Cancer Research and Treatment

Original Articles

General

Establishment of Patient-Derived Organoids Using Ascitic or Pleural Fluid from Cancer Patients: Wonyoung Choi, Yun-Hee Kim, Sang Myung Woo, Yebeen Yu, Mi Rim Lee, Woo Jin Lee, Jung Won Chun, Sung Hoon Sim, Heejung Chae, Hyoeun Shim, Keun Seok Lee, Sun-Young Kong; Cancer Res Treat. 2023;55(4):1077-1086. Published online June 12, 2023; DOI: https://doi.org/10.4143/crt.2022.1630

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Purpose
Patient-derived tumor cells can be a powerful resource for studying pathophysiological mechanisms and developing robust strategies for precision medicine. However, establishing organoids from patient-derived cells is challenging because of limited access to tissue specimens. Therefore, we aimed to establish organoids from malignant ascites and pleural effusions.
Materials and Methods
Ascitic or pleural fluid from pancreatic, gastric, and breast cancer patients was collected and concentrated to culture tumor cells ex vivo. Organoids were considered to be successfully cultured when maintained for five or more passages. Immunohistochemical staining was performed to compare the molecular features, and drug sensitivity was assayed to analyze the clinical responses of original patients.
Results
We collected 70 fluid samples from 58 patients (pancreatic cancer, n=39; gastric cancer, n=21; and breast cancer, n=10). The overall success rate was 40%; however, it differed with types of malignancy, with pancreatic, gastric, and breast cancers showing 48.7%, 33.3%, and 20%, respectively. Cytopathological results significantly differed between successful and failed cases (p=0.014). Immunohistochemical staining of breast cancer organoids showed molecular features identical to those of tumor tissues. In drug sensitivity assays, pancreatic cancer organoids recapitulated the clinical responses of the original patients.
Conclusion
Tumor organoids established from malignant ascites or pleural effusion of pancreatic, gastric, and breast cancers reflect the molecular characteristics and drug sensitivity profiles. Our organoid platform could be used as a testbed for patients with pleural and peritoneal metastases to guide precision oncology and drug discovery.

Citations

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PRMT1 promotes pancreatic cancer development and resistance to chemotherapy
Bomin Ku, David Eisenbarth, Seonguk Baek, Tae-Keun Jeong, Ju-Gyeong Kang, Daehee Hwang, Myung-Giun Noh, Chan Choi, Sungwoo Choi, Taejun Seol, Hail Kim, Yun-Hee Kim, Sang Myung Woo, Sun-Young Kong, Dae-Sik Lim
Cell Reports Medicine.2024; 5(3): 101461. CrossRef
Establishment and Advancement of Pancreatic Organoids
Dong Hyeon Lee
Keimyung Medical Journal.2024; 43(1): 3. CrossRef
Organoid as a promising tool for primary liver cancer research: a comprehensive review
Xuekai Hu, Jiayun Wei, Pinyan Liu, Qiuxia Zheng, Yue Zhang, Qichen Zhang, Jia Yao, Jingman Ni
Cell & Bioscience.2024;[Epub] CrossRef
The use of organoids in creating immune microenvironments and treating gynecological tumors
Ling-Feng Zhou, Hui-Yan Liao, Yang Han, Yang Zhao
Journal of Translational Medicine.2024;[Epub] CrossRef
Organoid: Bridging the gap between basic research and clinical practice
Guihu Weng, Jinxin Tao, Yueze Liu, Jiangdong Qiu, Dan Su, Ruobing Wang, Wenhao Luo, Taiping Zhang
Cancer Letters.2023; 572: 216353. CrossRef

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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

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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.

Citations

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Radiographic features predictive of recurrence and survival after surgical resection of perihilar cholangiocarcinoma
Julaluck Promsorn, Panjaporn Naknan, Aumkhae Sookprasert, Kosin Wirasorn, Jarin Chindaprasirt, Attapol Titapun, Piyapharom Intarawichian, Mukesh Harisinghani
Heliyon.2024; 10(7): e28805. CrossRef
Practice guidelines for managing extrahepatic biliary tract cancers
Hyung Sun Kim, Mee Joo Kang, Jingu Kang, Kyubo Kim, Bohyun Kim, Seong-Hun Kim, Soo Jin Kim, Yong-Il Kim, Joo Young Kim, Jin Sil Kim, Haeryoung Kim, Hyo Jung Kim, Ji Hae Nahm, Won Suk Park, Eunkyu Park, Joo Kyung Park, Jin Myung Park, Byeong Jun Song, Yong
Annals of Hepato-Biliary-Pancreatic Surgery.2024; 28(2): 161. CrossRef
Influence of Perineural (Pn), Lymphangio (L) and Vascular (V) Invasion on Survival after Resection of Perihilar Cholangiocarcinoma
Rabea Margies, Lisa-Katharina Gröger, Beate K. Straub, Fabian Bartsch, Hauke Lang
Cancers.2024; 16(20): 3463. CrossRef
Liver transplantation for unresectable Klatskin tumor: experience of two centers, first distant results
D. A. Granov, V. N. Zhuikov, I. I. Tileubergenov, A. V. Moiseenko, I. O. Rutkin, A. R. Sheraliev, A. A. Polikarpov, O. O. Rummo, A. E. Shcherba, I. P. Shturich, S. V. Korotkov, L. V. Kirkovsky, T. M. Chernishov
Annaly khirurgicheskoy gepatologii = Annals of HPB Surgery.2024; 29(3): 70. CrossRef
Molecular profiling and prognostic analysis in Chinese cholangiocarcinoma: an observational, retrospective single-center study
Changkun Zhang, Xia You, Qin Zhang, Dong Wang
Investigational New Drugs.2023;[Epub] CrossRef
Significance of dysplasia in bile duct resection margin in patients with extrahepatic cholangiocarcinoma: A retrospective analysis
Jung Wan Choe, Hyo Jung Kim, Jae Seon Kim
World Journal of Clinical Cases.2022; 10(10): 3078. CrossRef
Klatskin Tumor: A Survival Analysis According to Tumor Characteristics and Inflammatory Ratios
Vlad-Ionuţ Nechita, Emil Moiş, Luminiţa Furcea, Mihaela-Ancuţa Nechita, Florin Graur
Medicina.2022; 58(12): 1788. CrossRef
Impact of Remnant Carcinoma in Situ at the Ductal Stump on Long‐Term Outcomes in Patients with Distal Cholangiocarcinoma
Koya Yasukawa, Akira Shimizu, Hiroaki Motoyama, Koji Kubota, Tsuyoshi Notake, Kentaro Fukushima, Tomohiko Ikehara, Hikaru Hayashi, Akira Kobayashi, Yuji Soejima
World Journal of Surgery.2021; 45(1): 291. CrossRef
Comprehensive analysis of genomic alterations of Chinese hilar cholangiocarcinoma patients
Feiling Feng, Xiaobing Wu, Xiaoliang Shi, Qingxiang Gao, Yue Wu, Yong Yu, Qingbao Cheng, Bin Li, Bin Yi, Chen Liu, Qing Hao, Lin Zhang, Chunfang Gao, Xiaoqing Jiang
International Journal of Clinical Oncology.2021; 26(4): 717. CrossRef
Prognostic Impact of Perioperative CA19-9 Levels in Patients with Resected Perihilar Cholangiocarcinoma
Jong Woo Lee, Jae Hoon Lee, Yejong Park, Jaewoo Kwon, Woohyung Lee, Ki Byung Song, Dae Wook Hwang, Song Cheol Kim
Journal of Clinical Medicine.2021; 10(7): 1345. CrossRef
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 Research and Treatment.2020; 52(3): 886. CrossRef
Comparative study of laparoscopic‐assisted and open total gastrectomy for Siewert Types II and III adenocarcinoma of the esophagogastric junction
Jianchu Wang, Jin‐Cheng Wang, Bin Song, Xu‐Dong Dai, Xiao‐Yu Zhang
Journal of Cellular Physiology.2019; 234(7): 11235. CrossRef
Surgical management of carcinoma in situ at ductal resection margins in patients with extrahepatic cholangiocarcinoma
Toshifumi Wakai, Jun Sakata, Tomohiro Katada, Yuki Hirose, Daiki Soma, Pankaj Prasoon, Kohei Miura, Takashi Kobayashi
Annals of Gastroenterological Surgery.2018; 2(5): 359. CrossRef

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Induction Chemotherapy with Gemcitabine and Cisplatin Followed by Simultaneous Integrated Boost–Intensity Modulated Radiotherapy with Concurrent Gemcitabine for Locally Advanced Unresectable Pancreatic Cancer: Results from a Feasibility Study: Sang Myung Woo, Min Kyeong Kim, Jungnam Joo, Kyong-Ah Yoon, Boram Park, Sang-Jae Park, Sung-Sik Han, Ju Hee Lee, Eun Kyung Hong, Yun-Hee Kim, Hae Moon, Sun-Young Kong, Tae Hyun Kim, Woo Jin Lee; Cancer Res Treat. 2017;49(4):1022-1032. Published online January 19, 2017; DOI: https://doi.org/10.4143/crt.2016.495

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Purpose
This study assessed the feasibility and compliance of induction chemotherapy with gemcitabine and cisplatin followed by simultaneous integrated boost–intensity modulated radiotherapy (SIB-IMRT) with concurrent gemcitabine in patients with locally advanced unresectable pancreatic cancer.
Materials and Methods
In this trial, patients received induction chemotherapy consisting of gemcitabine (1,000 mg/m²) and cisplatin (25 mg/m2) on days 1, 8, and 15 of each treatment cycle. Patients were subsequently treated with gemcitabine (300 mg/m²/wk) during SIB-IMRT. The patients received total doses of 55 and 44 Gy in 22 fractions to planning target volume 1 and 2, respectively. As an ancillary study, digital polymerase chain reaction was performed to screen for the seven most common mutations in codons 12 and 13 of the KRAS oncogene of circulating cell free DNA (cfDNA).
Results
Forty-four patients were enrolled between 2012 and 2015. Of these, 33 (75%) completed the treatment. The most common toxicities during induction chemotherapy were grades 3 and 4 neutropenia (18.2%), grade 3 nausea (6.8%) and vomiting (6.8%). The most common toxicities during SIB-IMRT were grade 3 neutropenia (24.2%) and grade 3 anemia (12.1%). Ten patients (23%) underwent a curative resection after therapy. Median overall survival was significantly longer in patients who underwent curative resection (16.8 months vs. 11 months, p < 0.01). The median cfDNA concentration was significantly lower after treatment (108.5 ng/mL vs. 18.4 ng/mL, p < 0.001).
Conclusion
Induction chemotherapy with gemcitabine and cisplatin followed by concurrent SIB-IMRT was well tolerated and active.

Citations

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Executive Summary of the American Radium Society Appropriate Use Criteria for Neoadjuvant Therapy for Nonmetastatic Pancreatic Adenocarcinoma
Krishan R. Jethwa, Ed Kim, Jordan Berlin, Christopher J. Anker, Leila Tchelebi, Gerard Abood, Christopher L. Hallemeier, Salma Jabbour, Timothy Kennedy, Rachit Kumar, Percy Lee, Navesh Sharma, William Small, Vonetta Williams, Suzanne Russo
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Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review
Marisol Huerta, Susana Roselló, Luis Sabater, Ana Ferrer, Noelia Tarazona, Desamparados Roda, Valentina Gambardella, Clara Alfaro-Cervelló, Marina Garcés-Albir, Andrés Cervantes, Maider Ibarrola-Villava
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Efficacy and feasibility of proton beam radiotherapy using the simultaneous integrated boost technique for locally advanced pancreatic cancer
Tae Hyun Kim, Woo Jin Lee, Sang Myung Woo, Eun Sang Oh, Sang Hee Youn, Hye Young Jang, Sung-Sik Han, Sang-Jae Park, Yang-Gun Suh, Sung Ho Moon, Sang Soo Kim, Dae Yong Kim
Scientific Reports.2020;[Epub] CrossRef
Comprehensive Cancer Panel Sequencing Defines Genetic Diversity and Changes in the Mutational Characteristics of Pancreatic Cancer Patients Receiving Neoadjuvant Treatment
Kyong-Ah Yoon, Sang Myung Woo, Yun-Hee Kim, Sun-Young Kong, Min Kyoung Lee, Sung-Sik Han, Tae Hyun Kim, Woo Jin Lee, Sang-Jae Park
Gut and Liver.2019; 13(6): 683. CrossRef
Plasma Cell-Free DNA as a Predictive Marker after Radiotherapy for Hepatocellular Carcinoma
Sangjoon Park, Eun Jung Lee, Chai Hong Rim, Jinsil Seong
Yonsei Medical Journal.2018; 59(4): 470. CrossRef
Effectiveness and Safety of Simultaneous Integrated Boost-Proton Beam Therapy for Localized Pancreatic Cancer
Tae Hyun Kim, Woo Jin Lee, Sang Myung Woo, Hyunjung Kim, Eun Sang Oh, Ju Hee Lee, Sung-Sik Han, Sang-Jae Park, Yang-Gun Suh, Sung Ho Moon, Sang Soo Kim, Dae Yong Kim
Technology in Cancer Research & Treatment.2018;[Epub] CrossRef

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Phase I Dose-Escalation Study of Proton Beam Therapy for Inoperable Hepatocellular Carcinoma: Tae Hyun Kim, Joong-Won Park, Yeon-Joo Kim, Bo Hyun Kim, Sang Myung Woo, Sung Ho Moon, Sang Soo Kim, Young-Hwan Koh, Woo Jin Lee, Sang Jae Park, Joo-Young Kim, Dae Yong Kim, Chang-Min Kim; Cancer Res Treat. 2015;47(1):34-45. Published online September 11, 2014; DOI: https://doi.org/10.4143/crt.2013.218

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Purpose
The purpose of this study is to determine the optimal dose of proton beam therapy (PBT) in hepatocellular carcinoma (HCC) patients.
Materials and Methods
Inoperable HCC patients who had naïve, recurrent, or residual tumor to treatment were considered eligible for PBT. Patients received PBT with 60 GyE in 20 fractions (dose level 1; equivalent dose in 2 Gy fractions [EQD2], 65 GyE10); 66 GyE in 22 fractions (dose level 2; EQD2, 71.5 GyE10); or 72 GyE in 24 fractions (dose level 3; EQD2, 78 GyE10). Dose-limiting toxicity was determined by grade ≥ 3 acute toxicity.
Results
Twenty-seven patients were enrolled; eight, seven, and 12 patients were treated with dose levels 1, 2, and 3, respectively. Overall, treatment was well tolerated, with no dose-limiting toxicities. The complete response (CR) rates of primary tumors after PBT for dose levels 1, 2, and 3 were 62.5% (5/8), 57.1% (4/7), and 100% (12/12), respectively (p=0.039). The 3- and 5-year local progression-free survival (LPFS) rates among 26 patients, excluding one patient who underwent liver transplantation after PBT due to its probable significant effect on disease control, were 79.9% and 63.9%, respectively, and the 3- and 5-year overall survival rates were 56.4% and 42.3%, respectively. The 3-year LPFS rate was significantly higher in patients who achieved CR than in those who did not (90% vs. 40%, p=0.003).
Conclusion
PBT is safe and effective and an EQD2 ≥ 78 GyE10 should be delivered for achievement of local tumor control.

Citations

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Michael Bitzer, Sabrina Groß, Jörg Albert, Susanne Blödt, Judit Boda-Heggemann, Thomas Brunner, Reiner Caspari, Enrico De Toni, Frank Dombrowski, Matthias Evert, Markus Follmann, Paul Freudenberger, Cihan Gani, Andreas Geier, Eleni Gkika, Martin Götz, Tho
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