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Original Articles
Gastrointestinal cancer
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
Cancer Res Treat. 2025;57(2):492-506.   Published online September 27, 2024
DOI: https://doi.org/10.4143/crt.2024.667
AbstractAbstract PDFSupplementary MaterialPubReaderePub
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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Lung and Thoracic cancer
Factors Associated with Postoperative Recurrence in Stage I to IIIA Non–Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation: Analysis of Korean National Population Data
Kyu Yean Kim, Ho Cheol Kim, Tae Jung Kim, Hong Kwan Kim, Mi Hyung Moon, Kyongmin Sarah Beck, Yang Gun Suh, Chang Hoon Song, Jin Seok Ahn, Jeong Eun Lee, Jae Hyun Jeon, Chi Young Jung, Jeong Su Cho, Yoo Duk Choi, Seung Sik Hwang, Chang Min Choi, Seung Hun Jang, Jeong Uk Lim, Korean Association for Lung Cancer, Korea Central Cancer Registry
Cancer Res Treat. 2025;57(1):83-94.   Published online July 10, 2024
DOI: https://doi.org/10.4143/crt.2024.073
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Recent development in perioperative treatment of resectable non–small cell lung cancer (NSCLC) have changed the landscape of early lung cancer management. The ADAURA trial has demonstrated the efficacy of adjuvant osimertinib treatment in resectable NSCLC patients; however, studies are required to show which subgroup of patients are at a high risk of relapse and require adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment. This study evaluated risk factors for postoperative relapse among patients who underwent complete resection.
Materials and Methods
Data were obtained from the Korean Association for Lung Cancer Registry (KALC-R), a database created using a retrospective sampling survey by the Korean Central Cancer Registry (KCCR) and the Lung Cancer Registration Committee.
Results
A total of 3,176 patients who underwent curative resection was evaluated. The mean observation time was approximately 35.4 months. Among stage I to IIIA NSCLC patients, the EGFR-mutant subgroup included 867 patients, and 75.2%, 11.2%, and 11.8% were classified as stage I, stage II, and stage III, respectively. Within the EGFR-mutant subgroup, 44 (5.1%) and 121 (14.0%) patients showed early and late recurrence, respectively. Multivariate analysis on association with postoperative relapse among the EGFR-mutant subgroup showed that age, pathologic N and TNM stages, pleural invasion status, and surgery type were independent significant factors.
Conclusion
Among the population that underwent complete resection for early NSCLC with EGFR mutation, patients with advanced stage, pleural invasion, or limited resection are more likely to show postoperative relapse.
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Gastrointestinal cancer
A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer
Keun-Wook Lee, Sae-Won Han, Tae Won Kim, Joong Bae Ahn, Ji Yeon Baek, Sang Hee Cho, Howard Lee, Jin Won Kim, Ji-Won Kim, Tae-You Kim, Yong Sang Hong, Seung-Hoon Beom, Yongjun Cha, Yoonjung Choi, Seonhui Kim, Yung-Jue Bang
Cancer Res Treat. 2024;56(2):590-601.   Published online December 7, 2023
DOI: https://doi.org/10.4143/crt.2023.1117
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a).
Materials and Methods
Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study.
Results
RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0).
Conclusion
GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Citations

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  • Drug combinations of camptothecin derivatives promote the antitumor properties
    Zhen Liu, Yajie Yuan, Ning Wang, Peng Yu, Yuou Teng
    European Journal of Medicinal Chemistry.2024; 279: 116872.     CrossRef
  • 4,092 View
  • 143 Download
  • 1 Web of Science
  • 1 Crossref
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Breast cancer
Changes in Invasive Breast Carcinomas after Neoadjuvant Chemotherapy Can Influence Adjuvant Therapeutic Decisions
Bárbara Jaime dos Santos, Débora Balabram, Virginia Mara Reis Gomes, Carolina Costa Café de Castro, Paulo Henrique Costa Diniz, Marcelo Araújo Buzelin, Cristiana Buzelin Nunes
Cancer Res Treat. 2024;56(1):178-190.   Published online August 1, 2023
DOI: https://doi.org/10.4143/crt.2023.386
AbstractAbstract PDFPubReaderePub
Purpose
Neoadjuvant chemotherapy (NACT) can change invasive breast carcinomas (IBC) and influence the patients’ overall survival time (OS). We aimed to identify IBC changes after NACT and their association with OS.
Materials and Methods
IBC data in pre- and post-NACT samples of 86 patients were evaluated and associated with OS.
Results
Post-NACT tumors changed nuclear pleomorphism score (p=0.025); mitotic count (p=0.002); % of tumor-infiltrating inflammatory cells (p=0.016); presence of in situ carcinoma (p=0.001) and lymphovascular invasion (LVI; p=0.002); expression of estrogen (p=0.003), progesterone receptors (PR; p=0.019), and Ki67 (p=0.003). Immunohistochemical (IHC) profile changed in 26 tumors (30.2%, p=0.050). Higher risk of death was significatively associated with initial tumor histological grade III (hazard ratio [HR], 2.94), high nuclear pleomorphism (HR, 2.53), high Ki67 index (HR, 2.47), post-NACT presence of LVI (HR, 1.90), luminal B–like profile (HR, 2.58), pre- (HR, 2.26) and post-NACT intermediate mitotic count (HR, 2.12), pre- (HR, 4.45) and post-NACT triple-negative IHC profile (HR, 4.52). On the other hand, lower risk of death was significative associated with pre- (HR, 0.35) and post-NACT (HR, 0.39) estrogen receptor–positive, and pre- (HR, 0.37) and post-NACT (HR, 0.57) PR-positive. Changes in IHC profile were associated with longer OS (p=0.050). In multivariate analysis, pre-NACT grade III tumors and pre-NACT and post-NACT triple negative IHC profile proved to be independent factors for shorter OS.
Conclusion
NACT can change tumor characteristics and biomarkers and impact on OS; therefore, they should be reassessed on residual samples to improve therapeutic decisions.
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Lung and Thoracic cancer
Targeting CD73 to Overcomes Resistance to First-Generation EGFR Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer
Miso Kim, Soyeon Kim, Jeemin Yim, Bhumsuk Keam, Tae Min Kim, Yoon Kyung Jeon, Dong-Wan Kim, Dae Seog Heo
Cancer Res Treat. 2023;55(4):1134-1143.   Published online May 23, 2023
DOI: https://doi.org/10.4143/crt.2023.311
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
In patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors (TKIs) improve response rate and survival. However, most patients eventually develop resistance. This study aimed to identify the role of CD73 in EGFR-mutant NSCLC and explore whether CD73 inhibition may serve as a therapeutic strategy in NSCLC patients with acquired resistance to EGFR-TKIs.
Materials and Methods
We evaluated the prognostic role of CD73 expression in EGFR-mutant NSCLC using tumor samples from a single institution. We silenced CD73 in EGFR-TKI–resistant cell lines using short hairpin RNA (shRNA) targeting CD73 and also transfected a vector alone as a negative control. Using these cell lines, cell proliferation and viability assays, immunoblot assays, cell cycle analysis, colony-forming assays, flow cytometry, and apoptosis analysis were performed.
Results
High expression of CD73 was associated with shorter survival in patients with metastatic EGFR-mutant NSCLC treated with first-generation EGFR-TKI. CD73 inhibition synergistically inhibited cell viability with first-generation EGFR-TKI treatment compared with the negative control. When CD73 inhibition and EGFR-TKI treatment were combined, G0/G1 cell cycle arrest was induced through the regulation of p21 and cyclin D1. In addition, the apoptosis rate was increased in CD73 shRNA-transfected cells treated with EGFR-TKI.
Conclusion
High expression of CD73 adversely affects the survival of patients with EGFR-mutant NSCLC. The study demonstrated that inhibiting CD73 in EGFR-TKI–resistant cell lines resulted in increased apoptosis and cell cycle arrest, which overcame the acquired resistance to first-generation EGFR-TKIs. Further research is needed to determine whether blocking CD73 plays a therapeutic role in EGFR-TKI–resistant patients with EGFR-mutant NSCLC.

Citations

Citations to this article as recorded by  
  • Simultaneous blockade of the CD73/EGFR axis inhibits tumor growth
    Keivan Ardeshiri, Hadi Hassannia, Ghasem Ghalamfarsa, Hanieh Jafary, Farhad Jadidi
    IUBMB Life.2025;[Epub]     CrossRef
  • Exploring the Expression of CD73 in Lung Adenocarcinoma with EGFR Genomic Alterations
    Elodie Long-Mira, Christophe Bontoux, Guylène Rignol, Véronique Hofman, Sandra Lassalle, Jonathan Benzaquen, Jacques Boutros, Salomé Lalvée-Moret, Katia Zahaf, Virginie Lespinet-Fabre, Olivier Bordone, Sophia Maistre, Christelle Bonnetaud, Charlotte Cohen
    Cancers.2025; 17(6): 1034.     CrossRef
  • Comprehensive pan-cancer analysis of CD73: Explore its association with prognosis and tumor immune microenvironment
    Chen Chen, Sasa Liu, Yanfen Ma
    Heliyon.2024; 10(22): e40329.     CrossRef
  • 4,139 View
  • 284 Download
  • 3 Web of Science
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Final Report on Real-World Effectiveness of Sequential Afatinib and Osimertinib in EGFR-Positive Advanced Non–Small Cell Lung Cancer: Updated Analysis of the RESET Study
Taeyun Kim, Tae Won Jang, Chang Min Choi, Mi-Hyun Kim, Sung Yong Lee, Yoon Soo Chang, Kye Young Lee, Seung Joon Kim, Sei Hoon Yang, Jeong Seon Ryu, Jeong Eun Lee, Shin Yup Lee, Chan Kwon Park, Sang Hoon Lee, Seung Hun Jang, Seong Hoon Yoon, Hyung-Joo Oh
Cancer Res Treat. 2023;55(4):1152-1170.   Published online May 19, 2023
DOI: https://doi.org/10.4143/crt.2023.493
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor (EGFR)+ non–small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group).
Materials and Methods
In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes.
Results
The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5).
Conclusion
This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.

Citations

Citations to this article as recorded by  
  • KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer
    Jae-Sun Choi, Hye-Min Kang, Kiyong Na, Jiwon Kim, Tae-Woo Kim, Junyang Jung, Heejin Lim, Hyewon Seo, Seung Hyeun Lee
    Tuberculosis and Respiratory Diseases.2025; 88(1): 138.     CrossRef
  • J-REGISTER: real-world study of Japanese patients with EGFR mutation-positive NSCLC treated with first-line afatinib
    Teppei Yamaguchi, Haruko Daga, Hisashi Tanaka, Takashi Kijima, Masaya Mizushima
    Future Oncology.2025; : 1.     CrossRef
  • A real-world cohort study of first-line afatinib in patients with EGFR-mutant advanced non-small cell lung cancer in Vietnam
    Cam Phuong Pham, Thi Thai Hoa Nguyen, Anh Tu Do, Tuan Khoi Nguyen, Thi Anh Thu Hoang, Tuan Anh Le, Dinh Thy Hao Vuong, Dac Nhan Tam Nguyen, Van Khiem Dang, Thi Oanh Nguyen, Van Luan Pham, Minh Hai Nguyen, Thi Huyen Trang Vo, Hung Kien Do, Ha Thanh Vu, Thi
    BMC Cancer.2024;[Epub]     CrossRef
  • Real‐world evidence of brigatinib as second‐line treatment after crizotinib for ALK+ non‐small cell lung cancer using South Korean claims data (K‐AREAL)
    Jeong Eun Lee, Jin Hyun Nam, Sun Hong Kwon, Bo Kyung Kim, Seung Min Ha
    Cancer Medicine.2024;[Epub]     CrossRef
  • Serum Concentrations of IGF-1R, ERK2, and EGFR and Their Clinical Significance in Patients with Neuroendocrine Tumors
    Roksana Duszkiewicz, Janusz Strzelczyk, Elżbieta Chełmecka, Joanna Katarzyna Strzelczyk
    Applied Sciences.2024; 14(16): 6998.     CrossRef
  • Optimal first-line treatment for EGFR-mutated NSCLC: a comparative analysis of osimertinib and second-generation EGFR-TKIs
    Hsu-Yuan Chen, Chia-Hung Chen, Wei-Chih Liao, Yu-Chao Lin, Hung-Jen Chen, Te-Chun Hsia, Wen-Chien Cheng, Chih-Yen Tu
    BMC Pulmonary Medicine.2024;[Epub]     CrossRef
  • Osimertinib as Second- and ≥Third-Line Treatment in Advanced and Recurrence EGFR-Mutant NSCLC Patients Harboring Acquired T790M Mutation
    Mu-Han Peng, Yen-Hsiang Huang, Kuo-Hsuan Hsu, Jeng-Sen Tseng, Po-Hsin Lee, Kun-Chieh Chen, Gee-Chen Chang, Tsung-Ying Yang
    Cancers.2024; 16(24): 4174.     CrossRef
  • Effectiveness of first-line anticancer treatment may predict treatment response in further lines in stage III/IV patients with non-small cell lung cancer
    Monika Bratova, Jana Skrickova, Magda Matusikova, Karolina Hrabcova, Libor Havel, Leona Koubkova, Michal Hrnciarik, Jana Krejci, Ondrej Fischer, Martin Svaton, Kristian Brat
    Journal of Cancer Research and Clinical Oncology.2023; 149(19): 17123.     CrossRef
  • 5,251 View
  • 316 Download
  • 6 Web of Science
  • 8 Crossref
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Gynecologic cancer
Safety and Tolerability of Weekly Genexol-PM, a Cremophor-Free Polymeric Micelle Formulation of Paclitaxel, with Carboplatin in Gynecologic Cancer: A Phase I Study
So Hyun Nam, Shin-Wha Lee, Young-Jae Lee, Yong Man Kim
Cancer Res Treat. 2023;55(4):1346-1354.   Published online May 15, 2023
DOI: https://doi.org/10.4143/crt.2022.1436
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This phase I study was conducted to determine the maximum tolerated dose and the recommended phase II dose of weekly administered Genexol-PM combined with carboplatin in patients with gynecologic cancer.
Materials and Methods
This open-label, phase I, dose-escalation study of weekly Genexol-PM included 18 patients with gynecologic cancer, who were equally divided into three cohorts of dose levels. Cohort 1 received 100 mg/m2 Genexol-PM and 5 area under the curve (AUC) carboplatin, cohort 2 received 120 mg/m2 Genexol-PM and 5 AUC carboplatin, and cohort 3 received 120 mg/m2 Genexol-PM and 6 AUC carboplatin. The safety and efficacy of each dose were analyzed for each cohort.
Results
Of the 18 patients, 11 patients were newly diagnosed and seven patients were recurrent cases. No dose-limiting toxicity was observed. The maximum tolerated dose was not defined, but a dose up to 120 mg/m2 of Genexol-PM in combination with AUC 5-6 of carboplatin could be recommended for a phase II study. In this intention-to-treat population, five patients dropped out of the study (carboplatin-related hypersensitivity, n=1; refusal of consent, n=4). Most patients (88.9%) with adverse events recovered without sequelae, and no treatment-related death occurred. The overall response rate of weekly Genexol-PM in combination with carboplatin was 72.2%.
Conclusion
Weekly administered Genexol-PM with carboplatin demonstrated an acceptable safety profile in gynecologic cancer pati-ents. The recommended phase II dose of weekly Genexol-PM is up to 120 mg/m2 when combined with carboplatin.

Citations

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  • Multicore, SDS-Based Polyelectrolyte Nanocapsules as Novel Nanocarriers for Paclitaxel to Reduce Cardiotoxicity by Protecting the Mitochondria
    Marzena Szwed, Anastazja Poczta-Krawczyk, Katarzyna D. Kania, Kacper Wiktorowski, Kamila Podsiadło, Agnieszka Marczak, Krzysztof Szczepanowicz
    International Journal of Molecular Sciences.2025; 26(3): 901.     CrossRef
  • Potent therapeutic efficacy of intranasally deliverable paclitaxel modified with pH-sensitive and PEGylated polymeric micelle against glioblastoma
    Young-Beom Kim, Soo-Hwan Lee, Dayananda Kasala, Yuebin Zhao, Ao Jiao, JinWoo Hong, Jin Su Kim, A-Rum Yoon, Chae-Ok Yun
    Journal of Controlled Release.2025; 382: 113711.     CrossRef
  • Nanomaterials-driven in situ vaccination: a novel frontier in tumor immunotherapy
    Naimeng Liu, Xiangyu Wang, Zhongzhao Wang, Yonemori Kan, Yi Fang, Jidong Gao, Xiangyi Kong, Jing Wang
    Journal of Hematology & Oncology.2025;[Epub]     CrossRef
  • Advances in the use of nanomicelles to enhance the efficacy of antitumour substances (review)
    E. V. Sanarova, L. L. Nikolaeva, S. D. Shceglov, Zh. M. Kozlova, O. L. Orlova, N. A. Oborotova, A. V. Lantsova
    Drug development & registration.2025;[Epub]     CrossRef
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    Bence Sipos, Fatima Rajab, Gábor Katona, Ildikó Csóka
    Expert Opinion on Drug Delivery.2025; : 1.     CrossRef
  • Rational design of paclitaxel prodrugs for facile preparation of in-situ therapeutic system in antitumor applications
    Lanqing Wang, Zhaofan Yang, Guanyu Jin, Bingzheng Yu, Wei Zhang, Xuesi Chen, Haochen Yao, Cuiping Yao, Shixian Lv
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    Zhiqi Zhang, Xiaoxuan Xu, Jiawei Du, Xin Chen, Yonger Xue, Jianqiong Zhang, Xue Yang, Xiaoyuan Chen, Jinbing Xie, Shenghong Ju
    Nature Communications.2024;[Epub]     CrossRef
  • Therapeutic impacts of GNE‑477‑loaded H2O2 stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma
    Songmu Pan, Zhuan Zou, Xiaofeng Zhou, Jiyong Wei, Huijiang Liu, Zhongyi Su, Gui Liao, Guangyu Huang, Zonggui Huang, Yi Xu, Minan Lu, Ronghe Gu
    International Journal of Molecular Medicine.2024;[Epub]     CrossRef
  • Functionalized Polymeric Micelles for Targeted Cancer Therapy: Steps from Conceptualization to Clinical Trials
    Ana Serras, Célia Faustino, Lídia Pinheiro
    Pharmaceutics.2024; 16(8): 1047.     CrossRef
  • Simplified Gambogic Acid Prodrug Nanoparticles to Improve Efficiency and Reduce Toxicity for Clinical Translation Potential
    Ruyi Wang, Yuxiao Xiao, Zhongtao Zhang, Xiaoxian Huang, Wanfang Zhu, Xiao Ma, Feng Feng, Wenyuan Liu, Lingfei Han, Wei Qu
    Advanced Healthcare Materials.2024;[Epub]     CrossRef
  • 3,779 View
  • 194 Download
  • 10 Web of Science
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Lung and Thoracic cancer
Should We Perform Repeated Re-biopsy for the Detection of T790M Mutation?
Saerom Kim, Soo Han Kim, Jinmi Kim, Mi-Hyun Kim, Min Ki Lee, Jung Seop Eom
Cancer Res Treat. 2023;55(4):1190-1197.   Published online April 17, 2023
DOI: https://doi.org/10.4143/crt.2023.320
AbstractAbstract PDFPubReaderePub
Purpose
Epidermal growth factor receptor (EGFR) T790M mutations have been detected in the second or third rebiopsy, even if the T790M mutation was not identified in the first rebiopsy. This meta-analysis investigated the EGFR T790M mutation detection rates and its additional advantages with repeated rebiopsies.
Materials and Methods
We searched through the PubMed and EMBASE databases up to June 2022. Studies reporting rebiopsy to identify the EGFR T790M mutation in case of disease progression among patients with advanced non-small cell lung cancer and multiple rebiopsies were included. The quality of the included studies was checked using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool.
Results
Eight studies meeting the eligibility criteria, reporting 1,031 EGFR mutation–positive patients were selected. The pooled EGFR T790M mutation detection rate of the first and repeated rebiopsies were 0.442 (95% confidence interval [CI], 0.411 to 0.473; I2=84%; p < 0.01) and 0.465 (95% CI, 0.400 to 0.530; I2=69%; p < 0.01), respectively. Overall, the pooled detection rate of EGFR T790M mutation was 0.545 (95% CI, 0.513 to 0.576), which increased by 10.3% with repeated rebiopsies.
Conclusion
This meta-analysis identified that repeated rebiopsy increases the detection rate of EGFR T790M mutation by 10.3%, even if EGFR T790M mutation is not detected in the first rebiopsy. Our results indicate that the spatiotemporal T790M heterogeneity can be overcome with repeated rebiopsy.

Citations

Citations to this article as recorded by  
  • Clinical utility of repeated rebiopsy for EGFR T790M mutation detection in non-small cell lung cancer
    Eun Hye Lee, Se Hyun Kwak, Kyeong Yeon Kim, Chi Young Kim, Sang Hoon Lee, Seok-Jae Heo, Yoon Soo Chang, Eun Young Kim
    Frontiers in Oncology.2024;[Epub]     CrossRef
  • Repeated rebiopsy for detection of EGFR T790M mutation in patients with advanced-stage lung adenocarcinoma: Associated factors and treatment outcomes of Osimertinib
    Taeyun Kim, Junsu Choe, Sun Hye Shin, Byeong-Ho Jeong, Kyungjong Lee, Hojoong Kim, Se-Hoon Lee, Sang-Won Um, Hamidreza Montazeri Aliabadi
    PLOS ONE.2024; 19(9): e0310079.     CrossRef
  • Rebiopsie tumorale : quand ? pour qui ? pourquoi ? comment ?
    V. Fallet
    Revue des Maladies Respiratoires Actualités.2023; 15(2): 2S121.     CrossRef
  • 3,250 View
  • 206 Download
  • 2 Web of Science
  • 3 Crossref
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The Role of Brain Radiotherapy before First-Line Afatinib Therapy, Compared to Gefitinib or Erlotinib, in Patients with EGFR-Mutant Non–Small Cell Lung Cancer
Hyun Ae Jung, Sehhoon Park, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Jong-Mu Sun
Cancer Res Treat. 2023;55(2):479-487.   Published online December 27, 2022
DOI: https://doi.org/10.4143/crt.2022.1344
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Brain metastasis is common in patients with epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer (NSCLC) at initial presentation. A previous study showed that brain radiotherapy (RT) before first-generation (first-G) EGFR–tyrosine kinase inhibitor (TKI) therapy is associated with longer overall survival than TKI therapy alone. However, there is no data regarding the role of additional brain RT before afatinib therapy.
Materials and Methods
Between October 2014 and June 2019, EGFR-mutant NSCLC patients with brain metastases who started first-G EGFR-TKIs (gefitinib or erlotinib) or afatinib as first-line therapy were retrospectively analyzed. This study compared overall survival and intracranial progression-free survival (PFS) between patients who received EGFR-TKIs alone and EGFR-TKIs with brain RT and either a first-G EGFR-TKI or afatinib, respectively.
Results
The median follow-up duration was 29.6 months (range, 1.5 to 116.9 months). In the first-G EGFR-TKI group (n=155), 94 patients (60.6%) received the first-G EGFR-TKI alone and 61 patients (39.4%) received brain RT prior to their first-G EGFR-TKI. In the afatinib group (n=204), 126 patients (61.8%) received afatinib alone and 78 patients (38.2%) received brain RT prior to afatinib. There was no difference in overall survival rates between the groups with RT (35.6 months: 95% confidence interval [CI], 27.9 to 43.3) and without RT (31.4 months: 95% CI, 23.9 to 38.9) in the afatinib group (p=0.58), but there was a significant difference in overall survival in the first-G EGFR-TKI group in a manner favoring additional brain RT (41.1 months: 95% CI, 30.5 to 51.7 vs. 25.8 months: 95% CI, 20.1 to 31.5; p=0.02). Meanwhile, median intracranial PFS was not different between patients who received EGFR-TKI therapy alone vs. EGFR-TKI therapy with brain RT in both the first-G EGFR-TKI (p=0.39) and afatinib (p=0.24) groups.
Conclusion
Afatinib therapy alone showed comparable survival outcomes to those of afatinib with brain RT. The current study suggests that brain RT could be an optional, not mandatory, treatment modality when afatinib therapy is considered in patients with EGFR-mutant NSCLC.

Citations

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  • Integrated single cell and bulk RNA sequencing analyses reveal the impact of tryptophan metabolism on prognosis and immunotherapy in colon cancer
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Gynecologic cancer
Effectiveness of Concomitant Chemoradiotherapy with Gemcitabine in Locally Advanced Cervical Cancer Patients with Comorbidities
Hasan Brau-Figueroa, Eder Arango-Bravo, Denisse Castro-Eguiluz, Tatiana Galicia-Carmona, Leopoldo Abraham Lugo-Alferez, Ivette Cruz-Bautista, Roberto Jiménez-Lima, Lucely Cetina-Pérez
Cancer Res Treat. 2022;54(2):554-562.   Published online August 10, 2021
DOI: https://doi.org/10.4143/crt.2021.375
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The standard treatment for locally advanced cervical cancer (LACC) is concomitant chemoradiotherapy with cisplatin (CDDP) followed by brachytherapy. The presence of comorbidities are risk factors for nephrotoxicity and are associated with lower survival. Gemcitabine is a radiosensitizing drug that has shown efficacy and safety in this context. The effectiveness of concomitant chemoradiotherapy with gemcitabine was evaluated versus cisplatin in LACC patients with comorbidities and preserved renal function.
Materials and Methods
An observational, longitudinal and paired study was carried out that included patients treated between February 2003 and December 2015. The primary objectives were to evaluate response rates, progression-free survival, and overall survival; the secondary objectives were to evaluate toxicity and renal function.
Results
Sixty-three patients treated with gemcitabine at 300 mg/m2 weekly and 126 patients treated with CDDP 40 mg/m2 weekly were included. There were no significant differences in response rates and survival rates. Treatment with cisplatin presented a higher frequency of hematological toxicities, while gemcitabine presented a higher frequency of gastrointestinal toxicities. A decrease in glomerular filtration rate (GFR; baseline vs. 1-year post-treatment) was observed in the cisplatin group (p=0.002), while not in the gemcitabine group (p=0.667). In a multivariate analysis, it is observed that only CDDP correlates with the decrease in GFR (hazard ratio, 2.42; p=0.012).
Conclusion
In LACC patients with comorbidities, gemcitabine and CDDP show the same efficacy, with different toxicity profiles. Treatment with cisplatin is associated with a significant decrease in GFR during follow-up, compared to treatment with gemcitabine that does not decrease it.

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Lung and Thoracic cancer
The Clinical Outcomes of Different First-Line EGFR-TKIs Plus Bevacizumab in Advanced EGFR-Mutant Lung Adenocarcinoma
Yen-Hsiang Huang, Kuo-Hsuan Hsu, Chun-Shih Chin, Jeng-Sen Tseng, Tsung-Ying Yang, Kun-Chieh Chen, Kang-Yi Su, Sung-Liang Yu, Jeremy J.W. Chen, Gee-Chen Chang
Cancer Res Treat. 2022;54(2):434-444.   Published online August 2, 2021
DOI: https://doi.org/10.4143/crt.2021.671
AbstractAbstract PDFPubReaderePub
Purpose
The aim of this study was to investigate the efficacy of various epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) plus bevacizumab in advanced EGFR-mutant lung adenocarcinoma patients.
Materials and Methods
From August 2016 to October 2020, we enrolled advanced lung adenocarcinoma patients harboring exon 19 deletion or L858R receiving gefitinib, erlotinib and afatinib plus bevacizumab as the first-line treatment for the purposes of analysis.
Results
A total of 36 patients were included in the final analysis. Three patients received gefitinib, 17 received erlotinib, and 16 received afatinib combined with bevacizumab as the first-line treatment. The objective response rate was 77.8%, and disease control rate was 94.4%. The overall median progression-free survival (PFS) was 16.4 months, while the median PFS was 17.1 months in patients with exon 19 deletion, and 16.2 months in patients with L858R mutation (p=0.311). Regarding the use of different EGFR-TKIs, the median PFS was 17.1 months in the erlotinib group and 21.6 months in the afatinib group (p=0.617). In patients with brain metastasis at baseline, the median PFS was 18.9 months in the erlotinib group and 16.4 months in the afatinib group (p=0.747). Amongst patients harboring exon 19 deletion, the median PFS was 16.2 months in the erlotinib group and not-reached in the afatinib group (p=0.141). In patients with L858R mutation, the median PFS was 18.9 months in the erlotinib group and 16.2 months in the afatinib group (p=0.481).
Conclusion
Our research demonstrates that not only erlotinib combined with bevacizumab, but also afatinib plus bevacizumab as first-line treatment, provides solid clinical efficacy in advanced EGFR-mutant lung adenocarcinoma patients.

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    Wei-Fan Ou, Kuo-Hsuan Hsu, Jeng-Sen Tseng, Po-Hsin Lee, Kun-Chieh Chen, Yen-Hsiang Huang, Gee-Chen Chang, Tsung-Ying Yang
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    Ruijian Li, Weiyi Li, Fang Zhang, Shanshan Li
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    Yung-Hung Luo, Kung-Hao Liang, Hsu-Ching Huang, Chia-I Shen, Chi-Lu Chiang, Mong-Lien Wang, Shih-Hwa Chiou, Yuh-Min Chen
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    Suey-Haur Lee, Yu-Ching Lin, Li-Chung Chiu, Jia-Shiuan Ju, Pi-Hung Tung, Allen Chung-Cheng Huang, Shih-Hong Li, Yueh-Fu Fang, Chih-Hung Chen, Scott Chih-Hsi Kuo, Chin-Chou Wang, Cheng-Ta Yang, Ping-Chih Hsu
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Special Articles
Technological Advances in Charged-Particle Therapy
Jong Min Park, Jung-in Kim, Hong-Gyun Wu
Cancer Res Treat. 2021;53(3):635-640.   Published online June 21, 2021
DOI: https://doi.org/10.4143/crt.2021.706
AbstractAbstract PDFPubReaderePub
Charted-particle therapy (CPT) benefits cancer patients by localizing doses in the tumor volume while minimizing the doses delivered to normal tissue through its unique physical and biological characteristics. The world’s first CPT applied on humans was proton beam therapy (PBT), which was performed in the mid-1950s. Among heavy ions, carbon ions showed the most favorable biological characteristics for the treatment of cancer patients. Carbon ions show coincidence between the Bragg peak and maximum value of relative biological effectiveness. In addition, they show low oxygen enhancement ratios. Therefore, carbon-ion radiotherapy (CIRT) has become mainstream in the treatment of cancer patients using heavy ions. CIRT was first performed in 1977 at the Lawrence Berkeley Laboratory. The CPT technology has advanced in the intervening decades, enabling the use of rotating gantry, beam delivery with fast pencil-beam scanning, image-guided particle therapy, and intensity-modulated particle therapy. As a result, as of 2019, a total of 222,425 and 34,138 patients with cancer had been treated globally with PBT and CIRT, respectively. For more effective and efficient CPT, many groups are currently conducting further studies worldwide. This review summarizes recent technological advances that facilitate clinical use of CPT.

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  • Efficacy and safety of proton radiotherapy in treating choroidal melanoma: a systematic review and meta-analysis
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    Yufeng Li, Lei Ta, QingFeng Wu, Hongyu Zhang, Yuan Xu, Lu Gan, Jianli Liu
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    Yu-Hsuan Tseng, Chia-An Hsu, Yu-Bai Chou
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    Yixiao Guo, Zhiqiang Liu, Shifang Feng, Hongyi Cai, Qiuning Zhang
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    Hanguang Ruan, Masahiko Okamoto, Tatsuya Ohno, Yang Li, Yuan Zhou
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    Pankaj Chaudhary, Giuliana Milluzzo, Aodhan McIlvenny, Hamad Ahmed, Aaron McMurray, Carla Maiorino, Kathryn Polin, Lorenzo Romagnani, Domenico Doria, Stephen J McMahon, Stanley W Botchway, Pattathil P Rajeev, Kevin M Prise, Marco Borghesi
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    Eui Kyu Chie, Yong Chan Ahn
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Close layer
Who Will Benefit from Charged-Particle Therapy?
Kyung Su Kim, Hong-Gyun Wu
Cancer Res Treat. 2021;53(3):621-634.   Published online June 21, 2021
DOI: https://doi.org/10.4143/crt.2021.299
AbstractAbstract PDFPubReaderePub
Charged-particle therapy (CPT) such as proton beam therapy (PBT) and carbon-ion radiotherapy (CIRT) exhibit substantial physical and biological advantages compared to conventional photon radiotherapy. As it can reduce the amount of radiation irradiated in the normal organ, CPT has been mainly applied to pediatric cancer and radioresistent tumors in the eloquent area. Although there is a possibility of greater benefits, high set-up cost and dearth of high level of clinical evidence hinder wide applications of CPT. This review aims to present recent clinical results of PBT and CIRT in selected diseases focusing on possible indications of CPT. We also discussed how clinical studies are conducted to increase the number of patients who can benefit from CPT despite its high cost.

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  • Cost-effectiveness analysis for multi adverse events of proton beam therapy for pediatric medulloblastoma in Japan
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    Pankaj Chaudhary, Giuliana Milluzzo, Aodhan McIlvenny, Hamad Ahmed, Aaron McMurray, Carla Maiorino, Kathryn Polin, Lorenzo Romagnani, Domenico Doria, Stephen J McMahon, Stanley W Botchway, Pattathil P Rajeev, Kevin M Prise, Marco Borghesi
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    Yanliang Chen, Hongtao Luo, Ruifeng Liu, Mingyu Tan, Qian Wang, Xun Wu, Tianqi Du, Zhiqiang Liu, Shilong Sun, Qiuning Zhang, Xiaohu Wang
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Original Article
Genitourinary Cancer
Use of Gemcitabine plus Carboplatin is Associated with Poor Outcomes in Urothelial Carcinoma Patients with Chronic Kidney Disease Stage 4-5
Hyung-Don Kim, Hyeon-Su Im, Jwa Hoon Kim, Hyehyun Jeong, Shin Kyo Yoon, Inkeun Park, Jae Lyun Lee
Cancer Res Treat. 2021;53(4):1166-1173.   Published online March 4, 2021
DOI: https://doi.org/10.4143/crt.2021.091
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study aimed to investigate the clinical outcomes with gemcitabine-carboplatin (GCb), the standard treatment for patients with advanced urothelial carcinoma (UC) who are ineligible for cisplatin-based regimens, in advanced UC patients with a glomerular filtration rate (GFR) < 30 mL/min.
Materials and Methods
A retrospective cohort study involving GCb-treated advanced UC patients with GFR < 60 mL/min (n=89) was performed. Clinical outcomes were compared between subgroups with GFR < 30 mL/min and GFR ≥ 30 mL/min but < 60 mL/min.
Results
Most baseline characteristics were comparable between the two subgroups. Patients with GFR < 30 mL/min had a significantly lower objective response rate (12.5%) compared to those with higher GFR levels (56.7%) (p=0.004). The number of GCb cycles was significantly lower in patients with GFR < 30 mL/min (median 2 cycles) than in those with higher GFR levels (median 6 cycles) (p=0.002). Compared to those with GFR ≥ 30 mL/min but < 60 mL/min, patients with GFR < 30 mL/min showed significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.001 for both). Further stratification of patient subgroups according to their GFR (i.e., GFR ≥ 45 mL/min but < 60 mL/min vs. GFR ≥ 30 mL/min but < 45 mL/min vs. GFR < 30 mL/min) revealed significantly different PFS and OS (p < 0.001 for both).
Conclusion
The use of GCb is discouraged in advanced UC patients with GFR < 30 mL/min. Alternative therapeutic approaches with better efficacy are warranted for these patients.

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  • Real‐World Outcomes of First‐Line Systematic Treatment in Locally Advanced or Metastatic Upper Urinary Tract Urothelial Carcinoma With Renal Impairment (YUSHIMA Study)
    Tomoki Kimura, Motohiro Fujiwara, Yuya Maezawa, Kensaku Ishihara, Naoki Inoue, Kenji Tanabe, Keita Izumi, Masahiro Toide, Takanobu Yamamoto, Sho Uehara, Saori Araki, Masaharu Inoue, Ryoji Takazawa, Noboru Numao, Yukihiro Ohtsuka, Yuma Waseda, Hajime Tanak
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    Umut Selamet, Rebecca S. Ahdoot, Reed Salasnek, Lama Abdelnour, Ramy M. Hanna
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    Shingo Hatakeyama, Shintaro Narita, Kazutaka Okita, Takuma Narita, Hiromichi Iwamura, Naoki Fujita, Junichi Inokuchi, Yoshiyuki Matsui, Hiroshi Kitamura, Chikara Ohyama
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Close layer
Case Report
Identification of a Novel CSNK2A1-PDGFRB Fusion Gene in a Patient with Myeloid Neoplasm with Eosinophilia
Xiaoyu Xu, Qiongyu Lu, Zheng Wang, Ping Cai, Zhao Zeng, Ling Zhang, Man Wang, Liang Ma, Changgeng Ruan, Suning Chen
Cancer Res Treat. 2021;53(3):889-892.   Published online December 24, 2020
DOI: https://doi.org/10.4143/crt.2020.1272
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Platelet-derived growth factor receptor beta (PDGFRB) rearrangements play an important role in the pathogenesis of eosinophilia-associated myeloid/lymphoid neoplasms. Up to now, more than 70 PDGFRB fusions have been identified. Here, a novel PDGFRB fusion gene CSNK2A1-PDGFRB has been identified in myeloproliferative neoplasm (MPN) with eosinophilia by RNA-sequencing, which has been verified by reverse transcription polymerase chain reaction and Sanger sequencing. The new PDGFRB fusion partner gene CSNK2A1 encoded one of the two catalytic subunit of casein kinase II (CK2). To our knowledge, this is the first report on the involvement of CSNK2A1 in fusion genes, especially fusion with another kinase PDGFRB in MPN. In addition, the CSNK2A1-PDGFRB fusion retained the entire kinase domain of PDGFRB and response to imatinib at low concentration. The patient with CSNK2A1-PDGFRB was sensitive to imatinib treatment and acquired sustained complete remission.

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  • The novel TERF2::PDGFRB fusion gene enhances tumorigenesis via PDGFRB/STAT5 signalling pathways and sensitivity to TKI in ph‐like ALL
    Guo‐fa Xu, Zhao Zeng, Zhi‐bo Zhang, Xiao‐mei Zhang, Man Wang, Qing Xiao, Jun Li, Xiao‐qing Xie, Sanxiu He, Hui‐hui Fu, Yi Liu, Zai‐liang Yang, Yu Chen, Jie Shi, Biao Wang, Hui‐ying Qiu, Qi Zhou, Yao Liu, Su‐ning Chen
    Journal of Cellular and Molecular Medicine.2024;[Epub]     CrossRef
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    Katsuhiro Masago, Hiroaki Kuroda, Eiichi Sasaki, Yasuko Fujita, Shiro Fujita, Yoshitsugu Horio, Motoyoshi Endo, Hiromasa Ishihara, Nobuhiro Hanai, Hirokazu Matsushita
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    Tiantian Wang, Junjie Cao, Qingqing Lin, Xuhui Liu, Man Wang, Renzhi Pei, Ying Lu
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    Daniel Halloran, Venu Pandit, Anja Nohe
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    Zaira Spinello, Anna Fregnani, Laura Quotti Tubi, Livio Trentin, Francesco Piazza, Sabrina Manni
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    Sareshma Sudhesh Dev, Syafiq Asnawi Zainal Abidin, Reyhaneh Farghadani, Iekhsan Othman, Rakesh Naidu
    Frontiers in Pharmacology.2021;[Epub]     CrossRef
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Original Articles
Gastrointestinal Cancer
Risk of Death in Colorectal Cancer Patients with Multi-morbidities of Metabolic Syndrome: A Retrospective Multicohort Analysis
Qingting Feng, Lingkai Xu, Lin Li, Junlan Qiu, Ziwei Huang, Yiqing Jiang, Tao Wen, Shun Lu, Fang Meng, Xiaochen Shu
Cancer Res Treat. 2021;53(3):714-723.   Published online December 2, 2020
DOI: https://doi.org/10.4143/crt.2020.481
AbstractAbstract PDFPubReaderePub
Purpose
The prevalence of multi-morbidities with colorectal cancer (CRC) is known to be increasing. Particularly prognosis of CRC patients co-diagnosed with metabolic syndrome (MetSyn) was largely unknown. We aimed to examine the death risk of CRC patients according to the multiple MetSyn morbidities.
Materials and Methods
We identified CRC patients with MetSyn from the electronic medical records (EMR) systems in five independent hospitals during 2006-2011. Information on deaths was jointly retrieved from EMR, cause of death registry and chronic disease surveillance as well as study-specific questionnaire. Cox proportional hazards regression was used to calculate the overall and CRC-specific hazards ratios (HR) comparing MetSyn CRC cohort with reference CRC cohort.
Results
A total of 682 CRC patients in MetSyn CRC cohort were identified from 24 months before CRC diagnosis to 1 month after. During a median follow-up of 92 months, we totally observed 584 deaths from CRC, 245 being in MetSyn cohort and 339 in reference cohort. Overall, MetSyn CRC cohort had an elevated risk of CRC-specific mortality (HR, 1.49; 95% confidence interval [CI], 1.07 to 1.90) and overall mortality (HR, 1.43; 95% CI, 1.09 to 1.84) compared to reference cohort after multiple adjustment. Stratified analyses showed higher mortality risk among women (HR, 1.87; 95% CI, 1.04 to 2.27) and specific components of MetSyn. Notably, the number of MetSyn components was observed to be significantly related to CRC prognosis.
Conclusion
Our findings supported that multi-morbidities of MetSyn associated with elevated death risk after CRC. MetSyn should be considered as an integrated medical condition more than its components in CRC prognostic management.

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    Victoria Damerell, Niels Klaassen‐Dekker, Stefanie Brezina, Jennifer Ose, Arve Ulvik, Eline H. van Roekel, Andreana N. Holowatyj, Andreas Baierl, Jürgen Böhm, Martijn J. L. Bours, Hermann Brenner, Johannes H. W. de Wilt, William M. Grady, Nina Habermann,
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    Tung Hoang, Minjung Kim, Ji Won Park, Seung-Yong Jeong, Jeeyoo Lee, Aesun Shin
    BMC Microbiology.2023;[Epub]     CrossRef
  • Comparing Long-Term Survival Outcomes for Muscle-Invasive Bladder Cancer Patients Who Underwent with Radical Cystectomy and Bladder-Sparing Trimodality Therapy: A Multicentre Cohort Analysis
    Junlan Qiu, Haifeng Zhang, Dongkui Xu, Lin Li, Lingkai Xu, Yiqing Jiang, Tao Wen, Shun Lu, Fang Meng, Lin Feng, Xiaochen Shu, Pierfrancesco Franco
    Journal of Oncology.2022; 2022: 1.     CrossRef
  • Cosmc transfection decreases malignant behavior of Tn+ cells and enhances sensitivity to apoptosis when induced by Apo2L/TRAIL via alteration of O-glycan structure
    Ruisong Ding, Xingyou Hu, Wen Hu, Zhenzhen Du, Panpan Huang, Mengyang Wang, Jiaoyue Sheng, Yanchao Ma, Ailing Wang, Xiying Luan, Menghua Dong, Qizhi Cao, Yanfen Zou, Tao Hu
    Aging.2021; 13(19): 23393.     CrossRef
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Gastrointestinal cancer
Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells
Boonyakorn Boonsri, Kiren Yacqub-Usman, Pakpoom Thintharua, Kyaw Zwar Myint, Thannicha Sae-Lao, Pam Collier, Chinnawut Suriyonplengsaeng, Noppadol Larbcharoensub, Brinda Balasubramanian, Simran Venkatraman, Isioma U. Egbuniwe, Dhanwant Gomez, Abhik Mukherjee, Supeecha Kumkate, Tavan Janvilisri, Abed M Zaitoun, Thiti Kuakpaetoon, Rutaiwan Tohtong, Anna M Grabowska, David O. Bates, Kanokpan Wongprasert
Cancer Res Treat. 2021;53(2):457-470.   Published online October 7, 2020
DOI: https://doi.org/10.4143/crt.2020.585
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. Materials and Methods ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments.
Results
CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. Conclusion Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients.

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    Yumeng Gao, Ainv Zhang, Li Li, Fengxu Wu, Yanggen Hu
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  • 10,730 View
  • 397 Download
  • 7 Crossref
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Genitourinary cancer
Cause of Mortality after Radical Prostatectomy and the Impact of Comorbidity in Men with Prostate Cancer: A Multi-institutional Study in Korea
Sahyun Pak, Dalsan You, In Gab Jeong, Dong-Eun Lee, Sung Han Kim, Jae Young Joung, Kang-Hyun Lee, Jun Hyuk Hong, Choung-Soo Kim, Hanjong Ahn
Cancer Res Treat. 2020;52(4):1242-1250.   Published online July 3, 2020
DOI: https://doi.org/10.4143/crt.2020.286
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study aimed to examine the causes of death in Korean patients who underwent radical prostatectomy for prostate cancer and investigate the relationship between comorbidity and mortality.
Materials and Methods
We conducted a retrospective multicenter cohort study including 4,064 consecutive patients who had prostate cancer and underwent radical prostatectomy between January 1998 and June 2013. The primary endpoint of this study was all-cause mortality, and the secondary endpoints were cancer-specific mortality (CSM) and other-cause mortality (OCM). Charlson comorbidity index (CCI) was calculated to assess the comorbidities of each patient.
Results
Of 4,064 patients, 446 (11.0%) died during follow-up. The cause of death was prostate cancer in 132 patients (29.6%), other cancers in 121 patients (27.1%), and vascular disease in 57 patients (12.8%) in our cohort. The overall 10-year CSM rate was lower than the OCM rate (4.6% vs. 10.5%). The 10-year CSM rate was lower than the OCM rate in low- to intermediate-risk group patients (1.2% vs. 10.6%), whereas they were similar in high-risk group patients (11.8% vs. 10.1%). In the multivariable analysis, CCI was independently associated with all-cause mortality after radical prostatectomy, regardless of age and pathologic features.
Conclusion
Death from prostate cancer was rare in Korean men who underwent radical prostatectomy. Clinicians should be aware of the possibility of overtreatment of low-risk prostate cancer in men with significant comorbidity. Our findings may help to facilitate counseling and plan management in this patient group.
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Case Report
EGFR C797S as a Resistance Mechanism of Lazertinib in Non-small Cell Lung Cancer with EGFR T790M Mutation
Sehhoon Park, Bo Mi Ku, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Se-Hoon Lee, Keunchil Park, Myung-Ju Ahn
Cancer Res Treat. 2020;52(4):1288-1290.   Published online June 22, 2020
DOI: https://doi.org/10.4143/crt.2020.278
AbstractAbstract PDFPubReaderePub
The non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutation eventually acquires resistant to either first or second-generation EGFR tyrosine kinase inhibitor (TKI). As the following option, targeting EGFR T790M with third-generation EGFR TKI is now established as a standard treatment option. In this study, we are reporting the first case of resistance mechanism to the novel third-generation EGFR TKI, lazertinib, which showed promising clinical efficacy in phase 1-2 study. The patients showed resistance to the treatment by acquiring the additional EGFR C797S mutation in cis which is also confirmed from the patient-derived cell lines.

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    亚南 胡
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    Yue Fang, Qiankun Zhang, Weimin Wang, Juanjuan Tong, Xialin Li
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    Tanuja T. Yadav, Gulam Moin Shaikh, Maushmi S. Kumar, Meena Chintamaneni, Mayur YC
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    David E. Heppner, Florian Wittlinger, Tyler S. Beyett, Tatiana Shaurova, Daniel A. Urul, Brian Buckley, Calvin D. Pham, Ilse K. Schaeffner, Bo Yang, Blessing C. Ogboo, Earl W. May, Erik M. Schaefer, Michael J. Eck, Stefan A. Laufer, Pamela A. Hershberger
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Original Articles
Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes
Euna Cho, S M Bakhtiar Ul Islam, Fen Jiang, Ju-Eun Park, Bora Lee, Nam Deuk Kim, Tae-Ho Hwang
Cancer Res Treat. 2020;52(1):309-319.   Published online August 6, 2019
DOI: https://doi.org/10.4143/crt.2019.161
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The purpose of this study was to assess characteristics of SJ-815, a novel oncolytic vaccinia virus lacking a functional thymidine kinase-encoding TK gene, and instead, having two human transgenes: the IFNB1 that encodes interferon β1, and the CES2 that encodes carboxylesterase 2, which metabolizes the prodrug, irinotecan, into cytotoxic SN-38.
Materials and Methods
Viral replication and dissemination of SJ-815 were measured by plaque assay and comet assay, respectively, and compared to the backbone of SJ-815, a modified Western Reserve virus named WI. Tumor cytotoxicity of SJ-815 (or mSJ-815, which has the murine IFNB1 transgene for mouse cancers) was evaluated using human and mouse cancer cells. Antitumor effects of SJ-815, with/without irinotecan, were evaluated using a human pancreatic cancer-bearing mouse model and a syngeneic melanoma-bearing mouse model. The SN-38/ irinotecan ratios in mouse melanoma tissue 4 days post irinotecan treatment were compared between groups with and without SJ-815 intravenous injection.
Results
SJ-815 demonstrated significantly lower viral replication and dissemination, but considerably stronger in vitro tumor cytotoxicity than WI. The combination use of SJ-815 plus irinotecan generated substantial tumor regression in the human pancreatic cancer model, and significantly prolonged survival in the melanoma model (hazard ratio, 0.11; 95% confidence interval, 0.02 to 0.50; p=0.013). The tumor SN-38/irinotecan ratios were over 3-fold higher in the group with SJ-815 than those without (p < 0.001).
Conclusion
SJ-815 demonstrates distinct characteristics gained from the inserted IFNB1 and CES2 transgenes. The potent antitumor effects of SJ-815, particularly when combined with irinotecan, against multiple solid tumors make SJ-815 an attractive candidate for further preclinical and clinical studies.

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Crizotinib versus Chemotherapy in Asian Patients with ALK-Positive Advanced Non-small Cell Lung Cancer
Makoto Nishio, Dong-Wan Kim, Yi-Long Wu, Kazuhiko Nakagawa, Benjamin J. Solomon, Alice T. Shaw, Satoshi Hashigaki, Emiko Ohki, Tiziana Usari, Jolanda Paolini, Anna Polli, Keith D. Wilner, Tony Mok
Cancer Res Treat. 2018;50(3):691-700.   Published online July 6, 2017
DOI: https://doi.org/10.4143/crt.2017.280
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials.
Materials and Methods
This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and “as-treated” populations for efficacy and safety endpoints, respectively.
Results
In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity.
Conclusion
These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.

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Risk of Second Primary Cancer in People with Non-melanoma Skin Cancer: A Nationwide Cohort Study
Shu-Hui Wang, Ching-Chi Chi, Zi-Hao Zhao, Tao-Hsin Tung
Cancer Res Treat. 2018;50(2):428-435.   Published online May 10, 2017
DOI: https://doi.org/10.4143/crt.2017.110
AbstractAbstract PDFPubReaderePub
Purpose
Previous western studies have found Caucasians with skin cancer, either melanoma or nonmelanoma skin cancer (NMSC), have an elevated risk of second primary cancer. Our objective was to assess the risk of second primary cancer in Taiwanese with NMSC.
Materials and Methods
By using data from Taiwan’s National Health Insurance Research Database, we conducted a population-based cohort study to assess the risk of incident second primary cancer in Taiwanese affected by NMSC.
Results
We identified 505 subjects with NMSC and 2,020 matched controls. After adjustment for potential confounders including age, sex, urbanization, and Charlson Comorbidity Index, people who had NMSC had a 1.43-fold (95% confidence interval [CI], 1.05 to 1.96) risk for the development of second primary cancer as comparedwith control group. Menwith NMSC had a 2.99-fold (95% CI, 1.00 to 9.10) risk for second primary cancer involving the lip, oral cavity, and pharynx and a 3.51-fold (95% CI, 1.21 to 10.17) risk for second primary cancer involving the genitourinary organs when compared to the control group. By contrast, women with NMSC did not have an increased risk of second primary cancer.
Conclusion
This study revealed Asians with NMSC have an increased risk of second primary cancer. Our findings can be a useful reference for health care for people diagnosed with NMSC.

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FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2-Positive Gastric Cancer Cells Through MET Upregulation
Jinju Park, Yiseul Choi, Young San Ko, Younghoon Kim, Jung-Soo Pyo, Bo Gun Jang, Min A Kim, Jae-Seon Lee, Mee Soo Chang, Jong-Wan Park, Byung Lan Lee
Cancer Res Treat. 2018;50(1):239-254.   Published online March 24, 2017
DOI: https://doi.org/10.4143/crt.2016.580
AbstractAbstract PDFPubReaderePub
Purpose
Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells.
Materials and Methods
Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed.
Results
SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin.
Conclusion
FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.

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An Open-Label, Randomized, Parallel, Phase II Trial to Evaluate the Efficacy and Safety of a Cremophor-Free Polymeric Micelle Formulation of Paclitaxel as First-Line Treatment for Ovarian Cancer: A Korean Gynecologic Oncology Group Study (KGOG-3021)
Shin-Wha Lee, Yong-Man Kim, Chi Heum Cho, Young Tae Kim, Seok Mo Kim, Soo Young Hur, Jae-Hoon Kim, Byoung-Gie Kim, Seung-Cheol Kim, Hee-Sug Ryu, Soon Beom Kang
Cancer Res Treat. 2018;50(1):195-203.   Published online March 21, 2017
DOI: https://doi.org/10.4143/crt.2016.376
AbstractAbstract PDFPubReaderePub
Purpose
Genexol-PM is a biodegradable cremophor EL–free polymeric micelle formulation of paclitaxel. Here,we compared efficacy and safety of Genexol-PM plus carboplatin versus Genexol plus carboplatin for ovarian cancer treatment.
Materials and Methods
In this multicenter, randomized, phase II study, patients with International Federation of Gynecology and Obstetrics IC-IV epithelial ovarian cancer were randomly assigned (1:1) to receive Genexol-PM 260 mg/m2 or Genexol 175 mg/m2 with 5 area under the curve carboplatin every 3weeks (6 cycles). The primary endpointwas the carbohydrate antigen 125 and Response Evaluation Criteria In Solid Tumor composite overall response rate (ORR).
Results
Of 131 enrolled patients, 98 were included in intention-to-treat analysis. Mean dosages were 260.00±0.00 mg/m2 Genexol-PM or 174.24±3.81 mg/m2 Genexol. Median followup was 18.0 months (range, 6.1 to 33.8 months). ORR was 88.0% (95% confidence interval [CI], 80.4 to 95.6) with Genexol-PM, and 77.1% (95% CI, 67.1 to 87.1) with Genexol (noninferiority threshold, 16.3%). Median time to progression was 14.8 months (95% CI, 11.3 to 20.2) with Genexol-PM and 15.4 months (95% CI, 13.2 to 29.6) with Genexol (p=0.550). Overall, six patients died. Neutropenia was the most common toxicity (incidences of 86.0% vs. 77.1%, p=0.120). Peripheral neuropathy incidences were 84.0% versus 64.6% (p= 0.148). Peripheral neuropathy of ≥ grade 3 occurred in one patient receiving Genexol. All toxicities were manageable.
Conclusion
Genexol-PM plus carboplatin as first-line treatment in patients with epithelial ovarian cancer demonstrated non-inferior efficacy and well-tolerated toxicities compared with the standard paclitaxel regimen. Further studies are warranted to optimize the dose and schedule, and to investigate long-term outcomes.

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Clinicopathologic Characteristics and Prognosis of Tongue Squamous Cell Carcinoma in Patients with and without a History of Radiation for Nasopharyngeal Carcinoma: A Matched Case-Control Study
Peng Zhang, Li Zhang, Hui Liu, Lei Zhao, Yong Li, Jing-Xian Shen, Qing Liu, Meng-Zhong Liu, Mian Xi
Cancer Res Treat. 2017;49(3):695-705.   Published online October 11, 2016
DOI: https://doi.org/10.4143/crt.2016.317
AbstractAbstract PDFPubReaderePub
Purpose
Previous studies reported an association between an increased risk of tongue cancer and radiation treatment for nasopharyngeal carcinoma (NPC). This study compared the clinicopathologic characteristics and outcomes of tongue squamous cell carcinoma (TSCC) in patients with and without a history of radiotherapy for NPC.
Materials and Methods
From 1965 to 2009, a total of 73 patients were diagnosed with TSCC with a history of radiotherapy for NPC. The patients were matched in a 1:3 ratio with patients with sporadic TSCC according to age, sex, and year of the TSCC diagnosis. The primary endpoint was the overall survival.
Results
The median interval from NPC to TSCC was 82 months. The NPC survivors were more likely to be diagnosed with a more advanced T classification, less likely to have lymph node involvement, and more likely to have the tumor located in the dorsum of the tongue than sporadic TSCC. Regarding the histologic characteristics, the NPC survivors were more likely to have a weak lymphocytic host response, low tumor budding, and low risk of a worse pattern of invasion. The sporadic TSCC patients had a better overall survival (hazard ratio, 0.690; p=0.033) than the NPC survivors. In competing risks analysis, the cumulative incidence functions for the competing event (documented non-tongue cancer death) were significantly higher in the NPC survivors (Gray’s test, p=0.001).
Conclusion
TSCC patients with a history of radiotherapy for NPC appear to have particular clinicopathologic features, a poorer survival, and are more likely to die from non-tongue cancer causes than those with sporadic TSCC.

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The Expression of Carbonic Anhydrase (CA) IX/XII and Lymph Node Metastasis in Early Breast Cancer
Keun-Yong Eom, Min Hye Jang, So Yeon Park, Eun Young Kang, Sung Won Kim, Jee Hyun Kim, Jae-Sung Kim, In Ah Kim
Cancer Res Treat. 2016;48(1):125-132.   Published online March 3, 2015
DOI: https://doi.org/10.4143/crt.2014.243
AbstractAbstract PDFPubReaderePub
Purpose
The aim of study was to test by immunohistochemical (IHC) staining whether carbonic anhydrase (CA) 9 and 12 have an effect on sentinel lymph node (SLN) metastasis in early breast cancer and to find clinicopathologic factors associated with SLN metastasis.
Materials and Methods
Between June 2003 and June 2011, medical records of 470 patients diagnosedwith breast cancer with pT1-2, pN0-2, and M0 were reviewed. Of these 470, 314 patients who underwent SLN biopsy±axillary dissection were subjects of this study. Using tissue microarray, IHC staining for CA9 and CA12 was performed. Clinicopathologic factors such as patient age, tumour size, lymphatic invasion, hormone receptor status, and the Ki-67 labeling index were analysed together.
Results
The mean age of all patients was 51.7 years. The mean number of harvested SLN was 3.62, and 212 patients (67.5%) had negative SLN. Lymphatic invasion, the Ki-67 labelling index of primary tumours, and CA9 staining of stromal cells, were independent risk factors for SLN metastasis in the multivariate analysis. In 33 patients (10.5%) without the three risk factors, no patient had SLN metastasis. In 80 patients without lymphatic invasion of primary tumours or CA9 staining of stromal cells, only four patients (5%) had positive SLN.
Conclusion
CA9 staining of stromal cells is an independent risk factor for SLN metastasis as well as lymphatic invasion and a low Ki-67 labelling index of primary tumours in patients with early breast cancer. IHC staining of primary tumours for CA12was not associatedwith SLN metastasis.

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Peptide Nucleic Acid Clamping Versus Direct Sequencing for the Detection of EGFR Gene Mutation in Patients with Non-small Cell Lung Cancer
Seong-Hoon Yoon, Yoo-Duk Choi, In-Jae Oh, Kyu-Sik Kim, Hayoung Choi, Jinsun Chang, Hong-Joon Shin, Cheol-Kyu Park, Young-Chul Kim
Cancer Res Treat. 2015;47(4):661-669.   Published online February 23, 2015
DOI: https://doi.org/10.4143/crt.2014.282
AbstractAbstract PDFPubReaderePub
Purpose
Direct sequencing (DS) is the standard method for detection of epidermal growth factor receptor (EGFR) gene mutation in non-small cell lung cancer (NSCLC); however, low detection sensitivity is a problem. The aim of this study is to demonstrate higher detection rate of EGFR gene mutation with peptide nucleic acid (PNA) clamping compared with DS. Materials and Methods This is a single arm, prospective study for patients with stage IIIB/IV or relapsed NSCLC. Using tumor DNA from 138 patients, both DS and PNA clamping for EGFR gene in exon 18, 19, 20, and 21 were performed. Discrepant results between the two methods were verified using Cobas and a mutant enrichment based next generation sequencing (NGS). Patients with activating mutations were treated with EGFR tyrosine kinase inhibitor (EGFR-TKI, gefitinib, or erlotinib) as first line treatment.
Results
Of 138 paired test sets, 24 (17.4%) and 45 (32.6%) cases with activating mutations were detected by DS and PNA clamping, respectively. The difference of detection rate between the two methods was 15.2% (95% confidence interval, 8.7% to 17.8%; p < 0.001). Between the two methods, 25 cases showed discrepant results (n=23, PNA+/DS–; n=2, PNA–/DS+). Mutations were confirmed by Cobas or NGS in 22 of 23 PNA+/DS– cases. The response rates to EGFR-TKI were 72.2% in the PNA+/DS+ group and 85.0% in the PNA+/DS– group. Conclusion PNA clamping showed a significantly higher detection rate of EGFR gene mutation compared with DS. Higher sensitivity of PNA clamping was not compromised by the loss of predictive power of response to EGFR-TKI.

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Results of a Phase II Study to Evaluate the Efficacy of Docetaxel and Carboplatin in Metastatic Malignant Melanoma Patients Who Failed First-Line Therapy Containing Dacarbazine
Choong-kun Lee, Minkyu Jung, Hye Jin Choi, Hye Ryun Kim, Hyo Song Kim, Mi Ryung Roh, Joong Bae Ahn, Hyun Cheol Chung, Su Jin Heo, Sun Young Rha, Sang Joon Shin
Cancer Res Treat. 2015;47(4):781-789.   Published online February 16, 2015
DOI: https://doi.org/10.4143/crt.2014.261
AbstractAbstract PDFPubReaderePub
Purpose
There is no standard second-line regimen for malignant melanoma patients with disease progression after first-line chemotherapy, and platinum-alkylating agents combined with paclitaxel have shown modest efficacy. Materials and Methods We conducted a phase II, open-label, single-arm study to test the efficacy of docetaxel combined with carboplatin for malignant melanoma patients who failed previous treatment with dacarbazine. Intravenous docetaxel (35 mg/m2 on days 1 and 8 of each cycle) and carboplatin (area under the curve 3 on days 1 and 8 of each cycle) was administered every 21 days. Primary end point was objective response rate (ORR).
Results
Thirty patients were enrolled in the study, and the median follow-up duration was 19.8 months. Among 25 per-protocol patients, there were three responders (1 with complete response and 2 with partial response) and 17 stable disease patients (ORR, 12.0%). Among the per-protocol population, the median progression-free survival (PFS) was 4.3 months and the median overall survival (OS) was 9.6 months. Uveal melanoma patients (n=9) showed the best prognosis compared to other subtypes (median PFS, 7.6 months; OS, 9.9 months). The most common grade 3 or 4 adverse event was neutropenia (n=15, 50.0%). Conclusion Docetaxel combined with carboplatin showed association with an acceptable safety profile and overall efficacy for patients with malignant melanoma who had progressed on chemotherapy containing dacarbazine.

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APE1/Ref-1 as a Serological Biomarker for the Detection of Bladder Cancer
Ju Hyun Shin, Sunga Choi, Yu Ran Lee, Myoung Soo Park, Yong Gil Na, Kaikobad Irani, Sang Do Lee, Jin Bong Park, Jin Man Kim, Jae Sung Lim, Byeong Hwa Jeon
Cancer Res Treat. 2015;47(4):823-833.   Published online January 2, 2015
DOI: https://doi.org/10.4143/crt.2014.074
AbstractAbstract PDFPubReaderePub
Purpose
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that shows elevated expression in a number of cancers. We attempted to determine whether serum APE1/Ref-1 is elevated in patients with bladder cancer.
Materials and Methods
Serum APE1/Ref-1 levels were determined using enzyme-linked immunosorbent assay in serum from patients with bladder cancer who had not received chemotherapy or radiotherapy (n=51) and non-tumor controls (n=55). The area under the receiver operating characteristic area under the curve was applied to determine the correlation between clinical factors and the serum levels of APE1/Ref-1.
Results
Serum levels of APE1/Ref-1 in bladder cancer patients were significantly elevated compared to those of the control group (3.548±0.333 ng/100 μL [n=51] for bladder cancer vs. 1.547±0.319 ng/100 μL [n=55] for the control group), with a sensitivity and specificity of 93% and 59%, respectively. Serum APE1/Ref-1 levels are associated with tumor stage, grade, muscle invasion, and recurrence.
Conclusion
Serum APE1/Ref-1 might be useful as a potential serologic biomarker for bladder cancer.

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    Fenil Shah, Emery Goossens, Nadia M. Atallah, Michelle Grimard, Mark R. Kelley, Melissa L. Fishel
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    Seon-Ah Jin, Byung-Kwan Lim, Hee Seo, Sun Kim, Kye Ahn, Byeong Jeon, Jin-Ok Jeong
    International Journal of Molecular Sciences.2017; 18(12): 2664.     CrossRef
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    Chun-Ling Yuan, Fan He, Jia-Zhou Ye, Hui-Ni Wu, Jin-Yan Zhang, Zhi-Hui Liu, Yong-Qiang Li, Xiao-Ling Luo, Yan Lin, Rong Liang
    Oncotarget.2017; 8(35): 59720.     CrossRef
  • Urinary APE1/Ref-1: A Potential Bladder Cancer Biomarker
    Sunga Choi, Ju Hyun Shin, Yu Ran Lee, Hee Kyoung Joo, Ki Hak Song, Yong Gil Na, Seok Jong Chang, Jae Sung Lim, Byeong Hwa Jeon
    Disease Markers.2016; 2016: 1.     CrossRef
  • Secreted APE1/Ref-1 inhibits TNF-α-stimulated endothelial inflammation via thiol-disulfide exchange in TNF receptor
    Myoung Soo Park, Sunga Choi, Yu Ran Lee, Hee Kyoung Joo, Gun Kang, Cuk-Seong Kim, Soo Jin Kim, Sang Do Lee, Byeong Hwa Jeon
    Scientific Reports.2016;[Epub]     CrossRef
  • Altered Secretory Activity of APE1/Ref-1 D148E Variants Identified in Human Patients With Bladder Cancer
    Yu Ran Lee, Jae Sung Lim, Ju Hyun Shin, Sunga Choi, Hee Kyoung Joo, Byeong Hwa Jeon
    International Neurourology Journal.2016; 20(Suppl 1): S30.     CrossRef
  • Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein
    Sunga Choi, Hee Kyoung Joo, Byeong Hwa Jeon
    Chonnam Medical Journal.2016; 52(2): 75.     CrossRef
  • Serum APE1 as a predictive marker for platinum-based chemotherapy of non-small cell lung cancer patients
    Shiheng Zhang, Le He, Nan Dai, Wei Guan, Jinlu Shan, Xueqin Yang, Zhaoyang Zhong, Yi Qing, Feng Jin, Chuan Chen, Yuxin Yang, Hongyi Wang, Laura Baugh, Gianluca Tell, David M. Wilson, Mengxia Li, Dong Wang
    Oncotarget.2016; 7(47): 77482.     CrossRef
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  • 141 Download
  • 60 Web of Science
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The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer
Hae-Yun Jung, Hyun-Jung Joo, Jong Kuk Park, Yeul Hong Kim
Cancer Res Treat. 2012;44(4):251-261.   Published online December 31, 2012
DOI: https://doi.org/10.4143/crt.2012.44.4.251
AbstractAbstract PDFPubReaderePub
PURPOSE
c-Met is an attractive potential target for novel therapeutic inhibition of human cancer, and c-Met tyrosine kinase inhibitors (TKIs) are effective growth inhibitors of various malignancies. However, their mechanisms in anticancer effects are not clear. In the present study, we investigated the possibility that blocking c-Met signaling induces p53-mediated growth inhibition in lung cancer.
MATERIALS AND METHODS
The growth inhibitory effects of c-Met TKI (SU11274) on lung cancer cells and a xenograft model were assessed using the MTT assay, flow cytometry, and terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. The role of p53 protein in the sensitivity of c-Met TKI (SU11274) was examined by Western blot analysis and immunohistochemistry.
RESULTS
SU11274 significantly induced apoptosis in A549 cells with wild-type p53, compared with that in Calu-1 cells with null-type p53. SU11274 increased p53 protein by enhancing the stability of p53 protein. Increased p53 protein by SU11274 induced up-regulation of Bax and PUMA expression and down-regulation of Bcl-2 expression, subsequently activating caspase 3. In p53 knock-out and knock-in systems, we confirmed that SU11274 caused apoptosis through the p53-mediated apoptotic pathway. Likewise, in the A549 xenograft model, SU11274 effectively shrank tumor volume and induced apoptosis via increased p53 protein expression. Blocking c-Met signaling increased the level of p53 protein.
CONCLUSION
Our finding suggested that p53 plays an important role in SU11274-induced apoptosis, and p53 status seems to be related to the sensitivity to SU11274 in lung cancer.

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