., Japan and Korea). Next-generation sequencing (NGS) is rapidly being adopted as part of clinical practice in Korea and Japan, especially in patients with gastric cancer. Approximately 10% to 15% of the patients with gastric cancer who undergo NGS of their tumor specimen are allocated to target-matched clinical trials in Japan and Korea. In Japan and Korea, a cell-free DNA NGS panel is also actively being investigated as an alternative NGS test for patients with gastric cancer, which may reflect the tumor heterogeneity of gastric cancer. In Japan and Korea, multiple biomarkers, such as HER2, mismatch repair, Epstein-Barr virus, PD-L1 (combined positive score), EGFR, FGFR2, and CLDN18.2, are routinely assessed through immunohistochemistry or in situ hybridization before initiation of the first-line treatment in all patients with gastric cancer. Most tertiary cancer centers in Korea routinely perform HER2, mismatch repair, Epstein-Barr virus, and PD-L1 NGS before palliative chemotherapy in patients with gastric cancer. Biomarker evaluation for all patients with metastatic gastric cancer enables clinicians to identify available biomarker-based clinical trials early during the course of treatment, which expands treatment opportunities while patients are medically fit for clinical trials, if available. Comprehensive genomic profiling using a tissue or circulating tumor DNA NGS panel is considered necessary during second-line or subsequent treatment. It is hoped that a comprehensive molecular profiling strategy will facilitate greater use of precision medicine through molecularly targeted therapies for patients with gastric cancer in the near future.

As a general rule, our department has performed additional gastrectomy with lymph node dissection(radical surgery: RS) for non-curative endoscopic submucosal dissection(ESD)cases. This time, we performed a clinicopathological study on 81 patients who underwent RS after ESD for 10 years from May 2009 to April 2019. Lymph node metastasis(LNM)was observed in 5 cases and local cancer residue(LCR)was observed in 8 cases. Examination of the presence or absence of LNM and LCR by clinicopathological factors(histopathological type, tumor size, lymphatic invasion[ly], venous invasion[v], horizontal margin[HM], vertical margin[VM], submucosal invasion, ulceration[scar])revealed no significant risk factor for LNM, however, tumor size and HM were significant risk factors for LCR. The relationship between the eCura system and the case rate associated with LNM in our hospital was similar to that in the original report. Regarding the prognosis, there was one local recurrence and no death from the primary disease.

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.

Background: This is a phase 2 study aimed at evaluating the efficacy and safety of TAS-114, a novel deoxyuridine triphosphatase inhibitor, combined with S-1 in patients with advanced gastric cancer (AGC)., Methods: Eligible patients had AGC with measurable lesions, according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1), with two or more previous chemotherapy regimens including fluoropyrimidines, platinum agents, and taxanes or irinotecan. The primary endpoint was objective response rate (ORR) according to the RECIST, v1.1. Twenty-nine patients were required according to Simon's optimal two-stage design, with one-sided a = 5% and power = 80%. Threshold and expected ORRs were 5% and 25%. Patients received TAS-114 (400 mg/body, twice a day) and S-1 (30 mg/m 2 , twice a day) for 14 days, followed by 7 days of rest in one 3-week cycle. Protein expression levels of dUTPase and BRCA1 in tumor samples were determined by immunohistochemistry., Results: Accrual was terminated in June 2018 because meeting the predefined efficacy criteria was considered difficult. ORR and disease control rate were 5.0% [95% confidence interval (CI), 0.1-24.9%] and 70.0% (95% CI, 45.7-88.1%), respectively, for all 20 patients enrolled. Median progression-free survival (PFS) and overall survival were 2.4 months (95% CI, 1.2-3.3 months) and 7.1 months (95% CI, 5.2-9.4 months), respectively. Median PFS in the groups with high and low dUTPase protein expression in the cytoplasm was 2.8 months (95% CI, 1.4-3.9) and 1.6 months (95% CI, 0.6-2.4), respectively [hazard ratio, 0.40 (95% CI, 0.16-1.04), log-rank test two-sided p = 0.047]. Grade 3 or higher treatment-related adverse events included anemia (20%), leucopenia (15%), neutropenia (10%), rash (10%), thrombocytopenia (5%), and lymphopenia (5%) CONCLUSIONS: TAS-114 with S-1 showed only modest antitumor activity with acceptable safety profiles for patients heavily pretreated with AGC.

Gastric adenocarcinoma with enteroblastic differentiation(GAED)is a rare disease that is classified as a special type in the 15th edition Japanese Classification of Gastric Carcinoma. GAED is considered to have a poor prognosis. We report about a 76-year-old man with GAED who presented with complaints of poor appetite and weight loss. He was suspected of having gastric cancer based on ultrasonography and computed tomography findings and was referred to our hospital by his home doctor. Upper gastrointestinal endoscopy revealed a gastric cancer in the lesser curvature of the gastric antrum. Distal gastrectomy was performed. Histopathology showed a moderately differentiated adenocarcinoma with a clear cytoplasm. Immunostaining was positive for Sal-like protein 4(SALL4)and negative for α-fetoprotein(AFP). The patient was diagnosed as having GAED. Vascular and lymphatic invasion were not observed. He was discharged on the 9th day after surgery. At 5 months postoperatively, he was treated with adjuvant chemotherapy, and no recurrence was noted. GAED is a rare disease with a poor prognosis. We report this case and discuss relevant literature.

Background: Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients., Methods: Immuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6 J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with α-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry., Results: The number of CD8 + cells was significantly lower in PM lesions than in primary lesions (P < 0.01). Conversely, the number of CD163 + cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P = 0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P < 0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P = 0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8 + cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P < 0.05, P < 0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression., Conclusions: This model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

Background: Immune checkpoint inhibitors may enhance the efficacy of radiotherapy (RT) in cancer treatment but the effect remains unknown in metastatic gastric cancer (mGC). This study aimed to compare the tumor shrinkage by palliative RT for mGC patients with or without previous exposure to anti-PD-1 therapy., Methods: Data of 36 mGC patients who had received palliative RT from April 2013 to May 2019 were analyzed. Primary tumor responses were evaluated through a volumetric measurement-based method using computed tomography (CT) and endoscopic responses were evaluated in patients who underwent endoscopy before and after RT. Tumor microenvironment (TME) immune status was investigated by analyzing tumor-infiltrating lymphocytes by flow cytometry., Results: Among 36 patients, 18 had previous exposure to anti-PD-1 before RT showing no significant differences in baseline characteristics with the other 18 patients without exposure to anti-PD-1 treatment. Tumor responses were observed in 28% (5/18) and none (0/18) in the anti-PD-1-exposed vs. naïve group, respectively (P = 0.045). Five out of eight patients in the anti-PD-1-exposed group, who underwent endoscopy after RT showed partial response, but none in the anti-PD-1-naïve patients showed response (P = 0.026). Increase in the CD8 + T cell/effector regulatory T cell ratio in TILs after anti-PD-1 therapy was noted in three responders to RT, but not in the other three non-responders., Conclusions: Prior exposure to anti-PD-1 therapy increases tumor response to RT. Immune profiling suggests that anti-PD-1 therapy may enhance the efficacy of RT by immunoactivation in the TME.

Mitochondria-eating protein (Mieap) plays a critical role in mitochondrial quality control (MQC) and functions as a p53-inducible tumor suppressor. This study aimed to examine its role in gastric cancer (GC) and esophageal cancer (EC). GC cells were infected with Mieap-overexpressing adenovirus (Ad-Mieap) and subjected to fluorescence-activated cell sorting (FACS), western blotting, and caspase assays. Thereafter, we evaluated the potential disruption of the p53/Mieap-regulated MQC pathway in vivo. Methylation-specific PCR (MSP) for Mieap, NIX, and BNIP3 promoters was performed and p53 mutations were detected using cryopreserved surgical specimens. Exogenous Mieap in GC cells induced the formation of vacuole-like structures (called MIVs, Mieap-induced vacuoles) and caspase-dependent cell death, with the activation of both caspase-3 and caspase-9. Of the 47 GC patients, promoter methylation in Mieap, BNIP3, and NIX was identified in two (4.3%), 29 (61.7%), and zero (0%) specimens, respectively. In total, 33 GC patients (70.2%) inactivated this MQC pathway. Amazingly, BNIP3 promoter in the normal epithelium was highly methylated in 18 of the 47 GC patients (38.3%). In EC patients, this MQC pathway was also inactivated in ten of 12 patients (83.3%). These results indicate that p53/Mieap-regulated MQC plays an important role in upper gastrointestinal (GI) tumor suppression, possibly, in part, through the mitochondrial apoptotic pathway., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KY received personal fees, grants, and honoraria from Taiho Pharmaceutical Co., Ltd., and had a consultant or advisory relationship with Taiho Pharmaceutical Co., Ltd. KY has received personal fees and grants from Pfizer Inc., Chugai Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd., grants from Bristol-Myers Squibb and Kyowa Hakko Kirin Co., Ltd., honoraria from Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., and Yakult Honsha Co., Ltd., and had a consultant or advisory relationship with La Roche, Ltd. The other authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Although gastric cancer is one of the most common causes of cancer death in the world, mechanisms underlying this type of tumor have not been fully understood. In this study, we found that IQGAP3 , a member of the IQGAP gene family, was significantly up-regulated in human gastric cancer starting from the early stages of tumor progression. Overexpression of IQGAP3 in 293T and NIH3T3 cells, which have no endogenous IQGAP3 expression, resulted in morphological change with multiple dendritic-like protrusions and enhanced migration. Overexpression of IQGAP3 also led to reduced cell-cell adhesion in 293T cells, likely as a result of its interactions with e-cadherin or β-catenin proteins. Additionally, IQGAP3 accumulated along the leading edge of migrating cells and at the cleavage furrow of dividing cells. In contrast, suppression of IQGAP3 by short-interfering RNA (siRNA) markedly reduced invasion and anchorage-independent growth of MKN1 and TMK-1 gastric cancer cells. We further confirmed that IQGAP3 interacted with Rho family GTPases, and had an important role in cytokinesis. Taken together, we demonstrated that IQGAP3 plays critical roles in migration and invasion of human gastric cancer cells, and regulates cytoskeletal remodeling, cell migration and adhesion. These findings may open a new avenue for the diagnosis and treatment of gastric cancer.

Background: Pembrolizumab, an anti-PD-1 antibody, results in tumour response in around 15% of patients with advanced gastric cancer who have a PD-L1 combined positive score of at least 1. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased tumour-associated macrophages and increased infiltration of CD8 T cells, resulting in enhanced anti-tumour activity of PD-1 inhibitors in an in-vivo model. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in a phase 2 study., Methods: This study was an open-label, single-arm, phase 2 trial undertaken at the National Cancer Center Hospital East (Chiba, Japan). Eligible patients were aged 20 years or older and had metastatic or recurrent adenocarcinoma of the stomach or gastro-oesophageal junction, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), irrespective of the number of previous lines of treatment. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks until disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate according to RECIST, analysed in all patients who were eligible and received protocol treatment at least once. The safety analysis included all those who received protocol treatment at least once, regardless of eligibility. This study is registered at ClinicalTrials.gov, NCT03609359, and enrolment is complete., Findings: Between Oct 15, 2018, and March 25, 2019, 29 patients were enrolled in the first-line or second-line settings. At data cutoff (March 20, 2020), the median follow-up was 12·6 months (IQR 10·5-14·3). 20 (69%, 95% CI 49-85) of 29 patients had an objective response. The most common grade 3 treatment-related adverse events were hypertension (in 11 [38%] patients), proteinuria (five [17%]), and platelet count decrease (two [7%]). No grade 4 treatment-related adverse events, serious treatment-related adverse events, or treatment-related deaths occurred., Interpretation: Lenvatinib plus pembrolizumab showed promising anti-tumour activity with an acceptable safety profile in patients with advanced gastric cancer. On the basis of these results, a confirmatory trial will be planned in the future., Funding: Merck Sharp & Dohme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: We evaluated the association between molecular subtypes of advanced gastric cancer (AGC) and the efficacy of standard chemotherapy or immune checkpoint inhibitors., Experimental Design: Patients with AGC who received systemic chemotherapy from October 2015 to July 2018 with available molecular features were analyzed. We investigated the efficacy of standard first- (fluoropyrimidine + platinum ± trastuzumab) and second-line (taxanes ± ramucirumab) chemotherapy, and subsequent anti-PD-1 therapy in patients with four molecular subtypes: MMR-D (mismatch repair deficient), EBV + , HER2 + , and all negative., Results: 410 patients were analyzed: MMR-D 5.9%, EBV + 4.1%, HER2 + 13.7%, and all negative 76.3%. In 285 patients who received standard first-line chemotherapy, the median progression-free survival (PFS) times were 4.2, 6.0, 7.5, and 7.6 months and the objective response rates (ORR) were 31%, 62%, 60%, and 49% in MMR-D, EBV + , HER2 + , and all-negative subtypes, respectively. Multivariate analysis showed shorter PFS in MMR-D versus all-negative patients [HR, 1.97; 95% CIs, 1.09-3.53; P = 0.022]. In second-line setting, there were no significant differences in efficacy. In 110 patients who received anti-PD-1 therapy, median PFS times were 13.0, 3.7, 1.6, and 1.9 months and the ORRs were 58%, 33%, 7%, and 13%, respectively. Twelve patients with MMR-D received subsequent anti-PD-1 therapy and showed longer PFS compared with that in 10 (83%) patients who received earlier-line chemotherapy., Conclusions: MMR-D might result in shorter PFS with first-line chemotherapy for AGC. Subsequent anti-PD-1 therapy achieved higher ORR and longer PFS than prior chemotherapy in most patients with MMR-D, supporting the earlier use of immune checkpoint inhibitors., (©2020 American Association for Cancer Research.)

Background: The efficacy and safety of chemotherapy (CTx) after anti-PD-1 therapy in patients with advanced gastric cancer (AGC) remains unclear., Methods: Medical records of consecutive patients with AGC treated with both CTx (taxanes plus ramucirumab, taxanes monotherapy or irinotecan) and anti-PD-1 therapy from June 2015 to April 2019 were retrospectively analysed. Patients were divided into two groups based on prior exposure to anti-PD-1 therapy: anti-PD-1-exposed and anti-PD-1-naïve groups. CTx-related outcomes were compared between two groups in the overall population and each CTx population., Results: In total, 233 patients (67 anti-PD-1-exposed, 166 anti-PD-1-naïve) were included. In the overall population, the objective response rate (ORR) to CTX was 44.6% in the anti-PD-1-exposed group and 19.6% in the anti-PD-1-naïve group (p=0.001); the median progression-free survivals (PFS) were 3.7 months and 3.3 months (HR=0.82, p=0.20), respectively. Among patients receiving taxanes plus ramucirumab (n=149), ORR (60.6% vs 20.0%, p<0.001) and median PFS (4.8 vs 3.4 months, p=0.004, HR=0.56) were significantly better in the anti-PD-1-exposed group (n=39) compared with the anti-PD-1-naïve group (n=110). These differences were not observed in patients receiving taxane monotherapy (n=34) or irinotecan (n=50). CTx after anti-PD-1 therapy showed no severe or unexpected adverse events., Conclusions: Prior anti-PD-1 therapy might increase tumour response to taxanes plus ramucirumab without unexpected adverse events, which warrants further investigations in a large cohort., Competing Interests: Competing interests: AK reports research funding from Ono, Sumitomo Dainippon and Taiho. TE, MO, SM and KS have nothing to disclose. YN reports research funding from Ono pharmaceutical and Taiho Pharmaceutical. DK reports receiving honoraria from Takeda, Chugai, Lilly, Merck Serono, Taiho and Sysmex. YK reports a consulting or advisory role for Takeda; personal fees from Bayer, Lilly, Taiho, MSD and Sanofi; and research funding from Astra Zeneca, Daiichi-Sankyo, Incyte, Taiho, Ono, Boehringer Ingelheim, Chugai, Amgen, Genmab and Takeda. HT reports grants and personal fees from Takeda, personal fees from Taiho, personal fees from Chugai, grants from Sysmex, grants from Daiichi-Sankyo. TK reports personal fees from MSD; and research funding from Astellas, Bristol-Myers Squibb, MSD, Oncolys BioPharma, Ono, Shionogi. TD reports a consulting or advisory role for AbbVie, Amgen, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Sumitomo Dainippon, Rakuten Medical, Taiho and Takeda; honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Oncolys Biopharma, Ono and Taiho; and research funding from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Kyowa Hakko Kirin, Lilly, Merck Serono, MSD, Novartis, Pfizer, Quintiles, Sumitomo Group and Taiho. TY reports a consulting or advisory role for Chugai, Lilly, Merck Serono and Sanofi; honoraria from Chugai, Takeda, Eli Lily, Merck Biopharma; and research funding from Chugai, GlaxoSmithKline, MSD, Nippon Boehringer Ingelheim, Novartis, Sanofi, Ono, Daiichi-Sankyo, Parexel and Sumitomo Dainippon. KS reports paid consulting or advisory roles for Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono and MSD; honoraria from Novartis, AbbVie and Yakult; and research funding from Astellas, Lilly, Ono, Sumitomo Dainippon, Daiichi-Sankyo, Taiho, Chugai, MSD and Medi Science., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: Gastric cancer is heavily influenced by aberrant DNA methylation that alters multiple cancer-related pathways, and may respond to DNA demethylating agents, such as 5-aza-2'-deoxycytidine (5-aza-dC). Here, we aimed to analyze whether 5-aza-dC can sensitize gastric cancer cells to clinically used cytotoxic drugs., Methods: Ten gastric cancer cell lines were treated with 5-aza-dC for 72 h and their growth was analyzed by conducting WST assay. In vivo effect of the drugs was analyzed using xenografts of OCUM-2 M/SN38 cells. Genome-wide expression and DNA methylation analyses were conducted using microarrays, and biological functions were identified through ingenuity pathway analysis., Results: The cell lines most resistant to SN38 (an active metabolite of irinotecan), CDDP, PTX, and 5-FU, were identified. 5-Aza-dC pre-treatment of the resistant cell lines decreased the IC 50 values for SN38 (TMK1, 226.4 nM to 32.91 nM; 44As3, 128.2 nM to 19.32 nM; OCUM2 M/SN38, 74.43 nM to 16.47 nM) and CDDP (TMK1, 5.05 µM to 2.26 µM; OCUM2 M, 10.79 µM to 2.77 µM), but not PTX and 5-FU. The reactivation of apoptosis-related genes, such as RUNX3, PYCARD, TNF, FAS, and FASLG, was induced by pre-treatment with 5-aza-dC, and the DNA demethylation of promoter CpG islands of RUNX3 and PYCARD was confirmed. In a xenograft model with OCUM2 M/SN38, treatment with 5-aza-dC before irinotecan showed markedly enhanced tumor suppression., Conclusion: Epigenetic priming with 5-aza-dC can improve the sensitivity of gastric cancer cells to SN38 and CDDP.

Lynch syndrome (LS) is an autosomal dominantly inherited disease predisposed to not only colorectal cancer but also other LS-related tumors. Although the clinical and genetic characteristics of LS in Western countries have been well characterized, the information of Japanese LS is limited. As a collaborative study of Japanese Society for Cancer of the Colon and Rectum (JSCCR), we registered colorectal cancer (CRC) patients who fulfilled the modified Amsterdam II criteria including gastric cancer as an LS-related tumor. Among 4030 CRC patients initially registered in this project, 85 patients (2.1%) fulfilled the modified criteria. An additional 26 patients who met the same criteria were enrolled in the analysis. We analyzed three major responsible genes, MLH1, MSH2, and MSH6 by direct sequencing, and further performed multiplex ligation-dependent probe amplification for MLH1 and MSH2. Consequently, we identified pathogenic variants in 64 of the 111 patients comprising of 34 patients in MLH1, 28 in MSH2, and 2 in MSH6. It is of note that large structural alterations were found in 17 patients. Among the 64 patients, 11 patients would not have been enrolled in the analysis if gastric cancer were not included in the modified criteria. In addition, 10 of the 64 variant carriers (15.6%) had medical history of gastric cancer. Furthermore, the standardized incidence ratio of gastric cancer in the LS patients to the Japanese population is estimated to be as high as 20.2. These data underscore the importance of gastric cancer in the diagnosis and healthcare of Japanese LS patients.

Background: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a useful tool in pancreatic cancer diagnosis. However, the procedure itself may cause peritoneal dissemination and needle tract seeding at the puncture site. We herein report two cases of gastric wall metastasis due to needle tract seeding after EUS-FNA., Case Presentation: Case 1: A 68-year-old woman was admitted to our hospital for persistent cough. Computed tomography (CT) scan revealed inflammatory changes in the left lung field, and incidentally, a 15-mm hypovascular mass was detected in the pancreatic body. She underwent EUS-FNA and was diagnosed as pancreatic adenocarcinoma. She underwent distal pancreatectomy with splenectomy; however, a small hard mass was observed in the posterior gastric wall during surgery. We performed partial gastrectomy, and the resected specimen was diagnosed as a needle tract seeding following EUS-FNA. She then underwent adjuvant chemotherapy with TS-1, but the pancreatic cancer showed recurrence 6 months after surgery. She died due to peritoneal dissemination 18 months after surgery. Case 2: A 70-year-old man was incidentally detected with a pancreatic body mass on a CT scan as part of his follow-up for recurrence of basal cell carcinoma. He underwent EUS-FNA and was diagnosed as pancreatic adenocarcinoma. He had nodules in both lungs, and it was difficult to differentiate them from lung metastasis of pancreatic cancer. Therefore, he underwent neoadjuvant chemoradiotherapy, and thereafter, the lung nodules showed no changes; hence, he underwent distal pancreatectomy with splenectomy. During surgery, we observed a hard mass in the posterior gastric wall. We performed partial gastrectomy, and the resected specimen was diagnosed as needle tract seeding due to EUS-FNA. He underwent chemotherapy with TS-1, and he is still alive 18 months after surgery at the time of writing., Conclusion: For resectable pancreatic body or tail tumors, EUS-FNA should be carefully performed to prevent needle tract seeding and intraoperative as well as postoperative assessment for gastric wall metastasis is mandatory.

Background: Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC)., Methods: Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as ≥ two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated., Results: Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD., Conclusions: HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.

PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3 high CD45RA - CD4 + T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4 + or CD8 + effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67 + ) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1 + eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1 - eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1 + eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1 + eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy., Competing Interests: Conflict of interest statement: The Sponsor declares a conflict of interest. Y. Togashi has received honoraria and grants from Ono Pharmaceutical as to this work, honoraria and grants from Bristol-Myers Squibb and AstraZeneca, and honoraria from Chugai Pharmaceutical and Merck Sharp & Dohme (MSD) outside of this study. K.S. received honoraria and grants from Ono Pharmaceutical and Bristol-Myers Squibb and grants from MSD outside of this study. H.N. received honoraria and grants from Ono Pharmaceutical as to this work, honoraria and grants from Bristol-Myers Squibb and Chugai Pharmaceutical, and grants from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa-Hakko Kirin, Zenyaku Kogyo, Astellas Pharmaceutical, Sysmex, and BD Japan outside of this study. Other authors declare no competing financial interests., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Two phase 2 trials of oxaliplatin-containing adjuvant therapy for patients with gastric cancer (GC) after D2 gastrectomy were conducted in Japan. The SOXaGC trial evaluated the tolerability and safety of adjuvant therapy with S-1 plus oxaliplatin (SOX), whereas the J-CLASSIC trial evaluated the feasibility of adjuvant therapy with capecitabine plus oxaliplatin (CAPOX). Because both were studies that did not evaluate survival results as study end points, the authors evaluated the survival outcomes for the patients in the two trials., Methods: All 62 and 100 patients in the full analysis set of the SOXaGC and J-CLASSIC trials, respectively, were included in the current study. Their information about survival outcome was collected. The primary end point was relapse-free survival (RFS), and the secondary end point was overall survival (OS)., Results: For the pathologic stage (pStage 2) patients treated with CAPOX, the 3-year RFS rate was 87.8% and the 3-year OS rate was 92.7%. For the pStage 3 patients treated with SOX and CAPOX, the 3-year RFS rates were respectively 70.9% and 67.8% (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.50-1.72), whereas the 3-year OS rates were respectively 75.7% and 79.3% (HR, 1.10; 95% CI, 0.54-2.26). Subgroup analysis showed significant interactions between the treatment (SOX vs. CAPOX) and both sex (male vs. female; P = 0.024) and histologic type (diffuse vs. other, P = 0.069)., Conclusions: This exploratory analysis demonstrated that SOX and CAPOX are suggested to have similar efficacy for pStage 3 GC patients after D2 gastrectomy. Differences in the treatment effect according to sex and histologic type warrant further evaluation.

Background: Clinicopathological and molecular features of responders to nivolumab for advanced gastric cancer (AGC) are not well understood., Methods: Patients (pts) with AGC who were treated with nivolumab after two or more chemotherapy regimens in a single institution from September 2017 to May 2018 were enrolled in this study. PD-L1 expression in tumor cells (TC) and mismatch repair (MMR) were analyzed by immunohistochemistry. Epstein-Barr virus (EBV) was detected by in situ hybridization. Cancer genome alterations were evaluated by a next-generation sequencing-based panel. High tumor mutation burden (TMB) was defined as more than 10 mutations/megabase., Results: A total of 80 pts were analyzed in this study. Tumor response was evaluated in 72 pts with measurable lesions and 14 pts (19%) had an objective response. Overall response rate (ORR) was significantly higher in pts with ECOGPS 0 in those with PS 1 or 2, MMR-deficient (MMR-D) in those with MMR-proficient (MMR-P), PD-L1+ in TC in those with PD-L1- in TC and PIK3CA mutation in those with PIK3CA wild-type. ORR was 31% in pts with at least one of the following factors; MMR-D, high TMB, EBV+ and PD-L1+ in TC vs. 0% in those without these factors. Progression-free survival was significantly longer in pts with PS 0 than in those with PS 1 or 2, MMR-D than in those with MMR-P, and PD-L1+ in TC than in those with PD-L1- in TC., Conclusions: Some features were associated with favorable response to nivolumab for AGC. Combining these features might be useful to predict efficacy.

Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10 -8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10 -10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10 -13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10 -11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Orbital metastasis of gastric cancer occurs very rarely.A 76-year-old woman, who consulted another doctor with the chief complaints of palpitation, shortness of breath, and anorexia 1 month previously, was referred to our clinic for workup and treatment.Workup revealed type III advanced gastric cancer at the lesser curvature of the gastric antrum.Biopsy revealed a diagnosis of poorly differentiated adenocarcinoma.As computed tomography suggested periaortic lymph node metastasis, a diagnosis of T4a(SE)N3aM1(LYM), cStage IV was made.Two weeks later, ptosis was observed in the right eye, and positron emission tomography-computed tomography(PET-CT)revealed metastasis to the right superior rectus muscle.No intracranial tumor progression was observed.The Cyberknife system(20 Gy/1 Fr)was used for treating the orbital tumor. Increased LYM was observed even after 2 courses of S-1 plus oxaliplatin(SOX)therapy.Therefore, weekly combination therapy of paclitaxel and ramucirumab(wPTX plus Rmab)was administered as second-line therapy.No new distal metastasis has been detected in the 10 months since the orbital metastasis development, and the patient is still alive.

A 74-year-old man was referred to our hospital for further investigation of a cystic lesion in the pancreatic body, which had been detected by ultrasonography at a local hospital. He was diagnosed as intraductal papillary mucinous neoplasm(IPMN) and further preoperative examinations were conducted. Upper gastrointestinal endoscopy demonstrated a type 0-II c tumor of the greater curvature in the upper third of the stomach. Endoscopic ultrasonography showed no sign of submucosal invasion. Endoscopic submucosal dissection(ESD)was carried out and pathological examination of a specimen revealed well differentiated adenocarcinoma with submucosal invasion, which fulfilled the indication for additional gastrectomy with lymph node dissection. Laparoscopy-assisted proxymal gastrectomy with D1 plus lymph node dissection and distal pancreatectomy with splenectomy was performed. Pathological examination demonstrated intraductal papillary mucious adenoma(IPMA)in the pancreatic body and no residual gastric cancer in a specimen, however 7lymph node metastases from gastric cancer was confirmed(pN3a), including 3 metastatic lymph nodes incidentally-detected adjacent to the pancreatic parenchyma. We report a rare case of early gastric cancer with N3 lymph node metastases, with a brief literature review.

Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115-2128., (© 2017 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

The number of patients with end-stage heart failure treated by a left ventricular assist device (LVAD) is dramatically increasing, because the LVAD has been widely accepted for its clinical results. According to the initiation of destination therapy, the prevalence of malignancy in patients with an LVAD is estimated to increase. In patients with LVADs, abdominal surgery for visceral malignancy is associated with technical difficulties because of the presence of an LVAD pump or the driveline which is located transversely in the preperitoneal space. Herein, we describe the technical management for complete resection of gastric cancer in a patient with an LVAD.

We performed a clinical trial using HLA-A24-binding peptide vaccines containing a combination of novel cancer-testis antigens and anti-angiogenic peptides for advanced gastric cancer (GC). Thirty-five GC patients who had shown resistance to the standard therapy were enrolled in this clinical trial using vaccinations with a mixture of multiple peptides derived from DEPDC1, URLC10, FoxM1, Kif20A and VEGFR1. The safety, the overall survival (OS), and the immunological responses based on an ELISPOT assay were determined to assess differences in patients who were HLA-A24-positive [24(+)] and HLA-A24-negative [24(-)]. No severe adverse effects were observed except for severe skin reactions in 4 patients. The differences in OS were not significant between patients who were 24(+) and 24(-). In the 24(+) group, patients who showed T cell responses specific to antigen peptides had a tendency towards better survival than those who showed no response, especially to the DEPDC1 peptide. The patients with local skin reactions had significantly better OS than the others. Peptide vaccine therapy was found to be safe and is expected to induce specific T cell responses in patients with advanced GC. The survival benefit of peptide vaccine monotherapy may not have been shown and further trials are needed to confirm these results.

Background: Several studies have evaluated associations between the characteristics of patients with esophageal and gastric cancer and survival, but these associations remain unclear. We described the distribution of demographic and lifestyle factors among patients with esophageal and gastric cancer in Japan, and investigated their potential effects on survival., Methods: Between 2003 and 2007, 24- to 95-year-old Japanese patients with esophageal and gastric cancer were enrolled in the BioBank Japan Project. The analysis included 365 patients with esophageal squamous cell carcinoma (ESCC) and 1574 patients with gastric cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using medical institution-stratified Cox proportional hazards models., Results: During follow-up, 213 patients with ESCC (median follow-up, 4.4 years) and 603 patients with gastric cancer (median follow-up, 6.1 years) died. Among patients with ESCC, the mortality risk was higher in ever drinkers versus never drinkers (multivariable HR = 2.37, 95% CI: 1.24, 4.53). Among patients with gastric cancer, the mortality risk was higher in underweight patients versus patients of normal weight (multivariable HR = 1.66, 95% CI: 1.34, 2.05). Compared to patients with gastric cancer with no physical exercise habit, those who exercised ≥3 times/week had a lower mortality risk (multivariate HR = 0.75, 95% CI = 0.61, 0.93). However, lack of stage in many cases was a limitation., Conclusions: Among patients with ESCC, alcohol drinkers have a poor prognosis. Patients with gastric cancer who are underweight also have a poor prognosis, whereas patients with physical exercise habits have a good prognosis., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Fibroblasts are the commonest type of cancer stromal cells. Inflammation occurs in cancer tissue, and the inflammatory process has been suggested to be caused by interactions between immune cells and cancer cells. In this study, we clarified that site-specific fibroblasts regulate the formation of a site-specific inflammatory niche according to the depth of gastric cancer cell invasion., Methods: Immunohistochemistry was performed with paraffin-embedded tissues. The numbers of immune cells and the fibroblast area were calculated according to the cancer depth. The gene expression patterns of submucosal fibroblasts and subperitoneal fibroblasts stimulated with HSC44PE-conditioned medium were analyzed with a microarray. To examine the effects on the cancer microenvironment of differences in gene expressions between HSC44PE-stimulated submucosal fibroblasts and subperitoneal fibroblasts, assays of HSC44PE proliferation, T cell migration, and M2-like macrophage differentiation were performed., Results: The distributions of immune cells differed between the submucosal layer and the subserosal layer. The number of M2 macrophages was significantly higher and the fibroblast area was significantly larger in the subserosal layer compared with the submucosal layer. High expression levels of IL1B, TNFSF15, and CCL13 were observed in HSC44PE-stimulated submucosal fibroblasts, and higher expression levels of TGFB2, CSF1, CCL8, and CXCL5 were found in HSC44PE-stimulated subperitoneal fibroblasts. HSC44PE-stimulated subperitoneal fibroblast medium promoted the differentiation of monocytes into M2-like macrophages, whereas HSC44PE-stimulated submucosal fibroblasts significantly induced the migration of Jurkat cells and the growth of HSC44PE cells., Conclusion: The dynamic states of immune cells differ between the submucosal and subserosal layers in cancer tissues. Site-specific fibroblasts regulate site-specific inflammatory niche formation according to the depth of cancer cell invasion.

A 55-year-old man experienced weight loss, as noted by a physician who was examining him for hypertension. Upper gastrointestinal endoscopy revealed a tumor lesion with an ulcer on the posterior wall of the greater curvature. A biopsy confirmed the presence of an adenocarcinoma(HER2 negative), and demonstrated enlarged para-aortic lymph nodes. Thus, stage IV type 3 ulcer infiltration-type gastric cancer was diagnosed. Computed tomography was included in the examination, and demonstrated nodular shadows in the right lower lobe and enlarged mediastinal nodes, as well as bilateral multiple granular shadows. Hence, bronchoscopy was performed, and another adenocarcinoma(EGFR mutation negative/EML4-ALK gene fusion negative)was diagnosed. Immunostaining showed that the pulmonary and gastric adenocarcinoma tissues were different, and synchronous double cancer was diagnosed. Four courses of CDDP/S-1were administered, and both the lesions showed a partial response.