Cancer Research and Treatment

Original Articles

Molecular Mosaics: Unveiling Heterogeneity in Synchronous Colorectal Cancers: Hyun Gu Lee, Yeseul Kim, Mi-Ju Kim, Yeon Wook Kim, Sun-Young Jun, Deokhoon Kim, In Ja Park, Seung-Mo Hong; Received September 30, 2024 Accepted February 17, 2025 Published online February 18, 2025; DOI: https://doi.org/10.4143/crt.2024.947 [Accepted]

Abstract PDF: Purpose
Molecular characteristics of synchronous colorectal cancers (SCRCs) remain incompletely elucidated, despite their importance in targeted therapy selection. We compared the molecular characteristics and somatic mutations between SCRCs.
Materials and Methods
This retrospective study (2012-2014) included 98 consecutive patients with surgically resected SCRCs. Molecular characteristics, including microsatellite instability (MSI) and tumor-infiltrating lymphocytes (TILs), were analyzed for all cancer lesions. The intertumoral heterogeneity of SCRCs was evaluated using whole-exome sequencing (WES) for 18 cancers from 9 patients with at least one MSI-high (MSI-H) tumor.
Results
Twelve patients had at least one MSI-H tumor; five showed discordant MSI status. Mucinous adenocarcinoma frequency and TIL density were higher in patients with at least one MSI-H tumor than in those with only microsatellite-stable tumors. WES revealed that, except one patient (6.5%), most synchronous cancers shared few variants in each patient (0.09–0.36%). The concordance rates for BRAF, KRAS, NRAS, and PIK3CA in synchronous cancers from each patient were 66.7%, 66.7%, 66.7%, and 55.6%, respectively.
Conclusion
Although synchronous cancers shared a mutated gene, the mutation subtypes differed. SCRCs exhibited 5.1% MSI status discordance rate and a high discordance rate in somatic mutational variants. As intertumoral heterogeneity may affect the targeted therapy response, molecular analysis of all tumors is recommended for patients with SCRCs.

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Presence of RB1 or Absence of LRP1B Mutation Predicts Poor Overall Survival in Patients with Gastric Neuroendocrine Carcinoma and Mixed Adenoneuroendocrine Carcinoma: In Hye Song, Bokyung Ahn, Young Soo Park, Deok Hoon Kim, Seung-Mo Hong; Received July 19, 2024 Accepted September 25, 2024 Published online September 27, 2024; DOI: https://doi.org/10.4143/crt.2024.667 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Neuroendocrine carcinomas (NECs) of the stomach are extremely rare, but fatal. However, our understanding of the genetic alterations in gastric NECs is limited. We aimed to evaluate genomic and clinicopathological characteristics of gastric NECs and mixed adenoneuroendocrine carcinomas (MANECs).
Materials and Methods
Fourteen gastric NECs, three gastric MANECs, and 1,381 gastric adenocarcinomas were retrieved from the departmental next-generation sequencing database between 2017 and 2022. Clinicopathological parameters and next-generation sequencing test results were retrospectively collected and reviewed.
Results
Gastric NECs and MANECs frequently harbored alterations of TP53, RB1, SMARCA4, RICTOR, APC, TOP1, SLX4, EGFR, BRCA2, and TERT. In contrast, gastric adenocarcinomas exhibited alterations of TP53, CDH1, LRP1B, ARID1A, ERBB2, GNAS, CCNE1, NOTCH, and MYC. Mutations of AKT3, RB1, and SLX4; amplification of BRCA2 and RICTOR; and deletion of ADAMTS18, DDX11, KLRC3, KRAS, MAX, NFKBIA, NUDT7, and RB1 were significantly more frequent in gastric NECs and MANECs than in gastric adenocarcinomas. The presence of LRP1B mutation was significantly associated with longer overall survival (OS), whereas RB1 mutation and advanced TNM stage were associated with shorter OS.
Conclusion
We identified frequently mutated genes and potential predictors of survival in patients with gastric NECs and MANECs.

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Stage Evaluation of Cystic Duct Cancer: Yeseul Kim, You-Na Sung, Haesung Jung, Kyung Jin Lee, Daegwang Yoo, Sun-Young Jun, HyungJun Cho, Shin Hwang, Woohyung Lee, Seung-Mo Hong; Received July 16, 2024 Accepted September 15, 2024 Published online September 19, 2024; DOI: https://doi.org/10.4143/crt.2024.660 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Cystic duct cancers (CDCs) have been classified as extrahepatic bile duct cancers or gallbladder cancers (GBCs); however, it is unclear whether their clinical behavior is similar to that of distal extrahepatic bile duct cancers (DBDCs) or GBCs.
Materials and Methods
T category of the CDCs was classified using current T category scheme of the GBCs and DBDCs, and clinicopathological factors were compared among 38 CDCs, 345 GBCs, and 349 DBDCs. We modified Nakata’s classifications (type 1, confined within cystic duct [CD]; combined types 2-4, extension beyond CD) and compared them.
Results
No significant overall survival (OS) difference was observed between the patients with CDC, GBC, and DBDC. The T category of GBC staging was more accurate at distinguishing OS in patients with CDC than the DBDC staging. Patients with T3 CDC and GBC showed a significant OS difference when using the T category for GBC staging, while those with T1-T2 CDC and GBC showed no significant difference. In contrast, the T category of DBDC staging did not show any significant OS difference between patients with T1-T2 CDC and DBDC or T3 CDC and DBDC. Patients with type 1 CDC had significantly better OS than those with combined types.
Conclusion
Unlike GBCs and DBDCs, CDCs exhibit distinct clinicopathological characteristics. The OS is better when the CDC confines within the CD, compared to when it extends beyond it. Therefore, we propose a new T category scheme (T1, confined to CD; T2, invaded beyond CD) for better classifying CDCs.

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Gastrointestinal cancer

Analysis of Plasma Circulating Tumor DNA in Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Modified FOLFIRINOX: Clinical Relevance of DNA Damage Repair Gene Alteration Detection: Dong-Hoon Lim, Hyunseok Yoon, Kyu-pyo Kim, Baek-Yeol Ryoo, Sang Soo Lee, Do Hyun Park, Tae Jun Song, Dae Wook Hwang, Jae Hoon Lee, Ki Byung Song, Song Cheol Kim, Seung-Mo Hong, Jaewon Hyung, Changhoon Yoo; Cancer Res Treat. 2023;55(4):1313-1320. Published online May 4, 2023; DOI: https://doi.org/10.4143/crt.2023.452

Abstract PDF Supplementary Material PubReader ePub

Purpose
There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136).
Materials and Methods
Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or post-operation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival.
Results
Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, inclu-ding ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations.
Conclusion
Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of pati-ents with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker.

Citations

Citations to this article as recorded by

A Review of Circulating Tumor DNA (ctDNA) in Pancreatic Cancer: Ready for the Clinic?
Purvi Jonnalagadda, Virginia Arnold, Benjamin A. Weinberg
Journal of Gastrointestinal Cancer.2025;[Epub] CrossRef
A Practical Approach to Interpreting Circulating Tumor DNA in the Management of Gastrointestinal Cancers
Zexi Allan, David S Liu, Margaret M Lee, Jeanne Tie, Nicholas J Clemons
Clinical Chemistry.2024; 70(1): 49. CrossRef
High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study
Lei Huang, Yao Lv, Shasha Guan, Huan Yan, Lu Han, Zhikuan Wang, Quanli Han, Guanghai Dai, Yan Shi
Journal of Translational Medicine.2024;[Epub] CrossRef
Decoding the Dynamics of Circulating Tumor DNA in Liquid Biopsies
Khadija Turabi, Kelsey Klute, Prakash Radhakrishnan
Cancers.2024; 16(13): 2432. CrossRef
Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma
Ibone Labiano, Ana E. Huerta, Maria Alsina, Hugo Arasanz, Natalia Castro, Saioa Mendaza, Arturo Lecumberri, Iranzu Gonzalez-Borja, David Guerrero-Setas, Ana Patiño-Garcia, Gorka Alkorta-Aranburu, Irene Hernández-Garcia, Virginia Arrazubi, Elena Mata, Davi
Scientific Reports.2024;[Epub] CrossRef
Liquid biopsy analysis of lipometabolic exosomes in pancreatic cancer
Wei Guo, Peiyao Ying, Ruiyang Ma, Zuoqian Jing, Gang Ma, Jin Long, Guichen Li, Zhe Liu
Cytokine & Growth Factor Reviews.2023; 73: 69. CrossRef

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Real-World Efficacy Data and Predictive Clinical Parameters for Treatment Outcomes in Advanced Esophageal Squamous Cell Carcinoma Treated with Immune Checkpoint Inhibitors: Jwa Hoon Kim, Bokyung Ahn, Seung-Mo Hong, Hwoon-Yong Jung, Do Hoon Kim, Kee Don Choi, Ji Yong Ahn, Jeong Hoon Lee, Hee Kyoung Na, Jong Hoon Kim, Yong-Hee Kim, Hyeong Ryul Kim, Hyun Joo Lee, Sung-Bae Kim, Sook Ryun Park; Cancer Res Treat. 2022;54(2):505-516. Published online June 23, 2021; DOI: https://doi.org/10.4143/crt.2020.1198

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study aimed to evaluate the real-world efficacy of immune checkpoint inhibitors (ICIs), and to identify clinicolaboratory factors to predict treatment outcomes in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving ICIs.
Materials and Methods
Sixty patients with metastatic or unresectable ESCC treated with nivolumab (n=48) or pembrolizumab (n=12) as ≥ second-line treatment between 2016 and 2019 at Asan Medical Center were included.
Results
The median age of the patients was 68 years (range, 52 to 76 years), and 93.3% were male. Most patients had metastatic disease (81.7%) and had been previously treated with fluoropyrimidines, platinum, and taxane. In 53 patients with measurable disease, the overall response rate and disease control rate were 15.1% and 35.8%, respectively. With a median follow-up duration of 16.0 months, the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval [CI], 1.54 to 2.19) and 6.4 months (95% CI, 4.77 to 8.11), respectively. After multivariate analysis, recent use of antibiotics, low prognostic nutrition index (< 35.93), high Glasgow Prognosis Score (≥ 1) at baseline, and ≥ 1.4-fold increase in neutrophil-to-lymphocyte ratio after one cycle from baseline were significantly unfavorable factors for both PFS and OS. Younger age (< 65 years) was a significant factor for unfavorable PFS and hyponatremia (< 135 mmol/L) for unfavorable OS.
Conclusion
The use of ICIs after the failure of chemotherapy showed comparable efficacy in patients with advanced ESCC in real practice; this may be associated with host immune-nutritional status, which could be predicted by clinical and routine laboratory factors.

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Pretreatment neutrophil-to-lymphocyte ratio is associated with immunotherapy efficacy in patients with advanced cancer: a systematic review and meta-analysis
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Ryuichi Morita, Takeshi Ishikawa, Toshifumi Doi, Junichiro Itani, Daiki Sone, Naoto Iwai, Ken Inoue, Hirotaka Konishi, Osamu Dohi, Naohisa Yoshida, Atsushi Shiozaki, Kazuhiko Uchiyama, Tomohisa Takagi, Hitoshi Fujiwara, Hideyuki Konishi, Yoshito Itoh
Oncology Letters.2025;[Epub] CrossRef
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Yinfang Gu, Xiaofang Zou, Junlin Zhu, Guowu Wu
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Zhihao Lu, Guoping Sun, Jiancheng Li, Jun Zhao, Zishu Wang, Dong Qian, Zhe Yang, Na Li, Junsheng Wang, Shuanghu Yuan, Yusheng Wang, Suyi Li, Zhen Yang, Fengming Ran, Yinghua Ji, Shaojin Zhu, Yanqiao Zhang, Chen Wang, Lixin Wan, Rongrong Zheng, Wenjie Deng
Cancer Immunology, Immunotherapy.2025;[Epub] CrossRef
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Yi Yu, Tao Wu, Wei Gan, Can Liu, Ran Zhang, Jinxiu Zheng, Jianping Xiong, Jun Chen, Junhe Li
Clinical and Translational Oncology.2024; 26(9): 2360. CrossRef
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Efficacy and survival of nivolumab treatment for recurrent/unresectable esophageal squamous-cell carcinoma: real-world clinical data from a large multi-institutional cohort
Tomoki Makino, Shigeto Nakai, Kota Momose, Kotaro Yamashita, Koji Tanaka, Hiroshi Miyata, Sachiko Yamamoto, Masaaki Motoori, Yutaka Kimura, Yuki Ushimaru, Motohiro Hirao, Jin Matsuyama, Yusuke Akamaru, Yukinori Kurokawa, Hidetoshi Eguchi, Yuichiro Doki
Esophagus.2024; 21(3): 319. CrossRef
The impact of antibiotic use in gastrointestinal tumors treated with immune checkpoint inhibitors: systematic review and meta-analysis
Faizah M. Alotaibi, Ibrahim Abdullah S. Albalawi, Amna M. Anis, Hawazin Alotaibi, Seham Khashwayn, Kanan Alshammari, Jaffar A. Al-Tawfiq
Frontiers in Medicine.2024;[Epub] CrossRef
Prognostic factors of second-line nivolumab monotherapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study for 184 cases
Sho Sato, Takashi Suzuki, Takashi Chinen, Hironori Yamaguchi, Yusuke Suzuki, Nobukazu Hokamura, Zenichiro Saze, Koji Kono, Keita Takahashi, Fumiaki Yano, Tsutomu Sato, Takashi Kosaka, Itaru Endo, Yasushi Ichikawa, Yutaka Miyawaki, Hiroshi Sato, Hideaki Sh
Journal of Gastroenterology.2024; 59(11): 979. CrossRef
Prognostic biomarkers for immunotherapy in esophageal cancer
Xu Tong, Meiyuan Jin, Lulu Wang, Dongli Zhang, Yuping Yin, Qian Shen
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Prognostic nutritional index as a prognostic biomarker for gastrointestinal cancer patients treated with immune checkpoint inhibitors
Lilong Zhang, Wangbin Ma, Zhendong Qiu, Tianrui Kuang, Kunpeng Wang, Baohong Hu, Weixing Wang
Frontiers in Immunology.2023;[Epub] CrossRef
Impact of Patient Characteristics on the Outcomes of Patients with Gastrointestinal Cancers Treated with Immune Checkpoint Inhibitors
Hyejee Ohm, Omar Abdel-Rahman
Current Oncology.2023; 30(1): 786. CrossRef
A systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of cancer patients treated with immune checkpoint inhibitors
Athéna Crespin, Clément Le Bescop, Jean de Gunzburg, Fabien Vitry, Gérard Zalcman, Julie Cervesi, Pierre-Alain Bandinelli
Frontiers in Oncology.2023;[Epub] CrossRef
The Use of Antibiotics During Immune Checkpoint Inhibitor Treatment Is Associated with Lower Survival in Advanced Esophagogastric Cancer
Lilong Zhang, Tianrui Kuang, Dongqi Chai, Wenhong Deng, Peng Wang, Weixing Wang
International Immunopharmacology.2023; 119: 110200. CrossRef
Predictive Impact of Prognostic Nutritional Index in Patients with Cancer Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis
Xin-Tian Xu, Yu Qian, Meng-Xing Tian, Chen-Chen Ding, Huan Guo, Jing Tang, Guo-Liang Pi, Yuan Wu, Zhu Dai, Xin Jin
Nutrition and Cancer.2023; 75(6): 1413. CrossRef
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Ning Chen, Xiaoling Xu, Yun Fan
Therapeutic Advances in Medical Oncology.2023;[Epub] CrossRef
進行食道癌に対する化学療法，化学放射線療法における栄養管理
豊木村
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Thoracic Cancer.2022; 13(11): 1631. CrossRef
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Frontiers in Nutrition.2022;[Epub] CrossRef
The impact of antibiotic use on clinical features and survival outcomes of cancer patients treated with immune checkpoint inhibitors
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Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3^- CD4⁺ T Cells in Biliary Tract Cancer: Hyung-Don Kim, Jwa Hoon Kim, Yeon-Mi Ryu, Danbee Kim, Sunmin Lee, Jaehoon Shin, Seung-Mo Hong, Ki-Hun Kim, Dong‐Hwan Jung, Gi‐Won Song, Dae Wook Hwang, Jae Hoon Lee, Ki Byung Song, Baek-Yeol Ryoo, Jae Ho Jeong, Kyu-pyo Kim, Sang-Yeob Kim, Changhoon Yoo; Cancer Res Treat. 2021;53(1):162-171. Published online August 31, 2020; DOI: https://doi.org/10.4143/crt.2020.704

Abstract PDF Supplementary Material PubReader ePub

Purpose
The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated.
Materials and Methods
A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core.
Results
The density of CD8⁺ T cells, FoxP3^- CD4⁺ helper T cells, and FoxP3⁺ CD4⁺ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3- or TIM3-expressing CD8⁺ T cell and FoxP3^- CD4⁺ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3^-CD4⁺ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3^- CD4⁺ helper T cells in the tumor margin was independently associated with favorable PFS and OS.
Conclusion
The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3^-CD4⁺ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin.

Citations

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Infiltrating T lymphocytes and tumor microenvironment within cholangiocarcinoma: immune heterogeneity, intercellular communication, immune checkpoints
Yunyan Dai, Chenyang Dong, Zhiming Wang, Yunpeng Zhou, Yi Wang, Yi Hao, Pinggui Chen, Chaojie Liang, Gaopeng Li
Frontiers in Immunology.2025;[Epub] CrossRef
Advancing biliary tract malignancy treatment: emerging frontiers in cell-based therapies
Jianyang Ao, Mingtai Hu, Jinghan Wang, Xiaoqing Jiang
Frontiers in Immunology.2025;[Epub] CrossRef
Research progress of T cells in cholangiocarcinoma
Zhiming Wang, Yunyan Dai, Yunpeng Zhou, Yi Wang, Pinggui Chen, Yaoxuan Li, Yunfei Zhang, Xiaocui Wang, Ying Hu, Haonan Li, Gaopeng Li, Yukai Jing
Frontiers in Immunology.2025;[Epub] CrossRef
Mapping of the T-cell Landscape of Biliary Tract Cancer Unravels Anatomic Subtype-Specific Heterogeneity
Jianhua Nie, Shuyuan Zhang, Ying Guo, Caiqi Liu, Jiaqi Shi, Haotian Wu, Ruisi Na, Yingjian Liang, Shan Yu, Fei Quan, Kun Liu, Mingwei Li, Meng Zhou, Ying Zhao, Xuehan Li, Shengnan Luo, Qian Zhang, Guangyu Wang, Yanqiao Zhang, Yuanfei Yao, Yun Xiao, Sheng
Cancer Research.2025; 85(4): 704. CrossRef
Deciphering the tumor immune microenvironment from a multidimensional omics perspective: insight into next-generation CAR-T cell immunotherapy and beyond
Zhaokai Zhou, Jiahui Wang, Jiaojiao Wang, Shuai Yang, Ruizhi Wang, Ge Zhang, Zhengrui Li, Run Shi, Zhan Wang, Qiong Lu
Molecular Cancer.2024;[Epub] CrossRef
Tumor-infiltrating T lymphocytes: A promising immunotherapeutic target for preventing immune escape in cholangiocarcinoma
Sijia Hua, Xinyi Gu, Hangbin Jin, Xiaofeng Zhang, Qiang Liu, Jianfeng Yang
Biomedicine & Pharmacotherapy.2024; 177: 117080. CrossRef
Focusing on the Immune Cells: Recent Advances in Immunotherapy for Biliary Tract Cancer
Luohang Ni, Jianing Xu, Quanpeng Li, Xianxiu Ge, Fei Wang, Xueting Deng, Lin Miao
Cancer Management and Research.2024; Volume 16: 941. CrossRef
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Yeong Hak Bang, Choong-kun Lee, Kyunghye Bang, Hyung-Don Kim, Kyu-pyo Kim, Jae Ho Jeong, Inkeun Park, Baek-Yeol Ryoo, Dong Ki Lee, Hye Jin Choi, Taek Chung, Seung Hyuck Jeon, Eui-Cheol Shin, Chiyoon Oum, Seulki Kim, Yoojoo Lim, Gahee Park, Chang Ho Ahn, T
Clinical Cancer Research.2024; 30(20): 4635. CrossRef
Prognostic value of tumor-infiltrating lymphocytes in distal extrahepatic bile duct carcinoma
S.-Y. Jun, S. An, S.-M. Hong, J.-Y. Kim, K.-P. Kim
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Veysel Toprak, İlhan Özdemir, Şamil Öztürk, Orhan Yanar, Yusuf Ziya Kizildemir, Mehmet Cudi Tuncer
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The Immunomodulatory Role of Vitamin D in Regulating the Th17/Treg Balance and Epithelial–Mesenchymal Transition: A Hypothesis for Gallbladder Cancer
Ricardo Cartes-Velásquez, Agustín Vera, Rodrigo Torres-Quevedo, Jorge Medrano-Díaz, Andy Pérez, Camila Muñoz, Hernán Carrillo-Bestagno, Estefanía Nova-Lamperti
Nutrients.2024; 16(23): 4134. CrossRef
Tumor immune microenvironment and the current immunotherapy of cholangiocarcinoma (Review)
Siqi Yang, Ruiqi Zou, Yushi Dai, Yafei Hu, Fuyu Li, Haijie Hu
International Journal of Oncology.2023;[Epub] CrossRef
Therapeutic significance of tumor microenvironment in cholangiocarcinoma: focus on tumor-infiltrating T lymphocytes
Chaoqun Li, Lei Bie, Muhua Chen, Jieer Ying
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Dynamic increase of M2 macrophages is associated with disease progression of colorectal cancers following cetuximab-based treatment
Hyung-Don Kim, Sun Young Kim, Jihun Kim, Jeong Eun Kim, Yong Sang Hong, Buhm Han, Eunyoung Tak, Yeon-Mi Ryu, Sang-Yeob Kim, Tae Won Kim
Scientific Reports.2022;[Epub] CrossRef
Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma
Taek Chung, Young Nyun Park
Frontiers in Medicine.2022;[Epub] CrossRef
The role of tumor-infiltrating lymphocytes in cholangiocarcinoma
Dong Liu, Lara Rosaline Heij, Zoltan Czigany, Edgar Dahl, Sven Arke Lang, Tom Florian Ulmer, Tom Luedde, Ulf Peter Neumann, Jan Bednarsch
Journal of Experimental & Clinical Cancer Research.2022;[Epub] CrossRef
Clinical implications of the tumor microenvironment using multiplexed immunohistochemistry in patients with advanced or metastatic renal cell carcinoma treated with nivolumab plus ipilimumab
Jwa Hoon Kim, Gi Hwan Kim, Yeon-Mi Ryu, Sang-Yeob Kim, Hyung-Don Kim, Shin Kyo Yoon, Yong Mee Cho, Jae Lyun Lee
Frontiers in Oncology.2022;[Epub] CrossRef
Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response
Tong Fu, Lei-Jie Dai, Song-Yang Wu, Yi Xiao, Ding Ma, Yi-Zhou Jiang, Zhi-Ming Shao
Journal of Hematology & Oncology.2021;[Epub] CrossRef

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Efficacy and Safety of Pembrolizumab in Patients with Refractory Advanced Biliary Tract Cancer: Tumor Proportion Score as a Potential Biomarker for Response: Junho Kang, Jae Ho Jeong, Hee-Sang Hwang, Sang Soo Lee, Do Hyun Park, Dong Wook Oh, Tae Jun Song, Ki-Hun Kim, Shin Hwang, Dae Wook Hwang, Song Cheol Kim, Jin-hong Park, Seung-Mo Hong, Kyu-pyo Kim, Baek-Yeol Ryoo, Changhoon Yoo; Cancer Res Treat. 2020;52(2):594-603. Published online December 18, 2019; DOI: https://doi.org/10.4143/crt.2019.493

Abstract PDF PubReader ePub

Purpose
The current standard chemotherapy for advanced biliary tract cancer (BTC) has limited benefit, and novel therapies need to be investigated.
Materials and Methods
In this prospective cohort study, programmed death ligand-1 (PD-L1)–positive BTC patients who progressed on first-line gemcitabine plus cisplatin were enrolled. Pembrolizumab 200 mg was administered intravenously every 3 weeks.
Results
Between May 2018 and February 2019, 40 patients were enrolled. Pembrolizumab was given as second-line (47.5%) or ≥ third-line therapy (52.5%). The objective response rate was 10% and 12.5% by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 and immune- modified RECIST (imRECIST) and median duration of response was 6.3 months. Among patients with progressive disease as best response, one patient (1/20, 5.0%) achieved complete response subsequently. The median progression-free survival (PFS) and overall survival (OS) were 1.5 months (95% confidence interval [CI], 0.0 to 3.0) and 4.3 months (95% CI, 3.5 to 5.1), respectively, and objective response per imRECIST was significantly associated with PFS (p < 0.001) and OS (p=0.001). Tumor proportion score ≥ 50% was significantly associated with higher response rates including the response after pseudoprogression (vs. < 50%; 37.5% vs. 6.5%; p=0.049).
Conclusion
Pembrolizumab showed modest anti-tumor activity in heavily pretreated PD-L1–positive BTC patients. In patients who showed objective response, durable response could be achieved.

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Validation of the 8th Edition of the American Joint Committee on Cancer Staging System for Gallbladder Cancer and Implications for the Follow-up of Patients without Node Dissection: You-Na Sung, Minjeong Song, Jae Hoon Lee, Ki Byung Song, Dae Wook Hwang, Chul-Soo Ahn, Shin Hwang, Seung-Mo Hong; Cancer Res Treat. 2020;52(2):455-468. Published online October 17, 2019; DOI: https://doi.org/10.4143/crt.2019.271

Abstract PDF PubReader ePub

Purpose
The 8th edition of gallbladder cancer staging in the American Joint Committee on Cancer (AJCC) staging system changed the T and N categories.
Materials and Methods
In order to validate the new staging system, a total of 348 surgically resected gallbladder cancers were grouped based on the 8th edition of the T and N categories and compared with patients’ survival.
Results
Significant differences were noted between T1b-T2a (p=0.003) and T2b-T3 (p < 0.001) tumors, but not between Tis-T1a, T1a-T1b, and T2a-T2b tumors. However, significant survival differences were observed both by the overall and pair-wise (T1-T2, T2-T3) comparisons (all, p < 0.001) without dividing T1/T2 subcategories. When cases with ≥ 6 examined lymph nodes were evaluated, significant survival differences were observed among the entire comparison (p < 0.001) and pair-wise comparisons of N0-N1 (p=0.001) and N1-N2 (p=0.039) lesions. When cases without nodal dissection (NX) were additionally compared, significant survival differences were observed between patients with N0-NX (p=0.001) and NX-N1 (p < 0.001) lesions.
Conclusion
The T category in the 8th edition of the AJCC staging system did not completely stratify the prognosis of patients with gallbladder cancer. Modification by eliminating T subcategories can better stratify the prognosis. In contrast, the N category clearly determines patients’ survival with ≥ 6 examined lymph nodes. The survival time in patients of gallbladder cancers without nodal dissection is between N0 and N1 cases. Therefore, close postoperative followed up is recommended for those patients.

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Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study: Haeryoung Kim, Soyeon An, Kyoungbun Lee, Sangjeong Ahn, Do Youn Park, Jo-Heon Kim, Dong-Wook Kang, Min-Ju Kim, Mee Soo Chang, Eun Sun Jung, Joon Mee Kim, Yoon Jung Choi, So-Young Jin, Hee Kyung Chang, Mee-Yon Cho, Yun Kyung Kang, Myunghee Kang, Soomin Ahn, Youn Wha Kim, Seung-Mo Hong, on behalf of the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists; Cancer Res Treat. 2020;52(1):263-276. Published online July 12, 2019; DOI: https://doi.org/10.4143/crt.2019.192

Abstract PDF Supplementary Material PubReader ePub

Purpose
The most recent 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNENs) has refined the three-tiered 2010 scheme by separating grade 3 pancreatic neuroendocrine tumors (G3 PanNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). However, differentiating between G3 Pan- NETs and PanNECs is difficult in clinical practice.
Materials and Methods
Eighty-two surgically resected PanNENs were collected from 16 institutions and reclassified according to the 2017 WHO classification based on the histological features and proliferation index (mitosis and Ki-67). Immunohistochemical stains for ATRX, DAXX, retinoblastoma, p53, Smad4, p16, and MUC1 were performed for 15 high-grade PanNENs.
Results
Re-classification resulted in 20 G1 PanNETs (24%), 47 G2 PanNETs (57%), eight G3 well-differentiated PanNETs (10%), and seven poorly differentiated PanNECs (9%). PanNECs showed more frequent diffuse nuclear atypia, solid growth patterns and apoptosis, less frequent organoid growth and regular vascular patterns, and absence of low-grade PanNET components than PanNETs. The Ki-67 index was significantly higher in PanNEC (58.2%± 15.1%) compared to G3 PanNET (22.6%±6.1%, p < 0.001). Abnormal expression of any two of p53, p16, MUC1, and Smad4 could discriminate PanNECs from G3 PanNETs with 100% specificity and 87.5% sensitivity.
Conclusion
Histological features supporting the diagnosis of PanNECs over G3 PanNETs were the absence of a low-grade PanNET component in the tumor, the presence of diffuse marked nuclear atypia, solid growth pattern, frequent apoptosis and markedly increased proliferative activity with homogeneous Ki-67 labeling. Immunohistochemical stains for p53, p16, MUC1, and Smad4 may be helpful in distinguishing PanNECs from G3 PanNETs in histologically ambiguous cases, especially in diagnostic practice when only small biopsied tissues are available.

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Ancuța-Augustina Gheorghișan-Gălățeanu, Andreea Ilieșiu, Ioana Maria Lambrescu, Dana Antonia Țăpoi
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MicroRNAs associated with postoperative outcomes in patients with limited stage neuroendocrine carcinoma of the esophagus
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Lingaku Lee, Tetsuhide Ito, Robert T Jensen
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Validation of the Eighth American Joint Committee on Cancer Staging System for Distal Bile Duct Carcinoma: Sun-Young Jun, You-Na Sung, Jae Hoon Lee, Kwang-Min Park, Young-Joo Lee, Seung-Mo Hong; Cancer Res Treat. 2019;51(1):98-111. Published online March 2, 2018; DOI: https://doi.org/10.4143/crt.2017.595

Abstract PDF PubReader ePub

Purpose
T category of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for distal bile duct carcinoma (DBDC) was changed to include tumor invasion depth measurement, while the N category adopted a 3-tier classification system based on the number of metastatic nodes.
Materials and Methods
To validate cancer staging, a total of 200 surgically resected DBDCs were staged and compared according to the seventh and eighth editions.
Results
T categories included T1 (n=37, 18.5%), T2 (n=114, 57.0%), and T3 (n=49, 24.5%). N categories included N0 (n=133, 66.5%), N1 (n=50, 25.0%), and N2 (n=17, 8.5%). Stage groupings included I (n=33, 16.5%), II (n=150, 75.0%), and III (n=17, 8.5%). The overall 5-year survival rates (5-YSRs) of T1, T2, and T3 were 59.3%, 42.4%, and 12.2%, respectively. T category could discriminate patient survival by both pairwise (T1 and T2, p=0.011; T2 and T3, p < 0.001) and overall (p < 0.001) comparisons. The overall 5-YSRs of N0, N1, and N2 were 47.3%, 17.0%, and 14.7%, respectively. N category could partly discriminate patient survival by both pairwise (N0 and N1, p < 0.001; N1 and N2, p=0.579) and overall (p < 0.001) comparisons. The overall 5-YSRs of stages I, II, and III were 59.0%, 35.4%, and 14.7%, respectively. Stages could distinguish patient survival by both pairwise (I and II, p=0.002; II and III, p=0.015) and overall (p < 0.001) comparisons. On multivariate analyses, T and N categories (p=0.014 and p=0.029) and pancreatic invasion (p=0.006) remained significant prognostic factors.
Conclusion
The T andNcategories of the eighth edition AJCC staging system for DBDC accurately predict patient prognosis.

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Prognosis of Pancreatic Cancer Patients with Synchronous or Metachronous Malignancies from Other Organs Is Better than Those with Pancreatic Cancer Only: Su-Jin Shin, Hosub Park, You-Na Sung, Changhoon Yoo, Dae Wook Hwang, Jin-hong Park, Kyu-pyo Kim, Sang Soo Lee, Baek-Yeol Ryoo, Dong-Wan Seo, Song Cheol Kim, Seung-Mo Hong; Cancer Res Treat. 2018;50(4):1175-1185. Published online December 20, 2017; DOI: https://doi.org/10.4143/crt.2017.494

Abstract PDF Supplementary Material PubReader ePub

Purpose
Pancreatic cancer associated double primary tumors are rare and their clinicopathologic characteristics are not well elucidated.
Materials and Methods
Clinicopathologic factors of 1,352 primary pancreatic cancers with or without associated double primary tumors were evaluated.
Results
Of resected primary pancreatic cancers, 113 (8.4%) had associated double primary tumors, including 26 stomach, 25 colorectal, 18 lung, and 13 thyroid cancers. The median interval between the diagnoses of pancreatic cancer and associated double primary tumors was 0.5 months. Overall survival (OS) of pancreatic cancer patients with associated double primary tumors was longer than those with pancreatic cancer only (median, 23.1 months vs. 17.0 months, p=0.002). Patients whose pancreatic cancers were resected before the diagnosis of metachronous tumors had a better OS than patients whose pancreatic cancer resected after the diagnosis of metachronous tumors (48.9 months and 13.5 months, p=0.001) or those whose pancreatic cancers were resected synchronously with non-pancreas tumors (19.1 months, p=0.043). The OS of pancreatic cancer patients with stomach (33.9 months, p=0.032) and thyroid (117.8 months, p=0.049) cancers was significantly better than those with pancreas cancer only (17.0 months).
Conclusion
About 8% of resected pancreatic cancers had associated double primary tumors, and those from the colorectum, stomach, lung, and thyroid were common. Patients whose pancreatic cancer was resected before the diagnosis of metachronous tumors had better OS than those resected after the diagnosis of metachronous tumors or those resected synchronously.

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Motoki Ebihara, Kentoku Fujisawa, Shusuke Haruta, Hironori Uruga, Masaki Ueno
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Synchronous primary multiple cancer: distal cholangiocarcinoma of the intrapancreatic common bile duct and intraductal papillary mucinous tumor associated with ductal adenocarcinoma of the pancreatic tail
G.R. Setdikova, E.A. Stepanova, A.N. Verbovsky, A.V. Semenkov
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Alessandro D. Mazzotta, Pietro Addeo, Benedetto Ielpo, Michael Ginesini, Nicolas Regenet, Ugo Boggi, Philippe Bachellier, Olivier Soubrane
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Paired Primary and Metastatic Tumor Analysis of Somatic Mutations in Synchronous and Metachronous Colorectal Cancer: Kyu-pyo Kim, Jeong-Eun Kim, Yong Sang Hong, Sung-Min Ahn, Sung Min Chun, Seung-Mo Hong, Se Jin Jang, Chang Sik Yu, Jin Cheon Kim, Tae Won Kim; Cancer Res Treat. 2017;49(1):161-167. Published online July 4, 2016; DOI: https://doi.org/10.4143/crt.2015.490

Abstract PDF Supplementary Material PubReader ePub

Purpose
Although the mutation status of KRAS is highly concordant in primary and metastatic lesions, it has not been generalized to other major pathway genes.
Materials and Methods
In this study, 41 genes were evaluated and the mutational profiles were compared in 46 colorectal cancer patients with paired surgical specimens of primary and metastatic lesions: synchronous (n=27) and metachronous (n=19) lesions. A high-throughput mass spectrometry-based genotyping platform validated by orthogonal chemistry, OncoMap v.4.4, was used to evaluate the formalin-fixed, paraffin-embedded surgical specimens. The patients’ demographics, tumor characteristics, and microsatellite instability status were analyzed by a retrospective chart review.
Results
In this study,with OncoMap, mutationswere identified in 80.4% of patientswith the following frequency: KRAS (39.1%), TP53 (28.3%), APC (28.3%), PIK3CA (6.5%), BRAF (6.5%), and NRAS (4.3%). Although 19.6% (9/46) of the patients showed no gene mutations, 43.5% (20/46) and 37.0% (17/46) had mutations in one and two or more genes, respectively. The synchronous and metachronous lesions showed similar mutational profiles. Paired samples between primary and metastatic tumors differed in 7.4% (2/27) and 10.5% (2/19) for synchronous and metachronous according to OncoMap.
Conclusion
These findings indicate the major pathway genes, including KRAS, TP53, APC, PIK3CA, BRAF, and NRAS, are often concordant between the primary and metastatic lesions regardless of the temporal relationship of metastasis.

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