Cancer Research and Treatment

Integrative Genomic Analysis Reveals Molecular and Clinical Disparities between Bladder and Upper Tract Urothelial Carcinoma in K-MASTER Program: Jiwon Kim, Jwa Hoon Kim, Kyong Hwa Park, Seok Ho Kang, Jae Lyun Lee, Woo Kyun Bae, Miso Kim, Jong Gwon Choi, Inkeun Park, Ji Hyun Park, Sang Joon Shin, Jungmin Jo, Se Hoon Park, Kwonoh Park, Ji Yoon Lee, Youjin Song, Dayoung Lee, Namsung Moon, Jason K. Sa, Yoon Ji Choi; Received January 22, 2026 Accepted August 3, 2026 Published online August 4, 2026; DOI: https://doi.org/10.4143/crt.2026.0081 [Accepted]

Abstract PDF: Purpose
The clinical outcome of urothelial carcinoma presents significant variability, reflecting its molecular composition, epidemiologic attributes, and primary site of origin. Despite histological similarities, upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BLCA) represent two distinct disease entities with disparate treatment responses and mutational patterns.
Materials and Methods
To assess the impact of molecular heterogeneity on treatment outcomes, we conducted a comprehensive genomic analysis of 231 metastatic urothelial carcinoma patients, including 175 patients with BLCA and 56 patients with UTUC, in the K-MASTER program.
Results
Our investigation unveiled dynamic molecular properties and mutational patterns in key molecules, including TP53, FGFR3, CREBBP, and SPEN. BLCA patients demonstrated enrichment of APOBEC mutational signature activities, whereas UTUC patients were characterized by activation of the cell cycle pathway. Transcriptome analysis uncovered unique biological signatures, highlighting increased cell migration and WNT signaling in BLCA, while FGFR3 and stem-cell-like pathways predominated in UTUC. Moreover, our study highlighted increased resistance to platinum-based chemotherapy and immunotherapy among UTUC patients. Importantly, tumor mutational burden (TMB) emerged as a robust independent predictor of immunotherapy response in BLCA. Additionally, a machine learning-based multivariable model identified FGFR3 mutation as a molecular determinant associated with favorable clinical outcomes, in contrast to FGFR2 mutations, which were linked to increased resistance to chemotherapy. The study also has limitations, including a limited sample size of UTUC patients and a lack of functional validation of the identified molecular mechanism.
Conclusion
Our findings provide unprecedented insights into the significance of molecular and clinical disparities in urothelial carcinoma, facilitating disease-specific treatment interventions.

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Impact of Metabolic Syndrome on Risk of Lung Cancer among Korean Never-Smokers: A Nationwide Population-Based Cohort Study: Sung Woo Moon, Jiyeong Kim, Dong-Woo Han, Dong Won Park; Received January 31, 2026 Accepted July 29, 2026 Published online July 30, 2026; DOI: https://doi.org/10.4143/crt.2026.0116 [Accepted]

Abstract PDF: Purpose
To determine the association between metabolic syndrome (MetS) and lung cancer risk in a large population-based cohort of never-smokers in Korea.
Materials and Methods
Using the Korean National Health Insurance Service database, we identified adults who underwent national health screening in 2009 and consistently reported their never-smoker status at baseline and subsequent examinations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for lung cancer incidence, adjusting for age, sex, body mass index (BMI), physical activity, residential area, income, and alcohol consumption. Analyses were further stratified according to sex and BMI.
Results
Overall, 2,721,804 never-smokers were followed up for a mean of 14.0 years. The incidence of lung cancer was higher among participants with MetS than those without (adjusted HR: 1.04, 95% CI: 1.01–1.07). MetS was significantly associated with lung cancer risk in men (HR: 1.18, 95% CI 1.11–1.25) but not in women (HR: 1.03, 95% CI 0.99–1.07), with the risk evident in normal-weight and pre-obese men but, in women, mainly in those with obesity (HR: 1.10, 95% CI 1.03–1.16).
Conclusion
MetS was associated with a modest increase in the risk of lung cancer among Korean never-smokers, showing a significant association among men but not women. MetS risk was evident even among normal-weight men, whereas among women, it was more pronounced in those with obesity. These findings suggest that metabolic abnormalities, relatively underrecognized as cancer-related risk factors, could contribute to the risk of lung cancer, even in the absence of tobacco exposure.

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Possible Ribociclib-Associated Focal Nodular Hyperplasia–Like Lesion Mimicking Liver Metastasis in a Chemotherapy-Naïve Patient: First Case Report: Ece Ulukal Karancı, Armağan Günal, Ahmet Şükrü Alparslan, Banu Öztürk; Received February 22, 2026 Accepted July 11, 2026 Published online July 15, 2026; DOI: https://doi.org/10.4143/crt.2026.0178 [Accepted]

Abstract PDF: Hepatic focal nodular hyperplasia (FNH)–like lesions mimicking metastasis have been reported as rare complications of cytotoxic chemotherapy, but they have not previously been described in association with CDK4/6 inhibitors alone. We present the case of a 32-year-old chemotherapy-naïve woman with de novo hormone receptor (HR)–positive/HER2-negative metastatic breast cancer who was treated with first-line ribociclib and letrozole. After four cycles, imaging revealed a complete response of her bone metastases alongside a newly developed 5.5-cm hepatic lesion suspicious for visceral progression. Liver function tests remained normal. Two ultrasound-guided percutaneous core biopsies, performed three months apart and directly targeting the lesion, confirmed a benign FNH-like lesion without evidence of malignancy. Ribociclib was continued without modification; at last follow-up the patient remained in sustained complete oncologic response, with the hepatic lesion stable in size and no biochemical or clinical evidence of hepatic dysfunction. To our knowledge, this appears to be the first reported case of an FNH-like hepatic lesion temporally associated with ribociclib in a patient who had not received prior cytotoxic chemotherapy. The principal clinical message is that newly detected hepatic lesions arising during otherwise effective targeted therapy do not necessarily reflect disease progression, and that, in radiologically discordant cases, histopathologic confirmation may be required to avoid premature discontinuation or switching of effective treatment.

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Tumor-Intrinsic Hepatocyte Arm-Level Genomic States Shape Immunotherapy Response Heterogeneity in Hepatocellular Carcinoma: Kyuhyung Choi, Hojun Sung, Sunmin Kim, Tae-Min Kim; Received March 10, 2026 Accepted June 15, 2026 Published online June 17, 2026; DOI: https://doi.org/10.4143/crt.2026.0245 [Accepted]

Abstract PDF: Purpose
Bulk transcriptomic biomarkers for immune checkpoint inhibitor (ICI) response in hepatocellular carcinoma (HCC) often lack reproducibility because bulk RNA sequencing captures composite signals from malignant, immune, and stromal compartments. Variability in tumor purity and malignant cell composition can confound immune-based interpretations. We developed an integrative framework combining single-cell–derived digital cytometry with inference of tumor-intrinsic genomic states to better interpret transcriptomic variation associated with ICI response.
Materials and Methods
Single-cell RNA sequencing data from HCC tumors (GSE206325) were used to construct a nine–cell-type signature matrix for CIBERSORTx deconvolution and to infer chromosome arm-level copy number variation in malignant hepatocytes using inferCNV. Signature stability was evaluated through pseudobulk reconstruction and gradient simulations. Digital cytometry was applied to three bulk RNA-seq ICI cohorts (GSE202069, GSE215011, and GSE279750). Arm-level alterations were projected onto bulk transcriptomes by mapping arm-associated genes, standardizing expression within samples, and aggregating direction-adjusted Q90 statistics into a composite arm-axis score.
Results
Digital cytometry revealed cohort-dependent variability in malignant hepatocyte dominance and limited reproducibility of immune fraction differences. Differential expression analysis also showed poor cross-cohort concordance. InferCNV identified recurrent arm-level alterations (1q/8q gain, 12p/13q loss), defining a continuous genomic axis. In pooled analysis (n=36), integrating the arm-axis score with PD-L1 improved discrimination (AUC 0.775; 95% CI, 0.602–0.920). In TCGA-LIHC (n=361), arm-level burden was inversely associated with cytolytic activity and positively associated with proliferation.
Conclusion
Tumor-intrinsic hepatocyte genomic states provide complementary predictive information beyond immune activation alone and may help explain heterogeneity in ICI response across HCC cohorts.

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Randomized Phase II Study of Bortezomib, Lenalidomide, and Dexamethasone (VRD) Versus Lenalidomide and Dexamethasone (RD) in Elderly Patients with Newly Diagnosed Multiple Myeloma (KMM1910): Jun Ho Yi, Sang Eun Yoon, Ji Hyun Lee, Soo Mee Bang, Myung-won Lee, Joon Ho Moon, Je-Jung Lee, Hyeon-Seok Eom, Chang-Ki Min, Young Rok Do, Sungnam Lim, Ho-Jin Shin, Jae Hoon Lee, Hyo Jung Kim, Sung-Soo Yoon, Kihyun Kim; Received March 11, 2026 Accepted May 28, 2026 Published online May 29, 2026; DOI: https://doi.org/10.4143/crt.2026.0255 [Accepted]

Abstract PDF: Purpose
While triplet regimens are considered optimal for treatment of multiple myeloma (MM), the benefit of adding bortezomib to lenalidomide and dexamethasone remains prospective-wise unclear in elderly patients due to frailty and potential toxicities.
Materials and Methods
This multicenter, randomized phase II study evaluated the efficacy and safety of bortezomib/lenalidomide/dexamethasone (VRd) versus Rd (lenalidomide/ dexamethasone) in transplant-ineligible patients aged ≥ 70 years.
Results
Forty-nine patients were randomized to receive either VRd or Rd. The overall response rates were comparable between two arms (72.7% for Rd and 84.6% for VRd, p=0.312). Although VRd achieved a significantly higher minimal residual disease negativity rate compared to Rd (76.9% vs. 12.5%, p=0.004), this deeper response did not translate into a statistically significant improvement in the primary endpoint, the 3-year progression-free survival rate, which was 53.8% for VRd and 45.5% for Rd (p=0.520). Similarly, no significant difference was observed in overall survival OS between the two arms. Safety analysis revealed that grade 3–4 adverse events were comparable, occurring in 73.1% of the VRd arm and 77.3% of the Rd arm. Notably, infections were a major cause of treatment discontinuation and mortality, accounting for seven deaths overall.
Conclusion
While VRd induced numerically deeper responses, its clinical benefit in a real-world-representative elderly population may be limited by treatment tolerability and infection risks.

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Distinct Evolutionary Dynamics of HER2-Ultralow Versus HER2-Null from Residual to Metastatic Disease in Non-pCR Breast Cancer: Shunan Wang, Jingjing Liu, Tong Liu, Shichao Zhang, Xinyu Liu, Yu Liu, Jin Zhang; Received March 22, 2026 Accepted May 11, 2026 Published online May 12, 2026; DOI: https://doi.org/10.4143/crt.2026.0302 [Accepted]

Abstract PDF: Purpose
In breast cancer (BC) patients without pathological complete response (pCR) after neoadjuvant therapy, residual disease drives recurrence. The HER2 spectrum now includes HER2-low and HER2-ultralow. HER2-low tumors are eligible for HER2-targeted antibody-drug conjugates (ADCs), while T-DXd is approved for HR-positive HER2-ultralow metastatic BC after endocrine therapy. Evolution patterns of HER2-ultralow versus HER2-null from residual to metastatic disease remain unclear.
Materials and Methods
We retrospectively studied 488 non-pCR patients with refined HER2 classification; 92 with HER2-0 residual disease formed the analytic cohort for HER2-ultralow/HER2-null comparison. HER2 status was tested in paired residual and metastatic lesions. Logistic regression was used to identify factors linked to HER2 evolution.
Results
In the 92‑patient HER2‑0 analytic cohort, HER2-ultralow (46.7% of HER2-0) converted more frequently to HER2-low than HER2-null (51.2% vs 30.6%, p=0.045). This difference remained statistically significant in the multivariable logistic regression model. In the full 517-patient contextual cohort, HER2 expression gain in recurrent/metastatic lesions was independently associated with poorer post-recurrence survival (PRS) (adjusted HR=1.74, p=0.009). In the 488-patient primary cohort, conversion from HER2-0 to HER2-low was also associated with poorer PRS (adjusted HR=2.18, p<0.001). The broader HER2 expression evolution in the full 517‑patient cohort and the primary 488‑patient refined HER2 cohort was consistent with the core finding from the 92‑patient HER2‑0 analytic cohort and supported its biological plausibility.
Conclusion
HER2-ultralow shows distinct evolution and high HER2-low conversion potential, affecting ADC eligibility. Routine HER2-0 subclassification and metastatic HER2 reassessment appear clinically useful and warrant prospective validation.

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Synergistic Antitumor Activity of Combination Therapy with a MET TKI Vabametkib and a Third-Generation EGFR TKI Lazertinib in MET-Amplified EGFR-Mutant NSCLC: Dong Kwon Kim, Jin Woo Park, Hyeon Bin Cho, Su Jin Choi, Sung Sook Lee, YeongMun Kim, Jii Bum Lee, Sun Min Lim, Mi Ra Yu, Byoung Chul Cho; Received December 23, 2025 Accepted March 18, 2026 Published online March 31, 2026; DOI: https://doi.org/10.4143/crt.2025.1399 [Accepted]

Abstract PDF

Purpose
Third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKIs) improved outcomes in EGFR-mutant non-small cell lung cancer (NSCLC); however, the subsequent development of resistance emphasizes the necessity of overcoming this therapeutic limitation. MET amplification is one of the major resistance mechanism in EGFR-mutant NSCLC, bypassing EGFR inhibition by activating cell survival, proliferation, and metastasis. Combining MET- and EGFR-TKIs is thus emerging as a promising therapeutic strategy to overcome resistance to EGFR TKIs.
Materials and Methods
This study aimed to investigate the combination of the selective MET TKI vabametkib and a third-generation EGFR TKI lazertinib in MET-amplified EGFR TKI resistance models. Inhibition of downstream signaling and cell proliferation by vabametkib plus lazertinib were evaluated in osimertinib-resistance NSCLC cell lines (HCC827-AR) and patient-derived organoid (YUO-010) by western blot and Cell Titer-Glo assay.
Results
In vitro studies demonstrated that vabametkib plus lazertinib synergistically inhibited EGFR/MET phosphorylation, leading to markedly enhanced anti-proliferative effects through downstream PI3K/AKT and MAPK pathway blockade. To investigate the antitumor effects in in vivo, we employed two patient-derived xenograft (PDX) models (YHIM-1035(1) and YHIM-1053) harboring MET amplification, as characterized by whole-exome sequencing or droplet digital PCR (ddPCR). Consistent with the in vitro findings, treatment with vabametkib plus lazertinib produced pronounced suppression of tumor growth in both models through a synergistic mechanism.
Conclusion
These findings establish vabametkib plus lazertinib as a promising strategy for MET-amplified NSCLC, currently under evaluation in an ongoing phase II clinical trial (NCT05541822).

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Organoid models in lung cancer research: A multidimensional perspective from basic biology to precision medicine
Ruili Zhao, Huifang Cheng, Shiyu Mei, Haoran Li, Longhua Zhang, Ya Li
Letters in Drug Design & Discovery.2026; 23(3): 100424. CrossRef

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Phase II Efficacy and Safety of Pembrolizumab with Platinum Based Chemotherapy in Non-Small Cell Lung Cancer Patients with Untreated, Asymptomatic Brain Metastasis (PHOEBS): Junkyu Kim, Miran Han, Jinyong Kim, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Sun Hye Shin, Kyungjong Lee, Sang-Won Um, Myung-Ju Ahn; Received October 10, 2025 Accepted March 18, 2026 Published online March 19, 2026; DOI: https://doi.org/10.4143/crt.2025.1100 [Accepted]

Abstract PDF: Purpose
Brain metastases are a serious complication in non-small cell lung cancer (NSCLC). However, data regarding efficacy of immune checkpoint inhibitors and chemotherapy combinations are limited. This phase II study aimed to evaluate the intracranial efficacy and safety of pembrolizumab and chemotherapy in treatment-naïve NSCLC patients with asymptomatic brain metastases.
Materials and Methods
This single-arm, phase II trial was conducted at Samsung Medical Center, Korea. Eligible patients had stage IV NSCLC with asymptomatic, untreated brain metastases and no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations. Patients received pembrolizumab with chemotherapy every 3 weeks for 4 cycles, followed by pembrolizumab with or without maintenance chemotherapy up to 35 cycles. The primary endpoint was intracranial objective response rate (icORR). Secondary endpoints included intracranial progression free survival (icPFS), intracranial duration of response (icDoR), objective response rate (ORR), progression free survival (PFS), overall survival, and safety.
Results
Between February 2021 and June 2024, a total of 13 patients were enrolled. Due to challenges in recruiting patients, enrollment was discontinued after the 13 patients. The icORR was 46.2% (95% CI, 19.2–74.8), with 6 patients achieving partial response. The median icPFS was 9.8 months (95% CI, 5.2–21.5), and median icDoR was 9.3 months (95% CI, 4.0–20.3). Median PFS and overall survival was 7.2 months (95% CI, 2.4–12.3) and 10.7 months (95% CI, 7.2–21.5), respectively. Most treatment-related adverse events were grade 1–2.”
Conclusion
Pembrolizumab combined with chemotherapy demonstrated encouraging intracranial activity and manageable safety profile in NSCLC patients with untreated, asymptomatic brain metastases.

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Non-response to Durvalumab and Supraclavicular Nodal Involvement Predict Early Brain Metastasis after Concurrent Chemoradiotherapy Followed by Durvalumab Consolidation in Stage III Non–Small Cell Lung Cancer: Yoo Kyung Choi, Yeon-Sil Kim, Yoo-Kang Kwak, Yun Hee Lee, Sung-Hwan Kim, Soo-Yoon Sung, Seok Hyun Son, Kyu Hye Choi; Received November 11, 2025 Accepted February 19, 2026 Published online February 20, 2026; DOI: https://doi.org/10.4143/crt.2025.1244 [Epub ahead of print]

Abstract PDF: Purpose
This study aimed to identify predictors of brain metastasis in patients with unresectable stage III non–small cell lung cancer (NSCLC) treated with definitive concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation.
Materials and Methods
We retrospectively analyzed 138 patients with unresectable stage III NSCLC treated with definitive CCRT followed by durvalumab from 2018 to 2024. The primary endpoint was brain metastasis incidence. Univariate and multivariate logistic regression analyses identified factors associated with brain metastasis development.
Results
With a median follow-up of 18.7 months (range, 1.2 to 73.3 months), brain metastasis occurred in 18 of 138 patients (13.0%). In multivariate analysis, non-responders to durvalumab (odds ratio [OR], 4.86; 95% confidence interval [CI], 1.69 to 13.96; p=0.003) and initial supraclavicular nodal (SCN) involvement (OR, 2.89; 95% CI, 0.99 to 8.48; p=0.05) were independent predictors of brain metastasis. Non-responders demonstrated accelerated central nervous system (CNS) progression, with 63.6% developing brain metastases within 6 months versus 28.6% in responders. Programmed cell death ligand 1 ≥ 50% was associated with improved overall survival but not with brain metastasis incidence. All patients who developed brain metastases were epidermal growth factor receptor/anaplastic lymphoma kinase wild-type.
Conclusion
Non-responders to durvalumab and SCN involvement were significant predictors of brain metastasis in NSCLC treated with CCRT followed by durvalumab. These findings support risk-adapted CNS surveillance strategies in high-risk patients.

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Assessing Radiation Pneumonitis through Functional Lung Imaging: A Single Photon Emission Computed Tomography–Based Approach in Lung Cancer: Joo-Hyun Chung, Soo Jin Lee, Ji Young Kim, Hae Jin Park; Received November 13, 2025 Accepted February 18, 2026 Published online February 19, 2026; DOI: https://doi.org/10.4143/crt.2025.1248 [Epub ahead of print]

Abstract PDF Supplementary Material: Purpose
This study aimed to develop models to assess the risk of symptomatic radiation pneumonitis (SRP) (Common Terminology Criteria for Adverse Events ver. 4.03 grade ≥ 2) in lung cancer patients by utilizing single-photon emission computed tomography (SPECT) for functional lung volume identification and dosimetric analysis.
Materials and Methods
This retrospective study included 71 lung cancer patients who underwent SPECT before radiotherapy from 2018 to 2024. Perfusion and ventilation SPECT images were co-registered with planning computed tomography to define functional and anatomical lung volumes. Functional lung was defined as voxels with ≥ 20% of the maximum intensity on SPECT. Models to assess the risk of SRP were constructed using Cox regression and evaluated using corrected Akaike information criterion (AICc) and time-dependent receiver operating characteristic analysis.
Results
At a median follow-up of 16.8 months, 19 of 71 patients (26.8%) developed SRP. Factors significantly associated with SRP risk included planning target volume ≥ 150 mL, percentage of total perfusion-defined functional lung receiving ≥ 10 Gy (pVf10) exceeding that of total anatomical lung receiving ≥ 10 Gy (V10), percentage of total ventilation-defined lung receiving ≥ 10 Gy (vVf10) ≥ 45%, and ipsilateral vVf10 ≥ 60% (p=0.004, p=0.004, p=0.024, and p=0.007, respectively). Among the three models, the model incorporating additional ventilation-based parameters demonstrated the best performance (AICc, 85.81; area under the curve, 0.819).
Conclusion
SPECT-based dosimetric parameters derived from perfusion and ventilation are significantly associated with the risk of SRP. Incorporating SPECT may improve risk stratification and enable lung-sparing strategies.

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Platinum and 5-Fluorouracil Salvage Therapy for Severe Liver Crisis in Metastatic Breast Cancer: Efficacy and Analysis of Prognostic Factors: I-Wei Ho, Jiun-I Lai, Chun-Yu Liu, Wei-Chi Lin, Muh-Hwa Yang, Ling-Ming Tseng, Ta-Chung Chao; Received November 18, 2025 Accepted December 28, 2025 Published online December 29, 2025; DOI: https://doi.org/10.4143/crt.2025.1262 [Epub ahead of print]

Abstract PDF PubReader ePub: Purpose
Metastatic breast cancer (MBC) with severe hepatic dysfunction due to liver crisis presents a significant treatment challenge, as conventional chemotherapy often requires dose modifications, leading to reduced efficacy. The combination of platinum, 5-fluorouracil, and folinate (PFL) offers a rational treatment strategy. This study evaluates the efficacy and safety of PFL in MBC patients with liver crisis and explores predictive markers for treatment response.
Materials and Methods
This retrospective cohort study, conducted at Taipei Veterans General Hospital, Taiwan, included 44 MBC patients with bilirubin ≥ 3 mg/dL treated between January 2015 and June 2024. Outcomes included bilirubin response rate (≥ 50% reduction from baseline), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events. The area under the curve analysis was used to determine the optimal cutoff for liver function assessment models, and Cox regression identified independent prognostic factors.
Results
Among the 44 patients, 47.7% achieved a bilirubin response within a median of 19 days. Overall, the median PFS and OS were 1.4 and 1.9 months, respectively, but improved to 4.6 and 7.8 months in those achieving bilirubin response. The objective response rate was 22.7%, and the disease control rate was 29.5%. A fibrosis-4 (FIB-4) score < 9.1 predicted a 65% bilirubin response rate, while FIB-4 > 9.1 was also an independent predictor of OS. Grade 3 adverse events occurred in 36.4% of patients.
Conclusion
The PFL regimen is effective in MBC patients with severe liver crisis with hyperbilirubinemia. A FIB-4 score < 9.1 may serve as a potential prognostic factor for bilirubin response and is associated with improved survival outcomes.

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Immunosuppressive Tumor Microenvironment in Colorectal Cancer Lung Metastases: Implications for Recurrence after Metastasectomy: Minsuk Kwon, Min-Kyue Shin, Minae An, Yeong Jeong Jeon, Tae Hee Hong, Jung Kyong Shin, Sung Hee Lim, Yoonah Park, Yong Beom Cho, Seung Tae Kim, Yong Soo Choi, Jeeyun Lee; Received July 3, 2025 Accepted December 8, 2025 Published online December 17, 2025; DOI: https://doi.org/10.4143/crt.2025.691 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub

Purpose
Colorectal cancer (CRC) lung metastases exhibit high recurrence rates after resection, underscoring the need for improved therapeutic strategies. This study aimed to characterize the tumor microenvironment (TME) of CRC lung metastases and identify the factors associated with recurrence.
Materials and Methods
Fifteen CRC patients who underwent lung metastasectomy were enrolled. Multiplex immunohistochemistry (IHC), whole exome sequencing, transcriptome profiling, and single-cell RNA sequencing (scRNA-seq) were conducted on matched tumor, adjacent and distant normal lung tissues. Immune cell populations and gene expression profiles were analyzed and correlated with clinical recurrence outcomes.
Results
Exome and transcriptome analyses revealed frequent TP53, KRAS, and APC mutations. Most tumors corresponded to consensus molecular subtypes 2 and 4, characterized by immune-depleted and fibrotic features. Tumors showed downregulation of effector T and NK cell signatures. IHC revealed reduced density and increased distance of CD8+ T cells and macrophages from the epithelial cells. scRNA-seq demonstrated increased regulatory T cells and decreased NK and effector T cells in tumor. Tumor-associated macrophages (TAMs), particularly SPP1 (osteopontin)-expressing subsets, were markedly enriched in tumor and correlated with suppressed effector T-cell activity. High SPP1 expression was associated with early recurrence and poor overall survival. Patients with recurrence had higher proportion of PD-1+ CD8+ T cells in adjacent normal tissues.
Conclusion
Immunosuppressive features including enrichment of SPP1+ TAMs and depletion of effector T and NK cells contribute to recurrence after CRC lung metastasectomy. Therapeutic strategies targeting both TAMs and T cells may enhance clinical outcomes in this patient population.

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Obesity promotes aggressiveness of endometrial cancer via metabolic reprogramming and intercellular crosstalk in the tumor microenvironment
Yu Chen, Yijin Fang, Guozhi Zhao, Yuanqun Zhou, Dong-Hua Yang, Jian Han, Ying Zheng
Cancer Letters.2026; 656: 218649. CrossRef

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Clinical Outcomes and Histologic Subtype-Specific Patterns in Oligometastatic Soft Tissue Sarcoma of the Extremities and Trunk Wall: Implications for Curative Local Ablative Therapy: Eunkyu Yang, Han-Soo Kim, Jay Hoon Park, Yongsung Kim, Shinn Kim, Miso Kim, Jeonghwan Youk, Hak Jae Kim, Hyun-Cheol Kang, Ilkyu Han; Received September 9, 2025 Accepted October 29, 2025 Published online October 30, 2025; DOI: https://doi.org/10.4143/crt.2025.983 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Oligometastatic soft tissue sarcoma (STS) may offer the possibility of cure compared with polymetastatic disease, with progression patterns and treatment responses varying across histologic subtypes. This study investigated the clinical characteristics, oncologic outcomes, and histologic subtype-specific features of oligometastatic STS.
Materials and Methods
We reviewed records of 1,243 patients with extremity/trunk STS who underwent curative surgery between 2000 and 2023. Oligometastatic recurrence occurred in 170 (13.6%), 149 of whom received local ablative therapy (LAT). Disease-specific survival (DSS) and progression-free survival (PFS) were analyzed, along with prognostic factors and subtype-specific characteristics.
Results
The median follow-up was 52.5 months. Surgery alone was the most common LAT (71.2%), followed by surgery with radiotherapy, radiotherapy alone, and radiofrequency ablation. The median DSS was 50.0 months (95% confidence interval [CI], 31.5 to 68.5), with a 5-year DSS rate of 45.2%. The median PFS was 12.0 months (95% CI, 7.6 to 16.4), with a 5-year PFS of 28.1%. On multivariate analysis, LAT was independently associated with longer DSS (hazard ratio, 9.629; p < 0.001). Smaller oligometastatic lesion size and adequate local control of the primary tumor were also independently associated with longer DSS. Metastasis-free interval > 6 months independently predicted longer PFS. Histologic subtypes demonstrated distinct clinical behaviors; for example, myxofibrosarcoma had a lower metastatic rate but poorer DSS, whereas synovial sarcoma showed relatively favorable long-term survival.
Conclusion
Oligometastatic STS represents an intermediate disease state in which LAT can provide meaningful survival benefit. Subtype-specific differences in metastatic behavior and survival outcomes would support individualized, multimodal, and potentially curative treatment strategies.

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Disease Burden and Treatment Pattern of Advanced or Recurrent Endometrial Cancer in Korea: A Nationwide Database (DIRECTION) Study: Hyun-Woong Cho, Se Ik Kim, Min-Ji Bae, Kyoung-Eun Kwon, Choung Won Jung, Young Eun Lee, Ji Yoon Ahn, Kidong Kim; Received January 15, 2025 Accepted October 16, 2025 Published online October 20, 2025; DOI: https://doi.org/10.4143/crt.2025.065 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Advanced/recurrent endometrial cancer (EC) patients have a poor prognosis, with higher recurrence and mortality than early-stage. However, as the real-world disease burden in these patients remains unclear, we aimed to investigate systemic anticancer therapy (SACT) patterns, healthcare resource utilization (HCRU), and costs in advanced/recurrent EC patients.
Materials and Methods
This nationwide population-based study used Korean claims data from 2008 to 2022. Adult patients with advanced/recurrent EC who received first-line SACT were included. For advanced EC, first-line SACT was defined as the initial therapy following EC diagnosis, while for recurrent EC it was defined as the initial therapy after recurrence following completion of primary therapy. We analyzed SACT patterns, prognosis, all cause- and EC-related HCRU, and costs.
Results
A total of 2,704 EC patients were included. The most commonly used SACT was platinum-based regimen. From the first to third line, median values of SACT-free interval (18.40, 5.03, and 3.22 months) and time to next treatment (TTNT, 25.43, 9.27 and 6.44 months) showed decreasing trends. All-cause/EC-related HCRU and costs were increased with SACT progression; all-cause inpatient visits and total costs increased from 0.58 to 1.04 times per-patient-per-month (PPPM) and from $1,197.96 to $2,354.37 USD PPPM.
Conclusion
This study demonstrated significant variability in SACT regimen sequence, highlighting the lack of consensus on standard treatment after disease relapse. Shorter TTNT and SACT-free intervals and higher HCRU and costs in later lines indicate worsening prognosis and increasing disease burden. These findings suggest the urgent need for more effective treatments, including new therapeutic agents, to address the unmet clinical needs of advanced/recurrent EC patients.

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Trajectory of Lymph Node Metastasis Reflects the Molecular Features of Esophageal Squamous Cell Carcinoma: Jiho Park, Seong Yong Park, Ha Eun Kim, Se-Young Jo, Jeongsoo Won, Dae Joon Kim, Sangwoo Kim; Received March 5, 2025 Accepted October 14, 2025 Published online October 15, 2025; DOI: https://doi.org/10.4143/crt.2025.257 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Esophageal squamous cell carcinoma (ESCC) is frequently accompanied by lymph node metastasis (LNM) to the neck, chest, and abdomen. Despite its significance as a key prognostic factor, the genomic trajectory of LNM remains poorly understood. This study aimed to characterize the underlying patterns and genomic characteristics of LNM.
Materials and Methods
Whole-exome sequencing and transcriptome sequencing were performed on 45 multiregional samples (10 primary tumors, 10 normal esophageal tissues, and 25 lymph node tumors) from 10 ESCC patients who underwent esophagectomy with three-field lymphadenectomy. The temporal trajectory of metastasis was reconstructed through phylogenetic analysis, leveraging somatic mutations identified in the primary tumor and lymph nodes.
Results
Somatic mutations preceding metastasis included major driver mutations, such as TP53 and KMT2D, and displayed a mutational process associated with alcohol consumption (SBS16), emphasizing its influence on early tumorigenesis. In contrast, post–lymph node metastatic mutations were sporadic. Lymph nodes seeded later acquired mutations at a faster rate, suggesting increased genomic instability. In three of nine patients (33.3%), nodal skip metastasis (NSM) was observed, including two cases detected exclusively via genomic analysis, highlighting the necessity of phylogenetic assessment to avoid misclassification. Transcriptome analysis revealed activation of epithelial-mesenchymal transition and KRAS signaling pathways in NSM tumors, indicative of poor prognostic outcomes.
Conclusion
Our study provides a molecular understanding of LNM, emphasizes the potential importance of node-skipping patterns in ESCC, and underscores the utility of genomic analysis in elucidating the connection between LNM.

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Prognostic Impact of Organ-Specific Metastasis in Non–Small-Cell Lung Cancer: Woo Kyung Ryu, Munkhtsatsral Ganbaatar, Nuri Park, Hyun Young Lee, Hwan-Cheol Kim, Jeong-Seon Ryu, Jun Hyeok Lim; Received March 3, 2025 Accepted October 2, 2025 Published online October 10, 2025; DOI: https://doi.org/10.4143/crt.2025.238 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub

Purpose
Prognostic stratification is essential in non–small-cell lung cancer (NSCLC) to guide treatment decisions. While the TNM staging system has evolved to refine the M category based on metastatic burden, it does not account for differences in prognosis based on the specific organ affected. This study evaluates whether incorporating organ-specific metastasis improves prognostic discrimination in stage IV NSCLC.
Materials and Methods
We conducted a retrospective cohort study using data from the Korean Central Cancer Registry (2014-2018). Patients with stage IV NSCLC were classified according to the 9th edition TNM classification: M1b (single-organ, single metastasis), M1c1 (multiple metastases within a single organ), and M1c2 (multiple organ metastases). Survival outcomes were compared across groups using Kaplan-Meier analysis and Cox proportional hazards modeling.
Results
Among 3,165 patients, 56.5% had single-organ metastases, while 43.5% had multiple organ metastases. Median overall survival (OS) was longest in M1b (8.0 months), followed by M1c1 (6.0 months), and shortest in M1c2 (5.9 months) (p < 0.001). However, survival varied by metastatic organ. Liver, adrenal, and uncommon-site metastases were associated with significantly worse OS, even among M1b patients. Some M1b and M1c1 patients with high-risk organ metastases had worse survival than M1c2 patients, challenging the TNM-defined prognostic hierarchy.
Conclusion
The current TNM M category does not fully capture the prognostic impact of metastatic organ involvement. Incorporating organ-specific metastases into staging and prognostic models could refine risk stratification and improve personalized treatment approaches for stage IV NSCLC.

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Metastatic organ distribution characteristics and prognosis in patients with non-small cell lung cancer
Jianlei Zhu, Wenyan Pan, Yanyang Wang
Frontiers in Medicine.2026;[Epub] CrossRef

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98 Download
1 Crossref

Genomic Profiling Identified a Mutational Signature Related to Female in Nonsmoking Lung Adenocarcinoma: Jinman Zhuang, Yongsheng Yang, Xuezhen Chen, Guanying Zheng, Xiaopei Shen, Fei He, Baosong Xie; Received May 7, 2025 Accepted September 10, 2025 Published online September 11, 2025; DOI: https://doi.org/10.4143/crt.2025.489 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
This study aimed to illustrate mutational characteristics in nonsmoking lung adenocarcinoma (LUAD) and to explore its relationship with clinical factors.
Materials and Methods
We included 86 nonsmokers with LUAD and downloaded the clinical information, whole exome sequencing, and RNA sequencing data from cBioPortal and The Cancer Genome Atlas (TCGA) website. NMF algorithm, “SomaticSignatures,” and “DeconstructSigs” were used to reconstruct and infer new mutational signature. The similarity between Catalogue of Somatic Mutations in Cancer (COSMIC) and reconstructed mutational signature was measured by cosine similarity. The enrichment status of signaling pathways was derived by Gene Set Enrichment Analysis. “pRRophetic” package was used to predict the sensitivity of adjuvant drug for cancer treatments.
Results
The most frequent driver genes in nonsmoking LUAD were epidermal growth factor receptor (EGFR) (59% in cBioPortal cohort, 68% in Fujian nonsmoking LUAD cohort). We identified three new mutation signatures of LUAD in nonsmokers and identified S2 as the most enriched signature in these nonsmokers with LUAD. In cBioPortal and Fujian nonsmoking LUAD cohort, the proportion of S2 was higher in females (p < 0.05) and patients with tumor mutational burden (TMB) (p < 0.01). Similar results were observed in nonsmoking TCGA-LUAD cohort (p_female=0.0013, p_TMB < 0.001). OXIDATIVE_PHOSPHORYLATION signaling pathway was most enriched in S2-enriched group (NES=1.63). S2-enriched group had higher mutation rate of EGFR (p=0.003) and more drug sensitivity to metformin (p=0.035).
Conclusion
We identified a new mutational signature (S2) which is most enriched in LUAD in nonsmokers and related to female and low-TMB. S2 mutational signature may help reveal female-related mutagenesis mechanisms and develop strategies for therapeutic of never-smoker lung adenocarcinoma.

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Risk-Stratified Management of Antibody-Drug Conjugates Drug–Related Neutropenia: Integrating Clinical Trial Meta-Summary and Existing Guideline Principles: Zheling Chen, Keju Zhao, Jiahong Jiang, Liu Yang; Received May 16, 2025 Accepted September 9, 2025 Published online September 10, 2025; DOI: https://doi.org/10.4143/crt.2025.533 [Epub ahead of print]

Abstract PDF PubReader ePub: Purpose
Anti-tumor drugs have developed rapidly in recent years. Antibody-drug conjugates (ADCs), as a novel class of targeted biologics, demonstrate significant survival benefits but inevitably cause treatment-related toxicities, with hematologic toxicity—particularly severe neutropenia (grade ≥ 3)—representing the most prevalent and clinically consequential adverse effect. Currently, no standardized ADC-specific neutropenia management guidelines exist, resulting in fragmented prevention strategies where clinical practice relies on extrapolation from chemotherapy protocols and reactive approaches (e.g., post-onset growth factor support). This study aims to address this gap by proposing a structured preventive framework for ADC-induced neutropenia.
Materials and Methods
We conducted a systematic meta-summary of neutropenia data from clinical trials involving ADCs. This evidence was integrated with established principles from chemotherapy-induced neutropenia guidelines and expert consensus. The analysis focused on drug-specific risk profiles, patient-related factors, and evidence-based interventional strategies.
Results
We developed a risk-adapted preventive strategy centered on a “planning for a rainy day” approach. The framework incorporates: risk stratification based on the specific ADC drug and patient factors; primary prophylaxis with long-acting granulocyte colony-stimulating factor for high-risk patients; secondary prevention strategies for subsequent treatment cycles; and dynamic monitoring of absolute neutrophil counts around days 5-7 post-infusion.
Conclusion
Shifting from a reactive to a proactive, personalized prevention paradigm can potentially reduce the incidence of severe neutropenia, subsequent treatment interruptions, and infection-related mortality. This framework provides actionable guidance for standardizing ADC toxicity management and underscores the importance of prioritizing hematologic safety in future ADC development.

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Gastrointestinal cancer

Effectiveness of Radiotherapy for Hepatocellular Carcinoma with Lymph Node Metastasis: A Meta-Analysis: Sooyoung Hwang, Seoon Hur, Won Sup Yoon, Sunmin Park, Chai Hong Rim; Cancer Res Treat. 2026;58(3):884-896. Published online August 12, 2025; DOI: https://doi.org/10.4143/crt.2025.475

Abstract PDF Supplementary Material PubReader ePub: Purpose
Lymph node metastasis (LNM) of hepatocellular carcinoma (HCC) carries a poor prognosis; however, no standard treatment has been established. Radiotherapy (RT) has demonstrated favorable tumor response, with the advantage of being less affected by anatomical hindrances.
Materials and Methods
Databases were searched up to April 2024. The inclusion criteria were ≥ 5 patients with HCC LNM, studies that performed external RT, and reporting survival or response rate (RR). The main effect measures are pooled 1- and 2-year overall survival (OS) rates, RR, and grade ≥ 3 complications.
Results
Twelve studies involving 825 patients were included. The pooled 1-year OS rate and 2-year OS rate were 49.3% (95% confidence interval [CI], 39.2 to 59.4) and 24.5% (95% CI, 17.0 to 34.0), respectively. The median OS ranged from 5.8 to 29.7 months, with a median value of 9.7 months. In one study, 14.7% of patients were prescribed an immunoagent. In other studies, some patients received sorafenib, but no specific systemic therapy was performed for the majority. The pooled RR was 75.1% (95% CI, 66.9 to 81.8). The pooled RR of high dose and low dose groups was 83.8% (95% CI, 76.3 to 89.3) vs. 55.6% (95% CI, 44.4 to 66.3), respectively (p < 0.001). The pooled rate of grade ≥ 3 gastrointestinal toxicity was 3.7% (95% CI, 2.1 to 6.6).
Conclusion
RT is an effective and feasible palliative option for HCC LNM. Further research of combined treatment with novel systemic agents are necessary.

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Hematologic malignancy

BTG1 Mutation Correlates with Inferior Prognosis in Diffuse Large B-Cell Lymphoma: Chun-Yu Shang, Wei Hua, Tong-Yao Xing, Kai-Xin Du, Yi-fan Wu, Yue Li, Hua Yin, Hao-Rui Shen, Li Wang, Jian-Yong Li, Rui Gao, Wei Xu, Jin-Hua Liang; Cancer Res Treat. 2026;58(3):1002-1020. Published online July 30, 2025; DOI: https://doi.org/10.4143/crt.2025.494

Abstract PDF Supplementary Material PubReader ePub: Purpose
B-cell translocation gene 1 (BTG1) is a highly conserved gene and recurrently mutated in the MCD subtype of diffuse large B-cell lymphoma (DLBCL). The specific enrichment of BTG1 mutation (BTG1^mut) raises a potential hypothesis that they may actively contribute to DLBCL. However, the biological characteristics and prognostic signifi cance ofBTG1 in DLBCL remain to be explored. Therefore, the objective of our study was to evaluate the value of BTG1 in DLBCL.
Materials and Methods
The available clinical information and corresponding mutation data of DLBCL were obtained from published articles. Tumor tissue samples of DLBCL patients diagnosed in Jiangsu Province Hospital (JSPH) from 2021 to 2023 were collected for next-generation sequencing, 195 samples were analyzed for gene expression levels using RNA sequencing, among them, 40 samples were analyzed by untargeted metabolomics.
Results
We enrolled 2,379 DLBCL patients from fi ve published studies and 243 DLBCL patients from JSPH cohort. In external cohort, 11.0% (262/2,379) of patients were BTG1^mut, compared with 25.1% (61/243) in the JSPH cohort. BTG1^mut was associated with adverse clinical features and was prone to involve testis. Patients with BTG1^mut exhibit inferior overall survival. Furthermore, pathway enrichment analysis of the untargeted metabolomics showed that several meaningful pathways have been found such as amino acid metabolism and lipid metabolism.
Conclusion
BTG1 mutation was promising prognostic predictor for DLBCL. The mechanism driving different survival outcomes may be attributed to the tumor metabolic reprogramming.

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Breast cancer

Impact of High Lymph Node Burden on Brain Metastases in Patients Who Achieved Pathological Complete Response after Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer: Seung Ah Lee, Ki Jo Kim, Do Youn Woen, Su Min Lee, Kawon Oh, Cho Eun Lee, Woong Ki Park, Ji Won Yoo, Dong Seung Shin, Jai Min Ryu, Se Kyung Lee, Byung Joo Chae, Jonghan Yu, Seok Won Kim, Seok Jin Nam, Ji-Yeon Kim, Yeon Hee Park, Eun Young Ko, Eun Sook Ko, Jeong Eon Lee; Cancer Res Treat. 2026;58(3):780-789. Published online July 8, 2025; DOI: https://doi.org/10.4143/crt.2025.219

Abstract PDF Supplementary Material PubReader ePub: Purpose
This study aims to investigate the clinical characteristics, outcomes, and predictors of brain metastases in human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer patients who achieved pathological complete response (pCR) following neoadjuvant chemotherapy (NAC). This research seeks to inform surveillance strategies and optimize management for high-risk subgroups.
Materials and Methods
A retrospective analysis of 1,757 patients (2008-2022) classified them into pCR (n=914) and non-pCR (n=843) groups post-NAC. Collected data included demographics, clinical features, and metastasis parameters. Survival outcomes and brain metastasis predictors were assessed using Kaplan-Meier curves, Cox models, and logistic regression.
Results
Among pCR patients, brain metastases accounted for 54.2% of distant metastases, significantly affecting overall survival (p < 0.001). Median distant metastasis-free survival was shorter for brain metastases (13.4 months) compared to extracranial metastases (31.1 months) in the pCR group (p=0.005). Positive supraclavicular node (SCN) fine needle aspiration (FNA) and clinical N3 (cN3) category were the strongest predictors of brain metastases (SCN FNA: odds ratio [OR], 12.9; p < 0.001; cN3: OR, 12.1; p < 0.001). Multivariable Cox regression analysis revealed that positive SCN FNA and cN3 category were strong predictors of reduced distant metastasis-free survival (SCN FNA: hazard ratio, 2.5; 95% confidence interval [CI], 1.3 to 3.6; p < 0.001; cN3: hazard ratio, 11.3; 95% CI, 4.9 to 33.0; p < 0.001).
Conclusion
This study highlights the challenges of brain metastases in HER2-positive pCR patients, emphasizing the need for tailored therapeutic strategies and enhanced surveillance. High lymph node burden prior to NAC is a significant factor in risk assessment. Therefore, it may be advisable to recommend post-surgery surveillance for high-risk patients.

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Genitourinary cancer

Efficacy and Safety of Ifosfamide and Mesna in Metastatic Castration-Resistant Prostate Cancer after Taxane-Based Chemotherapy and Novel Hormonal Therapy Failure: Chang Gon Kim, Yeo Gyeong Ko, Jongjin Yoon, Chung Lee, Seung Hoon Beom, Young-Deuk Choi, Woong Kyu Han, Won Sik Ham, Hyunho Han, Jongsoo Lee, Ji Eun Heo, Daeseong Kim, Eun Sil Baek, Sangwoo Kim, Minsun Jung, Sang Joon Shin; Cancer Res Treat. 2026;58(2):603-612. Published online June 9, 2025; DOI: https://doi.org/10.4143/crt.2025.155

Abstract PDF Supplementary Material PubReader ePub: Purpose
Limited treatment options exist for patients with metastatic castration-resistant prostate cancer (mCRPC) after the failure of taxane-based chemotherapy and novel hormonal therapy. Here, we report the safety and efficacy of ifosfamide and mesna in patients with mCRPC after the failure of taxane-based chemotherapy and novel hormonal therapy (NCT06236789).
Materials and Methods
Patients with histologically confirmed prostate cancer who had failed taxane-based chemotherapy and novel hormonal therapy received ifosfamide 2,500 mg/m² and mesna 1,500 mg/m² on days 1–3, repeated every 21 days. Safety, objective response rate, disease control rate, reduction in serum prostate-specific antigen (PSA) concentration by >50% (PSA₅₀) or >90% (PSA₉₀), radiographic progression-free survival (rPFS), and overall survival (OS) were analyzed.
Results
A total of 47 patients with mCRPC were included in the study. The median number of lines of treatment was 5 (range, 3 to 7). All patients were previously administered docetaxel and novel hormonal therapies including abiraterone (51.1%) and/or enzalutamide (61.7%). Thirty-eight patients (80.9%) were administered cabazitaxel. The objective response and disease control rates were 21.3% and 80.9%, respectively. PSA50 and PSA90 were achieved in 31.9% and 10.6%, respectively. During a median follow-up duration of 54.3 months, rPFS and OS were 5.0 and 9.0 months, respectively. All the patients experienced treatment-related adverse events of any grades; however, no new safety signs were detected. Genomic biomarker analysis revealed that alterations in the TP53 pathway were associated with inferior rPFS and OS.
Conclusion
Ifosfamide and mesna showed appreciable efficacy and manageable safety profiles in heavily treated patients with mCRPC.

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Real-World Efficacy of Intravesical Gemcitabine for BCG-Unresponsive Non–muscle-Invasive Bladder Cancer: Hye Won Lee, Eui Hyun Jung, Kyung Hwan Kim, Hong Koo Ha, Jong Jin Oh, Seok Ho Kang, Seung-hwan Jeong, Hyeong Dong Yuk, Ji Eun Heo, Won Sik Ham, Eu Chang Hwang, Seung Il Jung, Wan Song, Bumjin Lim, Bumsik Hong, Byung Chang Jeong, Ho Kyung Seo; Cancer Res Treat. 2026;58(2):591-602. Published online May 12, 2025; DOI: https://doi.org/10.4143/crt.2025.100

Abstract PDF PubReader ePub: Purpose
This study aimed to report the real-world outcomes of intravesical gemcitabine for bacillus Calmette–Guérin (BCG)–unresponsive, high-risk, non–muscle-invasive bladder cancer (HR-NMIBC) in Korean patients who were unable or unwilling to undergo radical cystectomy (RC).
Materials and Methods
This retrospective study included 131 patients (median age, 69 years; 88.5% men) treated with intravesical gemcitabine for BCG-unresponsive HR-NMIBC at nine centers between May 2019 and April 2022. The primary endpoint was 1-year recurrence-free survival (RFS). The secondary endpoints included factors influencing RFS, progression-free survival (PFS), cystectomy- free survival, cancer-specific survival (CSS), overall survival (OS), and safety. Survival analysis was performed using the Kaplan-Meier method, and risk factors for recurrence were assessed using Cox regression models.
Results
Patients were followed up for a median duration of 25 months, with carcinoma in situ (CIS) in 41.9% of the patients. The 1-year and 2-year RFS rates were 68% and 42%, while the 1-year and 2-year PFS rates were 87% and 77%, respectively. No significant factors influencing RFS were identified. Seventeen patients underwent RC during a median follow-up of 16 months, with the condition in three patients progressing to muscle-invasive disease on final pathological analysis. The 2-year CSS and OS rates were 98% and 97%, respectively. Intravesical gemcitabine was well-tolerated, with only seven patients (5.3%) unable to complete the full induction course.
Conclusion
Our research highlights the potential of intravesical gemcitabine as a viable bladder-sparing treatment option for BCG-unresponsive HR-NMIBC, providing real-world evidence on its safety, efficacy, and tolerability.

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Gastrointestinal cancer

RASSF4 Suppresses Gastric Tumor Growth through Activation of Chk2-p53 Signaling Axis: Soon-Ki Park, Min-Ju Kang, Kyung-Phil Ko, Sung-Gil Chi; Cancer Res Treat. 2026;58(2):544-562. Published online April 18, 2025; DOI: https://doi.org/10.4143/crt.2025.135

Abstract PDF Supplementary Material PubReader ePub

Purpose
Ras association domain family 4 (RASSF4) is a putative tumor suppressor that is frequently inactivated in multiple human cancers. However, its candidacy as a suppressor in gastric tumorigenesis remains undefined. To understand the role for RASSF4 in gastric tumorigenesis, we investigated its expression status in cancer cell lines and tissues and regulatory role in tumor growth.
Materials and Methods
RASSF4 expression was analyzed in 13 cancer cell lines and 20 carcinoma tissues using polymerase chain reaction and immunoblot assays. RASSF4 effect on cell proliferation and apoptosis was examined by flow cytometry, colony formation, and [3H]thymidine incorporation assays and its regulation of p53 was determined using cycloheximide chase, promoter reporter, and immunoprecipitation assays. Mouse xenograft assay was performed to verify RASSF4 effect on tumor growth and therapeutic response.
Results
RASSF4 expression is epigenetically inactivated in eight of 13 (61.5%) cancer cell lines and 15 of 20 (75%) primary carcinomas. RASSF4 suppresses cell proliferation by inducing a G2/M cell cycle arrest and enhances apoptotic response to therapeutic drugs. RASSF4 is induced in response to genotoxic agents to facilitate stress-induced apoptosis in a highly p53-dependent fashion. Mechanistically, RASSF4 stabilizes p53 through Chk2 activation and its apoptotic function is profoundly impaired by depletion of either p53 or Chk2. RASSF4 attenuates xenograft tumor growth and enhances tumor response to 5-fluorouracil. Clinically, RASSF4 expression correlates strongly with the overall survival of gastric cancer patients.
Conclusion
RASSF4 suppresses gastric tumor growth through the activation of the Chk2-p53 axis, illuminating the mechanistic consequence of its inactivation in gastric tumorigenesis.

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The Dual Role of RASSF4 in Tumorigenesis: Mechanisms and Epigenetic Targeting Strategies
Rui Tian, Yixin Wu, Wenbin Yuan, Lingli Tian, Rui Zhang, Hao Lyu, Shuai Xiao, Dong Guo, Qi Zhang, Declan William Ali, Marek Michalak, Cefan Zhou, Jingfeng Tang, Xing-Zhen Chen
Biology.2025; 14(9): 1289. CrossRef

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107 Download
1 Web of Science
1 Crossref

Breast cancer

The Impact of Obesity on Treatment Outcomes in Patients with Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer Receiving CDK 4/6 Inhibitors: Yoo Bin Jung, Hee Kyung Ahn, Hyun-Young Shin, Ji Hyung Hong, Chai Hong Rim; Cancer Res Treat. 2026;58(1):198-207. Published online April 15, 2025; DOI: https://doi.org/10.4143/crt.2025.110

Abstract PDF Supplementary Material PubReader ePub

Purpose
Guidelines from the aromatase inhibitor era for early breast cancer (EBC) treatment recommend maintaining a body mass index (BMI) below 25. In the current era of cyclin-dependent kinase (CDK) 4/6 inhibitors, now standard in metastatic breast cancer (MBC), limited data exist on treatment outcomes in obese patients. This study investigates how adiposity affects the treatment outcome of CDK 4/6 inhibitors in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative MBC.
Materials and Methods
We searched PubMed, MEDLINE, and Embase databases, assessing efficacy outcomes such as progression-free survival (PFS) based on obesity markers, including BMI and visceral adipose tissue (VAT) index.
Results
Twelve studies were reviewed, with seven studies and 1,812 patients included in a pooled meta-analysis. Among patients with BMI ≥ 25, modest improvement in PFS was observed, with a pooled hazard ratio (HR) of 0.944 (95% confidence interval [CI], 0.909 to 0.980; p=0.003). Besides, add-on analysis using VAT to define obesity revealed a notable PFS improvement, with a pooled HR of 0.452 (95% CI, 0.256 to 0.798; p=0.006).
Conclusion
While BMI-defined obesity showed slight PFS improvement with CDK 4/6 inhibitors and endocrine therapy, using VAT to define obesity revealed significant PFS gains. This highlights the need for further research on biomarker to clarify the role of adiposity in MBC, which may differ from its impact in EBC.

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Association Between Body Mass Index and Clinical Outcomes of CDK4/6 Inhibitors in HR+/HER2− Metastatic Breast Cancer: A Real-World Cohort Study
Seval Orman, Miray Aydoğan, Nisanur Sarıyar Busery, Sedat Yıldırım, Hacer Şahika Yıldız, Hamit Bal, Utku Dönem Gündoğdu, Seval Ay Ersoy, Deniz Işık, Hatice Odabaş, Nedim Turan
Journal of Clinical Medicine.2026; 15(4): 1671. CrossRef
Body Mass Index and Outcomes in HR+/HER2− Metastatic Breast Cancer Treated with Palbociclib: Insights from a National Real-World Study
Larisa Maria Badau, Paul Epure, Madalin-Marius Margan, Roxana Margan, Andrei Dorin Ciocoiu, Cristina Marinela Oprean, Brigitha Vlaicu
Cancers.2026; 18(9): 1379. CrossRef
Assessing the risk of adverse drug events from combining aromatase inhibitors with CDK4/6 inhibitors using the FAERS and JADER databases
Zhipeng Fan, Peikai Sun, Lei Li
Frontiers in Medicine.2026;[Epub] CrossRef
Alternate actions of CDK4/6 inhibitors beyond cell cycle blockade: unexplored roles in therapy resistance
Domenica Scordamaglia, Marianna Talia, Azzurra Zicarelli, Adelina Assunta Mondino, Salvatore De Rosis, Marika Di Dio, Francesca Silvestri, Chiara Meliti, Francesca Cirillo, Ernestina Marianna De Francesco, Roberta Malaguarnera, Carlo Capalbo, Marcello Mag
Cancer and Metastasis Reviews.2025;[Epub] CrossRef

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153 Download
4 Web of Science
4 Crossref

Comparison of Long-term Oncological Outcome of Sentinel Lymph Node Mapping Methods (Dye-Only versus Dye and Radioisotope) in Breast Cancer Patients Following Neoadjuvant Chemotherapy: Jinyoung Byeon, Changjin Lim, Eunhye Kang, Ji-Jung Jung, Hong-Kyu Kim, Han-Byoel Lee, Hyeong-Gon Moon, Wonshik Han; Cancer Res Treat. 2026;58(1):175-181. Published online April 15, 2025; DOI: https://doi.org/10.4143/crt.2024.1253

Abstract PDF Supplementary Material PubReader ePub

Purpose
Sentinel lymph node biopsy (SLNB) using dye and isotope (DUAL) is recommended over the dye-only (DYE) method after neoadjuvant chemotherapy (NCT) due to potentially lower false-negative rates. However, the long-term outcome of either method is unclear. We aimed to compare the long-term oncological outcomes of DYE versus DUAL SLNB methods in patients who received NCT.
Materials and Methods
In this retrospective cohort study, 893 patients who underwent SLNB following NCT and had pathologically negative lymph nodes were included. After propensity score matching for cT, cN, and pT categories, 280 patients were in the DYE group and 560 in the DUAL group. Indigo carmine was used for dye and Tc-99m antimony trisulfate for isotope mapping.
Results
Median follow-up was 75.6 months in the DYE group and 83.0 months in the DUAL group. Mean (±standard deviation) number of harvested sentinel nodes was 6.7 (±3.9) and 6.7 (±3.3) in the DYE and DUAL groups (p=0.875). Five-year distant metastasisfree survival was 95.2% in DYE group and 93.3% in DUAL group (hazard ratio [HR], 1.45; 95% confidence interval [CI], 0.82 to 2.57; p=0.192). Disease-free survival (HR, 0.97; 95% CI, 0.69 to 1.50; p=0.914) and overall survival (HR, 0.98; 95% CI, 0.56 to 1.69; p=0.954) were not significantly different. Axillary recurrence rate was 1.8% and 2.5% in DYE and DUAL groups (p=0.647).
Conclusion
Long-term oncological outcomes did not significantly differ between DYE and DUAL SLNB methods. The dye-only method can be safely recommended for breast cancer patients who received NCT.

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Trajectory of Lymph Node Metastasis Reflects the Molecular Features of Esophageal Squamous Cell Carcinoma
Jiho Park, Seong Yong Park, Ha Eun Kim, Se-Young Jo, JeongSoo Won, Dae Joon Kim, Sangwoo Kim
Cancer Research and Treatment.2025;[Epub] CrossRef

2,571 View
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Gynecologic cancer

Validation of 2023 FIGO Stage IA1-IIIC2 Endometrial Carcinoma: A Retrospective Analysis of Two Tertiary Centers in South Korea and Taiwan: Myeong-Seon Kim, Yen-Ling Lai, Yurimi Lee, Hyun-Soo Kim, Yu-Li Chen, Yoo-Young Lee; Cancer Res Treat. 2025;57(4):1187-1197. Published online February 17, 2025; DOI: https://doi.org/10.4143/crt.2024.1190

Abstract PDF PubReader ePub

Purpose
As understanding of the molecular pathogenesis of endometrial carcinoma (EC) advanced, the International Federation of Gynecology and Obstetrics (FIGO) staging system was revised in 2023. This study compared EC survival outcomes using the 2009 and 2023 FIGO staging systems.
Materials and Methods
We retrospectively analyzed 3,029 patients diagnosed with 2009 FIGO stage I-III EC between 1985 and 2022 in South Korea, and between 2020 and 2022 in Taiwan. All patients were reclassified using the 2023 FIGO staging, and survival and risk factors were examined under both systems.
Results
Transitioning from the 2009 to 2023 FIGO resulted in 549 patients (18.0%) being upstaged and their survival curves being diversified, indicating significant prognostic value of the 2023 FIGO. Re-classification using the 2023 FIGO upstaged the 2009 FIGO stage IA high-risk ECs, allowing more intensive treatment and potentially improving survival outcomes. The most significant changes occurred in the 2009 FIGO stages IA, IB, and IIIA ECs: upstaging in 16.5%, 49.0%, and 2.0% of IA, IB, and IIIA tumors, respectively, and downstaging 0.3% and 40.8% of IB and IIIA tumors, respectively. The risk factors for poor survival included old age (≥ 60 years), menopause, diabetes, substantial lymphovascular space invasion, aberrant p53 expression, and some aggressive histological types (carcinosarcoma, undifferentiated carcinoma, mesonephric-like adenocarcinoma, and neuroendocrine carcinoma).
Conclusion
The 2023 FIGO staging provides more refined stratification of early-stage EC than the 2009 version. Thus, the 2023 FIGO may more accurately guide prognosis and therapeutic decision-making.

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Annual hazard rates for early-stage endometrial carcinoma after postoperative radiotherapy under FIGO 2023 staging system: results from a population-based single-center cohort study
Lingxia Xin, Kang Ren, Zihan Yan, Jiabin Ma, Wenhui Wang, Yunlong Sheng, Yaqi Wang, Xiaorong Hou, Fuquan Zhang
Journal of Gynecologic Oncology.2026;[Epub] CrossRef
Improved Prognostic Stratification with the FIGO 2023 Staging System in Endometrial Cancer: Real-World Validation in 2969 Patients
Jun-Hyeong Seo, Soo-Min Kim, Yoo-Young Lee, Tae-Joong Kim, Jeong-Won Lee, Byoung-Gie Kim, Chel Hun Choi
Cancers.2025; 17(17): 2871. CrossRef

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Gastrointestinal cancer

Evaluation of Nomenclature of Fatty Liver Disease in Association with Hepatocellular Carcinoma: A 14.5-Year Cohort Study in Korea: Tung Hoang, Jeonghee Lee, Bo Hyun Kim, Yuri Cho, Jeongseon Kim; Cancer Res Treat. 2025;57(4):1144-1155. Published online February 11, 2025; DOI: https://doi.org/10.4143/crt.2024.876

Abstract PDF Supplementary Material PubReader ePub

Purpose
New nomenclature has incorporated metabolic traits and/or alcohol intake history to replace nonalcoholic fatty liver disease (NAFLD). Concerning the performance of different terminologies in Asian population, this study aimed to investigate the risk of developing hepatocellular carcinoma (HCC) in persons meeting the criteria for subclasses of fatty liver disease.
Materials and Methods
Between 2002 and 2021, 28,749 participants from the cancer registry linkage, who had no prior history of HCC, were prospectively included. Fatty liver disease was defined using abdominal sonography and fatty liver index. Participants were classified as having NAFLD, metabolic dysfunction–associated fatty liver disease (MAFLD), metabolic dysfunction–associated steatotic liver disease (MASLD), steatotic liver disease with increased alcohol intake (MetALD), or alcohol-related liver disease (ALD) and their association with HCC risk was investigated using Cox regression models.
Results
During a median follow-up of 14.5 years, 143 HCC cases were newly diagnosed. The prevalences of NAFLD and MASLD were 19.7% and 18.7%, respectively, whereas MAFLD was observed in 32.3% of the study population. Given the low proportion of excessive alcohol consumption, we identified 3.3% MetALD and 3.5% ALD cases. Overall, MAFLD was suggestively associated with HCC risk (hazard ratio, 1.40; 95% confidence interval, 0.99 to 1.98). In contrast, the results for other nomenclature were not significant.
Conclusion
Our results suggest the importance of both fatty liver and the presence of metabolic dysfunction in relation to HCC risk and the need to reconsider alcohol intake thresholds in the diagnostic criteria for NAFLD and MASLD within the Korean population.

Citations

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Distinct Laboratory and Clinical Features of Metabolic and Alcohol-Related Liver Disease (MetALD): A Systematic Review and Meta-Analysis
Maria Tampaki, Vasileios Lekakis, Christos Chologkitas, Stergios Α. Polyzos, Evangelos Cholongitas
Current Obesity Reports.2026;[Epub] CrossRef
Dual etiology vs. MetALD: how MAFLD and MASLD address liver diseases coexistence
Shadi Zerehpooshnesfchi, Amedeo Lonardo, Jian-Gao Fan, Reda Elwakil, Tawesak Tanwandee, Munira Y. Altarrah, Necati Örmeci, Mohammed Eslam
Metabolism and Target Organ Damage.2025;[Epub] CrossRef
Comment on " posttreatment FIB-4 score change predicts hepatocellular carcinoma in chronic hepatitis C patients: Findings from the Taiwan hepatitis C registry program"
Junwei Guo, Dongsheng Huang
Journal of the Formosan Medical Association.2025;[Epub] CrossRef
MAFLD vs. MASLD: a year in review
Mingqian Jiang, Amna Subhan Butt, Ian Homer Cua, Ziyan Pan, Said A Al-Busafi, Nahum Méndez-Sánchez, Mohammed Eslam
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Risk of hepatic and extrahepatic outcomes associated with metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction and alcohol-associated steatotic liver disease: a systematic review and meta-analysis
Ciro Celsa, Grazia Pennisi, Adele Tulone, Giacinta Ciancimino, Marco Vaccaro, Fabiana Pecorella, Gabriele Di Maria, Marco Enea, Federico Midiri, Alessandro Mantovani, Giovanni Targher, Aleksander Krag, Mary E Rinella, Calogero Cammà, Salvatore Petta
The Lancet Gastroenterology & Hepatology.2025; 10(11): 998. CrossRef

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Stereotactic Ablative Radiotherapy versus Surgery in Patients with Pulmonary Metastases from Colorectal Cancer: Byung min Lee, Ha Eun Kim, Young Ho Yang, Seung Yoon Yang, Han Sang Kim, Seo Hee Choi, Woong Sub Koom, Byung Jo Park, Jee Suk Chang; Cancer Res Treat. 2025;57(4):1135-1143. Published online February 6, 2025; DOI: https://doi.org/10.4143/crt.2024.1040

Abstract PDF Supplementary Material PubReader ePub

Purpose
We compared the local control rate and toxicity of stereotactic ablative radiotherapy (SABR) versus wedge resection for colorectal pulmonary metastases.
Materials and Methods
We retrospectively reviewed medical charts and imaging of patients treated with SABR or wedge resection between 2010 and 2017 at a single institution.
Results
A total of 404 patients were treated with local therapy for 528 pulmonary metastatic lesions. While surgery was frequently used upfront for smaller, solitary metastases without other site involvement, SABR was often used for larger, multiple lesions and disease burdens beyond the lungs. The 3-year local control rate was 88.6% following surgery, which was not significantly different from that with SABR at 86.7% (p=0.174). No major postoperative complications or mortality were observed in the surgery group, and 2.8% of patients in the SABR group experienced grade 3-4 radiation pneumonitis.
Conclusion
SABR was used in patients with a higher risk of progression compared to those undergoing surgery, yet it has similar local control rates to wedge resection.

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Percutaneous Cryoablation Under Local Anesthesia for Pulmonary Metastases From Colorectal Cancer: Long‐Term Outcomes From a Single‐Institution Retrospective Cohort
Shun Yorimori, Kaoru Kaseda, Yusuke Aoki, Kosuke Sugino, Takahiro Suzuki, Yu Okubo, Shigeki Suzuki, Kyohei Masai, Masashi Tamura, Masanori Inoue, Hideki Yashiro, Seishi Nakatsuka, Yoshikane Yamauchi, Yotaro Izumi, Masafumi Kawamura, Masahiro Jinzaki, Keis
Cancer Reports.2026;[Epub] CrossRef
Emerging Applications of Stereotactic Ablative Radiotherapy in Oligometastatic Colorectal Cancer
Hasan Al-Sattar, Esele Okondo, Amir Mashia Jaafari, Inesh Sood, Jakob Hassan Dinif, Su Yin Lim, Charlotte Hafkamp, Irene Chong, Joao R. Galante, Sola Adeleke
International Journal of Molecular Sciences.2025; 26(21): 10302. CrossRef

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Pediatric cancer

Prognostic Value of POST-Treatment Extent of Tumor (POSTTEXT) System in Patients with Hepatoblastoma: Hana Jeong, Hee Mang Yoon, Pyeong Hwa Kim, Ah Young Jung, Young Ah Cho, Jin Seong Lee, Kyung-Nam Koh, Jung-Man Namgoong; Cancer Res Treat. 2025;57(4):1198-1206. Published online January 20, 2025; DOI: https://doi.org/10.4143/crt.2024.600

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study aimed to assess prognostic values of the POST-Treatment Extent of tumor (POSTTEXT) system and clinical factors after neoadjuvant chemotherapy in hepatoblastoma patients and evaluate benefits of post-treatment imaging and clinical factors concomitant with Children’s Hepatic Tumors International Collaboration–Hepatoblastoma Stratification (CHIC-HS) system.
Materials and Methods
This single-center retrospective study of hepatoblastoma cases (2006-2022) included pediatric patients receiving ≥ 4 cycles of neoadjuvant chemotherapy, with pre- and post-treatment imaging and complete medical records. Clinical data included age, sex, and serum α-fetoprotein (AFP) levels. Cox regression analyses identified predictors of event-free survival (EFS). Time-dependent receiver operating characteristic curves assessed the predictive power of combining the CHIC-HS risk stratification with post-treatment factors. Inter-reader agreement was analyzed using weighted kappa.
Results
Among the 109 hepatoblastoma patients, 73 (mean age, 2.2±2.7 years) met the inclusion criteria. Prognostic factors for EFS included AFP levels after the fourth cycle of neoadjuvant chemotherapy (hazard ratio [HR], 1.233; 95% confidence interval [CI], 1.086 to 1.400; p=0.001), tumor size change ratio (HR, 0.654; 95% CI, 0.448 to 0.955; p=0.030), and POSTTEXT annotation factor M (HR, 5.209; 95% CI, 1.639 to 16.553; p=0.005). Incorporating AFP levels after the fourth cycle of neoadjuvant chemotherapy into the CHIC-HS improved predictive power (p=0.043). POSTTEXT system showed better inter-reader agreement than PRE-Treatment Extent of tumor (PRETEXT).
Conclusion
Predictors of EFS in hepatoblastoma include AFP levels after the fourth cycle of neoadjuvant chemotherapy, tumor size change ratio, and metastasis (POSTTEXT M). Combining AFP levels after the fourth cycle of neoadjuvant chemotherapy to the CHIC-HS improved the predictive ability.

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Surgical management of biliary fistula following associating liver partition and portal vein ligation for staged hepatectomy in pediatric hepatoblastoma: a case report and literature review
Gang Shen, Yunpeng Zhai, Huashan Zhao, Rui Guo, Hongxiu Xu, Sai Huang, Shisong Zhang
Frontiers in Oncology.2025;[Epub] CrossRef

4,749 View
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