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Preoperative Prediction Model for Early Recurrence of Intrahepatic Cholangiocarcinoma After Surgical Resection: Development and External Validation Study
Dong Hwan Kim, Sang Hyun Choi, Sehee Kim, Hyungjin Rhee, Eun-Suk Cho, Suk-Keu Yeom, Sumi Park, Seung Soo Lee, Mi-Suk Park
Received December 10, 2024  Accepted February 4, 2025  Published online February 5, 2025  
DOI: https://doi.org/10.4143/crt.2024.1187    [Accepted]
AbstractAbstract PDF
Purpose
We aimed to develop a preoperative risk scoring system to predict early recurrence (ER) of intrahepatic cholangiocarcinoma (ICCA) after resection, utilizing clinical and computed tomography (CT) features.
Materials and Methods
This multicenter study included 365 patients who underwent curative-intent surgical resection for ICCA at six institutions between 2009 and 2016. Of these, 264 patients from one institution constituted the development cohort, while 101 patients from the other institutions constituted the external validation cohort. Logistic regression models were constructed to predict ER based on preoperative variables and were subsequently translated into a risk-scoring system. The discrimination performance of the risk-scoring system was validated using external data and compared to the American Joint Committee on Cancer (AJCC) TNM staging system.
Results
Among the 365 patients (mean age, 62±10 years), 153 had ER. A preoperative risk scoring system that incorporated both clinical and CT features demonstrated superior discriminatory performance compared to the postoperative AJCC TNM staging system in both the development (area under the curve [AUC], 0.78 vs. 0.68; p=0.002) and validation cohorts (AUC, 0.69 vs. 0.66; p=0.641). The preoperative risk scoring system effectively stratified patients based on their risk for ER: the 1-year recurrence-free survival rates for the low, intermediate, and high-risk groups were 85.5%, 56.6%, and 15.6%, respectively (p<0.001) in the development cohort, and 87.5%, 58.5%, and 25.0%, respectively (p<0.001) in the validation cohort.
Conclusion
A preoperative risk scoring system that incorporates clinical and CT imaging features was valuable in identifying high-risk patients with ICCA for ER following resection.
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Role and Effectiveness of Hypofractionated Proton Beam Therapy and Combinations with Systemic Chemotherapy in Inoperable Extrahepatic Cholangiocarcinoma
Sung Uk Lee, Tae Hyun Kim, Sang Myung Woo, Jung Won Chun, Hyunjae Shin, Yu Ri Cho, Bo Hyun Kim, Young-Hwan Koh, Sang Soo Kim, Yang-Gu Suh, Sung Ho Moon, Woo Jin Lee
Received August 19, 2024  Accepted December 16, 2024  Published online December 17, 2024  
DOI: https://doi.org/10.4143/crt.2024.805    [Accepted]
AbstractAbstract PDF
Purpose
This study aims to assess the clinical outcomes of hypofractionated proton beam therapy (PBT) for extrahepatic cholangiocarcinoma (EHCC) and to investigate the optimal sequencing for combining PBT with chemotherapy.
Materials and Methods
We retrospectively analyzed fifty-nine consecutive patients with inoperable EHCC treated with PBT. The median prescribed dose of PBT was 50 GyE (range, 45–66 GyE) in 10 fractions. The combination sequences of PBT and chemotherapy were categorized as ‘Pre-PBT chemo’ (chemotherapy before PBT), ‘Post-PBT chemo’ (chemotherapy after PBT), and ‘No pre-/post-PBT chemo’ (no chemotherapy before or after PBT). Overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were estimated using the Kaplan-Meier method.
Results
All patients completed the planned treatments without any interruptions, and ≥grade 3 acute adverse events were noted in 1.6% of the cases. The 1-year and 2-year FFLP rates were 86.1% and 66.4%, respectively, with a median time of FFLP of 30.9 months. The 1- and 2-year OS rates were 74.5% and 25.3%, respectively, with a median survival time of 16.7 months. For prognostic factor analysis, pre- or post-PBT chemo was associated with a significantly reduced hazard ratio of 0.473 (95% confidence interval 0.233-0.959, p=0.038) in the multivariate analysis. The median OS times for the groups receiving no pre-/post-PBT chemo, pre-PBT chemo, and post-PBT chemo were 14.6, 18.2, and 21.8 months, respectively (p<0.05 for each).
Conclusion
Hypofractionated PBT for inoperable EHCC has demonstrated promising FFLP and OS rates with a safe toxicity profile. The combination of PBT with chemotherapy shows potential to improve clinical outcomes.
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Gastrointestinal cancer
Prognostic Evaluation and Survival Prediction for Combined Hepatocellular-Cholangiocarcinoma Following Hepatectomy
Seok-Joo Chun, Yu Jung Jung, YoungRok Choi, Nam-Joon Yi, Kwang-Woong Lee, Kyung-Suk Suh, Kyoung Bun Lee, Hyun-Cheol Kang, Eui Kyu Chie, Kyung Su Kim
Cancer Res Treat. 2025;57(1):229-239.   Published online July 3, 2024
DOI: https://doi.org/10.4143/crt.2024.176
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study aimed to assess prognostic factors associated with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and to predict 5-year survival based on these factors.
Materials and Methods
Patients who underwent definitive hepatectomy from 2006 to 2022 at a single institution was retrospectively analyzed. Inclusion criteria involved a pathologically confirmed diagnosis of cHCC-CCA.
Results
A total of 80 patients with diagnosed cHCC-CCA were included in the analysis. The median progression-free survival was 15.6 months, while distant metastasis-free survival (DMFS), hepatic progression-free survival, and overall survival (OS) were 50.8, 21.5, and 85.1 months, respectively. In 52 cases of recurrence, intrahepatic recurrence was the most common initial recurrence (34/52), with distant metastasis in 17 cases. Factors associated with poor DMFS included tumor necrosis, lymphovascular invasion (LVI), perineural invasion, and histologic compact type. Postoperative carbohydrate antigen 19-9, tumor necrosis, LVI, and close/positive margin were associated with poor OS. LVI emerged as a key factor affecting both DMFS and OS, with a 5-year OS of 93.3% for patients without LVI compared to 35.8% with LVI. Based on these factors, a nomogram predicting 3-year and 5-year DMFS and OS was developed, demonstrating high concordance with actual survival in the cohort (Harrell C-index 0.809 for OS, 0.801 for DMFS, respectively).
Conclusion
The prognosis of cHCC-CCA is notably poor when combined with LVI. Given the significant impact of adverse features, accurate outcome prediction is crucial. Moreover, consideration of adjuvant therapy may be warranted for patients exhibiting poor survival and increased risk of local recurrence or distant metastasis.
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Global Expanded Access Program for Pemigatinib in Patients with Previously Treated Locally Advanced or Metastatic Cholangiocarcinoma and Fibroblast Growth Factor Receptor Gene Alterations
Anouk Lindley, Gerald Prager, Michael Bitzer, Timothy C. Burn, Christine F. Lihou, Elisabeth Croft
Cancer Res Treat. 2024;56(3):847-855.   Published online February 7, 2024
DOI: https://doi.org/10.4143/crt.2023.1197
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Pemigatinib is a fibroblast growth factor receptor-2 (FGFR2) inhibitor approved for use in patients with previously treated cholangiocarcinoma (CCA) and FGFR2 fusions or rearrangements. This ongoing global Expanded Access Program (EAP) allows physicians in regions where pemigatinib is not commercially available to request pemigatinib for patients with locally advanced or metastatic CCA who, in the physician’s opinion, could benefit from pemigatinib treatment.
Materials and Methods
Eighty-nine patients from Europe, North America, and Israel were treated from January 2020 through September 2021.
Results
Patients had FGFR gene fusions (68.5%), rearrangements (12.4%), translocations (5.6%), amplifications (2.2%), and other alterations (11.2%). Median duration of treatment in the EAP was 4.0 months (range, 0.1 to 13.6 months). The most frequently reported adverse event (AE) was hyperphosphatemia (22.5%); the most common serious AE was cholangitis (3.4%). Treatment discontinuation was associated with reports of AEs for seven patients (7.9%). AEs associated with pemigatinib were consistent with those observed in clinical trials.
Conclusion
Efficacy was not assessed in this EAP. However, some patients remained on treatment for up to a year, suggesting that they observed a benefit from treatment. Patients with CCA should undergo molecular testing to identify those who could benefit from targeted treatments such as pemigatinib.

Citations

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  • Precision oncology targeting FGFRs: A systematic review on pre-clinical activity and clinical outcomes of pemigatinib
    Ludovica Gnagni, Ilary Ruscito, Ilaria Grazia Zizzari, Marianna Nuti, Chiara Napoletano, Aurelia Rughetti
    Critical Reviews in Oncology/Hematology.2024; 202: 104464.     CrossRef
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Combined High-Dose Radiotherapy with Sequential Gemcitabine-Cisplatin Based Chemotherapy Increase the Resectability and Survival in Locally Advanced Unresectable Intrahepatic Cholangiocarcinoma: A Multi-institutional Cohort Study
Jung Ho Im, Jeong Il Yu, Tae Hyun Kim, Tae Gyu Kim, Jun Won Kim, Jinsil Seong
Cancer Res Treat. 2024;56(3):838-846.   Published online January 2, 2024
DOI: https://doi.org/10.4143/crt.2023.886
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The locally advanced unresectable intrahepatic cholangiocarcinoma (ICC) has detrimental oncological outcomes. In this study, we aimed to investigate the efficacy of radiotherapy in patients with locally advanced unresectable ICC.
Materials and Methods
Between 2001 and 2021, 116 patients were identified through medical record who underwent radiotherapy for locally advanced unresectable ICC. The resectability of ICC is determined by the multidisciplinary team at each institution. Overall survival (OS) were analyzed using the Kaplan-Meier method, and prognostic factors were analyzed using the Cox proportional hazards model.
Results
The median equivalent radiotherapy dose in 2 Gy fractions (EQD2) was 52 Gy (range, 30 to 110 Gy). Forty-seven patients (40.5%) received sequential gemcitabine-cisplatin based chemotherapy (GEM-CIS CTx). Multivariate analysis identified two risk factors, EQD2 of ≥ 60 Gy and application of sequential GEM-CIS CTx for OS. Patients were grouped by these two risk factors: group 1, EQD2 ≥ 60 Gy with sequential GEM-CIS CTx (n=25); group 2, EQD2 < 60 Gy with sequential GEM-CIS CTx or fluoropyrimidine-based concurrent chemoradiotherapy (n=70); and group 3, radiotherapy alone (n=21). Curative resection was more frequently undergone in group 1 than in groups 2 or 3 (28% vs. 8.6% vs. 0%, respectively). Consequently, OS was significantly better in group 1 than in groups 2 and 3 (p < 0.05).
Conclusion
Combined high-dose radiotherapy with sequential GEM-CIS CTx improved oncologic outcomes in patients with locally advanced unresectable ICC. Further prospective studies are required to validate these findings.
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The Oncologic Implications of Tumor Multiplicity in Intrahepatic Cholangiocarcinoma: Its Prognostic Value Might Be Underestimated
So Jeong Yoon, Sunghae Park, Hongbeom Kim, Sang Hyun Shin, Jin Seok Heo, Jinsoo Rhu, Gyu-Seong Choi, Jong Man Kim, Jae-Won Joh, In Woong Han
Cancer Res Treat. 2023;55(3):948-955.   Published online February 27, 2023
DOI: https://doi.org/10.4143/crt.2023.290
AbstractAbstract PDFPubReaderePub
Purpose
In the latest staging system of the American Joint Committee on Cancer for intrahepatic cholangiocarcinoma (IHCCC), solitary tumors with vascular invasion and multiple tumors are grouped together as T2. However, recent studies report that multifocal IHCCC has a worse prognosis than a single lesion. This study aimed to investigate the risk factors for IHCCC and explore the prognostic significance of multiplicity after surgical resection.
Materials and Methods
A total of 257 patients underwent surgery for IHCCC from 2010 to 2019 and the clinicopathological data were retrospectively reviewed. Risk factor analysis was performed to identify variables associated with survival after resection. Survival outcomes were compared between patients with solitary and multiple tumors.
Results
In multivariable analysis, the presence of preoperative symptoms, tumor size, lymph node ratio, multiplicity, and tumor differentiation were identified as risk factors for survival. Among 82 patients with T2, overall survival was significantly longer in patients with solitary tumors (sT2) than in those with multiple tumors (mT2) (p=0.017). Survival was compared among patients with stage II-sT2, stage II-mT2, and stage III. The stage II-sT2 group showed prolonged survival when compared with stage II-mT2 or stage III. Survivals of stage II-mT2 and stage III patients were not statistically different.
Conclusion
Tumor multiplicity was an independent risk factor for overall survival of IHCCC after surgical resection. Patients with multiple tumors showed poorer survival than patients with a single tumor. The oncologic significance of multiplicity in IHCCC should be reappraised and reflected in the next staging system update.

Citations

Citations to this article as recorded by  
  • Perihilar and Intrahepatic Cholangiocarcinoma after Resection: Clinicopathological Characteristics, Outcomes, and Implications for Addition of Chemoradiotherapy
    Amar Mukund, Namita Sharma, Ankur Jindal, Archana Sharma, Ajay Gupta, Guresh Kumar, Archana Rastogi, Puja Sahai, Nilesh S Patil, Nihar Mohapatra, Karthika Rudrakumar, Viniyendra Pamecha, Hanuman P Yadav
    Euroasian journal of hepato-gastroenterology.2024; 14(2): 134.     CrossRef
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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.

Citations

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  • Rational synthesis and evaluation of 2,4-diamino-thieno[2,3-d]pyrimidines as antitumor agents
    Yumeng Gao, Ainv Zhang, Li Li, Fengxu Wu, Yanggen Hu
    Journal of Saudi Chemical Society.2024; 28(1): 101794.     CrossRef
  • Identification and validation of a novel ferroptosis-related gene signature for prognosis and potential therapeutic target prediction in cholangiocarcinoma
    Apiwit Sae-fung, Apiwat Mutirangura, Siriporn Jitkaew
    Frontiers in Immunology.2023;[Epub]     CrossRef
  • Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma
    Kyaw Zwar Myint, Mireia Sueca-Comes, Pamela Collier, Brinda Balasubramanian, Simran Venkatraman, John Gordan, Abed M. Zaitoun, Abhik Mukherjee, Arvind Arora, Noppadol Larbcharoensub, Chinnawut Suriyonplengsaeng, Kanokpan Wongprasert, Tavan Janvilisri, Dha
    Frontiers in Oncology.2023;[Epub]     CrossRef
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    Jinchutha Duangdara, Boonyakorn Boonsri, Apinya Sayinta, Kittiya Supradit, Pakpoom Thintharua, Supeecha Kumkate, Chinnawut Suriyonplengsaeng, Noppadol Larbcharoensub, Somkit Mingphruedhi, Narongsak Rungsakulkij, Paramin Muangkaew, Pongsatorn Tangtawee, Wa
    Pharmaceuticals.2023; 17(1): 9.     CrossRef
  • Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis
    Ubonrat Thamrongwaranggoon, Marutpong Detarya, Wunchana Seubwai, Charupong Saengboonmee, Shinjiro Hino, Tomoaki Koga, Mitsuyoshi Nakao, Sopit Wongkham
    Life Sciences.2022; 302: 120648.     CrossRef
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    Hao Peng, Erwei Zhu, Yewei Zhang
    Biomarker Research.2022;[Epub]     CrossRef
  • RTK25: A Comprehensive Molecular Profiling Strategy in Cholangiocarcinoma Using an Integrated Bioinformatics Approach
    Brinda Balasubramanian, Simran Venkatraman, Tavan Janvilisri, Tuangporn Suthiphongchai, Siriporn Jitkaew, Jittiyawadee Sripa, Rutaiwan Tohtong
    Pharmaceuticals.2021; 14(9): 898.     CrossRef
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Long Non-coding RNA CASC15 Promotes Intrahepatic Cholangiocarcinoma Possibly through Inducing PRDX2/PI3K/AKT Axis
Yuan Zhang, Lufei Zhang, Sinan Lu, Yucheng Xiang, Cheng Zeng, Tianyu He, Yuan Ding, Weilin Wang
Cancer Res Treat. 2021;53(1):184-198.   Published online October 5, 2020
DOI: https://doi.org/10.4143/crt.2020.192
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Intrahepatic cholangiocarcinoma (ICC) is one of the most common liver primary tumors but its treatments are limited. Bioinformatics showed that the expression level of long non-coding RNA cancer-associated susceptibility 15 gene (CASC15) is correlated with ICC progression, but its functional mechanism remains unclear.
Materials and Methods
Tissues from ICC patients, tumor and adjacent tissue, were used for detection of the expression of CASC15. Clinical data were also collected for clinicopathologic and survival analysis. Short interfering RNA and lentiviral short hairpin RNA were used to knock down CASC15 and PRDX2 expression in ICC cell lines, for the analysis of changes of cell function and xenografts. RNA-pulldown and RNA immunoprecipitation assays were used to detect RNA-binding protein, PRDX2. Male nude mice were used for ICC xenografts, and livers were collected after 4 weeks for immunohistochemistry.
Results
CASC15 is highly expressed in ICC tissues and is related to higher TNM stage. Knockdown of CASC15 in ICC cells reduced cell proliferation, migration, invasiveness and increased apoptosis, and G1/S block. PRDX2 bound to CASC15. Knockdown of CASC15 decreased PRDX2 expression which was rescued by the inhibition of proteasome formation. Downregulation of PRDX2 resulted in G1/S block, reduced ICC cell invasion. Downregulation of CASC15 inhibited phosphoinositide 3-kinase (PI3K)/AKT/c-Myc pathway through downregulating of PRDX2 and overexpressed PRDX2 rescued the block. CASC15 knockout in ICC xenografts suppressed tumor development in vivo, decreased the expression of PRDX2 and Ki67 and inhibited PI3K/AKT pathway.
Conclusion
CASC15 promotes ICC possibly by targeting PRDX2 via the PI3K/AKT pathway, indicating poor prognosis and high degree of malignancy of ICC.

Citations

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  • Exploring the mechanism of LncRNA CASC15 affecting hepatocellular carcinoma through miRNA
    Qingshan Cai, Dongyang Wu, Yueling Shen, Shudong Li, Liyou Liu, Dong Liu, Yong Li, Xiaonan Chen, Limin Wang, Jianxing Zheng
    Medicine.2024; 103(5): e35859.     CrossRef
  • The effect of genetics and biochemistry on the pathogenesis of cholangiocarcinoma
    Mete Ucdal, Ayse Burus, Basak Celtikci
    International Journal of Hepatobiliary and Pancreatic Diseases.2024; 14(2): 1.     CrossRef
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    Xiaoyu Zhang, Lei Shi, Mengzhen Xing, Chunjing Li, Fengjun Ma, Yuning Ma, Yuxia Ma
    International Journal of Molecular Medicine.2024;[Epub]     CrossRef
  • A review on the role of ncRNAs in the pathogenesis of cholangiocarcinoma
    Soudeh Ghafouri-Fard, Arash Safarzadeh, Bashdar Mahmud Hussen, Mohammad Taheri, Majid Samsami
    International Journal of Biological Macromolecules.2023; 225: 809.     CrossRef
  • A Novel CASC15-ALK and TFG-ROS1 Fusion Observed in Uterine Inflammatory Myofibroblastic Tumor
    Bin Chang, Zhe Wang, Min Ren, Qianlan Yao, Lu Zhao, Xiaoyan Zhou
    International Journal of Gynecological Pathology.2023; 42(5): 451.     CrossRef
  • Development and validation of combined Ki67 status prediction model for intrahepatic cholangiocarcinoma based on clinicoradiological features and MRI radiomics
    Xianling Qian, Changwu Zhou, Fang Wang, Xin Lu, Yunfei Zhang, Lei Chen, Mengsu Zeng
    La radiologia medica.2023; 128(3): 274.     CrossRef
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    Jiehan Li, Haolin Bao, Ziyue Huang, Zixin Liang, Ning Lin, Chunjie Ni, Yi Xu
    Frontiers in Bioscience-Landmark.2023;[Epub]     CrossRef
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    Weiwei Chen, Wenqi Qian, Jun Nie, Mintao Dai
    Clinical and Experimental Medicine.2022;[Epub]     CrossRef
  • Long Non-Coding RNAs as Molecular Biomarkers in Cholangiocarcinoma
    Yanhua Wu, Khizar Hayat, Yufei Hu, Jianfeng Yang
    Frontiers in Cell and Developmental Biology.2022;[Epub]     CrossRef
  • Brusatol suppresses the growth of intrahepatic cholangiocarcinoma by PI3K/Akt pathway
    Ziyan Chen, Bangjie He, Jungang Zhao, Jiacheng Li, Yifeng Zhu, Leilei Li, Wenming Bao, Jiuyi Zheng, Haitao Yu, Gang Chen
    Phytomedicine.2022; 104: 154323.     CrossRef
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    Wen Chao Li, Li Liu, Zhen Dong Wang, Hui Chen, Guang Liu, Zhi Chun Feng
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  • A Study on Mesoporous Silica Loaded With Novel Photosensitizers HCE6 and Oxaliplatin for the Treatment of Cholangiocarcinoma
    Pei-Jian Zhang, Meng-Dong Liu, Fang-Yong Fan, Ke-Xia Liu
    Frontiers in Oncology.2021;[Epub]     CrossRef
  • LncRNA CASC15 promotes the proliferation of papillary thyroid carcinoma cells by regulating the miR-7151–5p/WNT7A axis
    Dongfang Bai, Chong Guo, Aimin Wang, Guolong Pang, Jing Gao, Chuan Wang, Dapeng Zhao, Jie Yang, Jianmin Ren
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    Chen Chen, Linjing Wang, Li Wang, Qi Liu, Chunying Wang
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  • Protein profiling reveals potential isomiR-associated cross-talks among RNAs in cholangiocarcinoma
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Prognostic Predictability of American Joint Committee on Cancer 8th Staging System for Perihilar Cholangiocarcinoma: Limited Improvement Compared with the 7th Staging System
Jong Woo Lee, Jae Hoon Lee, Yejong Park, Woohyung Lee, Jaewoo Kwon, Ki Byung Song, Dae Wook Hwang, Song Cheol Kim
Cancer Res Treat. 2020;52(3):886-895.   Published online March 12, 2020
DOI: https://doi.org/10.4143/crt.2020.023
AbstractAbstract PDFPubReaderePub
Purpose
This study was conducted to evaluate the prognostic values of the 7th and 8th American Joint Committee on Cancer (AJCC) staging systems for patients with resected perihilar cholangiocarcinoma (PHCC).
Materials and Methods
A total of 348 patients who underwent major hepatectomy for PHCC between 2008 and 2015 were identified from a single center. Overall survival (OS) was estimated using the Kaplan-Meier method and compared across stage groups with the log-rank test. The concordance index was used to evaluate the prognostic predictability of the 8th AJCC staging system compared with that of the 7th.
Results
In the 8th edition, the stratification of each group of T classification improved compared to that in the 7th, as the survival rate of T4 decreased (T2, 31.2%; T3, 13.9%; T4, 15.1%; T1- T2, p=0.260; T2-T3, p=0.001; T3-T4, p=0.996). Both editions showed significant survival differences between each N category, except between N1 and N2 (p=0.063) in 7th edition. Differences of point estimates between the 8th and 7th T and N classification and overall stages were +0.028, +0.006, and +0.039, respectively (T, p=0.005; N, p=0.115; overall stage, p=0.005). In multivariable analysis, posthepatectomy liver failure, T category, N category, distant metastasis, histologic differentiation, intraoperative transfusion, and resection margin status were associated with OS.
Conclusion
The prognostic predictability of 8th AJCC staging for PHCC improved slightly, with statistical significance, compared to the 7th edition, but its overall performance is still unsatisfactory.

Citations

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  • Postoperative factors predicting outcomes in patients with Perihilar cholangiocarcinoma undergoing curative resection—a 10-year single-center experience
    Hasan Ahmad Al-Saffar, Nicolai Schultz, Peter Nørrgaard Larsen, Eva Fallentin, Gro Linno Willemoe, Diana Elena Renteria Ramirez, Lucas Alexander Knøfler, Hans-Christian Pommergaard
    Scandinavian Journal of Gastroenterology.2025; 60(1): 73.     CrossRef
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    Shilei Bai, Xiaodong Shi, Yizhe Dai, Huifeng Wang, Yong Xia, Jian Liu, Kui Wang
    BMC Cancer.2024;[Epub]     CrossRef
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    HA Al-Saffar, PN Larsen, N Schultz, TS Kristensen, DE Renteria, LA Knøfler, HC Pommergaard
    Langenbeck's Archives of Surgery.2024;[Epub]     CrossRef
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    Zhi-Peng Liu, Qing-Yi Zhang, Wei-Yue Chen, Yu-Yan Huang, Yan-Qi Zhang, Yi Gong, Yan Jiang, Jie Bai, Zhi-Yu Chen, Hai-Su Dai
    Journal of Gastrointestinal Surgery.2022; 26(5): 1030.     CrossRef
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    Lynn E. Nooijen, Jesus M. Banales, Marieke T. de Boer, Chiara Braconi, Trine Folseraas, Alejandro Forner, Waclaw Holowko, Frederik J. H. Hoogwater, Heinz-Josef Klümpen, Bas Groot Koerkamp, Angela Lamarca, Adelaida La Casta, Flora López-López, Laura Izquie
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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
AbstractAbstract PDFPubReaderePub
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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An Integrated Nomogram Combining Clinical Factors and Microtubule-Associated Protein 1 Light Chain 3B Expression to Predict Postoperative Prognosis in Patients with Intrahepatic Cholangiocarcinoma
Liang Chen, Hongyuan Fu, Tongyu Lu, Jianye Cai, Wei Liu, Jia Yao, Jinliang Liang, Hui Zhao, Jiebin Zhang, Jun Zheng, Yingcai Zhang, Yang Yang
Cancer Res Treat. 2020;52(2):469-480.   Published online October 7, 2019
DOI: https://doi.org/10.4143/crt.2019.423
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Microtubule-associated protein 1 light chain 3B (LC3B) serves as a key component of autophagy, which is associated with the progression of carcinoma. Yet, it is still unclear whether LC3B is also an independent risk factor for intrahepatic cholangiocarcinoma (ICC). We aim to explore the predictive value of LC3B on prognosis of ICC, and to establish a novel and available nomogram to predict relapse-free survival (RFS) and overall survival (OS) for these patients after curative-intent hepatectomy.
Materials and Methods
From August 2004 to March 2017, 105 ICC patients were eligibly enrolled in the Third Affiliated Hospital of Sun Yat-sen University. Preoperative clinical information of enrolled patients was collected. Expression LC3B in the ICC specimen was detected by immunohistochemistry.
Results
The 5-year RFS and OS in this cohort were 15.7% and 29.6%, respectively. On multivariate Cox regression analysis, independent risk factors for 5-year OS were cancer antigen 125, microvascular invasion, LC3B expression and lymph node metastasis. Except for the above 4 factors, neutrophil/lymphocyte ratio and tumor differentiation were independent factors for 5-year RFS. The area under the curve of nomograms for OS and RFS were 0.820 and 0.747, respectively.
Conclusion
The nomograms based on LC3B can be considered as effective models to predict postoperative survival for ICC patients.

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Clinical Benefit of Maintenance Therapy for Advanced Biliary Tract Cancer Patients Showing No Progression after First-Line Gemcitabine Plus Cisplatin
Jaewon Hyung, Bumjun Kim, Changhoon Yoo, Kyo-pyo Kim, Jae Ho Jeong, Heung-Moon Chang, Baek-Yeol Ryoo
Cancer Res Treat. 2019;51(3):901-909.   Published online October 4, 2018
DOI: https://doi.org/10.4143/crt.2018.326
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Gemcitabine plus cisplatin (GemCis) is the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). In ABC-02 study, the BTC patients received up to 6-8 cycles of 3-weekly GemCis; however, those without progression often receive more than 6-8 cycles. The clinical benefit of maintenance treatment in patients without progression is uncertain.
Materials and Methods
Advanced BTC patients treated with GemCis between April 2010 and February 2015 at Asan Medical Center, Seoul, Korea, were retrospectively analysed. The patients without progression after 6-8 cycles were stratified according to further treatment i.e., with or without further cycles of GemCis (maintenance vs. observation groups). The primary endpoint was overall survival (OS) and progression-free survival (PFS).
Results
Among the 740 BTC patients in the initial screen, 231 cases (31.2%) were eligible for analysis (111 in the observation group, 120 in the maintenance group). The median OS from the GemCis initiation was 20.5 months (95% confidence interval [CI], 15.4 to 25.6) and 22.4 months (95% CI, 17.0 to 27.8) in the observation and maintenance groups, respectively (p=0.162). The median PFS was 10.4 months (95% CI, 7.0 to 13.8) and 13.2 months (95% CI, 11.3 to 15.2), respectively (p=0.320).
Conclusions
GemCis maintenance is not associated with an improved survival outcome.

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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
AbstractAbstract PDFPubReaderePub
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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Multicenter Phase II Study of Oxaliplatin, Irinotecan, and S-1 as First-line Treatment for Patients with Recurrent or Metastatic Biliary Tract Cancer
Changhoon Yoo, Boram Han, Hyeong Su Kim, Kyu-pyo Kim, Deokhoon Kim, Jae Ho Jeong, Jae-Lyun Lee, Tae Won Kim, Jung Han Kim, Dae Ro Choi, Hong Il Ha, Jinwon Seo, Heung-Moon Chang, Baek-Yeol Ryoo, Dae Young Zang
Cancer Res Treat. 2018;50(4):1324-1330.   Published online January 8, 2018
DOI: https://doi.org/10.4143/crt.2017.526
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Although gemcitabine plus cisplatin has been established as the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC), overall prognosis remains poor. We investigated the efficacy of a novel triplet combination of oxaliplatin, irinotecan, and S-1 (OIS) for advanced BTC.
Materials and Methods
Chemotherapy-naive patientswith histologically documented unresectable or metastatic BTC were eligible for this multicenter, single-arm phase II study. Patients received 65 mg/m2 oxaliplatin (day 1), 135 mg/m2 irinotecan (day 1), and 40 mg/m2 S-1 (twice a day, days 1-7) every 2 weeks. Primary endpoint was objective response rate. Targeted exome sequencing for biomarker analysis was performed using archival tissue.
Results
In total, 32 patients were enrolled between October 2015 and June 2016. Median age was 64 years (range, 40 to 76 years), with 24 (75%) male patients; 97% patients had metastatic or recurrent disease. Response rate was 50%, and median progression-free survival and overall survival (OS) were 6.8 months (95% confidence interval [CI], 4.8 to 8.8) and 12.5 months (95% CI, 7.0 to 18.0), respectively. The most common grade 3-4 adverse events were neutropenia (32%), diarrhea (6%), and peripheral neuropathy (6%). TP53 and KRAS mutations were the most frequent genomic alterations (42% and 32%, respectively), and KRAS mutations showed a marginal relationship with worse OS (p=0.07).
Conclusion
OIS combination chemotherapy was feasible and associated with favorable efficacy outcomes as a first-line treatment in patients with advanced BTC. Randomized studies are needed to compare OIS with gemcitabine plus cisplatin.

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Proximal Resection Margins: More Prognostic than Distal Resection Margins in Patients Undergoing Hilar Cholangiocarcinoma Resection
Tae Yoo, Sang-Jae Park, Sung-Sik Han, Seong Hoon Kim, Seung Duk Lee, Tae Hyun Kim, Soon-ae Lee, Sang Myung Woo, Woo Jin Lee, Eun Kyung Hong
Cancer Res Treat. 2018;50(4):1106-1113.   Published online November 16, 2017
DOI: https://doi.org/10.4143/crt.2017.320
AbstractAbstract PDFPubReaderePub
Purpose
Even though the therapeutic gold standard of hilar cholangiocarcinoma (HCCA) resection is cancer-free resection margin (RM), surgical treatment still remains challenging. This study evaluated the prognostic significance of RM status in resected HCCA patients and identified survival prognostic factors.
Materials and Methods
We reviewed records of 96 HCCA patients who underwent surgery from 2001 to 2012 and analyzed the RM status and prognostic factors that affecting survival.
Results
Negative RM (n=31, 33%) was significantly associated with better survival vs. positive RM (n=65, 67%) (mean survival time [MST], 33 months vs. 21 months; p=0.011). Margins with histological findings of non-dysplastic epithelium, low-grade dysplasia, and carcinoma in situ were not associated with survival differences (MST, 33 months vs. 33 months vs. 30 months; p=0.452), whereas positive margins were associated with poorer survival relative to carcinoma in situ (MST, 30 months vs. 21 months; p=0.050). Among patients with R0 resection, narrow (≤ 5 mm) and wide (> 5 mm) margins were not associated with survival differences (MST, 33 months vs. 30 months; p=0.234). Although positive proximal RM was associated with poorer survival compared to negative RM (MST, 19 vs. 33; p=0.002), no survival difference was observed between positive and negative distal RMs (MST, 30 vs. 33; p=0.628). Proximal RM positivity (hazard ratio [HR], 2.688; p=0.007) and nodal involvement (HR, 3.293; p < 0.001) were independent survival prognostic factors.
Conclusion
A clear RM, especially proximal RM status, was significant prognosticator, and proximal bile duct resection to the greatest technically feasible extent may be necessary, with careful consideration of the potential morbidity and oncologic outcomes after resection. However, an aggressive approach to obtain a negative distal RM might be controversial and should be considered carefully, depending on the patient's status.

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Declined Preoperative Aspartate Aminotransferase to Neutrophil Ratio Index Predicts Poor Prognosis in Patients with Intrahepatic Cholangiocarcinoma after Hepatectomy
Lingyun Liu, Wei Wang, Yi Zhang, Jianting Long, Zhaohui Zhang, Qiao Li, Bin Chen, Shaoqiang Li, Yunpeng Hua, Shunli Shen, Baogang Peng
Cancer Res Treat. 2018;50(2):538-550.   Published online June 1, 2017
DOI: https://doi.org/10.4143/crt.2017.106
AbstractAbstract PDFPubReaderePub
Purpose
Various inflammation-based prognostic biomarkers such as the platelet to lymphocyte ratio and neutrophil to lymphocyte ratio, are related to poor survival in patients with intrahepatic cholangiocarcinoma (ICC). This study aims to investigate the prognostic value of the aspartate aminotransferase to neutrophil ratio index (ANRI) in ICC after hepatic resection.
Materials and Methods
Data of 184 patients with ICC after hepatectomy were retrospectively reviewed. The cut-off value of ANRIwas determined by a receiver operating characteristic curve. Preoperative ANRI and clinicopathological variables were analyzed. The predictive value of preoperative ANRI for prognosis of ICC was identified by univariate and multivariate analyses.
Results
The optimal cut-off value of ANRI was 6.7. ANRI was associated with tumor size, tumor recurrence, white blood cell, neutrophil count, aspartate aminotransferase, and alanine transaminase. Univariate analysis showed that ANRI, sex, tumor number, tumor size, tumor differentiation, lymph node metastasis, resection margin, clinical TNM stage, neutrophil count, and carcinoembryonic antigen were markedly correlated with overall survival (OS) and disease-free survival (DFS) in patients with ICC. Multivariable analyses revealed that ANRI, a tumor size > 6 cm, poor tumor differentiation, and an R1 resection margin were independent prognostic factors for both OS and DFS. Additionally, preoperative ANRI also had a significant value to predict prognosis in various subgroups of ICC, including serum hepatitis B surface antigen‒negative and preoperative elevated carbohydrate antigen 19-9 patients.
Conclusion
Preoperative declined ANRI is a noninvasive, simple, and effective predictor of poor prognosis in patients with ICC after hepatectomy.

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Long-Term Outcome of Distal Cholangiocarcinoma after Pancreaticoduodenectomy Followed by Adjuvant Chemoradiotherapy: A 15-Year Experience in a Single Institution
Byoung Hyuck Kim, Kyubo Kim, Eui Kyu Chie, Jeanny Kwon, Jin-Young Jang, Sun Whe Kim, Do-Youn Oh, Yung-Jue Bang
Cancer Res Treat. 2017;49(2):473-483.   Published online August 23, 2016
DOI: https://doi.org/10.4143/crt.2016.166
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study was conducted to evaluate the long-term outcome in patients undergoing pancreaticoduodenectomy (PD) followed by adjuvant chemoradiotherapy for distal cholangiocarcinoma (DCC) in a high-volume center and to identify the prognostic impact of clinicopathologic factors.
Materials and Methods
A total of 132 consecutive patients who met the inclusion criteria were retrieved from the institutional database from January 1995 to September 2009. All patients received adjuvant treatments at a median of 45 days after the surgery. Median follow-up duration was 57 months (range, 6 to 225 months) for all patients and 105 months for survivors (range, 13 to 225 months).
Results
The 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 70.7%, 55.7%, 49.4%, and 48.1%, respectively. Univariate analysis revealed poorly differentiated (P/D) tumors and lymph node (LN) metastasis were significantly associated with DMFS and OS. Additionally, preoperative carbohydrate antigen 19-9 level was significantly correlated with DFS, LRRFS, and DMFS. Upon multivariate analysis for OS, P/D tumors (p=0.015) and LN metastasis (p=0.003) were significant prognosticators that predicted inferior OS. Grade 3 or higher late gastrointestinal toxicity occurred in only one patient (0.8%).
Conclusion
Adjuvant chemoradiotherapy after PD for DCC is an effective and tolerable strategy without significant side effects. During long-term follow-up, we found that prognosis of DCC was mainly influenced by histologic differentiation and LN metastasis. For patients with these risk factors, further research should focus on improving adjuvant strategies as well as other treatment approaches.

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Estimation of the Incidence of Hepatocellular Carcinoma and Cholangiocarcinoma in Songkhla, Thailand, 1989-2013, Using Multiple Imputation Method
Seesai Yeesoonsang, Surichai Bilheem, Edward McNeil, Sophon Iamsirithaworn, Chuleeporn Jiraphongsa, Hutcha Sriplung
Cancer Res Treat. 2017;49(1):54-60.   Published online May 18, 2016
DOI: https://doi.org/10.4143/crt.2016.045
AbstractAbstract PDFPubReaderePub
Purpose
Histological specimens are not required for diagnosis of liver and bile duct (LBD) cancer, resulting in a high percentage of unknown histologies. We compared estimates of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) incidences by imputing these unknown histologies.
Materials and Methods
A retrospective study was conducted using data from the Songkhla Cancer Registry, southern Thailand, from 1989 to 2013. Multivariate imputation by chained equations (mice) was used in re-classification of the unknown histologies. Age-standardized rates (ASR) of HCC and CCA by sex were calculated and the trends were compared. Results Of 2,387 LBD cases, 61% had unknown histology. After imputation, the ASR of HCC in males during 1989 to 2007 increased from 4 to 10 per 100,000 and then decreased after 2007. The ASR of CCA increased from 2 to 5.5 per 100,000, and the ASR of HCC in females decreased from 1.5 in 2009 to 1.3 in 2013 and that of CCA increased from less than 1 to 1.9 per 100,000 by 2013.
Results
of complete case analysis showed somewhat similar, although less dramatic, trends.
Conclusion
In Songkhla, the incidence of CCA appears to be stable after increasing for 20 years whereas the incidence of HCC is now declining. The decline in incidence of HCC among males since 2007 is probably due to implementation of the hepatitis B virus vaccine in the 1990s. The rise in incidence of CCA is a concern and highlights the need for case control studies to elucidate the risk factors.

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    Pianpian Cao, Laura S. Rozek, Donsuk Pongnikorn, Hutcha Sriplung, Rafael Meza
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  • Trends in Incidence of Two Major Subtypes of Liver and Bile Duct Cancer: Hepatocellular Carcinoma and Cholangiocarcinoma in Songkhla, Southern Thailand, 1989-2030
    Seesai Yeesoonsang, Edward McNeil, Shama Virani, Surichai Bilheem, Chakrarat Pittayawonganon, Chuleeporn Jiraphongsa, Hutcha Sriplung
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    Shama Virani, Surichai Bilheem, Wasan Chansaard, Imjai Chitapanarux, Karnchana Daoprasert, Somsak Khuanchana, Atit Leklob, Donsuk Pongnikorn, Laura Rozek, Surattaya Siriarechakul, Krittika Suwanrungruang, Sukit Tassanasunthornwong, Patravoot Vatanasapt, H
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Rare Incidence of ROS1 Rearrangement in Cholangiocarcinoma
Sun Min Lim, Jeong Eun Yoo, Kiat Hon Lim, David Wai Meng Tai, Byoung Chul Cho, Young Nyun Park
Cancer Res Treat. 2017;49(1):185-192.   Published online April 27, 2016
DOI: https://doi.org/10.4143/crt.2015.497
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The recent discovery and characterization of an oncogenic ROS1 gene rearrangement has raised significant interest because small molecule inhibitors are effective in these tumors. The aim of this study was to determine frequency and clinicopathological features associated with ROS1 rearrangement in patients with cholangiocarcinoma (CCA).
Materials and Methods
A total of 261 patients who underwent surgery for CCA between October 1997 and August 2013 were identified from an international, multi-institutional database. ROS1 rearrangement was evaluated by break-apart fluorescence in situ hybridization using tissue microarrays of these patients.
Results
Of 261 CCA evaluated, three cases (1.1%) showed ROS1 rearrangement by fluorescence in situ hybridization (FISH), all of which were derived from intrahepatic origin. ROS1 protein expression was observed in 38 samples (19.1%). Significantly larger tumor size was observed in ROS1 immunohistochemistry (IHC)–negative patients compared with ROS1 IHC–positive patients. ROS1 FISH–positive patients had a single tumor with a median size of 4 cm and well-to-moderate differentiation. Overall, there was no difference in terms of baseline characteristics, overall survival, and recurrence-free survival between ROS1-positive and -negative patients.
Conclusion
ROS1 rearrangement was detected in 1.1% of CCA patients. Although rare, conduct of clinical trials using ROS1 inhibitors in these genetically unique patients is warranted.

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    Jeremy Augustin, Caroline Gabignon, Aurélie Scriva, Laëtitia Menu, Claire Calmel, Olivier Scatton, François Paye, Jean-François Fléjou, Françoise Praz, Pascale Cervera, Dominique Wendum
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    Prodipto Pal, Zanobia Khan
    Journal of Clinical Pathology.2017; 70(12): 1001.     CrossRef
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Case Reports
Two Cases of Humoral Hypercalcemia of Malignancy in Metastatic Cholangiocarcinoma
Seungtaek Lim, Jungwoo Han, Kyeong Hye Park, Won Jai Jung, Yong Kang Lee, Ara Choi, Young Jae Kim, Jong-Chan Lee, Hye Jin Choi
Cancer Res Treat. 2013;45(2):145-149.   Published online June 30, 2013
DOI: https://doi.org/10.4143/crt.2013.45.2.145
AbstractAbstract PDFPubReaderePub
Humoral hypercalcemia of malignancy (HHM) is rarely associated with cholangiocarcinoma (CC), and represents dismal prognosis. A 63-year-old male was admitted for evaluation of an intrahepatic mass. He was diagnosed with HHM associated with locally advanced CC. As the tumor responded to the concurrent chemoradiotherapy with capecitabine and cisplatin, serum calcium level was normalized. However, according to the disease progression, he suffered recurrence of HHM and he expired approximately one year after initial diagnosis. A 68-year-old male who presented with abdominal pain was diagnosed with metastatic CC. After the eighth cycle of gemcitabine and cisplatin, progression of the disease was found with HHM. He was treated with the best supportive care, until his demise approximately one month after the diagnosis of HHM. We report on two cases of HHM associated with CC that demonstrate strong correlation between hypercalcemia and disease burden.

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    Laura Martínez-Sogues, Anna Vila, Xavier Roura, Josep Pastor, Rosa Novellas, Alberto Marco, Maria Cuvertoret-Sanz, Jorge Martínez, Laia Solano-Gallego
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A Case of Combined Hepatocellular-Cholangiocarcinoma with Favorable Response to Systemic Chemotherapy
Gun Min Kim, Hei-Cheul Jeung, Dokyung Kim, Joo Hoon Kim, Sang Hyun Yoon, Eun Suk Jung, Sang Joon Shin
Cancer Res Treat. 2010;42(4):235-238.   Published online December 31, 2010
DOI: https://doi.org/10.4143/crt.2010.42.4.235
AbstractAbstract PDFPubReaderePub

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare form of primary liver cancer composed of cells with histopathologic features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of its low incidence, the information on clinical outcomes of cHCC-CC is very limited and there are no published reports describing non-surgical treatment options for cHCC-CC. We report a case of cHCC-CC exhibiting a favorable response to systemic chemotherapy with doxorubicin and cisplatin. A 62-year-old man who recurred after a right lobectomy for cHCC-CC received sorafenib for palliative systemic therapy, but follow up imaging studies showed disease progression. He received 2nd line chemotherapy with doxorubicin at 60 mg/m2 together with cisplatin at 70 mg/m2. After 2 cycles of chemotherapy, a computed tomography scan of the chest showed markedly decreased size and number of the multiple lung metastases. After completing 8 cycles of 2nd line therapy, we changed the regimen to a fluorouracil (5-FU) mono therapy because of the toxicities associated with doxorubicin and cisplatin. To date, the patient has completed his 15th cycle of 5-FU mono therapy with the disease status remaining stable during 18 months of follow-up.

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Severe Hypothyroidism Induced by Thyroid Metastasis of Cholangiocarcinoma
Woo Kyun Bae, Hyun Jeong Shim, Yoo Duk Choi, Jin Woong Kim, Sang Hee Cho, Ho Cheol Kang, Ik Joo Chung
Cancer Res Treat. 2009;41(1):56-58.   Published online March 31, 2009
DOI: https://doi.org/10.4143/crt.2009.41.1.56
AbstractAbstract PDFPubReaderePub

We report a case of severe hypothyroidism in a cholangiocarcinoma patient with metastasis to the thyroid gland. A 58-year-old man was admitted for upper abdominal discomfort and multiple palpable neck nodules. Abdominal computed tomography (CT) demonstrated the presence of a 4.7-cm tumor in the right hepatic lobe, and core needle biopsy revealed it to be cholangiocarcinoma. Neck CT showed a diffuse, low attenuation thyroid gland, and fine-needle aspiration (FNA) demonstrated metastatic adenocarcinoma. Thyroid function tests were initially normal, but the size of the thyroid gland decreased and severe hypothyroidism developed after chemotherapy was implemented for cholangiocarcinoma. In a patient with malignant disease and a goiter, the possibility of a metastatic tumor involving the thyroid should be seriously considered. Metastatic thyroid cancer and thyroid dysfunction are probably infrequent, but diagnosis is important in the institution of appropriate therapy.

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Original Articles
Immunohistochemical Study for CD44v6 in Hepatocellular Carcinoma and Cholangiocarcinoma
Ki Jung Yun, Kwon Ha Yoon, Weon Cheol Han
Cancer Res Treat. 2002;34(3):170-174.   Published online June 30, 2002
DOI: https://doi.org/10.4143/crt.2002.34.3.170
AbstractAbstract PDF
PURPOSE
CD44 is a multifunctional adhesion molecule in cell-to-cell and cell-to-matrix interactions. This transmembrane glycoprotein exists in either standard or variant form, with the variation originating in alternative splicing. This study was designed to evaluate the role of CD44v6, one of the CD44 isoforms, in hepatocellular carcinoma and cholangiocarcinoma. MATERIALS AND METGODS: Immunohistochemical expression of CD44v6 was studied in 7 normal livers, 14 hepatocellular carcinomas and 16 cholangiocarcinomas, that were formalin fixed and paraffin embedded.
RESULTS
CD44v6 was frequently expressed in the normal hepatocytes and hepatocellular carcinomas. Expression was not noted in the normal bile duct within the portal tract. CD44v6 was positively expressed in some of the proliferating bile ducts (43%) and cholangiocarcinomas (69%).
CONCLUSION
CD44v6 expression may be more important in the stepwise carcinogenesis of the bile duct than in the normal hepatocyte, but further study is needed.

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    Jose J. G. Marin, Maria Reviejo, Meraris Soto, Elisa Lozano, Maitane Asensio, Sara Ortiz-Rivero, Carmen Berasain, Matias A. Avila, Elisa Herraez
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    Juthamas Yosudjai, Sopit Wongkham, Siwanon Jirawatnotai, Worasak Kaewkong
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    Juthamas Yosudjai, Chaturong Inpad, Sasitorn Chomwong, Paweena Dana, Kanlayanee Sawanyawisuth, Suchada Phimsen, Sopit Wongkham, Siwanon Jirawatnotai, Worasak Kaewkong
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    Sang Min Lee, Kyoung Eun Lee, Hye Jung Chang, Moon Young Choi, Min-Sun Cho, Seog Ki Min, Hyeon Kook Lee, Yeung Chul Mun, Eun Mi Nam, Chu Myong Seong, Soon Nam Lee
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  • 31 Download
  • 4 Crossref
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Immunohistochemical Study of beta-catenin Expression between Hepatocellular Carcinoma and Cholangiocarcinoma
Ki Jung Yun, Weon Cheol Han, Suck Chei Choi, Tae Hyeon Kim
Cancer Res Treat. 2002;34(2):117-121.   Published online April 30, 2002
DOI: https://doi.org/10.4143/crt.2002.34.2.117
AbstractAbstract PDF
PURPOSE
beta-catenin is an intracellular protein that is an integral component of the cadherin-mediated cell-cell interaction and a downstream transcriptional activator in the wnt signal transduction pathway. Inappropriate activation of beta-catenin has recently been implicated in the development of hepatocellular carcinoma and cholangiocarcinoma. Nuclear beta-catenin expression is strongly associated with gene mutation. This study was designed to evaluate the pattern of beta-catenin expression between hepatocellular carcinoma and cholangiocarcinoma.
MATERIALS AND METHODS
Immunohistochemical expression of beta-catenin was studied in 7 normal livers, 33 hepatocellular carcinomas and 20 cholangiocarcinomas, that were formalin fixed and paraffin embedded.
RESULTS
beta-catenin was expressed mainly in the cytoplasmic membrane of the normal hepatocytes and bile ducts. Nuclear expressions, not noted in the normal liver, were noted in 30% of the hepatocellular carcinomas and 10% of the cholangiocarcinomas. And, nuclear expression was more common in the high grade (50%) hepatocellular carcinomas than the low grade (18%) hepatocellular carcinomas (p<=0.05).
CONCLUSION
The above results indicate that nuclear expression of beta-catenin is observed in the carcinoma but not the normal liver, and is associated with high grade liver carcinoma.

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    Xifang Wang, Xiaomin Zhang, Jingying Sun, Yang Sun, Yuan Zhang, Li He, Ping Wang, Feng Li, Chao Sun
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Multiple Primary Cancers in the Stomach and Different Organs
Byung Moo Jeon, Nam Il Kim, Jung Soo Kim, Hae Myung Jeon, Seung Jin Yoo, Jae Sung Kim, Sung Hoon Kim, Eun Jung Lee
J Korean Cancer Assoc. 1996;28(2):394-404.
AbstractAbstract PDF
Multiple primary malingnant tumors are not rare recently with the development of the diagnostic methods. Billroth first documented the occurence of more than one independent cancer developing in the same patient a century ago and stated that each tumor must have an independent histologic appearences and must arise in different localities. Some studies have been reported on the possible relationship between multiple primary malignancies and excessive exposure to sunlight, occupational exposure, ionizing radiation, role of oncogenic viruses, tabacco usage, heavy alcohol consumption, and/or familial tendency, genetic factors. Many studies indicate that the prognosis of synchronous primary tumors is poorer than that of single tumor. The first case is the gastric cancer combined with chondrosarcoma of rib. Neoplasms of the ribes are rare and synchronous primary tumors are more rare. Most primary bony chest wall neoplasms are malignant, and chondrosarcoma is the most common malignant tumor in this location. The etiology of chondrosarcoma is unknown. Definitive diagnosis of chondrosarcoma can be made pathologically. The characteristic natural history of chest wall chondrosarcoma is slow growth and high local recurrence. Most tumors of the sternum require wide resection and reconstruction procedures, with potentially serious postoperative problems. The second case is the early gastric cancer combined synchronous cholangiocarcinoma that rarely associated with hepatolithiasis. It was nearly impossible to detect the malignant lesions preoperatively. And then patients with a long history of recurrent cholangitis due to hepatolithiasis should be admitted to a hospital, and precise examinations, including abdominal sonography, CT, cholangiography, aspiration cytology, choledochoscopy, frozen section biopsy pre-and intraoperatively, should be performed in order to rule out a coexisting cholangiocarcinoma especially in the operative findings of suspected malignant lesion. We experienced a 66 year-old man who was diagnosed stomach cancer with chondrosarcoma of ribs and a 63 year-old man who had early gastric cancer combined synchronous cholangiocarcinoma associated with hepatolithiasis. The patients underwent wide resection of tumor mass with Billroth-II suntotal gastrectomy. The patients had uneventful postoperative courses and discharged with adjuvant chemotheraphy.
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Cancer Res Treat : Cancer Research and Treatment
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