PURPOSE:We identified the risk factors for remnant gastric cancer (RGC) based on remnant gastric mucosal characteristics and gastritis morphology in patients undergoing distal gastrectomy. MATERIALS AND METHODS:This multicenter retrospective study included 100 patients with RGC after distal gastrectomy and 550 patients without RGC treated between 2013 and 2020. Endoscopic findings, including anastomotic redness, red streaks, enlarged folds, bile reflux as anastomotic findings, as well as disappearance of the regular arrangement of collecting venules (RAC), atrophic gastritis, and intestinal metaplasia as background gastric mucosal findings, were evaluated. Disease risk score matching (1:1) was adjusted for baseline characteristics. Logistic regression analysis was used to develop a risk score model to stratify RGC risk into low, moderate, and high categories. RESULTS:After matching, 96 patients with RGC and 96 controls were analyzed. Anastomotic redness and red streaks, as well as the disappearance of RAC and atrophic gastritis, were significantly more frequent in the RGC group than in the control group, whereas enlarged folds and bile reflux showed no significant differences. Risk scores were assigned as follows: anastomotic redness, 2; red streaks, 3; disappearance of RAC, 7; and atrophic gastritis, 3. The total score stratified patients into high (≥15), moderate (7-14), and low risk (≤6). The positive and negative predictive values were 67.7% and 83.3%, respectively. CONCLUSIONS:The endoscopic findings of anastomotic redness, red streaks, RAC disappearance, and atrophic gastritis were significantly associated with RGC development. The proposed risk-scoring model could serve as a stratification tool for RGC surveillance. TRIAL REGISTRATION:University Hospital Medical Information Network Identifier: UMIN000055884.
Purpose: Patient-derived cells (PDCs) and patient-derived organoids (PDOs) are complementary preclinical models widely used in translational cancer research. However, their molecular and functional differences have not been systematically characterized. This study established and analyzed paired PDC and PDO models derived from the same gastric cancer ascites to delineate platform-dependent molecular and functional profiles. Materials and Methods: Malignant ascites or pleural fluid obtained from 6 patients with advanced gastric cancer were used to establish paired PDC and PDO models. All pairs underwent comprehensive multi-omics profiling, integrating genomic, transcriptomic, and proteomic data. Phenotypic characterization included morphological, histological, proliferative, and cell cycle analyses. Drug sensitivity assays were performed using 4 chemotherapeutic agents commonly used to treat gastric cancer. Results: The 6 paired PDC and PDO models exhibited distinct morphological characteristics. Whole-genome analyses demonstrated high concordance among primary tumors, PDCs, and PDOs, confirming tumor representation across platforms. Multi-omics profiling identified platform-dependent molecular signatures; PDOs were enriched for extracellular matrix remodeling and stemness, whereas PDCs displayed proliferation-and immune-related signatures. Clinically relevant biomarkers, including HER2 and MET alterations, were concordant with primary tumors. Notably, drug responses differed between platforms and patients, indicating platform-dependent and patient-specific chemosensitivity. Conclusions: Paired PDC and PDO models derived from the same patients preserved core patient-specific tumor characteristics while exhibiting distinct molecular and functional profiles. These findings underscore the culture platform as a critical determinant of experimental outcomes and therapeutic responses. Therefore, careful selection of an appropriate preclinical model is essential to accurately address biological questions and optimize precision oncology strategies.
Although the clinical importance of esophagogastric junction (EGJ) cancer is being increasingly recognized, its definition and treatment strategies vary considerably across regions. Recently, new concepts such as the gastroesophageal junction zone have been proposed for classification of EGJ cancer. Moreover, EGJ adenocarcinoma has been shown to possess a heterogeneous molecular profile consisting of both esophageal- and gastric-like phenotypes, indicating the need for EGJ-specific therapeutic strategies. Although international clinical practice guidelines for EGJ cancer have been published, substantial regional differences remain. This review aimed to summarize recent updates on the biological characteristics and management of EGJ cancers. Trials such as TIME and MIRO have demonstrated that minimally invasive surgery (MIS) reduces postoperative complications and improves the early postoperative quality of life. More recently, the MONET trial showed that MIS is not inferior to open esophagectomy in terms of long-term oncological outcomes, and the REVATE trial demonstrated the advantages of robot-assisted surgery over thoracoscopic approaches. Perioperative treatment strategies also differ across regions. Western guidelines recommend 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT)-based perioperative chemotherapy, as supported by the FLOT4 and ESOPEC trials, whereas Asian studies, such as RESOLVE and PRODIGY, have demonstrated the efficacy of docetaxel, oxaliplatin, and S-1 or S-1 plus oxaliplatin regimens. The application of immune checkpoint inhibitors is also evolving; although KEYNOTE-585 did not show a survival advantage, the MATTERHORN trial demonstrated that durvalumab plus FLOT significantly improved event-free survival, establishing a new emerging global standard. Future directions include redefining EGJ classification, implementing molecular-guided treatment selection, advancing organ-preserving strategies, and optimizing perioperative immunochemotherapy.
Purpose: Immune checkpoint inhibitor plus chemotherapy is the standard first-line treatment for advanced gastric cancer; however, predictive biomarkers for optimal patient selection remain unsatisfactory. This study was aimed at evaluating the predictive value of tumor mutational burden (TMB) and insertion/deletion (Indel) rate in patients with gastric cancer treated with nivolumab plus chemotherapy. Materials and Methods: This retrospective study included 132 patients with gastric cancer treated with first-line nivolumab plus chemotherapy and 185 patients treated with chemotherapy alone, all of whom had next-generation sequencing data available. The TMB and Indel cut-offs were set at 15.63 mutations per megabase and 18.19%, respectively, as determined based on their ability to best distinguish progression-free survival (PFS) among the patients who received nivolumab plus chemotherapy. Results: PFS was favorable for nivolumab and chemotherapy than for chemotherapy alone in both the high and low TMB groups; nevertheless, survival benefits were observed only in the high Indel group. Among the subgroups defined based on both TMB and Indel rates, the high TMB and high Indel rate subgroup showed the greatest benefit from nivolumab plus chemotherapy compared with that from chemotherapy alone. The benefit of this subgroup remained significant in patients with proficient mismatch repair (MMR) tumors, whose survival outcomes were comparable to those of patients with deficient MMR tumors. Among patients treated with nivolumab plus chemotherapy, high TMB and Indel rate were independently associated with favorable survival outcomes. Conclusions: Thus, Indel rate, particularly in combination with TMB, may be a promising predictive biomarker for gastric cancer. However, further validation of their predictive value is warranted.
Purpose: Due to the preservation of the entire stomach after endoscopic resection, the occurrence of metachronous gastric cancer (MGC) remains a possibility. In this study, we investigated the incidence and risk factors for MGC in patients with early gastric cancer who underwent endoscopic submucosal dissection (ESD) and successfully eradicated Helicobacter pylori. Materials and Methods: A retrospective analysis was conducted of 1,191 patients who underwent ESD and successfully eradicated H. pylori at the Affiliated Drum Tower Hospital of Nanjing University. Endoscopic surveillance was performed at 3, 6, and 12 months post-resection, and annually thereafter. MGC was defined as the development of a new cancer at a site other than the primary gastric cancer site, at least 1 year after the initial endoscopic resection. Results: A total of 77 patients were diagnosed with MGC during a median follow-up of 41.5 months. Kaplan-Meier analysis showed a 5-year cumulative incidence of MGC of 9.4% after successful H. pylori eradication. Multivariate analysis of the training set using Cox proportional hazards models identified male sex, severe atrophic gastritis, multiple gastric cancers before H. pylori eradication, and smoking history as independent risk factors for MGC. The nomogram exhibited favorable discrimination, with area under the curves of 0.767 and 0.822 in the training set and 0.724 and 0.745 in the testing set at 3 and 5 years, respectively. Conclusions: Patients with gastric cancer who undergo endoscopic resection, even after successful H. pylori eradication, should undergo annual and continuous endoscopic surveillance for MGC.
The gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract. Between the 1990s and early 2000s, GIST was identified as a tumor characterized by KIT or PDGFRA mutations, resulting in imatinib being established as an effective targeted therapy. However, with advances in molecular diagnostics, approximately 10%-15% of GISTs have been reported to harbor alternative mutations, such as those in the succinate dehydrogenase subunit genes and BRAF, leading to the development of additional targeted therapies. GISTs exhibit a wide spectrum of clinical behaviors, ranging from indolent to highly aggressive, prompting the development of diverse risk classification systems. However, multiple systems remain in use, leading to inconsistent pathologic reports. Moreover, the mitotic counting method-a key factor in risk stratification-has become a major source of confusion among pathologists owing to the adoption of digital pathology and discrepancies between updated international guidelines and outdated reimbursement requirements. These inconsistencies have hindered pathologic reporting and communication between pathologists and clinicians. This review comprehensively overviews the historical background, molecular subtypes, and risk classification systems of GIST, focusing on evolving issues in mitotic rate evaluation and the application of risk classification systems in clinical practice.
Purpose: Although gastric cancer (GC) exhibits significant genomic heterogeneity, the clinical implications of its immune microenvironment remain poorly understood. Materials and Methods: We retrospectively evaluated patients with GC who underwent gastrectomies between 2011 and 2014. The tumors were analyzed for Epstein-Barr virus (EBV), microsatellite instability-high (MSI-H), tumor-infiltrating lymphocytes (CD3), tumor-associated macrophages (CD68 and CD163), and programmed death-ligand 1 (PD-L1) expression. Tumors were classified using the modified The Cancer Genome Atlas scheme, and their clinical characteristics were compared. Results: A total of 567 patients were classified into EBV (6%), MSI-H (10%), chromosomal instability-like (36%), and genomically stable-like (48%) subtypes. EBV tumors exhibited the highest PD-L1 expression (85%) and immune infiltration by CD3+ T cells (86%), CD68+ macrophages (58%), and CD163+ macrophages (40%). High CD68+ macrophage tumors were associated with advanced stages and worse 5-year disease-free survival (83% vs. 95%; P<0.001); however, this association was not independently significant after adjusting for the tumor-node-metastasis stage. PD-L1 expression did not significantly affect the survival outcomes. Conclusions: GC subtypes have distinct immune microenvironments that influence prognosis. Our findings highlight the prognostic and therapeutic potential of immune profiling in GC.
PURPOSE:Esophagojejunal anastomotic leakage (EJAL) represents a severe postoperative complication following total or proximal gastrectomy. Treatment strategies include conservative management, endoscopic interventions, and surgery; however, comparative data remain limited. This study aimed to compare clinical outcomes of different strategies to identify the optimal approach based on anastomotic defect size. MATERIALS AND METHODS:This retrospective study reviewed 100 patients diagnosed with EJAL between January 2015 and October 2024. Patients were categorized into four groups: conservative management, endoscopic vacuum-assisted closure (E-VAC), other endoscopic treatments, and surgery. The primary outcomes were leakage duration and length of hospital stay after EJAL diagnosis, whereas the secondary outcome was time to C-reactive protein normalization. Subgroup analyses were performed according to defect size. RESULTS:Among the 100 patients, 76 were male and 24 were female, with a mean age of 65.7 years. Conservative treatment was the most common modality (53%), followed by other endoscopic treatments (19%), E-VAC (14%), and surgery (14%). In patients with a defect size <1 cm, conservative treatment was associated with significantly shorter leakage duration (P=0.035) and earlier resumption of diet (P=0.029) compared with endoscopic treatment. Among those with defects ≥2 cm, E-VAC demonstrated the most favorable median outcomes across all variables; however, statistical significance was not achieved because of the small sample size. CONCLUSIONS:Conservative treatment appears to be the most effective treatment strategy for EJAL with anastomotic defects <1 cm. For larger defects (≥2 cm), E-VAC may offer clinical benefit, although further studies are needed to confirm its efficacy. These findings highlight the importance of individualized treatment selection based on defect size.
Objectives Endoscopic submucosal dissection (ESD) has become a standard minimally invasive treatment for selected patients with early gastric cancer (EGC). This study presents the first nationwide survey of patients with EGC treated with ESD in 2023, conducted by the Korean College of Helicobacter and Upper Gastrointestinal Research. Methods Data were retrospectively collected from participating referral centers across Korea using a standardized case report form covering patient characteristics, tumor features, procedural details, histopathological findings, and clinical outcomes. Descriptive and comparative analyses were conducted to summarize nationwide ESD practice patterns and outcomes. Results Data from 5460 ESD cases from 5250 patients across 27 institutions were analyzed. The mean age was 67.4 years, with 74.1% males. Multiple synchronous lesions were identified in 3.7%. Most lesions were located in the lower third of the stomach (64.0%), and differentiated-type adenocarcinomas accounted for 87.8%. The en bloc and complete resection rates were 99.2% and 91.4%, respectively. Curative resection was achieved in 80.5%, whereas local non-curative resection (L-NCR) and surgical non-curative resection (S-NCR) were identified in 2.8% and 16.7%, respectively. Additional surgery was performed more frequently in patients with S-NCR than in those with L-NCR (59.3% vs. 24.7%). The bleeding and perforation rates were 3.6% and 0.9%, respectively, and were mostly managed conservatively or endoscopically. The median length of hospitalization was 4.0 days. Conclusions This first nationwide survey provides a comprehensive overview of the current practice of EGC treatment using ESD in Korea, demonstrating high technical success and safety, and establishing a baseline dataset for future longitudinal research.
Gastric cancer remains a major global health burden, and accurate staging and response assessment are essential for optimal management. 2-[¹⁸F]-Fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) positron emission tomography (PET)/computed tomography (CT) is widely used in oncology. However, it exhibits variable sensitivity in gastric cancer, particularly in poorly cohesive, mucinous, and signet ring cell carcinomas with low glucose metabolism. These limitations have prompted interest in fibroblast activation protein-targeted imaging, which visualizes the tumor stroma rather than the tumor cells. Radiolabeled fibroblast activation protein inhibitors (FAPIs) exhibit high tumor-to-background contrast and consistent uptake across histological subtypes, offering improved lesion detectability even in [¹⁸F]FDG-negative tumors. This review outlines the evolving role of PET/CT in gastric cancer, with a focus on [¹⁸F]FDG and FAPI tracers. Comparative evidence indicates that FAPI PET/CT enhances diagnostic accuracy, provides complementary information for evaluating treatment response, and offers potential theranostic applications. Further prospective studies are needed to establish standardized protocols and define the clinical impact of FAPI PET/CT.
PURPOSE:This study evaluated long-term trends in gastric cancer epidemiology and survival with a focus on conditional relative survival (CRS). MATERIALS AND METHODS:Using the Korea Central Cancer Registry, we analyzed 665,184 patients who were newly diagnosed with gastric cancer between 1999 and 2022. The study period was divided into four intervals: Period I (1999-2005), Period II (2006-2011), Period III (2012-2017), and Period IV (2018-2022). Temporal trends in the incidence and mortality were assessed using crude and age-standardized rates. Relative survival was estimated using the Ederer II method, and the 5-year CRS was calculated according to the survival duration after diagnosis. RESULTS:The incidence of gastric cancer increased until 2011 and subsequently declined, with a marked decrease observed in 2020. Individuals aged ≥70 years consistently had the highest incidence rates. Mortality rates showed a sustained decline throughout the study period. The overall 5-year relative survival improved from 69.8% in Period II to 78.4% in Period IV. The 5-year CRS increased from 86.1% at 1 year after diagnosis to 96.3% at 5 years. Patients with localized stage maintained a 5-year CRS above 95% at 1 year after diagnosis, whereas those with regional and distant stages showed 5-year CRS that consistently remained below 95%. CONCLUSIONS:The incidence and mortality rates of gastric cancer in Korea have declined over the past two decades, accompanied by improved survival outcomes. The CRS analysis suggests that long-term follow-up is warranted, with the optimal duration varying according to patient characteristics.
Conversion therapy enables curative-intent resection in patients with initially unresectable or metastatic cancers after effective systemic therapy. Recently, advances in systemic therapy with molecular targeted agents and immune checkpoint inhibitors (ICIs) have renewed clinical and research interest in this approach, particularly for metastatic gastric cancer (GC). This review aimed to summarize the international guidelines and expert consensus informed by contemporary evidence on conversion therapy for metastatic GC, emphasizing the central role of systemic therapy, the emergence of biomarker-driven strategies, and the optimal timing for surgical intervention. Key consensus statements (Bertinoro, OMEC, and KINGCA WEEK 2024) and pivotal studies covering the cytotoxic, targeted, and immunotherapy eras were reviewed, focusing on regimen selection, treatment duration, and prognostic determinants associated with surgical outcomes. According to global guidelines, conversion surgery is not yet standard of care but may be considered for biologically and clinically selected patients demonstrating a major response to systemic therapy. Retrospective and prospective studies have reported a median overall survival of 24-36 months in the cytotoxic era and >48 months in the ICI/targeted era among patients who underwent R0 resection. Emerging evidence supports approximately 6 months of preoperative systemic therapy, followed by R0 resection, and up to one year of postoperative maintenance therapy. Therefore, conversion surgery should be viewed as the culmination of effective systemic therapy rather than as a substitute. A biology-driven, multidisciplinary strategy integrating treatment response assessment and prognostic factor evaluation represents the next frontier in potentially curative management of metastatic GC.
Despite the many advances in treatment methods for gastric cancer, it remains a leading cause of cancer-related mortality worldwide, with treatment outcomes intrinsically linked to the nutritional status of the patient. Malnutrition is a frequent and severe complication in patients with gastric cancer, arising from a confluence of factors including tumor-induced anorexia-cachexia syndrome, mechanical obstruction, and the metabolic stress of anti-cancer therapies including surgery and chemotherapy. Historically, nutritional support has often been a secondary consideration compared with surgical intervention or chemotherapy. However, a growing body of evidence has repositioned perioperative nutritional treatment as a cornerstone of comprehensive gastric cancer management. It is known that malnutrition can result in poorer clinical outcomes, including increased susceptibility to treatment-related toxicity, higher rates of postoperative complications, diminished quality of life, and a reduction in overall survival. Further, the paradigm shift toward proactive nutritional screening and assessment as standard clinical practice has allowed for timely and individualized prehabilitation. We conclude that advancements in nutritional science have fundamentally transformed gastric cancer management. The integration of tailored nutritional strategies throughout the journey of a patient from diagnosis through treatment and into survivorship is no longer just supportive, but a therapeutic modality in its own right. This symbiotic relationship emphasizes the necessity of a multidisciplinary approach, where oncologic and nutritional care are seamlessly interwoven to optimize patient outcomes and redefine the standards of gastric cancer treatment.
The indications for endoscopic resection (ER) and the criteria for the curability of early gastric cancer (EGC) have been expanding. Among Korea, Japan, and Europe, Korea has the most strictly defined indication for ER, followed by Europe and Japan, whereas the curability criteria are relatively similar. Additional surgery is the standard treatment after noncurative resection; however, it is not frequently performed in older patients in clinical practice. Several risk-scoring systems have been developed to further stratify the risk of lymph node metastasis after noncurative resection, and they may help refine the indications for ER and curability assessment in older patients. Nevertheless, the current evidence remains insufficient to establish recommendations specific to this population. In older patients, most deaths are attributable to non-gastric cancer-related causes, regardless of the post-resection treatment strategy. Therefore, in addition to gastric cancer-specific mortality, non-gastric cancer-related mortality and quality of life should be considered. Endoscopic submucosal dissection (ESD) techniques continue to evolve. Traction methods and multibending endoscopes are useful for achieving safe and reliable ESD in selected cases. Although no intervention has been proven effective in reducing delayed bleeding after gastric ESD in randomized controlled trials, several closure methods have shown promising results in retrospective or phase II studies. Furthermore, novel image-enhanced endoscopies may help improve the technical success of gastric ESD. This review provides an evidence-based perspective that may guide optimal management of patients with EGC.
Neoadjuvant and perioperative therapy have emerged as promising strategies for managing locally advanced gastric cancer (LAGC). Landmark phase III studies, such as PRODIGY and RESOLVE, have established neoadjuvant chemotherapy as a viable therapeutic option in Asia. More recently, the MATTERHORN trial demonstrated the potential of incorporating immune checkpoint inhibitors (ICIs) into perioperative treatment. However, the use of fluorouracil, leucovorin, oxaliplatin, and docetaxel in Asian populations warrants careful consideration, given regional treatment standards and concerns regarding chemotherapy-related toxicities, including neutropenia. This review summarizes key perioperative trials and highlights the evolving role of ICIs while also addressing emerging evidence on targeted therapies in LAGC. Key considerations include assessment of treatment response, as the validity of pathological response as a surrogate endpoint for survival remains unclear; risk- and biomarker-driven patient selection; and unresolved questions regarding the necessity and optimal duration of postoperative therapy. Personalizing postoperative treatment based on prognostic and molecular markers-including clinical stage, pathological response, and circulating tumor DNA status-represents an important next step toward improving outcomes.
Gastric cancer is a biologically heterogeneous disease. The advent of high-throughput multi-omic technologies has revolutionized our understanding of gastric cancer by deconstructing this heterogeneous entity into distinct and more homogeneous molecular subtypes. Early classifications based on gene expression, methylation, and histology have laid the groundwork for multi-omic frameworks proposed by The Cancer Genome Atlas and Asian Cancer Research Group, which established the foundation of modern molecular taxonomy. Subsequent integrative efforts, particularly the Consensus Genomic Subtypes (Super 6) model, have unified this collected information into clinically relevant subtypes that bridge prognostic stratification with treatment strategies. Established biomarkers such as human epidermal growth factor receptor 2 amplification, microsatellite instability, and programmed death-ligand 1 expression are now used clinically to guide treatment with targeted agents and immune checkpoint inhibitors. Emerging single-cell and spatial transcriptomic analyses have further refined this landscape by deconstructing tumor microenvironments and potential evolutionary trajectories associated with disease progression. This review examines the evolution of molecular classification systems for gastric cancer, highlights current consensus frameworks, and discusses how subtype-based stratification will transform clinical trial design and enable biomarker-driven precision therapy.
Young-onset gastric cancer (YOGC) is an increasingly recognized subtype that challenges traditional assumptions about gastric cancer (GC) biology. Although the overall global incidence of GC continues to decline, the rising burden among individuals aged <40 years has reshaped clinical perceptions, highlighting YOGC as a distinct entity with unique drivers and unmet needs. It is frequently associated with diffuse-type histology and enrichment of genomically stable or microsatellite stable/epithelial-mesenchymal transition molecular subtypes, diverging from conventional late-onset diseases. Family history remains the strongest risk factor; however, most cases are sporadic, suggesting a multifactorial interplay between inherited susceptibility, environmental exposure, and early-life carcinogenic pathways. YOGC is also associated with a unique genetic and molecular profile with predominance of CDH1, RHOA, and CLDN18-ARHGAP alterations, aligned with low human epidermal growth factor 2 expression. Clinically, nonspecific symptoms and lack of screening recommendations often result in diagnosis at advanced stages. Thus, current treatment approaches largely mirror those designed for older patients. This review synthesizes evolving knowledge on the epidemiology, molecular and genetic landscape, and clinical behavior of YOGC. We emphasize opportunities to refine risk stratification, integrate hereditary cancer management, and adopt emerging tools, such as liquid biopsy, for early detection and disease monitoring. Ultimately, defining the biological foundations of YOGC may enable tailored interventions and improve prognosis in this increasingly relevant and understudied population.
Claudin 18.2 (CLDN18.2), a tight junction protein selectively expressed in normal gastric epithelium and widely retained during carcinogenesis, has emerged as a promising therapeutic target for advanced gastric cancer (AGC). SPOTLIGHT and GLOW trials evaluated the anti-CLDN18.2 monoclonal antibody (mAb) zolbetuximab in combination with first-line chemotherapy, and established CLDN18.2 as a therapeutic target, initiating a paradigm shift toward a biomarker-driven treatment approach in AGC. In addition, from zolbetuximab to a diverse pipeline of promising high-affinity mAbs, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells, this target has established a new and highly effective therapeutic avenue for CLDN18.2-expressing AGC. Therefore, as research progresses, CLDN18.2-targeted therapy is poised to become a cornerstone of treatment across multiple disease stages and cancer types. This review describes the biological role of CLDN18.2 in normal gastric epithelium and gastric carcinogenesis and summarizes the current therapeutic landscape and future perspectives targeting CLDN18.2 in AGC.
