Cancer Research and Treatment

Accepted and E-pub version articles are published online before they appear in a regular issue of the journal. Accepted articles are PDF versions of manuscripts that have been peer reviewed and accepted for publication, but not yet copyedited or typeset, allowing readers the most rapid access to accepted papers. The accepted article remains on this page until the final proof version of the paper is posted in Epub Ahead-of Print page.
Accepted article is given its own Doi, so it can be citable as it has been linked to PubMed.

It may be cited as shown in the following example:
Park IH, Im SA, Jung KH, Sohn JH, Park YH, Lee KS, et al. Randomized Open Label Phase III Trial of Irinotecan Plus Capecitabine versus Capecitabine Monotherapy in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane: PROCEED Trial (KCSG BR 11-01). Cancer Res Treat. 2018 Feb 14 [Epub]. https://doi.org/10.4143/crt.2017.562.

Original Articles

The Roles of Ninjurin1 and Estrogen in Modulating AOM/DSS-Induced Colitis-Associated Colorectal Cancer in Male Mice: Chin-Hee Song, Nayoung Kim, Ryoung Hee Nam, Jae Young Jang, Eun Hye Kim, Sungchan Ha, Eun Shin, Ha-Na Lee, Hoon Choi, Kyu-Won Kim, Sejin Jeon, Goo Taeg Oh; Received October 2, 2024 Accepted January 10, 2025 Published online January 13, 2025; DOI: https://doi.org/10.4143/crt.2024.959 [Accepted]

Abstract PDF: Purpose
Ninjury-induced protein 1 (Ninj1) is associated with inflammation and tumor progression and shows increased expression in various cancers. This study aimed to investigate the role of Ninj1 in colitis-associated colorectal cancer (CRC) by focusing on its interaction with 17β-estradiol (E2).
Materials and Methods
Using an azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of colitis-associated CRC, wild-type (WT) and Ninj1 knockout (KO) male mice were treated with or without E2.
Results
At week 2, Ninj1 KO mice exhibited attenuated colitis symptoms than WT mice following AOM/DSS treatment. E2 administration significantly alleviated these symptoms in both WT and Ninj1 KO mice, with reductions in the disease activity index (DAI), colon length shortening, and histopathological damage. The levels of pro-inflammatory mediators were reduced by E2 treatment in both groups, with the Ninj1 KO group showing a more pronounced response. At week 13, tumor development in Ninj1 KO mice was significantly lower than that in WT mice, particularly in the distal colon. E2 treatment inhibited tumor formation in WT mice and had a stronger inhibitory effect on distal colon tumorigenesis in Ninj1 KO mice. Immune cell populations, including the populations of macrophages and T cells, were also modulated by E2 in WT mice; however, these effects were diminished in Ninj1 KO mice.
Conclusion
These findings suggest that Ninj1 plays a role in modulating colitis and CRC progression, with E2 exerting anti-inflammatory and anti-tumorigenic effects that are influenced by Ninj1 status.

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Factors Associated with Smoking Cessation of Participants in the National Lung Cancer Screening Program in Korea: Na-Young Yoon, Minji Seo, Nayoung Lee, Yeol Kim; Received July 16, 2024 Accepted January 10, 2025 Published online January 10, 2025; DOI: https://doi.org/10.4143/crt.2024.653 [Accepted]

Abstract PDF: Purpose
Smoking cessation interventions for participants in lung cancer screening are essential for increasing the effectiveness of screening to reduce lung cancer mortality. This study aimed to investigate the factors that lead to smoking cessation after lung cancer screening.
Materials and Methods
The Korean National Lung Cancer Screening (KNLCS) Satisfaction Survey was conducted from 2021 to 2022 with 1,000 samples per year among participants in KNLCS targets 30 or more pack-year smokers. Factors associated with smoking cessation were analyzed based on the survey.
Results
Among 1,525 current smokers in the survey participants, 728 (47.7%) received screening result counseling from physician after screening and showed significantly higher smoking cessation rate than non-counselling participants [OR 2.17, 95% CI 1.27–3.70]. The participants who considered the counseling helpful were more likely to quit smoking [OR 3.53, 95% CI 2.00–6.22] and to reduce smoking amount [OR 2.05, 95% CI 1.54–2.71]. Similarly, those who received physicians’ active recommendations to quit smoking were likely to quit smoking [OR 2.20, 95% CI 1.25–3.87] and to decrease smoking amount [OR 1.30, 95% CI 1.00-1.68]. In contrast, participants who had no abnormal findings from screening tended to have no significant change in smoking status despite the physicians’ active recommendations to quit smoking.
Conclusion
Physicians’ active recommendations and effective counseling to quit smoking could be a key factor in increasing smoking cessation among lung cancer screening participants. Further research should be conducted to develop more effective strategies for smoking cessation to participants without abnormal findings in lung cancer screening.

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Clinical Characteristics of and Treatment Pattern for EGFR-Amplified Colorectal Cancer: Seong-Eun Kim, Hyehyun Jeong, Sun Young Kim, Jeong Eun Kim, Yong Sang Hong, Deokhoon Kim, Jihun Kim, Ji Sung Lee, Tae-Won Kim; Received June 17, 2024 Accepted January 7, 2025 Published online January 10, 2025; DOI: https://doi.org/10.4143/crt.2024.569 [Accepted]

Abstract PDF: Purpose
To compare clinicopathologic features and clinical outcomes of metastatic colorectal cancer (mCRC) based on EGFR amplification status.
Materials and Methods
Patients with mCRC who underwent next-generation sequencing using a targeted 244-gene panel from 2016 to 2021 were identified and screened for EGFR copy numbers. Cases with at least 5 copies were reviewed for tumor purity adjustment, and those with an adjusted copy number of ≥6 were defined as EGFR-amplified (EGFR amp+). Their clinical characteristics were compared with those without EGFR amplification (EGFR amp-).
Results
Among 2,421 patients, 35 (1.4%) were EGFR amp+. Clinical characteristics did not significantly differ according to EGFR amplification status, but EGFR amp+ cases had fewer instances of peritoneal seeding (8.6% vs. 21.8%). Overall survival (OS) tended to be better in EGFR amp+ patients compared with EGFR amp- patients (median OS 76 vs. 37 months, p=0.15). Among 572 patients who received anti-EGFR antibody-based chemotherapy (anti-EGFR CTx) during disease course, mOS tended to be better in 16 EGFR amp+ patients (79 months) compared with 556 EGFR amp- patients (39 months, p=0.048). Seven out of 35 EGFR amp+ patients were treated with front-line anti-EGFR CTx, and their progression-free survival did not differ from that of EGFR amp- patients treated with front-line anti-EGFR CTx (20 vs. 14 months, p=0.344).
Conclusion
This study may suggest a favorable predictive impact of EGFR amplification in patients treated with anti-EGFR CTx. However, the benefit of front-line anti-EGFR antibody treatment in this group was not notable.

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Single-Cell Heterogeneity of EGFR Pathway Is Linked to Unique Signatures of Drug Response and Malignancy in Patient Derived Glioblastoma Stem Cells: Michael D. Masterman-Smith, Nicholas A. Graham, Eduard H. Panosyan, Jack Mottahedeh, Eric R. Samuels, Araceli Nunez, Tiffany Phillips, Meeryo Choe, Timothy F. Cloughesy, Jorge A. Lazareff, Linda M. Liau, William H. Yong, Thomas G. Graeber, Harley I. Kornblum, Ming-Fei Lang, Yanzhao Li, Jing Sun; Received September 4, 2024 Accepted January 6, 2025 Published online January 7, 2025; DOI: https://doi.org/10.4143/crt.2024.859 [Accepted]

Abstract PDF: Purpose
In glioblastoma, the therapeutically intractable and resistant phenotypes can be derived from glioma stem cells, which often have different underlying mechanisms from non-stem glioma cells. Aberrant signaling across the EGFR-PTEN-AKT-mTOR pathways have been shown as common drivers of glioblastoma. Revealing the inter and intra-cellular heterogeneity within glioma stem cell populations in relations to signaling patterns through these pathways may be key to precision diagnostic and therapeutic targeting of these cells.
Materials and Methods
Single cell parallel proteomic heterogeneity profiling of the EGFR-PTEN-AKT-mTOR pathways was conducted in a panel of fifteen glioma stem cell models derived from patient glioblastoma biopsies.
Results
The analysis included 59,464 data points from 14,866 cells and identified forty-nine molecularly distinct signaling phenotypes. High content bioinformatics resolved two unique patient clusters diverging on EGFR expression and AKT/TORC1 activation. Phenotypic validation indicated drug responsive phenotypes to EGFR blocking in the high EGFR expressing cluster with lower tumor initiating potential in comparison to the AKT/TORC1 activated cluster. High EGFR expression trended with improved patient prognosis while AKT/TORC1 activated samples trended with poorer patient outcomes. Genetic heterogeneity was observed in both clusters with proneural, classical and mesenchymal subtypes observed.
Conclusion
Quantitative single cell heterogeneity profiling reveals divergent EGFR-PTEN-AKT-mTOR pathways of patient derived glioma stem cells, which would inform future research and personalized therapeutic strategies.

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The Synergistic Effect of PARP Inhibitors and Irinotecan in Small Cell Lung Cancer Cells: Songji Oh, Soyeon Kim, Bhumsuk Keam, Jeonghwan Youk, Tae Min Kim, Dong-Wan Kim, Miso Kim; Received August 1, 2024 Accepted January 6, 2025 Published online January 7, 2025; DOI: https://doi.org/10.4143/crt.2024.728 [Accepted]

Abstract PDF: Purpose
This study focused on combining irinotecan with Poly (ADP-ribose) polymerase (PARP) inhibitors to explore the potential for novel combination therapeutics in small cell lung cancer (SCLC).
Materials and Methods
We selected 10 different SCLC cell lines with diverse mutational backgrounds in DNA damage response (DDR) pathway genes to evaluate the efficacy of the combination of three PARP inhibitors and irinotecan. After the cells were exposed to the drugs for seven days, cell viability was measured, and a combination index was calculated. Apoptotic signaling was assessed via western blot, and DNA damage was evaluated using an alkaline comet assay.
Results
We assessed the synergistic effects of PARP inhibitors and irinotecan in in vitro SCLC models, which revealed increased sensitivity, particularly in cells harboring BRCA mutations. However, even in cells lacking mutations in DNA damage response pathway genes, the combination of the two drugs exhibited a synergistic effect. When treated with 50 nM irinotecan, the IC₅₀ fold changes for PARP inhibitors were: olaparib, 1649 ± 4049; talazoparib, 25 ± 34.21; venadaparib, 336 ± 596.01. This combination enhanced apoptosis signaling and increased p-chk1 and p-p53 protein levels. Additionally, the treatment of PARP inhibitor with irinotecan increased DNA damage, as visualized by the alkaline comet assay.
Conclusion
This study provides preclinical evidence of the potential clinical benefits of combining irinotecan with PARP inhibitors in SCLC. Further clinical investigations are warranted to validate these findings for the development of more effective and personalized therapeutic strategies for SCLC patients.

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Outcomes of Stereotactic Body Radiation Therapy for Large Uveal Melanoma: A Retrospective Analysis of Asian Population: Jong Won Park, Seowoong Jun, Ki Chang Keum, Christopher Seungkyu Lee, Kyung Hwan Kim; Received June 20, 2024 Accepted December 28, 2024 Published online December 31, 2024; DOI: https://doi.org/10.4143/crt.2024.580 [Accepted]

Abstract PDF: Purpose
To investigate the clinical outcomes of stereotactic body radiation therapy (SBRT) in patients with large uveal melanoma (UM).
Materials and Methods
We conducted a retrospective review of 64 consecutive patients with UM treated with Cyberknife at Yonsei Cancer Center from September 2015 to October 2021. The median radiation dose was 60 Gy (range 48-64 Gy) administered in four fractions every alternate day. The local failure-free rate (LFFR), distant metastasis-free rate (DMFR), progression-free survival (PFS), and overall survival (OS) were assessed using the Kaplan–Meier method and log-rank test. Cox regression analysis was performed to analyze the predictive factors affecting survival outcomes and the factors associated with vision loss.
Results
The median tumor diameter and height were 11.5 mm and 8.4 mm, respectively. After a median follow-up of 32.1 months (range 4.9–89.9), the 3-year LFFR, DMFR, PFS, and OS were 89.5%, 70.5%, 65.5%, and 89.4%, respectively. Enucleation was performed in 13 (20.3%) patients, with three cases attributed to disease progression. A larger tumor diameter was associated with significantly worse DMFR (HR=1.35, p=0.015) and OS (HR=1.49, p=0.026) in the multivariate analysis. Regarding visual prognosis, 41 (64.1%) patients had baseline visual acuity ≥20/200, but only 4 (6.3%) patients maintained visual acuity ≥20/200 by the final follow-up. Initial visual acuity ≥20/40 (HR 0.45, p=0.030) was the single favorable significant factor predicting visual retention ≥20/200 in multivariate analysis.
Conclusion
SBRT using CyberKnife demonstrated a comparable local control rate to that observed in historical studies for patients with large UM. Distant metastasis and treatment-related ocular toxicity remain the limitations of this treatment.

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Long-Term Survival Outcomes of Surgical Resection for Lung Adenocarcinoma with Intraoperatively Diagnosed Pleural Metastasis: Target Treatment Era: Yelee Kwon, Jae Kwang Yun, Geun Dong Lee, Se Hoon Choi, Yong-Hee Kim, Hyeong Ryul Kim; Received October 15, 2024 Accepted December 27, 2024 Published online December 30, 2024; DOI: https://doi.org/10.4143/crt.2024.993 [Accepted]

Abstract PDF: Purpose
This study aimed to evaluate the clinical impact of main tumor resection on long-term survival compared with pleural biopsy alone in patients with lung adenocarcinoma who were intraoperatively diagnosed with pleural metastasis.
Materials and Methods
A total of 176 patients with adenocarcinoma who had unexpected pleural metastasis detected during surgery from 2002 to 2021 were retrospectively analyzed. Each surgeon decided whether to perform main tumor resection or pleural biopsy alone.
Results
The patients were grouped based on the surgical approaches: main tumor resection (Resection group; n=83) and pleural biopsy only (O&C group; n=93). The Resection group had better overall survival (OS, 10-year survival: 27.9% vs. 9.4%; median survival: 68.3 vs. 36.6 months; p<0.01) and locoregional progression-free survival (10-year survival: 12.5% vs. 7.1%; median survival: 19.6 vs. 10.6 months; p<0.01) than the O&C group. Similar results were found for OS in patients who received tyrosine kinase inhibitors (TKIs) as first-line therapy (10-year survival: 49.2% vs. 15.0%; median survival: 72.2 vs. 45.4 months; p=0.03), patients who did not undergo TKIs treatment (10-year survival: 29.4% vs. 9.2%; median survival: 82.4 vs. 23.8 months; p<0.01), and patients with positive target gene mutation (10-year survival: 31.7% vs. 10.1%; median survival: 72.2 vs. 33.7 months; p<0.01). In multivariate analysis, pleural biopsy only (hazard ratio, 1.73; p=0.04) was a significant predictor of OS.
Conclusion
Main tumor resection can improve survival in patients with lung adenocarcinoma who had unexpected pleural metastasis during operation.

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Sex-specific Molecular Markers NRF2 and PD-L1 in Colon Carcinogenesis: Implications for Right-sided Colon Cancer: Chin-Hee Song, Yonghoon Choi, Nayoung Kim, Ryoung Hee Nam, Jin Won Kim, Jae Young Jang, Eun Hye Kim, Sungchan Ha, Ha-Na Lee; Received August 22, 2024 Accepted December 26, 2024 Published online December 27, 2024; DOI: https://doi.org/10.4143/crt.2024.818 [Accepted]

Abstract PDF: Purpose
This study examined the roles of nuclear factor erythroid 2-related factor 2 (NRF2) and programmed death ligand 1 (PD-L1) in colon carcinogenesis, underscoring on sex and differences in tumor location.
Materials and Methods
A total of 378 participants were enrolled from Seoul National University Bundang Hospital: 88 healthy controls (HC), 139 patients with colorectal adenoma (AD), and 151 patients with colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (PCR), methylation-specific PCR, and immunohistochemistry (IHC) were performed utilizing tumor samples from patients and normal mucosa in the HC group.
Results
NRF2 mRNA expression was higher in the CRC group than in the HC and AD groups, with decreased NRF2 methylation in the AD and CRC groups. NRF2 protein expression, as evaluated by IHC, increased in the AD and CRC groups relative to that in the HC group. PD-L1 protein expression was remarkably higher in the CRC group than in the HC and AD groups. These patterns were consistent in both males and females. In sex- and CRC location-specific analyses, NRF2 methylation was lower in female than in male patients with CRC. NRF2 protein expression was significantly higher in females, particularly in patients with right-sided CRC. Moreover, females exhibited increased PD-L1 mRNA expression compared to males in the AD group, and PD-L1 mRNA levels were higher in females with right-sided CRC than in those with cancer at other locations.
Conclusion
Differences in NRF2 and PD-L1 expression indicate site-specific colon carcinogenesis based on sex, particularly in females with right-sided CRC.

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Pemetrexed Maintenance versus Observation in Patients with Advanced Urothelial Carcinoma Who Completed First-line Platinum-based Chemotherapy without Disease Progression (PREMIER, KCSG GU16-05): Inkeun Park, Shinkyo Yoon, Ilhwan Kim, Kwonoh Park, Suee Lee, Bhumsuk Keam, Joo-Hwan Park, Jin Young Kim, Yoon Ji Choi, Byeong Seok Sohn, Jae Lyun Lee; Received October 16, 2024 Accepted December 26, 2024 Published online December 27, 2024; DOI: https://doi.org/10.4143/crt.2024.1003 [Accepted]

Abstract PDF: Purpose
Platinum-based chemotherapy is the standard treatment for advanced urothelial carcinoma (aUC). Switch maintenance therapy after first-line (1L) treatment may delay disease progression. This study evaluated pemetrexed as switch maintenance therapy versus observation in aUC patients without disease progression after initial chemotherapy.
Materials and Methods
Eligible aUC patients who did not progress after 4–6 cycles of cisplatin or carboplatin-based chemotherapy were randomized 1:1 to receive maintenance pemetrexed (500 mg/m² IV every 3 weeks, up to 16 cycles) or observation. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and safety.
Results
The trial was closed early due to slow accrual after avelumab approval. From October 2016 to December 2022, 97 patients were randomized to pemetrexed (n=49) or observation (n=48). The median age was 69 years (range: 43–90) and 66 (range33–82), respectively, with 63% and 73% of patients being male, respectively. The median PFS was 6.0 months (95% CI, 3.4–8.5) with pemetrexed versus 2.3 months (1.8–2.7) with observation (p=0.044, HR 0.64; 95% CI, 0.41–0.99). The median OS was 18.1 months (95% CI, 6.9–29.4) for pemetrexed and 17.9 months (16.1–19.7) for observation (p=0.913, HR 1.03; 95% CI, 0.61–1.73). Common adverse events in the pemetrexed group included anemia (30%), fatigue (18%), and neutropenia (12%), primarily grade 1 or 2.
Conclusion
The PREMIER trial showed that switch maintenance pemetrexed significantly prolonged PFS in aUC patients post-1L platinum-based chemotherapy, with a favorable safety profile. Further studies on combination maintenance therapies are warranted.

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A Prospective, Single-Cohort, Open, Multi-Center, Observational Study of Sublingual Fentanyl for Breakthrough Cancer Pain: Effectiveness, Safety, and Tolerability in Korean Cancer Patients: Youn Seon Choi, Su-Jin Koh, Woo Kyun Bae, Se Hyung Kim, Seong Hoon Shin, So Yeon Oh, Sang Byung Bae, Yaewon Yang, Eun-Kee Song, Yoon Young Cho, Pyung Bok Lee, Ho-Suk Oh, MinYoung Lee, Jin Seok Ahn; Received June 13, 2024 Accepted December 24, 2024 Published online December 26, 2024; DOI: https://doi.org/10.4143/crt.2024.557 [Accepted]

Abstract PDF: Purpose
Fentanyl, a highly lipophilic opioid, was developed as a sublingual fentanyl tablet (SFT) for the management of breakthrough cancer pain (BTcP), and its efficacy and safety were confirmed in a randomized, controlled study. We investigated the effectiveness and safety of SFT administered to alleviate BTcP in a real-world setting.
Materials and Methods
In this prospective, open, single-cohort study, conducted in 13 referral hospitals in South Korea, opioid-tolerant cancer patients receiving around-the-clock opioids for persistent cancer pain were enrolled if the individual had BTcP ≥ 1 episode/day during the preceding week. The primary outcome was the SFT titration success rate.
Results
Among 113 patients evaluated for effectiveness, 103 patients (91.2%) had a successful titration of SFT, with an effective dose range between 100 µg and 400 µg. The most frequent dose was 100 µg, administered to 65.0%, 72.1%, and 81.8% of the patients at Week 1, 4, and 12, respectively. The proportion of patients achieving the personalized pain goal assessed in the first week was 75.2%. The mean change in pain intensity measured with a numeric rating scale at 30 and 60 minutes after taking SFT was -2.57 and -3.62, respectively (p<0.0001 for both). The incidence rate of adverse events related to SFT among 133 patients included for safety evaluation was 9.0% (12/133), which included vomiting (3.0%), nausea (2.3%), and headache (1.5%).
Conclusion
In a real-world setting, SFT provides rapid and effective analgesia in BTcP, even at the lowest dose (100 μg), and the safety profile was acceptable.

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CYBC1 Drives Glioblastoma Progression via ROS and NF-κB Pathways: Hyeon Ji Kim, Tae-Jun Kim, Jin-Hwa Cho, Mee-Seon Kim, Jin-Seok Byun, Do-Yeon Kim; Received August 27, 2024 Accepted December 23, 2024 Published online December 24, 2024; DOI: https://doi.org/10.4143/crt.2024.827 [Accepted]

Abstract PDF: Purpose
This study aims to investigate the role of Cytochrome b-245 chaperone 1 (CYBC1) in glioblastoma (GBM) progression, focusing on its involvement in reactive oxygen species (ROS) production and associated signaling pathways. Understanding the molecular mechanisms driven by CYBC1 could provide new therapeutic targets and prognostic markers for GBM.
Materials and Methods
Publicly available datasets were analyzed to assess CYBC1 expression in GBM and its correlation with patient survival. GBM cell lines were genetically manipulated using the CRISPR/Cas9 system to deplete CYBC1. The effects of CYBC1 deficiency on cell proliferation, migration, invasion, and cell cycle dynamics were experimentally evaluated. Additionally, the impact of CYBC1 on the expression of NOXA1, a subunit of NADPH oxidase, and downstream signaling pathways such as NF-κB was explored.
Results
CYBC1 expression was significantly elevated in GBM tissues and correlated with poor patient survival. CYBC1 deficiency in GBM cells resulted in reduced cell viability, migration, and invasion. Mechanistically, CYBC1 positively regulated NOXA1 expression, which in turn enhanced ROS production and activated the ERK·AKT/NF-κB pathways. The suppression of CYBC1 led to decreased ROS levels, reduced phosphorylation of NF-κB, and downregulation of genes involved in epithelial-mesenchymal transition.
Conclusion
CYBC1 is implicated in GBM progression by regulating NOXA1-mediated ROS production and activating the ERK·AKT/NF-κB pathways. This study suggests that CYBC1 could serve as a potential therapeutic target and prognostic marker in GBM, warranting further investigation into its molecular mechanisms and therapeutic potential.

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Unraveling the Genetic Landscape of Langerhans Cell Histiocytosis in Korean Patients: Comprehensive Insights from Mutational Profiles and Clinical Correlations: Kyung-Nam Koh, Ha Ra Jun, Ji-Young Lee, Ji Young Kim, Su Hyun Yoon, Young Kwon Koh, Sung Han Kang, Hyery Kim, Ho Joon Im, Sung-Min Chun; Received August 14, 2024 Accepted December 22, 2024 Published online December 24, 2024; DOI: https://doi.org/10.4143/crt.2024.782 [Accepted]

Abstract PDF: Purpose
This study aimed to conduct a comprehensive genetic analysis of patients with Langerhans cell histiocytosis (LCH), focusing on the frequency of MAPK pathway mutations, detailed mutation profiles of MAPK pathway genes, and their correlation with clinical features and prognosis in Korean LCH patients.
Materials and Methods
We performed targeted next-generation sequencing, capable of capturing exons from 382 cancer-related genes, on genomic DNA extracted from formaldehyde-fixed and paraffin-embedded samples of 45 pathologically confirmed LCH patients.
Results
The majority of patients (91.1%) exhibited single-system disease, with bone being the most common location (84.4%). Initial treatments varied, and no patients died during a median follow-up of 6.8 years. Our genetic assays revealed that all patients had MAPK pathway alterations, including BRAF mutations in 51.2%, MAP2K1 mutations in 42.2%, RAF1 mutations in 4.4%, and a KRAS mutation in 2.2%. These mutations were mutually exclusive. Detailed mutation profiles indicated that among the BRAF mutations, there were 18 point mutations and 5 in-frame deletions, while most MAP2K1 mutations were in-frame deletions, with only one missense mutation. We detected previously unreported variations of point mutations in BRAF, MAP2K1, KRAS, and the first instance of a RAF1-KLC1 fusion in LCH. MAP2K1 mutations occurred more frequently in older patients, whereas BRAF V600 mutations were commonly associated with unifocal bone disease. Genetic mutations did not correlate with high-risk features or event-free survival.
Conclusion
This study identified mutually exclusive MAPK pathway mutations in every LCH patient through comprehensive genetic analysis, highlighting the importance of inclusive testing in understanding the disease's genetics.

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Real-World Effectiveness and Safety of Intravenous Daratumumab in Patients with Multiple Myeloma: A Multicenter, Observational Study from Korea: Youngil Koh, Sung-Soo Yoon, Kihyun Kim, Je-Jung Lee, Sung-Hoon Jung, Sang Eun Yoon, Sung-Soo Park, YoungJu Park, Soomin Yoon, Chang-Ki Min; Received August 14, 2024 Accepted December 22, 2024 Published online December 24, 2024; DOI: https://doi.org/10.4143/crt.2024.781 [Accepted]

Abstract PDF: Purpose
Daratumumab is a novel, first-in-class monoclonal antibody approved for use as monotherapy and in combination with other treatments for patients with multiple myeloma (MM). The aim of this observational study was to evaluate the effectiveness and safety of daratumumab in real-world clinical practice.
Materials and Methods
This observational multicenter study collected data from patients with MM treated in Korea between June 1, 2018, and February 28, 2022.
Results
125 patients with a diagnosis of MM were included and followed until discontinuation or completion of 52 weeks’ follow-up. The median age was 67 years, and 97.6% of patients received more than three prior LOTs. The overall response rate was 52.5% (95% confidence interval [CI], 43.2 to 61.8), and a very good partial response was observed in 19.5% of patients (95% CI, 12.8 to 27.8). Of the patients who achieved a partial or higher response (52.5%), the median time to first response was 2.4 months (95% CI, 1.8 to 3.4), and the median time from start of daratumumab treatment until progressive disease was 4.1 months (95% CI, 2.9 to 5.1). Fever (24.0%) was the most frequently recorded adverse event (AE), while anemia (8.8%) and neutropenia (8.0%) were the most frequently observed grade 3-4 AEs. Overall, no unexpected safety signals were observed.
Conclusion
In a rapidly evolving treatment landscape, this analysis provides insight into the real-world outcomes for patients with MM receiving daratumumab in Korea and reveals that real-world outcomes were improved over results demonstrated in a clinical trial setting.

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Clinical Impact of TP53 Mutations in Patients with Head and Neck Cancer Who Were Treated with Targeted Therapies or Immunotherapy: Eun Joo Kang, Shinwon Hwang, Yun-Gyoo Lee, Jong-Kwon Choi, Seong Hoon Shin, Yoon Hee Choi, Keun-Wook Lee, Hyun Woo Lee, Min Kyoung Kim, Seung Taek Lim, Hwan Jung Yun, Sang-Gon Park, Sangwoo Kim, Sung-Bae Kim, Hye Ryun Kim; Received August 28, 2024 Accepted December 21, 2024 Published online December 23, 2024; DOI: https://doi.org/10.4143/crt.2024.836 [Accepted]

Abstract PDF: Purpose
TP53 mutations are common in head and neck squamous cell carcinoma (HNSCC). We evaluated their clinical impact in patients treated with targeted agents or immunotherapy in the KCSG HN15-16 TRIUMPH trial.
Materials and Methods
We analyzed clinical characteristics and outcomes of patients with TP53 mutations in the TRIUMPH trial, a multicenter, biomarker-driven umbrella trial in Korea. Patients were assigned to treatment groups based on genomic profiles: Group 1, alpelisib; Group 2, poziotinib; Group 3, nintedanib; and Group 4, abemaciclib. If there was no identifiable target, the patients were allocated to Group 5 (durvalumab ± tremelimumab).
Results
TP53 mutations were detected in 116/179 patients (64.8%), more frequently in HPV-negative and non-oropharyngeal cancers. Patients with TP53 mutations exhibited shorter progression-free survival (PFS) than TP53 wild-type in all the patients (1.7 vs. 3.8 months, p=0.002) and in those who received targeted treatments (2.5 vs. 7.3 months, p=0.009). Furthermore, TP53 mutations were strongly associated with poor overall survival than TP53 wild-type in all the patients (11.1 vs. 28.8 months, p=0.005) and in Group 5 (8.1 vs. 33.0 months, p=0.001).
Conclusion
TP53 mutations were associated with aggressive clinical characteristics and poor survival, particularly in HNSCC patients treated with immunotherapy.

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Prognostic Performance of the Next-Generation Sequencing-Based Multigene Assay in Early Breast Cancer Patients Treated According to the 21-Gene Assay Results: Eunhye Kang, Jong-Ho Cheun, Jeeyeon Lee, Jiwon Koh, Hyunwoo Lee, Ji-Young Park, Hee Jin Lee, Byeongju Kang, Woong Ki Park, Jeongeun Son, Bumjoon Kim, Woosung Chung, Wonshik Han, Han-Byoel Lee, Sae Byul Lee, Jai Min Ryu; Received October 28, 2024 Accepted December 22, 2024 Published online December 23, 2024; DOI: https://doi.org/10.4143/crt.2024.1035 [Accepted]

Abstract PDF: Purpose
Multigene assays guide treatment decisions in early-stage hormone receptor-positive breast cancer. OncoFREE, a next-generation sequencing assay using 179 genes, was developed for this purpose. This study aimed to evaluate the concordance between the Oncotype DX (ODX) Recurrence Score (RS) and the OncoFREE Decision Index (DI) and to compare their performance.
Materials and Methods
We retrospectively collected tumor blocks from patients who underwent ODX and treatment between 2012 and 2022 at four tertiary hospitals and performed OncoFREE on these samples. Distant metastasis-free survival (DMFS) was compared using RS and DI, with score cut-offs of 25 and 20, respectively.
Results
Among 838 patients, a strong correlation was observed between RS and DI (Pearson correlation coefficient 0.83). At a median follow-up of 54 months, patients with high DI had significantly worse DMFS compared to those with low DI (log-rank p < 0.001, hazard ratio [HR] 5.73, 95% confidence interval [CI] 1.87–17.57; multivariable p=0.048, HR 3.45, 95% CI 1.01–11.76). In 513 patients aged ≤50 years, DMFS was significantly different as a function of DI (p=0.035, HR 3.98, 95% CI 1.00–15.89) but not RS (p=0.792). Among 376 patients aged ≤50 years who avoided chemotherapy based on low RS, 64 with high DI had worse DMFS (p=0.015, HR 5.91, 95% CI 1.17–29.78).
Conclusion
OncoFREE showed strong concordance with ODX and effectively identified high-risk patients, particularly in younger individuals. It could be an affordable alternative to ODX for guiding treatment in hormone receptor-positive early breast cancer.

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Case Report

ALK Inhibition in a Patient with Inflammatory Myofibroblastic Tumor Harboring CARS1-ALK Fusion: Songji Choi, Miso Kim, Sheehyun Kim, Taekeun Park, Yoonjin Kwak, Jeong Mo Bae, Hongseok Yun, Jee Hyun Kim; Received December 10, 2024 Accepted December 14, 2024 Published online December 18, 2024; DOI: https://doi.org/10.4143/crt.2024.1184 [Accepted]

Abstract PDF: Inflammatory myofibroblastic tumor (IMT) is a rare entity, primarily affecting young individuals, often involving the abdomen, pelvis, or lung. Approximately 50% of IMTs harbor ALK gene rearrangements, making ALK inhibitors a viable treatment. We report a case of a 40-year-old female with metastatic IMT harboring a CARS1-ALK fusion. Initial chemotherapy failed, but targeted therapy with alectinib through the KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study led to significant tumor regression and ongoing, durable clinical improvement of 19 months. This case highlights the importance of precision medicine and raises the reappraisal of targeted agents outside of approved indications for rare cancers with actionable genomic alterations.

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Original Articles

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]

Abstract 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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A Machine Learning Risk Prediction Model for Gastric Cancer with SHapley Additive exPlanations: Bomi Park, Chung Ho Kim, Jae Kwan Jun, Mina Suh, Kui Son Choi, Il Ju Choi, Hyun Jin Oh; Received August 29, 2024 Accepted December 15, 2024 Published online December 16, 2024; DOI: https://doi.org/10.4143/crt.2024.843 [Accepted]

Abstract PDF: Purpose
Gastric cancer (GC) prediction models hold potential for enhancing early detection by enabling the identification of high-risk individuals, facilitating personalized risk-based screening, and optimizing the allocation of healthcare resources.
Materials and Methods
In this study, we developed a machine learning-based GC prediction model utilizing data from the Korean National Health Insurance Service, encompassing 10,515,949 adults who had not been diagnosed with GC and underwent GC screening during 2013–2014, with a follow-up period of at least five years. The cohort was divided into training and test datasets at an 8:2 ratio, and class imbalance was mitigated through random oversampling.
Results
Among various models, logistic regression demonstrated the highest predictive performance, with an area under the receiver operating characteristic curve (AUC) of 0.708, which was consistent with the AUC obtained in external validation (0.669). Importantly, the outcomes were robust to missing data imputation and variable selection. The SHapley Additive exPlanations (SHAP) algorithm enhanced the explainability of the model, identifying advancing age, being male, Helicobacter pylori infection, current smoking, and a family history of GC as key predictors of elevated risk.
Conclusion
This predictive model could significantly contribute to the early identification of individuals at elevated risk for gastric cancer, thereby enabling the implementation of targeted preventive strategies. Furthermore, the integration of noninvasive and cost-effective predictors enhances the clinical utility of the model, supporting its potential application in routine healthcare settings.

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Phase II Trial of Neoadjuvant Docetaxel/Cisplatin/5-Fluorouracil Combined with Pegteograstim for Unresectable, Locally Advanced Sinonasal Squamous Cell Carcinoma: KCSG HN18-07: Bhumsuk Keam, Ho Jung An, Seong Hoon Shin, Min Kyoung Kim, Jung Hae Cho, Seyoung Seo, Sung-Bae Kim; Received October 24, 2024 Accepted December 13, 2024 Published online December 16, 2024; DOI: https://doi.org/10.4143/crt.2024.1025 [Accepted]

Abstract PDF: Purpose
The role of neoadjuvant chemotherapy in locally advanced sinonasal squamous cell carcinoma (SNSCC) has not been established prospectively. We conducted a phase II trial of neoadjuvant chemotherapy (NAC) with docetaxel/cisplatin/5-fluorouracil (TPF) in this population.
Materials and Methods
Eligible patients had unresectable, locally advanced SNSCC, defined as T3/4 stage or potential compromise of critical organ function on surgery. Three TPF (docetaxel 75 mg/m² and cisplatin 75 mg/m² on day 1, 5-fluorouracil 1,000 mg/m² on days 1–4 every 3 weeks) cycles were administered with prophylactic pegteograstim. The primary outcome was the overall response rate (ORR); the secondary outcomes included 2-year progression-free survival (PFS), eyeball preservation rate, and safety.
Results
Among 28 patients screened, 25 were evaluable for efficacy (one screen-failure; two evaluable for safety only). The confirmed ORR was 72.0%. The definitive post-NAC treatment comprised chemoradiotherapy (n=15) and surgery (n=10). With a median follow-up of 25.5 months, median PFS was not reached and the 2-year PFS rate was 60.4%. Response to NAC was related to prolonged PFS (p=0.038). No patient underwent eyeball exenteration at the data cutoff point. Treatment-related adverse events of grade ≥3 were neutropenia (48.1%) including febrile neutropenia (14.8%), followed by acute kidney injury (22.2%), nausea/vomiting (11.1%), anemia (7.4%), thrombocytopenia (7.4%), and enterocolitis (3.7%).
Conclusion
TPF NAC showed a promising efficacy and might help preserve critical structures in this population, which needs to be validated in a large prospective trial (KCT0003377).

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Relationships between the Microbiome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: Hye In Lee, Bum-Sup Jang, Ji Hyun Chang, Eunji Kim, Tae Hoon Lee, Jeong Hwan Park, Eui Kyu Chie; Received June 2, 2024 Accepted December 13, 2024 Published online December 16, 2024; DOI: https://doi.org/10.4143/crt.2024.521 [Accepted]

Abstract PDF: Purpose
This study aimed to investigate the dynamic changes in the microbiome of patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (nCRT), focusing on the relationship between the microbiome and response to nCRT.
Materials and Methods
We conducted a longitudinal study involving 103 samples from 26 patients with LARC. Samples were collected from both the tumor and normal rectal tissues before and after nCRT. Diversity, taxonomic, and network analyses were performed to compare the microbiome profiles across different tissue types, pre- and post-nCRT time-points, and nCRT responses.
Results
Between the tumor and normal tissue samples, no differences in microbial diversity and composition were observed. However, when pre- and post-nCRT samples were compared, there was a significant decrease in diversity, along with notable changes in composition. Non-responders exhibited more extensive changes in their microbiome composition during nCRT, characterized by an increase in pathogenic microbes. Meanwhile, responders had relatively stable microbiome communities with more enriched butyrate-producing bacteria. Network analysis revealed distinct patterns of microbial interactions between responders and non-responders, where butyrate-producing bacteria formed strong networks in responders, while opportunistic pathogens formed strong networks in non-responders. A Bayesian network model for predicting the nCRT response was established, with butyrate-producing bacteria playing a major predictive role.
Conclusion
Our study demonstrated a significant association between the microbiome and nCRT response in LARC patients, leading to the development of a microbiome-based response prediction model. These findings suggest potential applications of microbiome signatures for predicting and optimizing nCRT treatment in LARC patients.

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Identifying Anti-Cancer Effects and Exploring the Mechanism of an MPS1/TTK Inhibitor in Gastric Cancer: Eunseo Kim, Woo Sun Kwon, Tae Soo Kim, Jihyun Hwang, Sunghwan Kim, Sun Young Rha; Received August 14, 2024 Accepted December 10, 2024 Published online December 12, 2024; DOI: https://doi.org/10.4143/crt.2024.780 [Accepted]

Abstract PDF: Purpose
To identify the anti-cancer effect and investigate the underlying mechanism of MPS1/TTK (Monopolar spindle 1; also known as threonine tyrosine kinase) inhibitor in gastric cancer (GC) cell lines.
Materials and Methods
This study used compound-9, a highly selective MPS1/TTK inhibitor, to evaluate its anticancer effects on GC cell lines. Cell viability assay was performed to determine sensitivity to the inhibitor. Cell cycle analysis and apoptosis assays were performed using Flow cytometry to evaluate the effects of the inhibitor. Protein-expression levels were analyzed through western blotting after the inhibitor treatment.
Results
The EBV and MSI-H groups tended to be sensitive to the inhibitor, while the GS-likely group tended to be moderate-to-resistant. In contrast, the CIN-likely group was extremely sensitive or resistant. Within the CIN group, TP53^WT cell lines were sensitive, whereas TP53^MUT cell lines were sensitive or resistant. Upon treatment of the inhibitor, the TP53^WT-sensitive cell line underwent cell death more rapidly compared to the TP53^MUT-sensitive cell line. In contrast, the TP53^MUT-sensitive cell experienced higher levels of aneuploidy or polyploidy and underwent cell death at later time point than the TP53^WT-sensitive cell line. The TP53^MUT-resistant line can tolerate aneuploidy or polyploidy and exhibits drug resistance.
Conclusion
Our study explores the potential of an MPS1/TTK inhibitor, compound-9, as a targeted therapy in gastric cancer cells and investigates its mechanism of action.

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The HDAC Inhibitor Entinostat Mediates HER2 Downregulation in Gastric Cancer, Providing the Basis for Its Particular Efficacy in HER2 Amplified Tumors and in Combination Therapies: Tamara Zenz, Robert Jenke, René Thieme, Tim Kahl, Hannes Borchardt, Ines Gockel, Finn K Hansen, Achim Aigner, Thomas RH Büch; Received June 10, 2024 Accepted November 28, 2024 Published online December 10, 2024; DOI: https://doi.org/10.4143/crt.2024.546 [Accepted]

Abstract PDF: Purpose
HER2 inhibition represents a therapeutic approach with proven clinical efficacy in gastric cancer. However, resistance against HER2-directed therapeutics highlights the need for alternative approaches or drug combinations. Histone deacetylase inhibitors (HDACi) display a broad spectrum of antitumor properties, which may include effects on receptor tyrosine kinases.
Materials and Methods
We analyzed the effects of the class I HDACi entinostat in a panel of HER2-amplified and non-amplified gastric adenocarcinoma cells in 2D cell culture as well as in tumor slice models ex vivo and in patient-derived xenografts in vivo. Effects on protein expression / signal transduction were evaluated by immunoblotting and quantitative RT-PCR.
Results
HDAC inhibition reduced HER2 protein expression independently of initial HER2 expression levels. This was associated with the upregulation of the HER2-inhibiting microRNA miR-205. The downregulation of HER2 resulted in reduced AKT phosphorylation, apoptosis induction and antiproliferative effects, with particularly high efficiency in HER2-amplified gastric cancer cells. Inhibiting HER2 by a specific kinase inhibitor in gastric cancer cells with low basal HER2 expression led to HER2 upregulation. This was reversed by entinostat treatment and provided the basis for synergistic cell inhibition upon double treatment.
Conclusion
We describe the downregulation of HER2 in gastric carcinoma cells upon HDACi treatment. Concomitantly, cells with high basal or treatment-induced HER2 expression showed most profound sensitivities towards HDACi. These findings may thus provide the basis for HDACi treatment as a therapeutic option (1) particularly valuable in HER2-amplified gastric cancer and (2) particularly useful in combination therapies with HER2 inhibitors.

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Psychometric Validation of Sheffield Profile for Assessment and Referral to Care (SPARC) in Korean Cancer Patients: Hong Jun Kim, Eun Hee Jung, Jung Hye Kwon, Yu Jung Kim, Su-Jin Koh, Myung Ah Lee, Jung Hun Kang, Sun Young Rha, Eun Mi Nam, Sun Kyung Baek, Ha Yeon Lee, Hun Ho Song, Young-Woong Won, Hanbyul Lee; Received July 26, 2024 Accepted December 4, 2024 Published online December 5, 2024; DOI: https://doi.org/10.4143/crt.2024.706 [Accepted]

Abstract PDF: Purpose
Identifying the palliative care needs of patients with advanced cancer is important for maintaining quality of life and timely transition to palliative care. We aimed to validate the Korean Sheffield Profile for Assessment and Referral for Care (K-SPARC) in such patients and establish its psychometric properties, including reliability, validity, and responsiveness to change.
Materials and Methods
We used the forward-back translated version of SPARC, which was verified through a pilot study, to assess the palliative care needs of patients with advanced cancer. Reliability was evaluated by internal consistency using Cronbach's alpha coefficients and test-retest reliability. Criterion validity was analyzed against other questionnaires, including the Korean versions of the Functional Assessment of Cancer Therapy-General (FACT-G Korean) and Korean versions of the Edmonton Symptom Assessment System (K-ESAS). Factor analysis was used to assess construct validity.
Results
Two hundred fifty-nine patients were included from 2019 to 2022. Forty-nine percent of all patients were women, and the median age was 63 years. Cronbach’s alpha coefficient (range, 0.642–0.903) and test-retest reliability (range, 0.574–0.749) indicated acceptable reliability. The correlation coefficients between K-SPARC and FACT-G Korean suggested significant criterion validity. The correlation coefficients for the physical, social, emotional, and functional domains were 0.701, 0.249, 0.718, and 0.511, respectively (p-value <0.001, all). Factor analysis demonstrated satisfactory construct validity of the tool.
Conclusion
This study demonstrated the utility of K-SPARC as an evaluation tool for providing palliative care to patients with advanced cancer through psychometric validation; the tool had good internal consistency, reliability, and acceptable validity.

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Normal Brain-Sparing Radiotherapy versus Whole Brain Radiotherapy for Multiple Brain Metastasis from Non-Small Cell Lung Cancer: Sangjoon Park, Jaeho Cho, Kyung Hwan Kim, Hong In Yoon, Chang Geol Lee; Received July 23, 2024 Accepted December 2, 2024 Published online December 3, 2024; DOI: https://doi.org/10.4143/crt.2024.679 [Accepted]

Abstract PDF: Purpose
The efficacy and lower neurotoxicity of normal brain-sparing radiotherapy (NBS-RT) with systemic therapy in treating multiple brain metastases from non-small cell lung cancer (NSCLC) is underexplored. This study compares whole-brain radiotherapy (WBRT) and NBS-RT for multiple brain metastases in NSCLC, focusing on treatment outcomes and leukoencephalopathy.
Materials and Methods
This retrospective study included 503 patients with NSCLC with multiple brain metastases at a single center, treated with either WBRT or NBS-RT. Post-RT treatments included chemotherapy, targeted therapy, or immunotherapy. Main outcomes measured were intracranial control, overall survival (OS), and leukoencephalopathy incidence.
Results
In this study, 441 patients received WBRT and 62 received NBS-RT, with median ages of 62 and 61 years, respectively. A significant portion of both groups, 77.3% in WBRT and 80.6% in NBS-RT, received post-RT systemic therapy. The median number of brain metastases was 10 for WBRT and 12 for NBS-RT, with median maximal diameters of 11.7 mm in WBRT and 14.4 mm in NBS-RT. After a median follow-up of 10.9 months for WBRT and 11.8 months for NBS-RT, there were no significant differences in intracranial progression (p=0.516) or OS (p=0.492) between the groups. However, WBRT patients had a higher incidence of leukoencephalopathy than NBS-RT patients (p=0.013).
Conclusion
NBS-RT combined with systemic therapy was as effective in treating multiple brain metastases as WBRT and was less toxic. NBS-RT-based strategies deserve further investigation in a prospective setting.

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Which Chemotherapy-Related Terms were Difficult for Cancer Patients, and Who Would Have the Most Difficulties?: Mangyeong Lee, Nayeon Kim, Ho-Young Kim, Ayoung Lee, Junghee Yoon, Juhee Cho; Received May 22, 2024 Accepted December 2, 2024 Published online December 3, 2024; DOI: https://doi.org/10.4143/crt.2024.485 [Accepted]

Abstract PDF: Purpose
This cross-sectional study aimed to examine which chemotherapy (CTx) terms were most difficult to understand for cancer patients and identify vulnerable patient populations who might need extra support to understand the terms.
Materials and Methods
We listed 56 CTx-related terms based on the experts’ review, then 300 cancer patients and their caregivers completed a questionnaire that assessed literacy in CTx terms (LCT), functional health literacy, and empowerment. Descriptive analysis was performed to examine which CTx-related terms were most difficult for them. Logistic regression analyses were performed to identify factors associated with LCT level.
Results
Of the total 300 people, 162 (54.0%) were in the low-scoring (LS) group in LCT. LS group had a higher proportion of males, lower monthly income, and lived at the province, compared to the high scoring (HS) group. The participants tended to have difficulties in understanding terms related to blood count, risk of infection, and symptoms written in Sino-Korean. In the multivariable logistic regression, male participants (Adjusted Odds Ratio [aOR] = 2.59, 95% confidence interval [CI]: 1.48–4.62), those with no cancer-related information-seeking (aOR = 4.32, 95% CI: 1.75–12.33), and those with low empowerment (aOR = 3.07, 95% CI: 1.83–5.23) were more likely to have a low level of LCT.
Conclusion
There were still linguistic health literacy challenges faced by cancer patients and their caregivers, specifically in understanding chemotherapy-related terms. Minimizing medical jargon and Sino-Korean terms and empowering patients to be ready for treatment are necessary.

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Associations of Financial Toxicity with Employment Concerns and Cancer-Related Distress: A Cross-Sectional Survey among Korean Working-Age Cancer Survivors: Hyun-Ju Seo, Dal-Lae Jin, Young Ae Kim, Su Jung Lee, Seok-Jun Yoon; Received January 24, 2024 Accepted December 2, 2024 Published online December 3, 2024; DOI: https://doi.org/10.4143/crt.2024.090 [Accepted]

Abstract PDF: Purpose
Although South Korea’s health insurance has a co-payment-decreasing policy for cancer survivors, information on the extent of financial toxicity and its related factors is limited. We assessed the level of financial toxicity and the association of high levels of financial toxicity with employment concerns after diagnosis and cancer-related distress in working-age cancer survivors.
Materials and Methods
A cross-sectional study was conducted. Study participants were recruited from the National Cancer Survivorship Center between November and December 2022. Financial burden was assessed using the Korean version of the Comprehensive Score for Financial Toxicity, and cancer-related distress was measured using the NCCN Distress Thermometer. Multivariate logistic regression analyses were used to explore the associations between high financial toxicity, cancer-related distress, and changes in employment status after cancer diagnosis.
Results
Of 1,403 working-age cancer survivors, approximately 62% reported high levels of financial distress. Survivors reporting early retirement and taking time off work with the intent to return were more likely to report high financial toxicity (adjusted OR 1.69, 95% CI 1.14-2.5; and adjusted OR 2.82, 95% CI 1.24-6.43, respectively) than those with a full-time or part-time job. Moreover, cancer survivors with high distress levels were more likely to report high financial toxicity than those with low distress levels (adjusted OR 4.36, 95% CI 3.17-5.99).
Conclusion
High financial toxicity is associated with adverse employment concerns and cancer-related distress among working-age cancer survivors. Therefore, developing cancer survivorship interventions within the healthcare system is necessary to ensure improvements in financial well-being.

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Evaluating the Effects of Mindfulness-Based Self-Help via an OTT Platform on Breast Cancer Patients Undergoing Radiotherapy: A Prospective Non-Randomized Controlled Trial: Hyejo Ryu, Si Nae You, Sohee Oh, Bora Kim, Jeong-Hyun Kim, In Ah Kim; Received October 1, 2024 Accepted November 20, 2024 Published online November 25, 2024; DOI: https://doi.org/10.4143/crt.2024.955 [Accepted]

Abstract PDF: Purpose
Previous research showed the benefits of mindfulness meditation on the mental health and quality of life of breast cancer patients. Traditionally, these programs relied on in-person interactions, but the COVID-19 pandemic necessitated alternative delivery methods. This study evaluated the effectiveness and feasibility of a mindfulness-based self-help (MBSH) program via Netflix for breast cancer patients undergoing radiotherapy.
Materials and Methods
This prospective non-randomized controlled study assigned patients to a control or MBSH group based on age and preference. The MBSH group watched episodes of "Headspace Guide to Meditation" on Netflix and practiced guided meditation at least twice per week for four weeks. Participants completed questionnaires assessing depression, anxiety, stress, insomnia, mindfulness, mental adjustment to cancer, and quality of life at weeks 0 and 8. Data were analyzed using a two-way repeated measures ANOVA.
Results
Ninety-six patients participated, with 84 eligible for final analysis (44 control, 40 MBSH). Intention-to-treat analysis revealed a significant improvement in depression (f=4.306, p=0.041). Half of the experimental group (n = 20) adhered to the study protocol. At week 8, the experimental group showed significant improvement compared to the control group in cognitive avoidance (f=8.530, p=0.005) and positive attitude (f=5.585, p=0.021), both indicative of adaptive coping strategies.
Conclusion
This study firstly investigated the effect and feasibility of a Netflix-based MBSH program for breast cancer patients undergoing radiotherapy. Findings suggest MBSH on Netflix can improve mental health and adaptive mental adjustment, highlighting the potential of self-help mindfulness interventions to enhance the well-being of cancer patients and need for further research.

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Estimation of Population Attributable Fraction by Hormone and Reproductive Factors on Female Cancer in the Republic of Korea, 2015 to 2030: Youjin Hong, Soseul Sung, Woojin Lim, Sungji Moon, Kwang-Pil Ko, Jung Eun Lee, Inah Kim, Sun Ha Jee, Sun-Seog Kweon, Min-Ho Shin, Sangmin Park, Seung-Ho Ryu, Sun Young Yang, Jeongseon Kim, Sang-Wook Yi, Yoon-Jung Choi, Jeong-Soo Im, Hong Gwan Seo, Sue K. Park; Received July 26, 2024 Accepted November 18, 2024 Published online November 19, 2024; DOI: https://doi.org/10.4143/crt.2024.707 [Accepted]

Abstract PDF: Purpose
Population attributable fractions (PAFs) for hormone and reproductive factors have been estimated in several countries. IARC designated as Group 1 and Group 2A carcinogen for hormone factors in breast, ovarian, endometrial and uterine cervix cancer. This study aimed to estimate the PAFs of hormone/reproductive factor attributed to cancer incidence and deaths in Korean women and projected trends from 2015 to 2030.
Materials and Methods
The PAF was estimated with using the 2005 standardized prevalence rates and 2020 incidence and deaths with a 15-year latency. Based on the Levin’s formula, prevalence rates were calculated using the Korea National Health and Nutrition Examination Survey (KNHANES) and the relative risks (RRs), which were the risk of selected female cancer associated with oral contraceptive, hormone replacement therapy and duration of breastfeeding, were estimated from the meta-analysis of studies performed in Korean women population. Studies based on the Asian and Global populations were calculated as a sensitivity analysis.
Results
The estimation PAFs for hormone was 1.02% with 1,192 cases and reproductive was 2.67% with 3,112 cases. Moreover, 0.40% (125 deaths) and 1.09% (342 deaths) in female-related cancer deaths in order. EP combined HRT accounted the most proportion in hormone factors and breastfeeding in reproductive factors. Also, the breast cancer had the highest percent in both hormone and reproductive factors.
Conclusion
Through this study, 1.02% and 2.67% of female-related cancer incidence will be reduced by encouraging avoiding the use of oral contraceptives (OCs) and hormone replacement therapy (HRT) and breastfeeding for more than 6 months in reproductive factors. Additionally, among four selected female cancers in this study, breast cancer was observed to be a significant level of prevention.

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Association of Pro-inflammatory Cytokines with Gastric Cancer Risk: A Case-Cohort Study: Seungju Baek, Eunjung Park, Eun Young Park; Received July 29, 2024 Accepted November 18, 2024 Published online November 19, 2024; DOI: https://doi.org/10.4143/crt.2024.718 [Accepted]

Abstract PDF: Purpose
This study aimed to assess the association between inflammatory cytokines and the risk of gastric cancer (GC).
Materials and Methods
We conducted a case-cohort study using Korean National Cancer Center Community (KNCCC) cohort data to investigate the associations between pro-inflammatory, anti-inflammatory cytokines, inflammatory mediators, and GC risk in the Korean general population (GC cases: n=159, subcohort: n=822). Serum levels of inflammatory cytokines were measured using Quantikine® ELISA and analyzed using a Cox proportional hazards regression model.
Results
Compared to those with the lowest serum interleukin 6 (IL-6) levels, the risk of GC significantly increased in the second (HR: 3.48 [1.73-6.99]), third (HR: 3.74 [1.91-7.29], and fourth quartiles (HR: 3.79 [1.93-7.48]). Elevated levels of interleukin 1β (IL-1β) (HR: 1.57 [1.12-2.21]) and interferon gamma (IFN-γ) (HR: 2.49 [1.73-3.58]) were also associated with an increased risk of GC.
Conclusion
The findings of this study indicate associations between pro-inflammatory cytokines (IL-6, IL-1β, and IFN-γ) and the risk of GC, suggesting that regulating these cytokine levels may aid in GC prevention.

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Machine Learning-Based Prognostic Gene Signature for Early Triple Negative Breast Cancer: Ju Won Kim, Jonghyun Lee, Sung Hak Lee, Sangjeong Ahn, Kyong Hwa Park; Received September 26, 2024 Accepted November 18, 2024 Published online November 19, 2024; DOI: https://doi.org/10.4143/crt.2024.937 [Accepted]

Abstract PDF: Purpose
This study aimed to develop a machine learning-based approach to identify prognostic gene signatures for early-stage Triple Negative Breast Cancer (TNBC) using next-generation sequencing data from Asian populations.
Materials and Methods
We utilized next-generation sequencing data to analyze gene expression profiles and identify potential biomarkers. Our methodology involved integrating various machine learning techniques, including feature selection and model optimization. We employed logistic regression, Kaplan-Meier survival analysis, and receiver operating characteristic (ROC) curves to validate the identified gene signatures.
Results
We identified a gene signature significantly associated with relapse in TNBC patients. The predictive model demonstrated robustness and accuracy, with an area under the ROC curve (AUROC) of 0.9087, sensitivity of 0.8750, and specificity of 0.9231. The Kaplan-Meier survival analysis revealed a strong association between the gene signature and patient relapse, further validated by logistic regression analysis.
Conclusion
This study presents a novel machine learning-based prognostic tool for TNBC, offering significant implications for early detection and personalized treatment. The identified gene signature provides a promising approach for improving the management of TNBC, contributing to the advancement of precision oncology.

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