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Background: Peritoneal metastasis of gastric cancer is closely associated with dismal prognosis. In previous preclinical proof-of-concept studies, an amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotide (ASO), designated ASO-4733 that targets the gene encoding synaptotagmin XIII (SYT13), inhibited cellular functions required for the formation of peritoneal metastasis of gastric cancer cells. ASO-4733 achieved therapeutic effects when intra-abdominally administered to mouse xenograft models. Here, we conducted an analysis of Syt13-deficient mice to determine the pharmacokinetics and toxicity of intra-abdominal administration of ASO-4733. Methods: The effects of Syt13-deficiency in mice were determined. Good Laboratory Practice toxicity tests and the toxicokinetics of intra-abdominal administration of ASO-4733 were conducted in cynomolgus monkeys and rats. The pharmacokinetics of ASO-4733 administered intravenously or intra-abdominally to rats were investigated. Results: Syt13-deficient mice exhibited normal reproduction, organ functions, and motor functions. Weekly intra-abdominal administration of ASO-4733 (125 mg/kg), corresponding to a 50-fold increase of the estimated clinical dose for 4 weeks, was well tolerated by cynomolgus monkeys. In rats, off-target toxicity (not attributable to hybridization) was observed after weekly intra-abdominal administration of ASO-4733. Blood concentrations of ASO-4733 were lower and rose more slowly after intra-abdominal administration compared with intravenous administration. Conclusions: The preclinical profile of intra-abdominal administration of ASO-4733 demonstrated its suitability for entry into clinical trials of patients with peritoneal metastasis of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Large type 3 (diameter ≥ 8 cm) and type 4 gastric cancers have been arbitrarily combined in Japan as a single entity. However, whether these two types are oncologically similar remain unclear. This study aimed to clarify this issue. Methods: In this retrospective study, we analyzed a database of 3,575 patients from nine institutions who underwent gastrectomy between 2010 and 2014. Using propensity scores to balance significant variables, we compared prognoses and tumor recurrences. Results: Of patients with clinical T3/T4 who underwent R0 resection, 75 and 73 had large type 3 and 4 tumors, respectively. Patients with type 4 tumors had significantly lower overall survival rates than those of patients with large type 3 tumors (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.14–2.74). However, among the large type 3 tumors, a remarkable difference in prognosis was observed between the differentiated and undifferentiated histological types. A comparison was made between large type 3 with undifferentiated phenotype and type 4, each with 39 patients after propensity score matching. Outcomes in both groups were similar in terms of overall survival (HR 1.28; 95% CI 0.73–2.25) and relapse-free survival (HR 1.34; 95% CI 0.80–2.27). No statistically significant differences were observed in the incidence of peritoneal recurrence (35.9% vs. 46.1%, P = 0.36) and lymph node recurrence (25.6% vs. 12.8%, P = 0.15). Conclusions: Large type 3 tumors with undifferentiated phenotype and type 4 tumors were oncologically similar. This subgroup could be considered as a new entity for future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Lipolysis-stimulated lipoprotein receptor (LSR), a lipid receptor, is associated with cancer progression. However, detailed effects on intracellular metabolism are unclear. We aimed to elucidate the mechanism of LSR-mediated lipid metabolism in gastric cancer. Methods: We investigated lipid metabolic changes induced by lipoprotein administration in gastric cancer cells and evaluated the significance of LSR expression and lipid droplets formation in gastric cancer patients. The efficacy of inhibiting β-oxidation in gastric cancer cells was also examined in vitro and vivo. Results: In gastric cancer cells, LSR promoted cellular uptake of lipoprotein and cell proliferation. Furthermore, the inhibition of LSR in gastric cancer cells expressing high levels of LSR counteracted both effects. Immunohistochemical analysis of human gastric cancer tissues showed that the increase in lipid droplets via LSR is a factor that influences prognosis. Lipidomics analysis of LSR-high-expressing gastric cancer cells revealed an increase in β-oxidation. Based on these results, we used etomoxir, a β-oxidation inhibitor, and found that it inhibited cell proliferation as well as the suppression of LSR. Similarly, in a mouse xenograft model of LSR-highly expressing gastric cancer cells, the tumor growth effect of high-fat diet feeding was counteracted by etomoxir, consistent with the Ki-67 labeling index. Conclusions: We demonstrated that lipids are taken up into gastric cancer cells via LSR and cause an increase in β-oxidation, resulting in the promotion of cancer progression. Controlling LSR-mediated lipid metabolism may be a novel therapeutic strategy for gastric cancer. [ABSTRACT FROM AUTHOR]

Background: The significance of reinforcement of the duodenal stump with seromuscular sutures and the effectiveness of reinforced staplers in preventing duodenal stump leakage remain unclear. We aimed to explore the importance of duodenal stump reinforcement and determine the optimal reinforcement method for preventing duodenal stump leakage. Methods: This retrospective cohort study was conducted between January 1, 2012 and December 31, 2021, with data analyzed between December 1, 2022 and September 30, 2023. This multicenter study across 57 institutes in Japan included 16,475 patients with gastric cancer who underwent radical gastrectomies. Elective open or minimally invasive (laparoscopic or robotic) gastrectomy was performed in patients with gastric cancer. Results: Duodenal stump leakage occurred in 153 (0.93%) of 16,475 patients. The proportions of males, patients aged ≥ 75 years, and ≥ pN1 were higher in patients with duodenal stump leakage than in those without duodenal stump leakage. The incidence of duodenal stump leakage was significantly lower in the group treated with reinforcement by seromuscular sutures or using reinforced stapler than in the group without reinforcement (0.72% vs. 1.19%, p = 0.002). Duodenal stump leakage incidence was also significantly lower in high-volume institutions than in low-volume institutions (0.70% vs. 1.65%, p = 0.047). The rate of duodenal stump leakage-related mortality was 7.8% (12/153). In the multivariate analysis, preoperative asthma and duodenal invasion were identified as independent preoperative risk factors for duodenal stump leakage-related mortality. Conclusions: The duodenal stump should be reinforced to prevent duodenal stump leakage after radical gastrectomy in patients with gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC. Methods: We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups. Results: Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151–0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy. Conclusions: Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC. [ABSTRACT FROM AUTHOR]

Background: Clinical findings and postoperative follow-up data on remnant gastric cancer (RGC) are limited due to its rarity. Additionally, the preoperative staging, radical surgery, and managing recurrence in RGC present significant clinical challenges. Methods: We analyzed the clinicopathological findings, adjuvant chemotherapy, and patterns of postoperative recurrence of 313 consecutive patients who underwent curative surgery for RGC at 17 Japanese institutions. This study investigated the optimal management of RGC and the impact of adjuvant chemotherapy (AC) on recurrence-free survival (RFS). Results: Pathological stages I, II, and III were observed in 55.9% (N = 175), 24.9% (N = 78), and 19.2% (N = 60) of the patients, respectively. The overall concordance rate between clinical and pathological T staging was 58.3%, with a clinical T4 sensitivity of 41.4% for diagnosing pathological T4. During the median follow-up period of 4.6 years, disease recurrence occurred in 24.3% of patients. Most recurrences (over 80%) occurred within 2.5 years, and 96.1% within 5 years after RGC surgery. Peritoneal recurrence was the most common in patients with advanced RGC, accounting for 14.1% in stage II and 28.3% in stage III. Multivariable regression analysis showed that AC was significantly associated with a longer RFS, with a hazard ratio of 0.45 (95% confidence interval: 0.26–0.76). Conclusions: Our study underscores the importance of early detection, accurate preoperative staging, and postoperative surveillance in managing advanced RGC cases. Despite some limitations, our findings indicate that AC may provide survival benefits comparable to those seen in primary gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Previous studies have investigated cardiovascular disease (CVD) risks in cancer patients, but there is limited knowledge concerning the CVD risk in adult and young adolescent (AYA) survivors of gastric cancer. Objectives: This study aims to investigate the incidence of CVD in AYA gastric cancer survivors, analyzing it by treatment type and identifying associated risk factors. Methods: We conducted a retrospective cohort study using Korean National Health Insurance Service data collected from 2006 to 2019. Propensity score matching (1:3, caliper < 0.1) was performed using the variables age, sex, income, residential area, and presence of comorbidities, and we classified participants into gastric cancer (n = 6562) and non-cancer control (n = 19,678) groups. Cox regression models were used to calculate hazard ratios (HRs) for CVD incidence. The study assessed CVD incidence by cancer treatment and identified risk factors through multivariable Cox regression. Results: During a median 6.5-year follow-up, AYA gastric cancer survivors consistently exhibited greater CVD incidence. Their risk of CVD was significantly elevated compared to that of controls (HR, 1.18; 95% confidence interval [CI] 1.05–1.33). In particular, deep vein thrombosis (HR, 3.93; 95% CI 3.06–14.67) and pulmonary embolism (HR, 6.58; 95% CI 3.06–14.67) risks were notably increased. Chemotherapy was associated with an increased risk of stroke, heart failure, atrial fibrillation, deep vein thrombosis, and pulmonary embolism. Hypertension (HR, 1.58; 95% CI 1.10–2.26) and dyslipidemia (HR, 1.46; 95% CI 1.06–2.20) emerged as risk factors for CVD development. Conclusion: This study reports elevated risks of CVD in AYA gastric cancer survivors and emphasizes the need for vigilant monitoring of CVD in this population. [ABSTRACT FROM AUTHOR]

Background: Gastric foveolar type neoplasia is a rare histological variant of gastric tumors. It is very difficult to differentiate between benign and malignant intraepithelial foveolar neoplasia (IFN). Although limited molecular alterations have been identified in IFNs, somatic copy number alterations (SCNAs), which are linked to tumor progression, have not been systematically evaluated in IFN. Methods: The aim of the present study was to comprehensively examine SCNAs using a SNP array in 37 cases of IFN, compared with intestinal type dysplasia, including 39 low grade (LGD) and 32 high grade dysplasia (HGD) cases. In addition, gene mutations were evaluated using a gene panel. Finally, we attempted to determine molecular profiles using a hierarchical clustering analysis. Results: Two patterns could be categorized according to the SCNAs in 108 tumors examined: high (subgroup 1) and low (subgroup 2) frequencies of SCNAs. Although IFN and LGD were associated with subgroup 2, HGD was found in both subgroups. The median numbers of total SCNAs and copy number gains were higher in IFN or HGD than in LGD. In addition, the IFN genotype was characterized by altered genes located at 4p13–4q35.2, including RAP1GDS1 and LEF1, which may be associated with IFN development. Finally, no significant mutations were found in IFNs using a gene panel. Conclusions: The current molecular profiles of IFN may help elucidate the mechanisms of IFN development. [ABSTRACT FROM AUTHOR]

Background: The impact of economic engagement on the health of cancer survivors is notable. Our study aims to explore the association between early loss of economic activity (EA) and the risk of all-cause mortality among gastric cancer survivors. Methods: This retrospective cohort study utilized data from Korea's National Health Insurance Service, focusing on 30–59-year-old gastric cancer patients who received either surgery or endoscopic procedures from January 2009 to December 2013. The primary outcome measure was all-cause mortality. Early loss of EA was identified when a patient's insurance status shifted to dependent within one year following treatment. Adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality were estimated using multivariable Cox proportional hazards models, conducting separate analyses for surgical and endoscopic groups. Results: Among 24,159 patients (median follow-up, 9.9 years), 2976 (12.3%) experienced all-cause mortality. Specifically, 2835 of these deaths occurred in patients who underwent surgery, while 141 were in the endoscopic procedure group. Early loss of EA was recorded in 14.4% of the surgery group and 7.7% of the endoscopic procedure group. Adjusted HRs (95% CI) for all-cause mortality associated with early loss of EA were 1.39 (1.27–1.54) for the surgery group and 2.27 (1.46–3.52) for the endoscopic procedure group. Conclusions: This study highlights a significant association between the early loss of EA and an increased risk of all-cause mortality in those who have undergone curative treatments for gastric cancer. It underscores the crucial role of sustaining EA in enhancing the health outcomes of these survivors. [ABSTRACT FROM AUTHOR]

Background: Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited. Methods: ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician's choice of SOX (oral S-1 [tegafur–gimeracil–oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints—centrally assessed progression-free survival (PFS) and overall survival (OS)—and landmark analyses of OS among patients alive using 3-year follow-up data. Results: At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55–0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75–1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy. Conclusion: This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer. Trial registration: NCT02746796 [ABSTRACT FROM AUTHOR]

Background: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy. Methods: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments. Results: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR. Conclusion: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy. [ABSTRACT FROM AUTHOR]

Background: The purpose of the study was to conduct a comprehensive genomic characterization of gene alterations, microsatellite instability (MSI), and tumor mutational burden (TMB) in submucosal-penetrating (Pen) early gastric cancers (EGCs) with varying prognoses. Methods: Samples from EGC patients undergoing surgery and with 10-year follow-up data available were collected. Tissue genomic alterations were characterized using Trusight Oncology panel (TSO500). Pathway instability (PI) scores for a selection of 218 GC-related pathways were calculated both for the present case series and EGCs from the TCGA cohort. Results: Higher age and tumor location in the upper-middle tract are significantly associated with an increased hazard of relapse or death from any cause (p = 0.006 and p = 0.032). Even if not reaching a statistical significance, Pen A tumors more frequently present higher TMB values, higher frequency of MSI-subtypes and an overall increase in PI scores, along with an enrichment in immune pathways. ARID1A gene was observed to be significantly more frequently mutated in Pen A tumors (p = 0.006), as well as in patients with high TMB (p = 0.027). Tumors harboring LRP1B alterations seem to have a higher hazard of relapse or death from any cause (p = 0.089), being mutated mainly in relapsed patients (p = 0.093). Conclusions: We found that the most aggressive subtype Pen A is characterized by a higher frequency of ARID1A mutations and a higher genetic instability, while LRP1B alterations seem to be related to a lower disease-free survival. Further investigations are needed to provide a rationale for the use of these markers to stratify prognosis in EGC patients. [ABSTRACT FROM AUTHOR]

Background: Robot-assisted minimally invasive gastrectomy (RAMIG) is increasingly used as a surgical approach for gastric cancer. This study assessed the effectiveness of RAMIG and studied which stages of the IDEAL-framework (1 = Idea, 2A = Development, 2B = Exploration, 3 = Assessment, 4 = Long-term follow-up) were followed. Methods: The Cochrane Library, Embase, Pubmed, and Web of Science were searched for studies on RAMIG up to January 2023. Data collection included the IDEAL-stage, demographics, number of participants, and study design. For randomized controlled trials (RCTs) and long-term studies, data on intra-, postoperative, and oncologic outcomes, survival, and costs of RAMIG were collected and summarized. Results: Of the 114 included studies, none reported the IDEAL-stage. After full-text reading, 18 (16%) studies were considered IDEAL-2A, 75 (66%) IDEAL-2B, 4 (4%) IDEAL-3, and 17 (15%) IDEAL-4. The IDEAL-stages were followed sequentially (2A-4), with IDEAL-2A studies still ongoing. IDEAL-3 RCTs showed lower overall complications (8.5–9.2% RAMIG versus 17.6–19.3% laparoscopic total/subtotal gastrectomy), equal 30-day mortality (0%), and equal length of hospital stay for RAMIG (mean 5.7–8.5 days RAMIG versus 6.4–8.2 days open/laparoscopic total/subtotal gastrectomy). Lymph node yield was similar across techniques, but RAMIG incurred significantly higher costs than laparoscopic total/subtotal gastrectomy ($13,423–15,262 versus $10,165–10,945). IDEAL-4 studies showed similar or improved overall/disease-free survival for RAMIG. Conclusion: During worldwide RAMIG implementation, the IDEAL-framework was followed in sequential order. IDEAL-3 and 4 long-term studies showed that RAMIG is similar or even better to conventional surgery in terms of hospital stay, lymph node yield, and overall/disease-free survival. In addition, RAMIG showed reduced postoperative complication rates, despite higher costs. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics. [ABSTRACT FROM AUTHOR]

Background: In 2019, the Gastrectomy Complications Consensus Group (GCCG) published a standardized set of complications aiming toward uniform reporting of post-gastrectomy complications. This study aimed to report outcomes after gastrectomy in the Netherlands according to GCCG definitions and compare them to previously reported national results and the European database reported by the GCCG. Methods: This nationwide, population-based cohort study included all patients undergoing gastrectomy for gastric cancer registered in the DUCA in 2020–2021. Postoperative morbidity and 30-day/in-hospital mortality were analyzed according to the GCCG definitions. For all patients, baseline characteristics and outcomes were compared with the GCCG cohort consisting of 27 European expert centers (GASTRODATA; 2017–2018). Results: In 2020–2021, 782 patients underwent gastrectomy in the Netherlands. Variation was seen in baseline characteristics between the Dutch and the GCCG cohort (N = 1349), most notably in minimally invasive surgery (80.6% vs 19.6%, p < 0.001). In the Netherlands, 223 (28.5%) patients developed a total of 407 complications, the most frequent being non-surgical infections (28.5%) and anastomotic leakage (13.4%). The overall complication and 30-day mortality rates were similar between the Dutch and GCCG cohort (28.5% vs 29.8%, p = 0.563; 3.7% vs 3.6%, p = 0.953). Higher surgical and endoscopic/radiologic reintervention rates were observed in the Netherlands compared to the GCCG cohort (10.7% vs 7.8%, p = 0.025; 10.9% vs 2.9%, p < 0.001). Conclusion: Reporting outcomes according to the standardized GCCG definitions allows for international benchmarking. Postoperative outcomes were comparable between Dutch and GCCG cohorts, but both exceed the international benchmark for expert gastrectomy care, highlighting targets for national and international quality improvement. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine. [ABSTRACT FROM AUTHOR]

Background: Accurate prediction of pathologic results for early gastric cancer (EGC) based on endoscopic findings is essential in deciding between endoscopic and surgical resection. This study aimed to develop an artificial intelligence (AI) model to assess comprehensive pathologic characteristics of EGC using white-light endoscopic images and videos. Methods: To train the model, we retrospectively collected 4,336 images and prospectively included 153 videos from patients with EGC who underwent endoscopic or surgical resection. The performance of the model was tested and compared to that of 16 endoscopists (nine experts and seven novices) using a mutually exclusive set of 260 images and 10 videos. Finally, we conducted external validation using 436 images and 89 videos from another institution. Results: After training, the model achieved predictive accuracies of 89.7% for undifferentiated histology, 88.0% for submucosal invasion, 87.9% for lymphovascular invasion (LVI), and 92.7% for lymph node metastasis (LNM), using endoscopic videos. The area under the curve values of the model were 0.992 for undifferentiated histology, 0.902 for submucosal invasion, 0.706 for LVI, and 0.680 for LNM in the test. In addition, the model showed significantly higher accuracy than the experts in predicting undifferentiated histology (92.7% vs. 71.6%), submucosal invasion (87.3% vs. 72.6%), and LNM (87.7% vs. 72.3%). The external validation showed accuracies of 75.6% and 71.9% for undifferentiated histology and submucosal invasion, respectively. Conclusions: AI may assist endoscopists with high predictive performance for differentiation status and invasion depth of EGC. Further research is needed to improve the detection of LVI and LNM. [ABSTRACT FROM AUTHOR]

Background: For the elderly patients with gastric cancer, it may be more challenging to tolerate complete neoadjuvant therapy (NAT). The impact of discontinued NAT on the surgical safety and pathological outcomes of elderly patients with poor tolerance remains poorly understood. Methods: Gastric cancer patients received gastrectomy with curative intent from the Dutch upper GI cancer audit (DUCA) database were included in this study. The independent association of age with not initiating and discontinuation of NAT was assessed with restricted cubic splines (RCS). According to the RCS results, age ≥ 70 years was defined as elderly. Short-term postoperative outcomes and pathological results were compared between elderly patients who completed and discontinued NAT. Results: Between 2011- 2021, total of 3049 patients were included. The risk of not initiating NAT increased from 70 years. In 1954 (64%) patients receiving NAT, the risk of discontinuation increased from 55 years, reaching the peak around 74 years. In the elderly, discontinued NAT was not independently associated with worse 30-day mortality, overall complications, anastomotic leakage, re-intervention, and pathologic complete response, but was associated with a higher risk of R1/2 resection (p-value = 0.001), higher ypT stage (p-value = 0.004), ypN + (p-value = 0.008), and non-response (p-value = 0.012). Conclusion: A decreased utilization of NAT has been observed in Dutch gastric cancer patients from 70 years due to old age considerations, possibly because of their high risk of discontinuation. Increasing the utilization of NAT may not adversely impact the surgical safety of gastric cancer population ≥ 70 years and may contribute to better pathological results. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP) is a basic chemotherapy drug for gastric cancer (GC). With the increase of DDP drug concentration in clinical treatment, cancer cells gradually became resistant. Therefore, it is necessary to find effective therapeutic targets to enhance the sensitivity of GC to DDP. Studies have shown that Transmembrane protein 205 (TMEM205) is overexpressed in DDP-resistant human epidermoid carcinoma cells and correlates with drug resistance, and database analyses show that TMEM 205 is also overexpressed in GC, but its role in cisplatin-resistant gastric cancer remains unclear. In this study, we chose a variety of experiments in vivo and vitro, aiming to investigate the role of TMEM 205 in cisplatin resistance in gastric cancer. The results showed that TMEM 205 promoted proliferation, stemness, epithelial–mesenchymal transition (EMT), migration and angiogenesis of gastric cancer cells through activation of the Wnt/β-catenin signaling pathway. In addition, TMEM205 promotes GC progression by inducing M2 polarization of tumor-associated macrophages (TAMs). These results suggest that TMEM205 may be an effective target to regulate the sensitivity of GC to DDP, providing a new therapeutic direction for clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Limited data exist for global prevalence of claudin 18 isoform 2 (CLDN18.2) positivity and association of CLDN18.2 status with clinical and tumor characteristics in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. We report prevalence of CLDN18.2 positivity (phase 3; SPOTLIGHT, NCT03504397; GLOW, NCT03653507) and concordance of CLDN18.2 status between a subset of pair-matched tumor samples (phase 2, ILUSTRO, NCT03505320; phase 1, NCT03528629) from clinical studies of zolbetuximab. Methods: Tumor samples from patients with LA unresectable or mG/GEJ adenocarcinoma were tested for CLDN18.2 status by immunohistochemistry. Human epidermal growth factor receptor 2 (HER2) expression was tested per central or local assessment. Results: Across SPOTLIGHT and GLOW, the prevalence of CLDN18.2 positivity (≥ 75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 38.4%. Prevalence was similar in gastric versus GEJ adenocarcinoma samples and regardless of collection method (biopsy versus resection) or collection site (primary versus metastatic). CLDN18.2 positivity was most prevalent in patients with diffuse-type tumors. In ILUSTRO and the phase 1 study, concordance of CLDN18.2 positivity was 61.1% between archival (i.e., any time before treatment) and baseline (i.e., ≤ 3 months before first treatment) samples, and concordance of any CLDN18 staining (≥ 1% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 88.9%. Conclusions: CLDN18.2 was a highly prevalent biomarker in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 positivity remained relatively stable over time in many patients. Biomarker testing for CLDN18.2 should be considered in standard clinical practice in these patients. [ABSTRACT FROM AUTHOR]

Background: Adjuvant chemotherapy following curative surgery for locally advanced gastric cancer (AGC) significantly improves long-term patient prognosis. However, delayed chemotherapy (DC), in which patients are unable to receive timely treatment, is a common phenomenon in clinical practice for various reasons. This study aimed to investigate the impact of DC on the prognosis of patients with stage II–III locally AGC and explore the associated risk factors. Methods: Data from four prospective studies were included in the pooled analysis. The planned chemotherapy (PC) group was defined as the time interval between surgery and the first chemotherapy ≤ 49 d, while the DC group was defined as the time interval between surgery and chemotherapy > 49 d. The prognosis, recurrence, and risk factors were compared, and a nomogram for predicting DC was established. Results: In total, 596 patients were included, of whom 531 (89.1%) had PC and 65 (10.9%) had DC. Survival analysis revealed that the 5-year overall survival (OS) and disease-free survival (DFS) were significantly lower in the DC group than those in the PC group (log-rank P < 0.001). Cox univariable and multivariable analyses showed that DC was an independent risk factor for OS and DFS in stage II–III patients (P < 0.05). Based on the significant factors for DC, a prediction model was established that had a good fit, high accuracy (AUC = 0.780), and clinical applicability in both the training and validation sets. Conclusion: Delayed chemotherapy after gastrectomy is associated with poor long-term prognosis in patients with locally advanced stage II–III GC disease. But standardized, full-cycle adjuvant chemotherapy after surgery may play a remedial role, and can to a certain extent compensate the poor effects caused by delayed chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The CDKN2A gene is frequently affected by somatic copy number variations (SCNVs, including deletions and amplifications [SCNdel and SCNamp]) in the cancer genome. Using surgical gastric margin tissue samples (SMs) as the diploid reference in SCNV analysis via CDKN2A/P16-specific real-time PCR (P16-Light), we previously reported that the CDKN2A SCNdel was associated with a high risk of metastasis of gastric carcinoma (GC). However, the status of CDKN2A SCNVs in SMs and their clinical significance have not been reported. Methods: Peripheral white blood cell (WBC) and frozen GC and SM tissue samples were collected from patients (n = 80). Droplet digital PCR (ddPCR) was used to determine the copy number (CN) of the CDKN2A gene in tissue samples using paired WBCs as the diploid reference. Results: A novel P16-ddPCR system was initially established with a minimal proportion (or limit, 10%) of the detection of CDKN2A CN alterations. While CDKN2A SCNamp events were detected in both SMs and GCs, fewer CDKN2A SCNdel events were detected in SMs than in GCs (15.0% vs. 41.3%, P = 4.77E-04). Notably, significantly more SCNamp and fewer SCNdel of the CDKN2A gene were detected in SMs from GC patients without metastasis than in those from patients with lymph node metastasis by P16-ddPCR (P = 0.023). The status of CDKN2A SCNVs in SM samples was significantly associated with overall survival (P = 0.032). No cancer deaths were observed among the 11 patients with CDKN2A SCNamp. Conclusion: CDKN2A SCNVs in SMs identified by P16-ddPCR are prevalent and significantly associated with GC metastasis and overall survival. [ABSTRACT FROM AUTHOR]

Undifferentiated gastric carcinoma, characterized by anaplastic cells lacking distinct features of cytological or architectural differentiation, poses diagnostic and therapeutic challenges. Recent studies have suggested an association between this carcinoma and deficiencies in the SWI/SNF complex, particularly mutations in subunits such as SMARCA4. We herein report six cases of SMARCA4-deficient undifferentiated gastric carcinoma with molecular findings, highlighting the rarity and diagnostic pitfalls of this malignancy. Predominantly occurring in males over 50 years, these cases presented with nonspecific symptoms and were often diagnosed at an advanced stage. Histologically, the tumors exhibited a sheet-like growth pattern, reduced or absent epithelial markers, and loss of BRG-1 expression, with molecular analysis confirming SMARCA4 gene mutations. The response to conventional chemotherapy was poor, underscoring the importance of complete surgical resection and the development of alternative treatment modalities. [ABSTRACT FROM AUTHOR]

Background: While dietary salt intake has been linked with gastric cancer risk in Asian studies, findings from Western populations are sparse and limited to case—control studies. Our aim was to evaluate the frequency of adding salt to food at table in relation to gastric cancer risk among UK adults. Methods: We evaluated associations between the frequency of adding salt to food and the risk of gastric cancer in the UK Biobank (N = 471,144) using multivariable Cox regression. Frequency of adding salt to food was obtained from a touchscreen questionnaire completed at baseline (2006–2010). 24-h urinary sodium excretion was estimated using INTERSALT formulae. Cancer incidence was obtained by linkage to national cancer registries. Results: During a median follow-up period of 10.9 years, 640 gastric cancer cases were recorded. In multivariable models, the gastric cancer risk among participants reporting adding salt to food at table "always" compared to those who responded "never/rarely" was HR = 1.41 (95% CI: 1.04, 1.90). There was a positive linear association between estimated 24-h urinary sodium levels and the frequency of adding salt to food (p-trend <0.001). However, no significant association between estimated 24-h urinary sodium with gastric cancer was observed (HR = 1.19 (95% CI: 0.87, 1.61)). Conclusions: "Always adding salt to food" at table was associated with a higher gastric cancer risk in a large sample of UK adults. High frequency of adding salt to food at table can potentially serve as a useful indicator of salt intake for surveillance purposes and a basis for devising easy-to-understand public health messages. [ABSTRACT FROM AUTHOR]

Background: Microsatellite instability-high (MSI-H) tumors are distinct molecular subtypes in gastric cancer. However, a few studies have comprehensively reported the molecular features of MSI-H tumors and their prognostic factors in locally advanced gastric cancer. This study aimed to clarify the molecular features and prognostic factors of locally advanced MSI-H gastric cancer. Methods: This study included 499 patients with locally advanced gastric cancer who underwent radical gastrectomy. We evaluated the MSI status and compared with previously published whole-exome sequencing, panel sequencing, and gene expression profiling data. Clinicopathological characteristics and molecular profiles were compared between patients with MSI-H and microsatellite stable (MSS) gastric cancer. A subgroup analysis of survival was performed in patients with MSI-H gastric cancer. Results: MSI-H tumors were detected in 79 of 499 patients (15.8%). MSI-H tumors were associated with an increased tumor mutational burden, MLH1 downregulation, CD274 (PD-L1) upregulation, and enrichment of cell cycle pathways. Among patients with MSI-H gastric cancer, the disease-specific survival (DSS) tended to be better in the surgery plus tegafur, gimeracil, and oteracil potassium (S-1) adjuvant chemotherapy group than in the surgery alone group, especially for stage III patients. Furthermore, DSS was better in the T cell-inflamed gene expression signature-high group, and it tended to be worse in the non-solid type poorly differentiated adenocarcinoma group. Conclusions: The molecular features and prognostic factors of locally advanced MSI-H gastric cancer were clarified. S-1 adjuvant chemotherapy appears to be beneficial, and the T cell-inflamed gene expression signature and histopathological type are prognostic factors in MSI-H tumors. [ABSTRACT FROM AUTHOR]

Background: Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a heterogeneous GC subtype characterized by the overexpression of HER2. To date, few specific targeted therapies have demonstrated durable efficacy in HER2-positive GC patients, with resistance to trastuzumab typically emerging within 1 year. However, the mechanisms of resistance to trastuzumab remain incompletely understood, presenting a significant challenge to clinical practice. Methods: In this study, we integrated genetic screening and bulk transcriptome and epigenomic profiling to define the mechanisms mediating adaptive resistance to HER2 inhibitors and identify potential effective therapeutic strategies for treating HER2-positive GCs. Results: We revealed a potential association between adaptive resistance to trastuzumab in HER2-positive GC and the expression of YES-associated protein (YAP). Notably, our investigation revealed that long-term administration of trastuzumab triggers extensive chromatin remodeling and initiates YAP gene transcription in HER2-positive cells characterized by the initial inhibition and subsequent reactivation. Furthermore, treatment of HER2-positive GC cells and cell line-derived xenografts (CDX) models with YAP inhibitors in combination with trastuzumab was found to induce synergistic effects through the AKT/mTOR and ERK/mTOR pathways. Conclusion: These findings underscore the pivotal role of reactivated YAP and mTOR signaling pathways in the development of adaptive resistance to trastuzumab and may serve as a promising joint target to overcome resistance to trastuzumab. [ABSTRACT FROM AUTHOR]

Introduction: Gastric cancer with fusion genes involving the Rho GTPase-activating protein domain (RhoGAP-GC) is mainly included in the genomically stable type of The Cancer Genome Atlas classification. Clinical implications and histological characteristics of RhoGAP-GC in the early phase remain unclear. Methods: We analyzed 878 consecutive pT1b GCs for RhoGAP and its partner genes using fluorescence in situ hybridization assay. Results: RhoGAP fusion was detected in 57 (6.5%) GCs. Univariate analysis revealed that female sex, middle–lower third tumor location, advanced macroscopic type, tumor diameter > 2 cm, pT1b2, lymphatic invasion, venous invasion, negative EBER-ISH, and RhoGAP fusion were significantly associated with lymph node metastasis (LNM). Multivariate analysis presented RhoGAP fusion, lymphatic invasion, tumor diameter > 2 cm, advanced macroscopic type, venous invasion, and middle–lower third tumor location as independent risk factors for LNM. Notably, RhoGAP fusion had the highest odds ratio (3.92) for LNM among analyzed parameters (95% CI 2.12–7.27; p < 0.001). Compared to non-RhoGAP-GCs, RhoGAP-GCs were significantly frequent in younger females and showed the highest incidence of lymphatic invasion (56.2%) and LNM (49.1%) (p < 0.001). Histologically, microtubular architecture with pseudo-trabecular interconnection and small aggregations of tumor cells with a varied amount of cytoplasmic mucin, named "microtubular–mucocellular (MTMC) histology," was found in 93.0% (53 of 57) of RhoGAP-GCs in the intramucosal area. MTMC histology showed high sensitivity and negative predictive value (93.0% and 99.4%, respectively) for RhoGAP fusion, albeit positive predictive value is low (34.9%). Conclusion: RhoGAP-GC is linked to a characteristic MTMC histology and a high incidence of LNM. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer with peritoneal dissemination (PD) has a dismal prognosis, and current treatments have shown little efficacy. CLDN18.2-targeted therapies have shown promising efficacy against gastric cancers that express high levels of CLDN18. Because of the limited information regarding CLDN18.2 status in PD, we analyzed PD-positive gastric cancers for CLDN18 status in both primary and PD, along with HER2 and PD-L1 combined positive score (CPS). Methods: Immunohistochemical analyses were performed on 84 gastric cancer cases using paired primary and PD tissue samples. Results: At 40% cut-off, CLDN18 was positive in 57% (48/84) primary tumors and in 44% (37/84) PDs. At 75% cut-off, 28.6% (24/84) primary tumors and 20.2% (17/84) PDs were CLDN18-positive. The concordance rate between primary tumors and PD was 79.8% at 40% cut-off and 75% at 75% cut-off. When comparing biopsy and surgical specimens, the concordance rates were 87.5% at 40% cut-off and 81.3% at 75% cut-off. Within a tumor, the superficial area tended to have a higher CLDN18-positive rate than the invasive front (P = 0.001). Although HER2 -positivity was only 11.9% in this cohort, CLDN18 positivity in HER2-negative tumors (n = 74) was relatively high: 60.8% at 40% cut-off and 28.4% at 75% cut-off. Among double-negative (HER2 − and PD-L1 CPS < 1) tumors, CLDN18 positivity was 67.6% at 40% cut-off and 26.5% at 75% cut-off. Conclusions: CLDN18 expression is generally maintained in PD and is relatively high even in double-negative tumors, making it a promising therapeutic target for PD-positive gastric cancer. [ABSTRACT FROM AUTHOR]

Background: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). Methods: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed β-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. Results: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. Conclusions: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed. [ABSTRACT FROM AUTHOR]

Background: This study examined temporal shifts in adjuvant therapy patterns in Japanese patients with resectable gastric cancer (GC) and treatment patterns of first-line and subsequent therapy among those with recurrent disease. Methods: This retrospective analysis of hospital-based administrative claims data (April 1, 2008 to March 31, 2022) included adults (aged ≥ 20 years) with GC who started adjuvant therapy on or after October 1, 2008 (adjuvant cohort) and patients in the adjuvant cohort with disease recurrence (recurrent cohort), further defined by the time to recurrence (≤ 180 or > 180 days after adjuvant therapy). Results: In the adjuvant cohort (n = 17,062), the most common regimen during October 2008–May 2016 was tegafur/gimeracil/oteracil potassium (S-1; 95.7%). As new standard adjuvant regimen options were established, adjuvant S-1 use decreased to 65.0% and fluoropyrimidine plus oxaliplatin or docetaxel plus S-1 use increased to 15.0% and 20.0%, respectively, in September 2019–March 2022. In the recurrent cohort with no history of trastuzumab/trastuzumab deruxtecan treatment (n = 1257), the most common first-line regimens were paclitaxel plus ramucirumab (34.0%), capecitabine plus oxaliplatin (CapeOX; 17.0%), and nab-paclitaxel plus ramucirumab (10.1%) in patients with early recurrence, and S-1 plus oxaliplatin (26.3%), S-1 plus cisplatin (15.3%), CapeOX (14.0%), S-1 (13.2%), and paclitaxel plus ramucirumab (10.8%) in those with late recurrence. Conclusions: This study demonstrated temporal shifts in adjuvant treatment patterns that followed the establishment of novel regimens, and confirmed that post-recurrent treatment patterns were consistent with the Japanese Gastric Cancer Association guideline recommendations. [ABSTRACT FROM AUTHOR]

Background: The family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case–control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study. Methods: We included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes. Results: During the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32–1.58), similarly in males (1.44, 1.31–1.59) and females (1.45, 1.23–1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00–1.60) and non-cardia subsites (1.49, 1.35–1.65), and with intestinal- (1.48, 1.30–1.70) and diffuse-type (1.59, 1.35–1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19–1.41). Conclusions: In this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: While gastric cancer is generally declining globally, the temporal trend of young-onset (< 40 years) gastric cancer remains uncertain. We performed this analysis to determine the temporal trends of young-onset gastric cancer compared to late-onset cancer (≥ 40 years). Methods: We extracted cross-sectional data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. The burden of gastric cancer from 1990 to 2019 was assessed through indicators including incidence and mortality rates, which were classified at global, national, and regional levels, and according to socio-demographic indexes (SDI) and age or sex groups. Joinpoint regression analysis was used to identify specific years with significant changes. The correlation between AAPC with countries' average SDI was tested by Pearson's Test. Results: The global incidence rate of young-onset gastric cancer decreased from 2.20 (per 100,000) in 1990 to 1.65 in 2019 (AAPC: − 0.95; 95% confidence interval [CI] − 1.25 to − 0.65; P < 0.001). Late-onset cancer incidence also decreased from 59.53 (per 100,000) in 1990 to 41.26 in 2019 (AAPC: − 1.23; 95% CI − 1.39 to − 1.06, P < 0.001). Despite an overall decreasing trend, the incidence rate of young-onset cancer demonstrated a significant increase from 2015 to 2019 (annual percentage change [APC]: 1.39; 95% CI 0.06 to 2.74; P = 0.041), whereas no upward trend was observed in late-onset cancer. Mortality rates of young- and late-onset cancer both exhibited a significant decline during this period (AAPC: − 1.82; 95% CI − 2.15 to − 1.56; P < 0.001 and AAPC: − 1.69, 95% CI − 1.79 to − 1.59; P < 0.001). The male-to-female rate ratio for incidence and mortality in both age groups have been increasing since 1990. While countries with high SDI have had a greater decline in the incidence of late-onset gastric cancer (slope of AAPC change: − 0.20, P = 0.004), it was not observed in young-onset cancer (slope of AAPC change: − 0.11, P = 0.13). Conclusions: The global incidence and mortality rates of both young- and late-onset gastric cancer have decreased since 1990. However, the incidence rate of young-onset cancer has demonstrated a small but significant upward trend since 2015. There was disparity in the decline in young-onset gastric cancer among male and high SDI countries. These findings could help to inform future strategies in preventing gastric cancer in younger individuals. [ABSTRACT FROM AUTHOR]

Background and aims: When treating undifferentiated-type early gastric cancer (UD-EGC) that is limited to the mucosa (clinically T1a), endoscopic submucosal dissection (ESD) can be considered if the tumor is 2 cm or less and is not ulcerated. However, there is insufficient evidence to determine the relationships between tumor size and oncological safety of ESD in UD-EGC. Methods: The pathology reports of Korean patients who were diagnosed with UD-EGC (n = 5286) were retrospectively reviewed. The cumulative incidence of lymph node metastasis (LNM) according to tumor size was evaluated in subgroups. The tumor-size cut-off was identified as the upper limit of the 95% confidence interval (CI) of cumulative LNM incidence that did not exceed 1.0%. Results: We identified 1516 patients with non-ulcerated T1a tumors ≤2 cm in size. Among patients without lymphatic invasion, 1.5% (95% CI 0.91–2.16%) had LNM. In patients with poorly differentiated tubular adenocarcinoma (PD), LNM increased from 0 to 0.74% based on a tumor size of 1.0 cm. Regardless of tumor size, smaller percentages of undifferentiated-type (UD) and poorly cohesive carcinoma (PCC) patients experienced LNM than did those with PD. In non-ulcerated mucosal cancer without lymphatic invasion and tumor size ≤0.9 cm, no LNM was observed in patients with UD (95% CI 0–0.53%), PCC (95% CI 0–0.59%), or PD (95% CI 0–0.86%) histologic type. Conclusion: In patients diagnosed with non-ulcerated T1a UD-EGC, ESD can be performed if the tumor size is 0.9 cm or less, regardless of histologic type. [ABSTRACT FROM AUTHOR]

Background: During sentinel node navigation surgery in patients with gastric cancer, intraoperative pathologic examination of sentinel nodes is crucial in determining the extent of surgery. In this study, we evaluated the feasibility and accuracy of intraoperative pathologic protocols using data from a prospective, multicenter, randomized trial. Methods: A retrospective analysis was conducted using data from the SEntinel Node ORIented Tailored Approach trials from 2013 to 2016. All sentinel lymph nodes were evaluated during surgery with hematoxylin–eosin (HE) staining using a representative section at the largest plane for lymph nodes. For permanent histologic evaluation, sentinel basin nodes were stained with HE and cytokeratin immunohistochemistry in formalin-fixed, paraffin-embedded (FFPE) sections and examined with HE for three deeper-step sections at 200-μm intervals. The failure rate of identification by frozen section and the metastasis rate in non-sentinel basins were investigated. Results: Of the 237 patients who underwent sentinel node basin dissection, 30 had lymph node metastases on permanent pathology. Thirteen patients had macrometastasis confirmed in frozen sections as well as FFPE sections (failure rate: 0%). Patients with negative sentinel nodes in frozen sections but micrometastasis in FFPE sections had no lymph node recurrence during the follow-up period (0%, 0/6). However, in cases with tumor-positive nodes in frozen sections, metastases in non-sentinel basins were detected in the paraffin blocks (8.3%, 2/24). Conclusions: The single-section HE staining method is sufficient for detecting macrometastasis via intraoperative pathological examination. If a negative frozen-section result is confirmed, sentinel basin dissection can be performed safely. Otherwise, standard surgery is required. [ABSTRACT FROM AUTHOR]

Background: The EORTC QLQ-STO22 (QLQ-STO22) is a firmly established and validated measure of health-related quality of life (HRQoL) for people with gastric cancer (GC), developed over two decades ago. Since then there have been dramatic changes in treatment options for GC. Also, East Asian patients were not involved in the development of QLQ-STO22, where GC is most prevalent and the QLQ-STO22 is widely used. A review with appropriate updating of the measure was planned. This study aims to capture HRQoL issues associated with new treatments and the perspectives of patients and health care professionals (HCPs) from different cultural backgrounds, including East Asia. Methods: A systematic literature review and open-ended interviews were preformed to identify potential new HRQoL issues relating to GC. This was followed by structured interviews where HCPs and patients reviewed the QLQ-STO22 alongside new issues regarding relevance, importance, and acceptability. Results: The review of 267 publications and interviews with 104 patients and 18 HCPs (48 and 9 from East Asia, respectively) generated a list of 58 new issues. Three of these relating to eating small amounts, flatulence, and neuropathy were recommended for inclusion in an updated version of the QLQ-STO22 and covered by five additional questions. Conclusions: This study supports the content validity of the QLQ-STO22, suggesting its continued relevance to patients with GC, including those from East Asia. The updated version with additional questions and linguistic changes will enhance its specificity, but further testing is required. [ABSTRACT FROM AUTHOR]

Background: 5-Hydroxymethylcytosine-enriched gene profiles and regions show tissue-specific and tumor specific. There is a potential value to explore cell-free DNA 5-hydroxymethylcytosine feature biomarkers for early gastric cancer detection. Methods: A matched case‒control study design with 50 gastric cancer patients and 50 controls was performed to sequence the different 5-hydroxymethylcytosine modification features of cell free DNA. Significantly differential 5-hydroxymethylcytosine modification genes were identified to construct a gastric cancer diagnostic model. Data set from GEO was used as an external testing set to test the robustness of the diagnostic model. Results: Accounting for more than 90% of 5-hydroxymethylcytosine peaks were distributed in the gene body in both the gastric cancer and control groups. The diagnostic model was developed based on five different 5-hydroxymethylcytosine modification genes, FBXL7, PDE3A, TPO, SNTG2 and STXBP5. The model could effectively distinguish gastric cancer patients from controls in the training (AUC = 0.95, sensitivity = 88.6%, specificity = 94.3%), validation (AUC = 0.87, sensitivity = 73.3%, specificity = 93.3%) and testing (AUC = 0.90, sensitivity = 81.9%, specificity = 90.2%) sets. The risk scores of the controls from the model were significantly lower than those of gastric cancer patients in both our own data (P < 0.001) and GEO external testing data (P < 0.001), and no significant difference between different TNM stage patients (P = 0.09 and 0.66). Furthermore, there was no significant difference between the healthy control and benign gastric disease patients in the testing set from GEO (P = 0.10). Conclusions: The characteristics of 5-hydroxymethylcytosine in cell free DNA are specific to gastric cancer patients, and the diagnostic model constructed by five genes' 5-hydroxymethylcytosine features could effectively identify gastric cancer patients. [ABSTRACT FROM AUTHOR]

Background: Although endoscopy is commonly used for gastric cancer screening in South Korea, predictive models that integrate endoscopy results are scarce. We aimed to develop a 5-year gastric cancer risk prediction model using endoscopy results as a predictor. Methods: We developed a predictive model using the cohort data of the Kangbuk Samsung Health Study from 2011 to 2019. Among the 260,407 participants aged ≥20 years who did not have any previous history of cancer, 435 cases of gastric cancer were observed. A Cox proportional hazard regression model was used to evaluate the predictors and calculate the 5-year risk of gastric cancer. Harrell's C-statistics and Nam-D'Agostino χ2 test were used to measure the quality of discrimination and calibration ability, respectively. Results: We included age, sex, smoking status, alcohol consumption, family history of cancer, and previous results for endoscopy in the risk prediction model. This model showed sufficient discrimination ability [development cohort: C-Statistics: 0.800, 95% confidence interval (CI) 0.770–0.829; validation cohort: C-Statistics: 0.799, 95% CI 0.743–0.856]. It also performed well with effective calibration (development cohort: χ2 = 13.65, P = 0.135; validation cohort: χ2 = 15.57, P = 0.056). Conclusion: Our prediction model, including young adults, showed good discrimination and calibration. Furthermore, this model considered a fixed time interval of 5 years to predict the risk of developing gastric cancer, considering endoscopic results. Thus, it could be clinically useful, especially for adults with endoscopic results. [ABSTRACT FROM AUTHOR]

Background: We examined the impact of mismatch repair (MMR) status on efficacy of first-line fluoropyrimidine plus platinum (FP) chemotherapy in patients with HER2-negative metastatic, recurrent, or unresectable gastric cancer (mGC). Methods: Patients with mGC receiving first-line FP between 2015 and 2018 at Asan Medical Center, Korea, were reviewed. We evaluated the clinical characteristics and the efficacy of chemotherapy according to MMR status in patients with available immunohistochemistry results. Results: Of 895 patients, we analyzed 543 with available MMR protein expression results, and deficient MMR (dMMR) was detected in 4.4% (n = 24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p = 0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR. Objective response rate was 27.3% in dMMR and 34.3% in pMMR (p = 0.556). No difference in progression-free survival was noted between patients with dMMR and pMMR (median, 5.6 vs. 5.8 months, p = 0.266). Patients with dMMR tended to have better overall survival than those with pMMR although this difference was not statistically significant (median, 17.9 vs. 12.2 months, p = 0.183). Conclusions: Efficacy of first-line FP was not different by MMR status in mGC patients. [ABSTRACT FROM AUTHOR]

Background: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible. Methods: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement. Results: The assembly agreed to define oligometastases as a "dynamic" disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy. Conclusion: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a poor prognosis for patients with advanced disease. Since the oncogenic role of KRAS mutants has been poorly investigated in GC, this study aims to biochemically and biologically characterize different KRAS-mutated models and unravel differences among KRAS mutants in response to therapy. Methods: Taking advantage of a proprietary, molecularly annotated platform of more than 200 GC PDXs (patient-derived xenografts), we identified KRAS-mutated PDXs, from which primary cell lines were established. The different mutants were challenged with KRAS downstream inhibitors in in vitro and in vivo experiments. Results: Cells expressing the rare KRAS A146T mutant showed lower RAS-GTP levels compared to those bearing the canonical G12/13D mutations. Nevertheless, all the KRAS-mutated cells displayed KRAS addiction. Surprisingly, even if the GEF SOS1 is considered critical for the activation of KRAS A146T mutants, its abrogation did not significantly affect cell viability. From the pharmacologic point of view, Trametinib monotherapy was more effective in A146T than in G12D-mutated models, suggesting a vulnerability to MEK inhibition. However, in the presence of mutations in the PI3K pathway, more frequently co-occurrent in A146T models, the association of Trametinib and the AKT inhibitor MK-2206 was required to optimize the response. Conclusion: A deeper genomic and biological characterization of KRAS mutants might sustain the development of more efficient and long-lasting therapeutic options for patients harbouring KRAS-driven GC. [ABSTRACT FROM AUTHOR]

Standard adjuvant treatment for locally advanced gastric cancer (LAGC) is regionally different. Whereas perioperative chemotherapy is the standard in Western populations, D2 gastrectomy followed by adjuvant chemotherapy has been the standard in East Asia. Recently, the pivotal phase 3 PRODIGY and RESOLVE studies have demonstrated survival benefits of adding neoadjuvant chemotherapy to surgery followed by adjuvant chemotherapy over up-front surgery followed by adjuvant chemotherapy in Asian patients. Based on these results, neoadjuvant chemotherapy is considered one of the viable options for patients with LAGC. In this review, various aspects of neoadjuvant chemotherapy will be discussed for its optimal application in Asia. Candidates for neoadjuvant chemotherapy should be carefully chosen in consideration of the inaccurate aspects of radiological clinical staging and its potential benefit over up-front surgery followed by a decision on adjuvant chemotherapy according to the pathological stage. Efforts should continuously be made to optimally apply neoadjuvant chemotherapy to patients with LAGC, considering various factors, including a more accurate radiological assessment of the tumor burden and the optimization of post-operative chemotherapy. Future neoadjuvant trials involving novel agents for Asian patients should be designed based on proven Asian regimens rather than adopting Western regimens. [ABSTRACT FROM AUTHOR]

Background: Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets. Methods: Killer cell lectin-like receptor G2 (KLRG2) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated KLRG2 knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor KLRG2 mRNA expression. Results: KLRG2 knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G2/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by KLRG2 knockdown. High tumor levels of KLRG2 mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I–III GC (5-year OS rate: 64.4% vs. 80.0%, P = 0.009; 5-year RFS rate: 62.8% vs. 78.1%, P = 0.030). Conclusions: KLRG2 knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC. [ABSTRACT FROM AUTHOR]

Background: PET–CT-based patient metabolic profiling is a novel concept to incorporate patient-specific metabolism into gastric cancer care. Methods: Staging PET–CTs, demographics, and clinicopathologic variables of gastric cancer patients were obtained from a prospectively maintained institutional database. PET–CT avidity was measured in tumor, liver, spleen, four paired muscles, and two paired fat areas in each patient. The liver to rectus femoris (LRF) ratio was defined as the ratio of SUVmean of liver to the average SUVmean of the bilateral rectus femoris muscles. Kaplan–Meier and Cox-proportional hazards models were used to identify the impact of LRF ratio on OS. Results: Two hundred and one patients with distal gastroesophageal (48%) or gastric (52%) adenocarcinoma were included. Median age was 65 years, and 146 (73%) were male. On univariate analysis, rectus femoris PET–CT avidity and LRF ratio were significantly associated with overall survival (p < 0.05). LRF ratio was significantly higher in males, early-stage cancer, patients with an ECOG 0 or 1 performance status, patients with albumin > 3.5 mg/dL, and those with moderately differentiated tumor histology. In multivariable regression, gastric cancer stage, albumin, and LRF ratio were significant independent predictors of overall survival (LRF ratio HR = 0.73 (0.56–0.96); p = 0.024). Survival curves showed that the prognostic impact of LRF was associated with metastatic gastric cancer (p = 0.009). Conclusions: Elevated LRF ratio, a patient-specific PET–CT-based metabolic parameter, was independently associated with an improvement in OS in patients with metastatic gastric cancer. With prospective validation, LRF ratio may be a useful, host-specific metabolic parameter for prognostication in gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer with peritoneal metastasis (PM-GC), recognized as one of the deadliest cancers. However, whether and how the tumor cell-extrinsic tumor microenvironment (TME) is involved in the therapeutic failure remains unknown. Thus, this study systematically assessed the immunosuppressive tumor microenvironment in ascites from patients with PM-GC, and its contribution to dissemination and immune evasion of ascites-disseminated tumor cells (aDTCs). Methods: Sixty-three ascites and 43 peripheral blood (PB) samples from 51 patients with PM-GC were included in this study. aDTCs in ascites and circulating tumor cells (CTCs) in paired PB were immunophenotypically profiled. Using single-cell RNA transcriptional sequencing (scRNA-seq), crosstalk between aDTCs and the TME features of ascites was inspected. Further studies on the mechanism underlying aDTCs-immune cells crosstalk were performed on in vitro cultured aDTCs. Results: Immune cells in ascites interact with aDTCs, prompting their immune evasion. Specifically, we found that the tumor-associated macrophages (TAMs) in ascites underwent a continuum lineage transition from cathepsinhigh (CTShigh) to complement 1qhigh (C1Qhigh) TAM. CTShigh TAM initially attracted the metastatic tumor cells to ascites, thereafter, transitioning terminally to C1Qhigh TAM to trigger overproliferation and immune escape of aDTCs. Mechanistically, we demonstrated that C1Qhigh TAMs significantly enhanced the expression of PD-L1 and NECTIN2 on aDTCs, which was driven by the activation of the C1q-mediated complement pathway. Conclusions: For the first time, we identified an immunosuppressive macrophage transition from CTShigh to C1Qhigh TAM in ascites from patients with PM-GC. This may contribute to developing potential TAM-targeted immunotherapies for PM-GC. Schematic of the immune TME of ascites and the crosstalk with aDTCs in patients with PM-GC. In ascites with TAM-dominant TME, the ascitic TAMs undergo CTS-to-C1Q transition to support multiple phases of aDTC dissemination, including aDTC homing, proliferation, immune escape, and therapeutic resistance. While in ascites with T-cell-dominant TME, enriched T cells do not imply "immune-hot" TME. Infiltrated CD8+ T cells are GZMK+ precursor-exhausted cells that have lost their capacity to kill tumor cells. (Abbreviations: aDTC ascites-disseminated tumor cells, CTS cathepsin, TAM Tumor-associated macrophages, TME tumor microenvironment) [ABSTRACT FROM AUTHOR]

Background: Fluorescent lymphography (FL) using indocyanine green (ICG) allows for the visualization of all draining lymph nodes (LNs), thereby increasing LN retrieval. However, no studies have assessed the efficacy of FL in high body mass index (BMI) gastric cancer patients, even as LN yield decreases with increasing BMI in gastrectomy. This study aimed to investigate the influence of FL on LN retrieval in high BMI gastric cancer patients. Methods: Gastric cancer patients who underwent laparoscopic or robotic gastrectomies from 2013 to 2021 were included. Patients were classified into two groups, with FL (FL group) or without FL (non-FL group). The effect of FL on LN retrieval was assessed by BMI. Inverse probability of treatment weighting (IPTW) was used to ensure comparability between groups. Results: Retrieved LN number decreased as BMI increased regardless of FL application (P < 0.001). According to the IPTW analysis, the mean retrieved LN number was significantly higher in the FL group (48.4 ± 18.5) than in the non-FL group (39.8 ± 16.3, P < 0.001), irrespective of BMI. The FL group exhibited a significantly higher proportion of patients with 16 or more LNs (99.5%) than the non-FL group (98.1%, P < 0.001). The FL group also had a significantly higher proportion of patients with 30 or more LNs (86.6%) than the non-FL group (72.2%, P < 0.001). In both the normal and high-BMI patients, the FL group had a significantly larger percentage of patients with a higher nodal classification than the non-FL group. Conclusion: FL resulted in more LN retrieval, even in high BMI patients. FL ensures accurate staging by maintaining the appropriate retrieved LN number in high BMI gastric cancer patients. [ABSTRACT FROM AUTHOR]

Background: HER2-targeted therapies have improved the outcomes of HER2-positive gastric cancer (GC), yet resistance remains a challenge. We sought to explore the effects of reversible and irreversible HER2 tyrosine kinase inhibitors (TKIs) alone or in combination with the HER2-targeting antibody drug conjugate trastuzumab deruxtecan (T-Dxd). Methods: The effects of HER2-TKIs on HER2 and downstream signaling were evaluated via Western blotting. Proteasomal inhibitors and co-immunoprecipitation assays were performed to explore the role of proteasomal degradation in HER2 expression modulation, and immunofluorescence assays were employed to explore mechanisms of HER2 internalization. The synergistic potential of the irreversible HER2-TKI pyrotinib in combination with T-Dxd was validated using growth and viability assays in anti-HER2-positive GC cell cultures and tumor growth and immunohistochemical staining assays in a mouse xenograft model. Results: Our study revealed that reversible HER2-TKIs elevated HER2 protein levels, whereas irreversible HER2-TKIs decreased them. Pyrotinib triggered HER2 degradation within the proteasome by promoting ubiquitination and dissociation from HSP90. Furthermore, pyrotinib substantially induced HER2 internalization, which led to improved cellular uptake of T-Dxd. The increased T-Dxd uptake was accompanied by greater efficacy in suppressing the growth of GC cells and enhanced anti-tumor effects in an animal model. Conclusion: In summary, our research reveals the molecular mechanisms of irreversible HER2-TKIs in regulating HER2 protein expression by promoting HER2 internalization. These findings advance our comprehension of targeted therapy for GC and provide a promising therapeutic combination strategy with enhanced efficacy against HER2-positive GC. [ABSTRACT FROM AUTHOR]

Background: The relationship between high-density lipoprotein cholesterol (HDL-C) and gastroesophageal cancer is not constant. Methods: In this population-based cohort study, 4.518 million cancer-free individuals among those who underwent national cancer screening in 2010 were enrolled and followed up until December 2017. HDL-C level was classified into eight groups at 10 mg/dL intervals. The risk of gastroesophageal cancers by HDL-C was measured using adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Results: During 8 years of follow-up, 38,362 gastric and 3022 esophageal cancers developed. Low HDL-C level was associated with an increased risk of gastric cancer; aHR was 1.19 (95% CI 1.09–1.30) for HDL-C < 30 mg/dL, 1.07 (95% CI 1.03–1.12) for HDL-C of 30–39 mg/dL, and 1.07 (95% CI 1.03–1.12) for HDL-C of 40–49 mg/dL comparing to HDL-C of 60–69 mg/dL. HDL-C was positively associated with esophageal cancer risk; aHR was 1.30 (1.12–1.51) for HDL-C of 70–79 mg/dL, 1.84 (1.53–2.22) for HDL-C of 80–89 mg/dL, 2.10 (1.67–2.61) for HDL-C ≥ 90 mg/dL. These site-specific effects of HDL-C were robust in sensitivity analyses. The range of HDL-C for the lowest cancer risk was different by sex and site. The hazardous effect of low HDL-C on gastric cancer was prominent in never and past smokers, and extremely high HDL-C increased gastric cancer risk (aHR 1.19; 95% CI 1.04–1.36) only in current smokers. Unfavorable effect of high HDL-C on gastroesophageal cancer risk was remarkable in smokers. Conclusions: Low HDL-C increased the risk of gastric cancer, wherein high HDL-C was associated with esophageal cancer risk with discrepancies by sex and smoking status. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest that dietary vitamin C is inversely associated with gastric cancer (GC), but most of them did not consider intake of fruit and vegetables. Thus, we aimed to evaluate this association within the Stomach cancer Pooling (StoP) Project, a consortium of epidemiological studies on GC. Methods: Fourteen case–control studies were included in the analysis (5362 cases, 11,497 controls). We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the association between dietary intake of vitamin C and GC, adjusted for relevant confounders and for intake of fruit and vegetables. The dose–response relationship was evaluated using mixed-effects logistic models with second-order fractional polynomials. Results: Individuals in the highest quartile of dietary vitamin C intake had reduced odds of GC compared with those in the lowest quartile (OR: 0.64; 95% CI: 0.58, 0.72). Additional adjustment for fruit and vegetables intake led to an OR of 0.85 (95% CI: 0.73, 0.98). A significant inverse association was observed for noncardia GC, as well as for both intestinal and diffuse types of the disease. The results of the dose–response analysis showed decreasing ORs of GC up to 150–200 mg/day of vitamin C (OR: 0.54; 95% CI: 0.41, 0.71), whereas ORs for higher intakes were close to 1.0. Conclusions: The findings of our pooled study suggest that vitamin C is inversely associated with GC, with a potentially beneficial effect also for intakes above the currently recommended daily intake (90 mg for men and 75 mg for women). [ABSTRACT FROM AUTHOR]

Gastric cancer is the fifth most common cancer diagnosis and fourth leading cause of cancer-related death globally. The incidence of gastric cancer in the USA shows significant racial and ethnic disparities with gastric cancer incidence in Korean Americans being over five times higher than in non-Hispanic whites. Since gastric cancer is not common in the USA, there are no current screening guidelines. In countries with higher incidences of gastric cancer, screening guidelines have been implemented for early detection and intervention and this has been associated with a reduction in mortality. Immigrants from high incidence countries develop gastric cancer at lower rates once outside of their country of origin, but continue to be at higher risk for developing gastric cancer. This risk does seem to decrease with subsequent generations. With increasing availability of endoscopy, initiating gastric cancer screening guidelines for high-risk groups can have the potential to improve survival by diagnosing and treating gastric cancer at an earlier stage. This article aims to provide context to gastric cancer epidemiology globally, review risk factors for developing gastric cancer, highlight racial and ethnic disparities in gastric cancer burden in the USA, examine current guidelines that exist in high incidence countries, and suggest future studies examining the efficacy of additional screening in high-risk populations to reduce gastric cancer mortality and disparate burden on ethnic minorities in the USA. [ABSTRACT FROM AUTHOR]

Background: The relationship between preoperative prealbumin levels and long-term prognoses in patients with gastric cancer after gastrectomy has not been fully investigated. This study clarified the effect of preoperative prealbumin levels on the long-term prognosis of patients with gastric cancer after gastrectomy. Methods: This retrospective cohort study included consecutive patients who underwent radical gastrectomy for primary pStage I–III gastric cancer and whose preoperative prealbumin levels were measured between May 2006 and March 2017. Participants were categorized according to their preoperative prealbumin levels into high (≥22 mg/dL), moderate (15–22 mg/dL), and low (<15 mg/dL) groups. The overall survival (OS) in the three groups was compared using the log-rank test, and prognostic factors were identified using Cox proportional hazards regression analysis. Results: The median follow-up duration was 66 months. Of 4732 patients, 3649 (77.2%) were classified as high, 925 (19.6%) as moderate, and 158 (3.3%) as low. Lower prealbumin levels were associated with poorer prognoses (P < 0.001). Multivariate analysis showed that prealbumin levels of 15–22 mg/dL [hazard ratio (HR): 1.576, 95% confidence interval (CI): 1.353–1.835, P < 0.001] and <15 mg/dL (HR: 1.769, 95% CI: 1.376–2.276, P < 0.001) were independent poor prognostic factors for OS. When analyzed according to the cause of death, prealbumin levels were associated with other-cause survival, but not cancer-specific survival. Conclusions: Preoperative prealbumin levels correlated with OS in patients with gastric cancer after gastrectomy; the lower the prealbumin level, the worse is the prognosis. Prealbumin levels may be associated with other-cause survival. [ABSTRACT FROM AUTHOR]