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 [Epub ahead of print]

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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-Barr virus (EBV) infection (odds 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 (hazard ratio, 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 highlight the importance of sex-based immunobiology in tailoring GC treatment strategies.

Citations

Citations to this article as recorded by

Prognostic implications of PD-L1 expression in gastric cancer: systematic review and meta-analysis of studies published between 2018 and 2025
Gulnaz Yessultanova, Zhanat Komekbay, Indira Karibayeva, Anar Tulyayeva, Nurgul Kereyeva, Aigul Zhumasheva, Lunara Ishimova
BMC Cancer.2026;[Epub] CrossRef

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Lung cancer

Genetic Alterations in Preinvasive Lung Synchronous Lesions: Soyeon Ahn, Jisun Lim, Soo Young Park, Hyojin Kim, Hyun Jung Kwon, Yeon Bi Han, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung; Cancer Res Treat. 2020;52(4):1120-1134. Published online June 5, 2020; DOI: https://doi.org/10.4143/crt.2020.307

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Purpose
Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD)
Materials and Methods
We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing.
Results
Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions.
Conclusion
Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.

Citations

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Gene Expression Profiles of Multiple Synchronous Lesions in Lung Adenocarcinoma
Jisun Lim, Yeon Bi Han, Soo Young Park, Soyeon Ahn, Hyojin Kim, Hyun Jung Kwon, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung
Cells.2021; 10(12): 3484. CrossRef

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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

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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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MTHFR polymorphism is associated with increased adverse events and poor clinical outcomes in gastric cancer patients with adjuvant S-1 chemotherapy
Minsu Kang, Jin Won Kim, Ju Hyun Lee, Lyoung Hyo Kim, Woochan Park, So Hyun Kang, Young Suk Park, Ji-Won Kim, Hyeon Jeong Oh, Sang-Hoon Ahn, Yun-Suhk Suh, Do Joong Park, Hye Seung Lee, Hyung-Ho Kim, Keun-Wook Lee
Scientific Reports.2026;[Epub] CrossRef
Ocular complication induced by anticancer drug S-1: association with drug concentrations in tears
Masakazu Yamada, Tomoyuki Kamao, Atsushi Shiraishi, Jo Sakai, Yuichi Ohashi, Masashi Mimura, Yoshitsugu Inoue, Kazuyoshi Ohtomo, Tai-ichiro Chikama, Chika Miyazaki, Yuka Hosotani
Japanese Journal of Ophthalmology.2025; 69(3): 447. CrossRef
Efficacy and Safety of a 3‐Weekly TS‐1 Adjuvant Regimen in Advanced Gastric Cancer: A Pilot Study
Jihong Bae, Joo‐Hwan Park, Young Saing Kim, Hee Kyung Ahn, Eun Kyung Cho, Dong Bok Shin, Ji‐Hyeon Park, Jun‐Young Yang, Woon Kee Lee, Sun Jin Sym
Cancer Medicine.2025;[Epub] CrossRef
Comparing Analyte Concentrations in Paired Tear Fluid and Blood Samples
Yutong Wang, Li Liang, Rudy M. M. A. Nuijts, Marlies Gijs
Current Eye Research.2025; : 1. CrossRef
Influenza A Virus Utilizes the Nasolacrimal System to Establish Respiratory Infection after Ocular Exposure in the Swine Model
Shubin Li, Xuebin Peng, MinJie Wang, Wenqian Wang, Yuye Liu, Qian Yang, Makoto Ozawa
Transboundary and Emerging Diseases.2024;[Epub] CrossRef
Nasolacrimal Duct Obstruction in the Patients Receiving Treatment for Cancer
Vasily D. Yartsev, Eugenia L. Atkova
International Ophthalmology Clinics.2023; 63(3): 137. CrossRef
Obstrução lacrimal pós-tratamento oncológico: revisão de literatura
Camilla Duarte Silva, Fabricio Lopes da Fonseca, Juliana Mika Kato, Suzana Matayoshi
Revista Brasileira de Oftalmologia.2022;[Epub] CrossRef
A Case of Nasolacrimal Duct Obstruction During S-1 Treatment For Breast Cancer
Hisataka Ominato, Michihisa Kono, Hidekiyo Yamaki, Takumi Kumai, Miki Takahara, Akihiro Katada, Tatsuya Hayashi
Practica Oto-Rhino-Laryngologica.2022; 115(6): 503. CrossRef
Corneal nerve changes following treatment with neurotoxic anticancer drugs
Jeremy Chung Bo Chiang, David Goldstein, Susanna B. Park, Arun V. Krishnan, Maria Markoulli
The Ocular Surface.2021; 21: 221. CrossRef
The impact of anticancer drugs on the ocular surface
Jeremy Chung Bo Chiang, Ilyanoon Zahari, Maria Markoulli, Arun V. Krishnan, Susanna B. Park, Annalese Semmler, David Goldstein, Katie Edwards
The Ocular Surface.2020; 18(3): 403. CrossRef
Pharmacokinetics of S-1 monotherapy in plasma and in tears for gastric cancer patients
Hirofumi Yasui, Takeshi Kawakami, Hiroya Kashiwagi, Keita Mori, Katsuhiro Omae, Jun Kasai, Kunihiro Yoshisue, Masahiro Kawahira, Takahiro Tsushima, Nozomu Machida, Akira Fukutomi, Ken Yamaguchi
International Journal of Clinical Oncology.2019; 24(6): 660. CrossRef

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Validation of Prediction Models for Mismatch Repair Gene Mutations in Koreans: Soo Young Lee, Duck-Woo Kim, Young-Kyoung Shin, Myong Hoon Ihn, Sung Min Lee, Heung-Kwon Oh, Ja-Lok Ku, Seung-Yong Jeong, Jae Bong Lee, Soyeon Ahn, Sungho Won, Sung-Bum Kang; Cancer Res Treat. 2016;48(2):668-675. Published online June 5, 2015; DOI: https://doi.org/10.4143/crt.2014.288

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Purpose
Lynch syndrome, the commonest hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair (MMR) genes. Three recently developed prediction models for MMR gene mutations based on family history and clinical features (MMRPredict, PREMM1,2,6, and MMRPro) have been validated only in Western countries. In this study, we propose validating these prediction models in the Korean population.
Materials and Methods
We collected MMR gene analysis data from 188 individuals in the Korean Hereditary Tumor Registry. The probability of gene mutation was calculated using three prediction models, and the overall diagnostic value of each model compared using receiver operator characteristic (ROC) curves and area under the ROC curve (AUC). Quantitative test characteristics were calculated at sensitivities of 90%, 95%, and 98%.
Results
Of the individuals analyzed, 101 satisfied Amsterdam criteria II, and 87 were suspected hereditary nonpolyposis colorectal cancer. MMR mutations were identified in 62 of the 188 subjects (33.0%). All three prediction models showed a poor predictive value of AUC (MMRPredict, 0.683; PREMM1,2,6, 0.709; MMRPro, 0.590). Within the range of acceptable sensitivity (> 90%), PREMM1,2,6 demonstrated higher specificity than the other models.
Conclusion
In the Korean population, overall predictive values of the three models (MMRPredict, PREMM1,2,6, MMRPro) for MMR gene mutations are poor, compared with their performance in Western populations. A new prediction model is therefore required for the Korean population to detect MMR mutation carriers, reflecting ethnic differences in genotype-phenotype associations.

Citations

Citations to this article as recorded by

Performance evaluation of predictive models for detecting MMR gene mutations associated with Lynch syndrome in cancer patients in a Chinese cohort in Taiwan
Fei‐Hung Hung, Hung‐Pin Peng, Chen‐Fang Hung, Ling‐Ling Hsieh, An‐Suei Yang, Yong Alison Wang
International Journal of Cancer.2024; 155(12): 2201. CrossRef
Absence of constitutional MLH1 promoter methylation in Pakistani colorectal cancer patients
Ayesha Azeem, Humaira Naeemi, Noor Muhammad, Asif Loya, Muhammed Aasim Yusuf, Muhammad Usman Rashid
Gene Reports.2024; 36: 101995. CrossRef
Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients
Muhammad Usman Rashid, Humaira Naeemi, Noor Muhammad, Asif Loya, Jan Lubiński, Anna Jakubowska, Muhammed Aasim Yusuf
Hereditary Cancer in Clinical Practice.2019;[Epub] CrossRef
Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers
A. Goverde, M. C. W. Spaander, D. Nieboer, A. M. W. van den Ouweland, W. N. M. Dinjens, H. J. Dubbink, C. J. Tops, S. W. ten Broeke, M. J. Bruno, R. M. W. Hofstra, E. W. Steyerberg, A. Wagner
Familial Cancer.2018; 17(3): 361. CrossRef
Advances in Hereditary Colorectal and Pancreatic Cancers
Meghan L. Underhill, Katharine A. Germansky, Matthew B. Yurgelun
Clinical Therapeutics.2016;[Epub] CrossRef

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