Cancer Research and Treatment

Original Articles

Genitourinary cancer

Invasiveness of Upper Tract Urothelial Carcinoma: Clinical Significance and Integrative Diagnostic Strategy: Bokyung Ahn, Doeun Kim, Kye Jin Park, Ja-Min Park, Sun Young Yoon, Bumsik Hong, Yong Mee Cho, Deokhoon Kim; Cancer Res Treat. 2024;56(3):856-870. Published online December 18, 2023; DOI: https://doi.org/10.4143/crt.2023.1150

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Purpose
In this study, we aimed to determine the clinicopathologic, radiologic, and molecular significance of the tumor invasiveness to further stratify the patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) who can be treated less aggressively.
Materials and Methods
Clinicopathologic and radiologic characteristics of 166 surgically resected HG UTUC (48 noninvasive, and 118 invasive) cases were evaluated. Six noninvasive UTUC cases with intratumoral tumor grade heterogeneity were selected for whole-exome sequencing (WES) to understand the underlying molecular pathophysiology. Barcode-tagging sequencing was done for validation of the target genes from WES data.
Results
Patients with noninvasive UTUC showed no cancer-specific death with better cancer-specific survival (p < 0.001) and recurrence-free survival (p < 0.001) compared to the patients with invasive UTUC. Compared to the invasive UTUC, noninvasive UTUC was correlated to a low grade (LG) on the preoperative abdominal computed tomography (CT) grading system (p < 0.001), histologic intratumoral tumor grade heterogeneity (p=0.018), discrepancy in preoperative urine cytology diagnosis (p=0.018), and absence of urothelial carcinoma in situ (p < 0.001). WES of the heterogeneous components showed mutually shared HRAS and FGFR3 mutations shared between the HG and LG components. HRAS mutation was associated with the lower grade on preoperative abdominal CT and intratumoral tumor grade heterogeneity (p=0.045 and p < 0.001, respectively), whereas FGFR3 mutation was correlated to the absence of carcinoma in situ (p < 0.001).
Conclusion
According to our comprehensive analysis, HG noninvasive UTUC can be preoperatively suspected based on distinct preoperative radiologic, cytologic, histologic, and molecular features. Noninvasive HG UTUC shows excellent prognosis and thus should be treated less aggressively.

Citations

Citations to this article as recorded by

Papillary renal neoplasm with reverse polarity shows benign behavior: Results from a 77-case clinicopathological and molecular study
Yong Il Lee, Ja-Min Park, Sun Young Yoon, Cheryn Song, Yong Mee Cho
Annals of Diagnostic Pathology.2026; 80: 152498. CrossRef
Diagnostic accuracy of upper tract urothelial carcinoma using biopsy, urinary cytology, and nephroureterectomy specimens: A tertiary cancer center experience
Jianping Zhao, Yuan Shen, Ming Guo, Surena F Matin, Donna E Hansel, Charles C Guo
American Journal of Clinical Pathology.2024;[Epub] CrossRef
Clinical Significance of Tumor Location for Ureteroscopic Tumor Grading in Upper Tract Urothelial Carcinoma
Satoshi Katayama, Benjamin Pradere, Nico C. Grossman, Aaron M. Potretzke, Stephen A. Boorjian, Alireza Ghoreifi, Siamak Daneshmand, Hooman Djaladat, John P. Sfakianos, Andrea Mari, Zine-Eddine Khene, David D’andrea, Nozomi Hayakawa, Kazutoshi Fujita, Axel
Journal of Endourology.2024; 38(11): 1156. CrossRef
Development and validation of a radiomics-based nomogram for predicting pathological grade of upper urinary tract urothelial carcinoma
Yanghuang Zheng, Hongjin Shi, Shi Fu, Haifeng Wang, Xin Li, Zhi Li, Bing Hai, Jinsong Zhang
BMC Cancer.2024;[Epub] CrossRef

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PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI–Resistant Metastatic Clear Cell Renal Cell Carcinoma: Se Un Jeong, Hee Sang Hwang, Ja-Min Park, Sun Young Yoon, Su-Jin Shin, Heounjeong Go, Jae-Lyun Lee, Gowun Jeong, Yong Mee Cho; Cancer Res Treat. 2023;55(1):231-244. Published online March 2, 2022; DOI: https://doi.org/10.4143/crt.2021.1526

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Purpose
Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism.
Materials and Methods
To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib.
Results
Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway.
Conclusion
These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI–resistant mCCRCC patients via the mTOR pathway.

Citations

Citations to this article as recorded by

Hedgehog signaling activation rescues hypoxia-induced ferroptosis in human brain organoids
Simeng Yi, Min Huang, Chunmei Xian, Xi Kong, Shigang Yin, Jianhua Peng, Hongda Li, Yong Jiang, Bingqing Xie, Huangfan Xie
Neural Regeneration Research.2026; 21(9): 4378. CrossRef
VEGFR signalling and hemoptysis: mechanisms, critical appraisal of the evidence, and the double-edged role of VEGFR-2 inhibition — a narrative review
Langmei Wu, Ling Luo
The Egyptian Journal of Bronchology.2026;[Epub] CrossRef
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Cancer Medicine.2025;[Epub] CrossRef
Potential repurposing of lapatinib and pazopanib as neuroprotective agents in a rat model of Huntington’s disease
Nada Ezeldine-Elmahalawy, Noha F. Abdelkader, Hala F. Zaki, Amany I. Elbrairy, Sameh S. Gad
Inflammopharmacology.2025; 33(10): 6211. CrossRef
Significant increase in calcification and ossification observed after the second relapse of low-grade myofibroblast sarcoma treated with radiotherapy followed by anlotinib and toripalimab: a case report
Juan Lang, Zhongkui Xiong
Frontiers in Immunology.2025;[Epub] CrossRef
IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma
Se Un Jeong, Ja-Min Park, Sun Young Yoon, Hee Sang Hwang, Heounjeong Go, Dong-Myung Shin, Hyein Ju, Chang Ohk Sung, Jae-Lyun Lee, Gowun Jeong, Yong Mee Cho
Investigative and Clinical Urology.2024; 65(1): 84. CrossRef
Targeting apoptosis in clear cell renal cell carcinoma
Adam Kowalewski, Jędrzej Borowczak, Mateusz Maniewski, Karol Gostomczyk, Dariusz Grzanka, Łukasz Szylberg
Biomedicine & Pharmacotherapy.2024; 175: 116805. CrossRef
Therapeutic advances of targeting receptor tyrosine kinases in cancer
Ciprian Tomuleasa, Adrian-Bogdan Tigu, Raluca Munteanu, Cristian-Silviu Moldovan, David Kegyes, Anca Onaciu, Diana Gulei, Gabriel Ghiaur, Hermann Einsele, Carlo M. Croce
Signal Transduction and Targeted Therapy.2024;[Epub] CrossRef
Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics
Yunxia Wang, Xiaolin Liu, Luyao Gong, Weihong Ding, Wenjing Hao, Yeheng Peng, Jun Zhang, Weimin Cai, Yuan Gao
British Journal of Pharmacology.2023; 180(23): 2937. CrossRef
Prior Anti-Angiogenic TKI-Based Treatment as Potential Predisposing Factor to Nivolumab-Mediated Recurrent Thyroid Disorder Adverse Events in mRCC Patients: A Case Series
Luigi Liguori, Angelo Luciano, Giovanna Polcaro, Alessandro Ottaiano, Marco Cascella, Francesco Perri, Stefano Pepe, Francesco Sabbatino
Biomedicines.2023; 11(11): 2974. CrossRef

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