Cancer Research and Treatment

Original Articles

Clinicopathological Factors Influencing PD-L1 Expression and The Effect of Immune Checkpoint Inhibitors on Survival Outcomes in Patients with Gastric Cancer Depending on Sex in a Tertiary Hospital in South Korea: Jeong hwan Lee, Nayoung Kim, Ji-Hyun Kim, Hyeon Jeong Oh, Yeejin Kim, Yonghoon Choi, Hyemin Jo, Ho-Kyoung Lee, Jinju Choi, Yu Kyung Jun, Hyuk Yoon, Cheol Min Shin, Young Soo Park, Dong Ho Lee, Hye Seung Lee, So Hyun Kang, Young Suk Park, Sang-Hoon Ahn, Yun-Suhk Suh, Do Joong Park, Hyung Ho Kim, Ji-Won Kim, Jin Won Kim, Keun-Wook Lee, Won Chang, Yoon Jin Lee, Kyoung Ho Lee, Young Hoon Kim, Soyeon Ahn; Received January 31, 2025 Accepted August 5, 2025 Published online August 13, 2025; DOI: https://doi.org/10.4143/crt.2025.126 [Accepted]

Abstract PDF: Purpose
Programmed cell death ligand-1 (PD-L1) negatively regulates T-cell activation, and exhibits sex-based differences in expression and immune responses. This study investigated sex-related differences in clinicopathological factors influencing PD-L1 expression and the effect of immune checkpoint inhibitors (ICIs) on survival in gastric cancer (GC) patients in South Korea.
Materials and Methods
We analyzed a prospective cohort of 468 GC patients who underwent PD-L1 immunohistochemistry. Age, tumor characteristics, molecular features, and survival outcomes were compared by sex. Multivariate analyses, including Cox proportional hazards modeling with an interaction term for sex, were performed.
Results
Among 468 patients, 280 (59.8%) were PD-L1 positive. In the overall cohort, PD-L1 positivity was significantly associated with Epstein-BarrVirus (EBV) infection (odd ratio [OR]=7.46, p<0.001), antral location of GC (OR=1.84, p=0.027), and macrosatellite instability-High (MSI-H) (OR=5.04, p=0.027). Diffuse-type histology was inversely associated (OR=0.22, p=0.041). In males, EBV (OR=36.27) and antral location (OR=2.38) were significant. In females, only MSI-H was significant (OR=11.63). ICI-containing therapy significantly improved survival in males (p=0.012) but not in females (p=0.415). Cox regression showed a survival benefit from ICIs (HR=0.70, p=0.080), with a borderline-significant interaction by sex (p=0.073).
Conclusion
PD-L1 expression and therapeutic efficacy of ICIs differ by sex in GC. EBV infection and antral tumor location were independent factors in males, while MSI-H status was significant in females. These findings highlights the importance of sex-based immunobiology in tailoring GC treatment strategies.

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Microbial Dynamics Across Molecular Subtypes and Prognostic Significance of Lactobacillus in Gastric Cancer: Soo Kyung Nam, Juhyeong Park, Sujin Oh, Yoonjin Kwak, Cheol Min Shin, Kyoung Un Park, Nak-Jung Kwon, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Han-Kwang Yang, Hye Seung Lee; Received April 25, 2025 Accepted July 16, 2025 Published online July 17, 2025; DOI: https://doi.org/10.4143/crt.2025.449 [Accepted]

Abstract PDF: Purpose
Recent studies have revealed a diverse gastric microbiota beyond Helicobacter pylori, suggesting a role in gastric cancer (GC). We aimed to investigate the composition and characteristics of the microbiota in GC and non-cancerous gastric mucosa (NC), with a particular focus on their relationship to molecular subtypes.
Materials and Methods
We conducted 16S rRNA sequencing and whole transcriptomic analysis on fresh-frozen GC and NC tissue samples from 192 GC patients, as well as saliva samples from 12 GC patients and 18 healthy individuals. Microsatellite instability (MSI), Epstein-Barr virus (EBV) in situ hybridization, and immunohistochemistry for p53 and E-cadherin were used to define molecular subtypes.
Results
GC tissues exhibited significantly higher diversity compared to matched NC tissues, with microbial profiles marked by decreased Helicobacter and increased Streptococcus, Prevotella, and Lactobacillus. Saliva samples predominantly contained oral bacteria and exhibited distinct microbial profiles from gastric tissues. In GC tissue, Helicobacter abundance was negatively correlated with key immune checkpoint genes (CTLA-4, PDCD1, CD274, and LAG3), whereas Prevotella, Streptococcus, and Fusobacterium were positively correlated. MSI-high and EBV-positive subtypes showed lower levels of Helicobacter but higher levels of Lactobacillus, Prevotella, and Streptococcus compared to the epithelial-mesenchymal transition (EMT)-like subtype. Notably, within MSI-H GC, a subgroup characterized by Lactobacillus-enriched and otherwise microbiota-depleted profiles was significantly associated with poorer overall and disease-free survival.
Conclusion
These findings underscore distinct microbial patterns across GC molecular subtypes, suggesting potential biomarkers for GC diagnosis and treatment.

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Gastrointestinal cancer

Survival Rates of Patients with Gastric Cancer According to Age and Sex: A Large-Scale Study Using Data from 14,739 Patients: Yonghoon Choi, Nayoung Kim, Ji Hyun Kim, Hyeong Ho Jo, Hyeon Jeong Oh, Hye Seung Lee, Yu Kyung Jun, Hyuk Yoon, Cheol Min Shin, Young Soo Park, Dong Ho Lee, So Hyun Kang, Young Suk Park, Sang-Hoon Ahn, Yun-Suhk Suh, Do Joong Park, Hyung Ho Kim, Ji-Won Kim, Jin Won Kim, Keun-Wook Lee, Won Chang, Yoon Jin Lee, Kyoung Ho Lee, Young Hoon Kim; Cancer Res Treat. 2026;58(1):252-263. Published online April 16, 2025; DOI: https://doi.org/10.4143/crt.2025.149

Abstract PDF Supplementary Material PubReader ePub: Purpose
The male predominance in the incidence of gastric cancer (GC) is established; however, sex differences in the prognosis of GC remain controversial. As such, this study analyzed the prognosis of patients with GC based on age and sex.
Materials and Methods
Data from 14,739 patients diagnosed with GC at Seoul National University Bundang Hospital between 2003 and 2023 were analyzed. Baseline characteristics, histological types of GC, overall and GC-specific survival rates (age and stage stratification), and associated risk factors were analyzed.
Results
Females were significantly younger (p < 0.001) and exhibited more gastric body cancers (p < 0.001) and tumors with diffuse-type or poorly differentiated histology (p < 0.001) than males. Females exhibited an advantage over males in terms of overall survival (p=0.004), but not in GC-specific survival. However, age stratification revealed significant sex differences, that females < 50 years of age exhibited survival disadvantages (p < 0.001); however, this trend was reversed with age, and females > 60 years exhibited survival advantages (p < 0.001) for both overall and GC-specific survival. This may be explained by the lower ratio of diffuse-type GC as females age. Furthermore, in the analysis according to stage, females with stage IV disease exhibited significant survival disadvantages, with significantly younger age and a higher proportion of diffuse-type GC which exhibits aggressive features, resulting in poorer survival than in males.
Conclusion
Age and stage stratification revealed significant differences in survival between the sexes, which can be helpful for public health strategies.

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Detection Ability of Quality of Life Changes and Responsiveness of the KOQUSS-40 and the EORTC QLQ-C30/STO22 in Patients Who Underwent Gastrectomy: A Prospective Comparative Study: Bang Wool Eom, Keun Won Ryu, Ji Yeong An, Yun-Suhk Suh, In Cho, Sung Geun Kim, Ji-Ho Park, Hoon Hur, Hyung-Ho Kim, Sang-Hoon Ahn, Sun-Hwi Hwang, Hong Man Yoon, Ki Bum Park, Hyoung-Il Kim, In-Gyu Kwon, Han-Kwang Yang, Byoung-Jo Suh, Sang-Ho Jeong, Tae-Han Kim, Oh Kyoung Kwon, Hye-Seong Ahn, Ji Yeon Park, Ki Young Yoon, Myoung Won Son, Seong-Ho Kong, Young-Gil Son, Geum Jong Song, Jong Hyuk Yun, Jung-Min Bae, Do Joong Park, Sol Lee, Jun-Young Yang, Kyung Won Seo, You-Jin Jang, So Hyun Kang, Joongyub Lee, Hyuk-Joon Lee, on behalf of KOrean QUality of life in Stomach cancer patients Study group (KOQUSS); Cancer Res Treat. 2026;58(1):221-231. Published online March 5, 2025; DOI: https://doi.org/10.4143/crt.2024.1104

Abstract PDF Supplementary Material PubReader ePub

Purpose
The aim of this study is to compare the detection ability of quality of life (QoL) changes and responsiveness of the KOrean QUality of life in Stomach cancer patients Study group (KOQUSS)-40 and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ).
Materials and Methods
A multicenter prospective observational study was conducted to evaluate QoL changes after various gastrectomies between January 2021 and April 2022. Participants were instructed to complete the KOQUSS-40 and EORTC QLQ-C30/STO22 preoperatively and at 1, 3, 6, and 12 months postoperatively. QoL changes over time and QoL responsiveness were assessed for each questionnaire.
Results
Data from 491 patients who underwent curative gastrectomy for gastric cancer at 22 institutions were analyzed. The summary scores of the KOQUSS-40 and EORTC QLQ-STO22 showed significant differences between the total and proximal gastrectomy groups (p=0.044 and p=0.038, respectively), but no difference was observed for the EORTC QLQ-C30. Dysphagia on the KOQUSS-40 was significantly different between the total and proximal gastrectomy groups (p=0.031); however, dysphagia on the EORTC QLQ-STO22 did not differ. The responsiveness of the KOQUSS-40 was similar to that of the EORTC QLQ in patients who experienced ≥ 10% body weight loss, but approximately 10% less in patients receiving adjuvant chemotherapy than the EORTC QLQ.
Conclusion
KOQUSS-40 has several advantages over EORTC QLQ-C30/STO22 when comparing QoL between the total and proximal gastrectomy groups. The findings provide information for researchers investigating the QoL of patients who have undergone curative gastrectomy for gastric cancer.

Citations

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The efficacy of early progressive resistance exercise in the postoperative management of pancreaticoduodenectomy for pancreatic cancer: a randomized controlled trial
Xuexue Liu, Neng Shi, Rui Li, Yuan Song
Frontiers in Surgery.2025;[Epub] CrossRef
Improvement in Quality of Life After Early Interactive Human Coaching via a Mobile App in Postgastrectomy Patients With Gastric Cancer: Prospective Randomized Controlled Trial
Bang Wool Eom, Mira Han, Hong Man Yoon, Young-Woo Kim, So Young Kim, Jin Myoung Oh, Gyung Ah Wie, Keun Won Ryu
JMIR mHealth and uHealth.2025; 13: e75445. CrossRef

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Effector Function Characteristics of Exhausted CD8+ T-Cell in Microsatellite Stable and Unstable Gastric Cancer: Dong-Seok Han, Yoonjin Kwak, Seungho Lee, Soo Kyung Nam, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Nak-Jung Kwon, Hye Seung Lee, Han-Kwang Yang; Cancer Res Treat. 2024;56(4):1146-1163. Published online April 12, 2024; DOI: https://doi.org/10.4143/crt.2024.317

Abstract PDF PubReader ePub

Purpose
Gastric cancer exhibits molecular heterogeneity, with the microsatellite instability–high (MSI-H) subtype drawing attention for its distinct features. Despite a higher survival rate, MSI-H gastric cancer lack significant benefits from conventional chemotherapy. The immune checkpoint inhibitors, presents a potential avenue, but a deeper understanding of the tumor immune microenvironment of MSI-H gastric cancer is essential.
Materials and Methods
We explored the molecular characteristics of CD8+ T-cell subtypes in three MSI-H and three microsatellite stable (MSS) gastric cancer samples using single-cell RNA sequencing and spatial transcriptome analysis.
Results
In MSI-H gastric cancer, significantly higher proportions of effector memory T cell (Tem), exhausted T cell (Tex), proliferative exhausted T cell (pTex), and proliferative T cell were observed, while MSS gastric cancer exhibited significantly higher proportions of mucosal-associated invariant T cell and natural killer T cell. In MSI-H gastric cancer, Tex and pTex exhibited a significant upregulation of the exhaustion marker LAG3, as well as elevated expression of effector function markers such as IFNG, GZMB, GZMH, and GZMK, compared to those in MSS gastric cancer. The interferon γ (IFN-γ) signaling pathway of Tex and pTex was retained compared to those of MSS gastric cancer. The spatial transcriptome analysis demonstrates the IFN-γ signaling pathway between neighboring Tex and malignant cell, showcasing a significantly elevated interaction in MSI-H gastric cancer.
Conclusion
Our study reveals novel finding indicating that IFN-γ signaling pathway is retained in Tex and pTex of MSI-H gastric cancer, offering a comprehensive perspective for future investigations into immunotherapy for gastric cancer.

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Gallic acid potentiates the tumour-killing function of CD8+ T cells in gastric cancer
Si Chen, HaiBin Wang, Meixu Lei, Yumin Li, Qi Wang, Hengxin Wang, Yifei Shen, Xuejie Su, Yali Zhou
Journal of Pharmacy and Pharmacology.2026;[Epub] CrossRef
Neurogranin facilitates maintaining the immunosuppressive state of hepatocellular carcinoma by promoting TGF-β1 secretion
Dongjie Ye, Zhu Zhang, Yuxin Yao, Banglun Pan, Hao Wu, Xinyu Zhang, Xiaoqian Wang, Nanhong Tang
International Journal of Biological Macromolecules.2025; 311: 143716. CrossRef
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Jia Cheng, Jian Zheng, Chen Ma, Yongzhang Li, Hua Hao
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Hybrid model for predicting microsatellite instability in colorectal cancer using hematoxylin & eosin-stained images and clinical features
Hangping Wei, Xiaowei Zhang, Zhen Zhou, Jianbin Xie, Weidong Han, Xiaofang Dong
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Yumei Ning, Shilin Fang, Runan Zhang, Jun Fang, Kun Lin, Yang Ding, Haihang Nie, Jingkai Zhou, Qiu Zhao, Hengning Ke, Haizhou Wang, Fan Wang
International Immunopharmacology.2024; 142: 113244. CrossRef

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Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer: Seung-Young Oh, Giyong Jang, Jaeryuk Kim, Kyoung-Yun Jeong, Hyun Myong Kim, Yoon Jin Kwak, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Sung-Yup Cho, Jong-Il Kim, Han-Kwang Yang; Cancer Res Treat. 2024;56(4):1126-1135. Published online April 11, 2024; DOI: https://doi.org/10.4143/crt.2024.328

Abstract PDF PubReader ePub

Purpose
Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression.
Materials and Methods
Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation, and enrichment analysis were performed.
Results
As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in-silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the Rhoa^R129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked Rhoa^R129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families.
Conclusion
The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.

Citations

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Hereditary diffuse gastric cancer: the evolution of a cancer syndrome
Lyvianne Decourtye-Espiard, Tanis Godwin, Parry Guilford
Journal of the Royal Society of New Zealand.2025; 55(6): 2636. CrossRef
A Comprehensive Review of Genetic Mutations Occurring in the Development and Progression of Gastric Cancer
Yalan Li, Qianqian Xu, Zhuo Chen, Mengting Chen, Kunyu Han, Zhuqing Zhang, Aling Shen, Xiaoyan Fu
Digestive Diseases.2025; 43(6): 630. CrossRef
Helicobacter pylori infection status and evolution of gastric cancer
Wenlin Zhang, Yuxin Zhang, Jing Ning, Weiwei Fu, Shigang Ding
Chinese Medical Journal.2025; 138(23): 3083. CrossRef
Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review
L. van der Sluis, J.M. van Dieren, R.S. van der Post, T.M. Bisseling
Hereditary Cancer in Clinical Practice.2024;[Epub] CrossRef

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Genomic and Transcriptomic Characterization of Gastric Cancer with Bone Metastasis: Sujin Oh, Soo Kyung Nam, Keun-Wook Lee, Hye Seung Lee, Yujun Park, Yoonjin Kwak, Kyu Sang Lee, Ji-Won Kim, Jin Won Kim, Minsu Kang, Young Suk Park, Sang-Hoon Ahn, Yun-Suhk Suh, Do Joong Park, Hyung Ho Kim; Cancer Res Treat. 2024;56(1):219-237. Published online August 11, 2023; DOI: https://doi.org/10.4143/crt.2023.340

Abstract PDF Supplementary Material PubReader ePub

Purpose
Bone metastasis (BM) adversely affects the prognosis of gastric cancer (GC). We investigated molecular features and immune microenvironment that characterize GC with BM compared to GC without BM.
Materials and Methods
Targeted DNA and whole transcriptome sequencing were performed using formalin-fixed paraffin-embedded primary tumor tissues (gastrectomy specimens) of 50 GC cases with distant metastases (14 with BM and 36 without BM). In addition, immunohistochemistry (IHC) for mucin-12 and multiplex IHC for immune cell markers were performed.
Results
Most GC cases with BM had a histologic type of poorly cohesive carcinoma and showed worse overall survival (OS) than GC without BM (p < 0.05). GC with BM tended to have higher mutation rates in TP53, KDR, APC, KDM5A, and RHOA than GC without BM. Chief cell-enriched genes (PGA3, PGC, and LIPF), MUC12, MFSD4A, TSPAN7, and TRIM50 were upregulated in GC with BM compared to GC without BM, which was correlated with poor OS (p < 0.05). However, the expression of SERPINA6, SLC30A2, PMAIP1, and ITIH2 were downregulated in GC with BM. GC with BM was associated with PIK3/AKT/mTOR pathway activation, whereas GC without BM showed the opposite effect. The densities of helper, cytotoxic, and regulatory T cells did not differ between the two groups, whereas the densities of macrophages were lower in GC with BM (p < 0.05).
Conclusion
GC with BM had different gene mutation and expression profiles than GC without BM, and had more genetic alterations associated with a poor prognosis.

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PD-L1 Testing in Gastric Cancer by the Combined Positive Score of the 22C3 PharmDx and SP263 Assay with Clinically Relevant Cut-offs: Yujun Park, Jiwon Koh, Hee Young Na, Yoonjin Kwak, Keun-Wook Lee, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Hye Seung Lee; Cancer Res Treat. 2020;52(3):661-670. Published online January 10, 2020; DOI: https://doi.org/10.4143/crt.2019.718

Abstract PDF Supplementary Material PubReader ePub

Purpose
We provide a comparison between 22C3 pharmDx and SP263 assay, for evaluating programmed death ligand 1 (PD-L1) expression in advanced gastric cancer (GC) patients.
Materials and Methods
The PD-L1 immunohistochemistry by 22C3 pharmDx and SP263 assays was performed in the center of the tumor (CT) and invasive margin (IM) in 379 GC tissues using tissue microarrays and interpreted as combined positive score (CPS) and tumor proportion score (TPS). Of the total samples, 55 samples were independently reviewed by five pathologists.
Results
The two assays showed a high correlation in both the CPS and TPS. At a CPS ≥ 1 cut-off, 219 (57.8%) and 231 (60.9%) GCs were positive for PD-L1 with the 22C3 and SP263 assays, and at ≥ 10 cut-off, 37 (9.8%) and 36 (9.5%) GCs were positive, respectively. The overall percent agreement (OPA) was greater than 90% with CPS ≥ 1 and ≥ 10 cut-offs, and TPS ≥ 1% and ≥ 10% cut-offs. There was higher OPA between the two assays with a CPS cut-off ≥ 10 (99.2%) than ≥ 1 (94.7%). The percent agreement between the CT and IM was higher with a CPS cut-off ≥ 10 (92.9%) than ≥ 1 (77.6%). Patient with positive expression at CPS ≥ 5 cut-off had a significantly better outcomes in both assays. Interobserver variability among five pathologists was higher than the assay variability.
Conclusion
Two assays for PD-L1 expression in GC showed high agreement. These results provide guidance for selecting eligible patients with GC for pembrolizumab treatment.

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S-1–Induced Lacrimal Drainage Obstruction and Its Association with Ingredients/Metabolites of S-1 in Tears and Plasma: A Prospective Multi-institutional Study: Namju Kim, Jin Won Kim, Je-Hyun Baek, Jin-Soo Kim, Ho-Kyung Choung, Tae-Yong Kim, Kyung-Hun Lee, Yung-Jue Bang, Sang In Khwarg, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Jae-Yong Chung, Soyeon Ahn, Keun-Wook Lee; Cancer Res Treat. 2018;50(1):30-39. Published online February 27, 2017; DOI: https://doi.org/10.4143/crt.2016.569

Abstract PDF Supplementary Material PubReader ePub

Purpose
This prospective study was conducted to determine the incidence of lacrimal drainage obstruction (LDO) during S-1 chemotherapy and evaluate the association between the development of LDO and the concentrations of ingredients/metabolites of S-1 in tears and plasma.
Materials and Methods
A total of 145 patients with gastric cancer who received adjuvant S-1 therapy were enrolled. Ophthalmologic examinations were performed regularly during S-1 chemotherapy. Concentrations of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and 5-fluorouracil at steady-state trough level were measured in both tears and plasma.
Results
Fifty-three patients (37%) developed LDO. The median time to the onset of LDO was 10.9 weeks, and LDO developed most frequently in the nasolacrimal duct. Univariable analyses revealed that an older age (≥ 70 years), creatinine clearance rate (Ccr) < 80 mL/min, 5-fluorouracil concentration in plasma ≥ 22.3 ng/mL (median), CDHP concentration in plasma ≥ 42.0 ng/mL (median), and tegafur concentration in tears ≥ 479.2 ng/mL (median) were related to increased development of LDO. Multivariable analysis indicated that a high plasma 5-fluorouracil concentration was predictive of increased development of LDO (hazard ratio, 2.02; p=0.040), along with older age and decreased Ccr. Patients with LDO also developed S-1–related non-hematologic toxicity more frequently than those without LDO (p=0.016).
Conclusion
LDO is a frequent adverse event during S-1 chemotherapy. An older age, decreased Ccr, and high plasma 5-fluorouracil concentration were found to be independent risk factors for LDO. The high incidence of LDO warrants regular ophthalmologic examination and early intervention in patients receiving S-1 therapy.

Citations

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