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Abrantes AM, Caetano-Oliveira R, Oliveiros B, Cipriano MA, Tralhão JG. Association Between Colorectal Cancer Primary Features and Liver Metastases Histological Growth Patterns: Inflammation on the Primary Tumor is Associated with Desmoplastic Growth Pattern. Clin Colorectal Cancer 2025; 24:239-247. [PMID: 40021416 DOI: 10.1016/j.clcc.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 01/04/2025] [Accepted: 01/29/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND More than 50% of patients diagnosed with colorectal cancer (CRC) will develop liver metastases (CRCLM), which is the main cause of death for more than 60% of these patients. The aim of this study was to correlate the clinical and pathological characteristics of the primary CRC and CRCLM, with emphasis in predicting the histological growth pattern of the CRCLM. METHODS Cohort of 73 patients with CRC. Analysis of clinical data and blinded pathological review was performed related with primary tumor and CRCLM features. The analysis was performed in SPSS (version 27) with a significance level of 5%. RESULTS A statistically significant association was found between tumor size and metastasis growth pattern (P = .002), with larger tumors giving rise to metastases with a nondesmoplastic growth pattern. Lymphovascular invasion (LVI) was associated with metachronous CRCLM (P = .043). In the absence of LVI, the time required for CRCLM to appear was significantly longer (P = .011). The number of metastases was significantly higher (P = .049) in tumors without LVI when compared to tumors with LVI. There was a statistically significant association between CRC high-grade inflammation and the desmoplastic metastases growth pattern of the CRCLM (P = .017). CONCLUSION The possibility of predicting the CRCLM histological growth pattern resorting to primary CRC characteristics would be useful for proper patient selection for surgery and adapting biological therapies.
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Affiliation(s)
- Ana Margarida Abrantes
- Biophysics Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Coimbra Centor Académico e Clínico (CACC), Coimbra, Portugal
| | - Rui Caetano-Oliveira
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Coimbra Centor Académico e Clínico (CACC), Coimbra, Portugal; Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Centro de Anatomia Patológica Germano de Sousa, Coimbra, Portugal; General Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
| | - Bárbara Oliveiros
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Coimbra Centor Académico e Clínico (CACC), Coimbra, Portugal
| | | | - José Guilherme Tralhão
- Biophysics Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Coimbra Centor Académico e Clínico (CACC), Coimbra, Portugal; General Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
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Nopour R. Optimizing prediction of metastasis among colorectal cancer patients using machine learning technology. BMC Gastroenterol 2025; 25:272. [PMID: 40251500 PMCID: PMC12007332 DOI: 10.1186/s12876-025-03841-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 04/02/2025] [Indexed: 04/20/2025] Open
Abstract
BACKGROUND AND AIM Colorectal cancer is among the most prevalent and deadliest cancers. Early prediction of metastasis in patients with colorectal cancer is crucial in preventing it from the advanced stages and enhancing the prognosis among these patients. So far, previous studies have been conducted to predict metastasis in colorectal cancer patients using clinical data. The current research attempts to leverage a combination of demographic, lifestyle, nutritional, and clinical factors, such as diagnostic and therapeutical factors, to construct an ML model with more predictive insights and generalizability than previous ones. MATERIALS AND METHODS In this retrospective study, we used 1156 CRC patients referred to the Masoud internal clinic in Tehran City from January 2017 to December 2023. The chosen machine learning algorithms, including LightGBM, XG-Boost, random forest, artificial neural network, support vector machine, decision tree, K-Nearest Neighbor and logistic regression, were utilized to establish prediction models for predicting metastasis among colorectal cancer patients. We also assessed features based on the best-performing model to improve clinical usability. To show the generalizability of the established prediction model for predicting CRC metastasis, we leveraged the data of 115 CRC patients from Imam Khomeini Hospital in Sari City. We assessed the predictive ability of LightGBM as the best-performing model based on external data. RESULTS The LightGBM model with a PPV of 97.32%, NPV of 84.67%, sensitivity of 83.14%, specificity of 93.14%, accuracy of 88.14%, F1-score of 87.51%, and an AU-ROC of 0.9 [Formula: see text]0.01 obtained satisfactory performance for prediction purposes on this topic. Factors including the history of IBD, family history of CRC, number of lymph nodes involved, fruit intake, and tumor size were considered as more strengthful predictors for metastasis in colorectal cancer and clinical usability. The external validation cohort showed a PPV of 0.8, NPV of 0.85, sensitivity of 0.78, specificity of 0.86, accuracy of 0.834, F1-score of 0.795, and AU-ROC of 0.77[Formula: see text]0.03, demonstrating satisfactory generalizability when leveraging external data from other clinical settings. CONCLUSION The current empirical results indicated that LighGBM has predictive competency that can be leveraged by physicians in clinical environments for early prediction of metastasis and enhanced prognosis in patients with colorectal cancer. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Raoof Nopour
- Department of Health Information Management, School of Health Management and Information Sciences, Iran University of Medical Sciences, Tehran, Iran.
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Chen G, Liu W, Lin Y, Zhang J, Huang R, Ye D, Huang J, Chen J. Predicting bone metastasis risk of colorectal tumors using radiomics and deep learning ViT model. J Bone Oncol 2025; 51:100659. [PMID: 39902382 PMCID: PMC11787686 DOI: 10.1016/j.jbo.2024.100659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/13/2024] [Accepted: 12/23/2024] [Indexed: 02/05/2025] Open
Abstract
Background Colorectal cancer is a prevalent malignancy with a significant risk of metastasis, including to bones, which severely impacts patient outcomes. Accurate prediction of bone metastasis risk is crucial for optimizing treatment strategies and improving prognosis. Purpose This study aims to develop a predictive model combining radiomics and Vision Transformer (ViT) deep learning techniques to assess the risk of bone metastasis in colorectal cancer patients using both plain and contrast-enhanced CT images. Materials and methods We conducted a retrospective analysis of 155 colorectal cancer patients, including 81 with bone metastasis and 74 without. Radiomic features were extracted from segmented tumors on both plain and contrast-enhanced CT images. LASSO regression was applied to select key features, which were then used to build traditional machine learning models, including Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Random Forest, LightGBM, and XGBoost. Additionally, a dual-modality ViT model was trained on the same CT images, with a late fusion strategy employed to combine outputs from the different modalities. Model performance was evaluated using AUC-ROC, accuracy, sensitivity, and specificity, and differences were statistically assessed using DeLong's test. Results The ViT model demonstrated superior predictive performance, achieving an AUC of 0.918 on the test set, significantly outperforming all traditional radiomics-based models. The SVM model, while the best among traditional models, still underperformed compared to the ViT model. The ViT model's strength lies in its ability to capture complex spatial relationships and long-range dependencies within the imaging data, which are often missed by traditional models. DeLong's test confirmed the statistical significance of the ViT model's enhanced performance, highlighting its potential as a powerful tool for predicting bone metastasis risk in colorectal cancer patients. Conclusion The integration of radiomics with ViT-based deep learning offers a robust and accurate method for predicting bone metastasis risk in colorectal cancer patients. The ViT model's ability to analyze dual-modality CT imaging data provides greater precision in risk assessment, which can improve clinical decision-making and personalized treatment strategies. These findings underscore the promise of advanced deep learning models in enhancing the accuracy of metastasis prediction. Further validation in larger, multicenter studies is recommended to confirm the generalizability of these results.
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Affiliation(s)
- Guanfeng Chen
- Radiology Department of Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China
| | - Wenxi Liu
- Radiology Department of The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Yingmin Lin
- Thyroid and Breast Surgery Department of the Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Jie Zhang
- Radiology Department of Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China
| | - Risheng Huang
- Radiology Department of Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China
| | - Deqiu Ye
- Radiology Department of Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China
| | - Jing Huang
- Radiology Department of The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Jieyun Chen
- Radiology Department of Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China
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Trailin A, Ali E, Ye W, Pavlov S, Červenková L, Vyčítal O, Ambrozkiewicz F, Hošek P, Daum O, Liška V, Hemminki K. Prognostic assessment of T-cells in primary colorectal cancer and paired synchronous or metachronous liver metastasis. Int J Cancer 2025; 156:1282-1292. [PMID: 39508720 PMCID: PMC11736993 DOI: 10.1002/ijc.35252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 11/15/2024]
Abstract
Prognostic value of T-cells between primary colorectal cancer (pCRC) and its paired synchronous and metachronous liver metastasis (LM) is underinvestigated and is the subject of the present study. We enrolled into this retrospective cohort study patients, who underwent resection of both pCRC and synchronous LM (N = 55) or metachronous LM (N = 44). After immunohistochemical staining for CD3+, CD8+, and CD45R0+ whole slides were scanned and T-cell densities were quantified using QuPath software in tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of pCRC and LM. High densities of CD8+ T-cells in TC, OM and PT of synchronous LM were associated with longer disease-free survival (DFS). Greater densities of CD3+ T-cells in IM and PT and CD8+ T-cells in IM, OM and PT in synchronous LM over pCRC were associated with longer DFS. Greater densities of CD8+ T-cells in the TC and IM and CD3+ T-cells in the IM of pCRC were found in the metachronous over synchronous group. The first novel finding demonstrated that high density of CD8+ T cells in synchronous LM were associated with favorable outcome. The second finding of high CD8+ cell density in pCRC in metachronous over synchronous CRC may provide a mechanistic basis for the delay of metastatic spread. Both findings could be applied clinically with own reference values.
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Affiliation(s)
- Andriy Trailin
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Esraa Ali
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Wenjing Ye
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Sergii Pavlov
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Lenka Červenková
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Ondřej Vyčítal
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Filip Ambrozkiewicz
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Petr Hošek
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Ondřej Daum
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Václav Liška
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
| | - Kari Hemminki
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic
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Qiu QS, Chen XS, Wang WT, Wang JH, Yan C, Ji M, Dong SY, Zeng MS, Rao SX. Image quality, diagnostic performance of reduced-dose abdominal CT with artificial intelligence model-based iterative reconstruction for colorectal liver metastasis: a prospective cohort study. Quant Imaging Med Surg 2025; 15:2106-2118. [PMID: 40160620 PMCID: PMC11948387 DOI: 10.21037/qims-24-1570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 01/17/2025] [Indexed: 04/02/2025]
Abstract
Background The optimization of regularization strategies in computed tomography (CT) iterative reconstruction may allow for a reduced dose (RD) without compromising image quality, thus the diagnostic ability of RD imaging must be considered, especially for low-contrast lesions. In this study, we evaluated the image quality and diagnostic performance of 50% RD CT for low-contrast colorectal liver metastasis (CRLM) with artificial intelligence model-based iterative reconstruction (AIIR) and standard-dose (SD) CT with hybrid iterative reconstruction (HIR). Methods In this prospective study, consecutive participants with pathologically proven colorectal cancer and suspected liver metastases who underwent portal venous phase CT scans both at SD and RD between June and November 2022 were included. All images were reconstructed by HIR and AIIR. Two radiologists detected and characterized liver lesions with RD HIR, SD HIR, and RD AIIR and scored the image quality. The contrast-to-noise ratio (CNR) for metastases were recorded. The diagnostic performance for CRLM of each reconstruction algorithm was analyzed and compared using the receiver operating characteristic curve and the area under the curves (AUC). Results A total of 56 participants with 422 liver lesions were recruited. The mean volume CT dose indices of the SD and RD scans were 9.5 and 4.8 mGy. RD AIIR exhibited superior subjective image quality and higher CNR for liver metastases than did RD/SD HIR. In all liver lesions and lesions ≤10 mm, the detection rates of RD AIIR (83.3% and 71.5%) were both significantly higher than those of RD HIR (76.3% and 62.4%; P=0.002 and P=0.003); meanwhile, they were similar to those of SD HIR (81.4% and 69.6%; P=0.307 and P=0.515). The AUCs of RD AIIR for all liver lesions and lesions ≤10 mm (0.858 and 0.764) were greater than those of RD HIR (0.781 and 0.661; P<0.001) and were similar to those of SD HIR (0.863 and 0.762; P=0.616 and 0.845). Conclusions AIIR can improve CT image quality at 50% RD while preserving diagnostic performance and confidence for low-contrast CRLM in all lesions and lesions ≤10 mm and may thus serve as a promising tool for follow-up monitoring in patients with colorectal cancer while inflicting less radiation damage.
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Affiliation(s)
- Qian-Sai Qiu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China
- Department of Radiology, Affiliated Tumor Hospital of Nantong University, Nantong University, Nantong, China
| | - Xiao-Shan Chen
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China
| | - Wen-Tao Wang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China
| | - Jia-Hui Wang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China
| | - Cheng Yan
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China
| | - Min Ji
- Shanghai United Imaging Healthcare Co., Ltd., Shanghai, China
| | - San-Yuan Dong
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China
| | - Meng-Su Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China
| | - Sheng-Xiang Rao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China
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Sugiura K. What is the significance of mismatch repair deficiency in stage IV colon cancer? J Gastrointest Oncol 2025; 16:330-332. [PMID: 40115933 PMCID: PMC11921172 DOI: 10.21037/jgo-2025-74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 02/17/2025] [Indexed: 03/23/2025] Open
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Kim S, Kim H, Hong I, Lee M, Kim H, Kwak H, Kim CJ, Kang D, Ahn T, Baek M, Jeong D. CYP4X1 Expression Is Associated with Metastasis and Poor Prognosis in Patients with Colorectal Cancer. Int J Mol Sci 2025; 26:1867. [PMID: 40076494 PMCID: PMC11899201 DOI: 10.3390/ijms26051867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 01/25/2025] [Accepted: 01/30/2025] [Indexed: 03/14/2025] Open
Abstract
Globally, the mortality rate of colorectal cancer (CRC) remains high. Despite the development of various treatments, such as targeted therapy and immunotherapy, colorectal cancer continues to be a serious health issue worldwide. Identifying new biomarkers is essential for improving prognosis and tailoring targeted therapies for CRC. This study aims to elucidate the role of CYP4X1 in CRC and its association with patient survival and clinicopathological parameters. Using TCGA databases like GENT2, UALCAN, and GEPIA, we analyzed CYP4X1 expression in CRC and normal tissues. Our analysis revealed a significant increase in CYP4X1 expression in CRC tissues compared to normal tissues. And CYP4X1 high expression was strongly associated with advanced TNM stage, poor tumor differentiation, deeper invasion, and lymph node metastasis. Kaplan-Meier analysis revealed that high CYP4X1 expression correlated with shorter survival times. To investigate the relationship between CYP4X1 expression and colon cancer, WST-1, Transwell, and colony formation assays were performed using colon cancer cells with siRNA-mediated CYP4X1 downregulation. CYP4X1 downregulation significantly inhibited cell proliferation, invasion, migration, and colony formation in vitro. Furthermore, the tumor-forming ability in mice injected with cell lines where CYP4X1 expression was suppressed decreased. In conclusion, CYP4X1 overexpression is closely linked to CRC progression as an independent prognostic marker and potential therapeutic target.
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Affiliation(s)
- Sooyoun Kim
- Department of Pathology, College of Medicine, Soonchunhyang University, 31 Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Chungcheongnam-do, Republic of Korea; (S.K.); (I.H.); (M.L.)
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan 31151, Chungcheongnam-do, Republic of Korea
| | - Hakchun Kim
- Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan 31151, Chungcheongnam-do, Republic of Korea;
| | - Inpyo Hong
- Department of Pathology, College of Medicine, Soonchunhyang University, 31 Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Chungcheongnam-do, Republic of Korea; (S.K.); (I.H.); (M.L.)
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan 31151, Chungcheongnam-do, Republic of Korea
| | - Minho Lee
- Department of Pathology, College of Medicine, Soonchunhyang University, 31 Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Chungcheongnam-do, Republic of Korea; (S.K.); (I.H.); (M.L.)
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan 31151, Chungcheongnam-do, Republic of Korea
| | - Hyeongjoo Kim
- R&D Center Pharmaceutical Laboratory, Korean Drug Co., Ltd., 34, Nonhyeon-ro 28-gil, Gangnam-gu, Seoul 06300, Republic of Korea;
| | - Hyoungjong Kwak
- Research Institute of Clinical Medicine, Woori Madi Medical Center, 111 Baekjedae-ro, Wansan-gu, Jeonju 55082, Jeollabuk-do, Republic of Korea; (H.K.); (C.-J.K.)
| | - Chang-Jin Kim
- Research Institute of Clinical Medicine, Woori Madi Medical Center, 111 Baekjedae-ro, Wansan-gu, Jeonju 55082, Jeollabuk-do, Republic of Korea; (H.K.); (C.-J.K.)
| | - Donghyun Kang
- Department of Surgery, College of Medicine, Soonchunhyang University, 31 Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Chungcheongnam-do, Republic of Korea; (D.K.); (T.A.); (M.B.)
| | - Taesung Ahn
- Department of Surgery, College of Medicine, Soonchunhyang University, 31 Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Chungcheongnam-do, Republic of Korea; (D.K.); (T.A.); (M.B.)
| | - Moojun Baek
- Department of Surgery, College of Medicine, Soonchunhyang University, 31 Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Chungcheongnam-do, Republic of Korea; (D.K.); (T.A.); (M.B.)
| | - Dongjun Jeong
- Department of Pathology, College of Medicine, Soonchunhyang University, 31 Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Chungcheongnam-do, Republic of Korea; (S.K.); (I.H.); (M.L.)
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan 31151, Chungcheongnam-do, Republic of Korea
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Cheng C, Zhang K, Lu M, Zhang Y, Wang T, Zhang Y. RPF2 and CARM1 cooperate to enhance colorectal cancer metastasis via the AKT/GSK-3β signaling pathway. Exp Cell Res 2025; 444:114374. [PMID: 39674359 DOI: 10.1016/j.yexcr.2024.114374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/03/2024] [Accepted: 12/08/2024] [Indexed: 12/16/2024]
Abstract
RPF2 plays a crucial role in promoting epithelial-mesenchymal transition (EMT) and regulating metastasis in colorectal cancer (CRC). By analyzing data from the TCGA and GEO databases, we observed significantly elevated RPF2 expression in CRC, which correlated with EMT markers. Further investigations using stable RPF2 overexpression and knockdown cell lines demonstrated that RPF2 facilitates EMT activation through the AKT/GSK-3β signaling pathway. Notably, CARM1 was identified as a key downstream effector of RPF2. Selective inhibition of CARM1 effectively suppressed the activation of the AKT/GSK-3β pathway and EMT induced by RPF2 overexpression. Both in vitro and in vivo experiments confirmed that RPF2 expression levels positively correlate with the metastatic potential of CRC cells. Moreover, treatment with a CARM1 inhibitor significantly reduced the invasive and migratory capabilities of RPF2-overexpressing cells. These findings suggest that RPF2 drives CRC metastasis by modulating EMT via the AKT/GSK-3β pathway, with CARM1 serving as a critical mediator, offering potential therapeutic targets for CRC.
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Affiliation(s)
- Cong Cheng
- Department of General Surgery, Changshu No. 1 People's Hospital, Changshu, Jiangsu, 215500, China.
| | - KeMing Zhang
- Department of General Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214043, China.
| | - MaCheng Lu
- Department of General Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214043, China
| | - Yuan Zhang
- Department of General Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214043, China
| | - Tong Wang
- Department of General Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214043, China.
| | - Ye Zhang
- Department of General Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214043, China.
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Gamage CDB, Kim JH, Zhou R, Park SY, Pulat S, Varlı M, Nam SJ, Kim H. Plectalibertellenone A suppresses colorectal cancer cell motility and glucose metabolism by targeting TGF-β/Smad and Wnt pathways. Biofactors 2025; 51:e2120. [PMID: 39291722 DOI: 10.1002/biof.2120] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 07/29/2024] [Indexed: 09/19/2024]
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related death and represents a serious worldwide health problem. CRC metastasis decreases the survival rate of cancer patients, underscoring the need to identify novel anticancer agents and therapeutic targets. Here, we introduce Plectalibertellenone A (B) as a promising agent for the inhibition of CRC cell motility and glucose metabolism and explore its mechanism of action in CRC cells. Plectalibertellenone A suppressed TGF-β gene expression and the activation of the TGF-β/Smad signaling pathway, leading to reverse epithelial to mesenchymal transition (EMT) by modulating the expressions of EMT markers and transcriptional factors such as E-cadherin, N-cadherin, vimentin, Slug, Snail, Twist, and ZEB1/2. Furthermore, disruption of Wnt signaling inhibited CRC motility and glucose metabolism including glycolysis and oxidative phosphorylation, primarily affecting glycolytic enzymes, GLUT1, HK2, PKM2, LDHA, and HIF-1α under hypoxic condition. Therefore, Plectalibertellenone A is a potential drug candidate that can be developed into a promising anticancer treatment to prevent CRC metastasis and inhibit glucose metabolism.
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Affiliation(s)
| | - Jeong-Hyeon Kim
- Department of Chemistry and Nanoscience, Ewha Woman University, Seoul, Korea
| | - Rui Zhou
- College of Pharmacy, Sunchon National University, Sunchon, Jeonnam, Korea
| | - So-Yeon Park
- College of Pharmacy, Sunchon National University, Sunchon, Jeonnam, Korea
| | - Sultan Pulat
- College of Pharmacy, Sunchon National University, Sunchon, Jeonnam, Korea
| | - Mücahit Varlı
- College of Pharmacy, Sunchon National University, Sunchon, Jeonnam, Korea
| | - Sang-Jip Nam
- Department of Chemistry and Nanoscience, Ewha Woman University, Seoul, Korea
| | - Hangun Kim
- College of Pharmacy, Sunchon National University, Sunchon, Jeonnam, Korea
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Schaub D, Gunderson J, Thompson S, Saeed S, Batzli E, Mittal R, Tecle D, Pavleszek K, Nfonsam V. Mismatch repair deficiency confers worse survival in stage IV colon cancer. J Gastrointest Oncol 2024; 15:2521-2532. [PMID: 39816023 PMCID: PMC11732351 DOI: 10.21037/jgo-24-387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 11/18/2024] [Indexed: 01/18/2025] Open
Abstract
Background Metastatic colon cancer (MCC) is a debilitating condition with a poor prognosis. Currently, there is limited data that investigates MCC in relation to mismatch repair (MMR) status. The aims of this study are to compare sociodemographic and clinicopathologic features and mortality between patients with MMR-proficient (MMR-P) and MMR-deficient (MMR-D) MCC. Methods We performed an 8-year retrospective review of the National Cancer Database (NCDB) to identify patients age ≥18 years with MCC and reported MMR status. Data collection included sociodemographic characteristics, primary tumor sites and histopathologic features, and treatment modalities. Outcomes included 90-day, 180-day, 1-year, and 2-year overall mortality. Bivariate logistic regression and multivariate Cox regression identified differences between MMR-P and MMR-D and identified predictors of mortality, respectively. Results A total of 10,922 MCC cases were identified; 8,796 (80.53%) were MMR-P and 2,126 (19.47%) were MMR-D. MMR-D was independently associated with older age at diagnosis, female sex, mucinous adenocarcinoma, medullary carcinoma, and lymph-vascular invasion. MMR-P was independently associated with perineural invasion and left-sided colonic primary tumor predominance. When adjusted for demographics, histology, and treatment modalities, MMR-D was associated with mortality at 180 days, 1 year, and 2 years. Conclusions Our study identified several key sociodemographic and clinicopathologic features of MMR-D MCC. MMR-D appears to confer increased overall mortality at 180 days, 1 year, and 2 years after diagnosis in MCC.
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Affiliation(s)
- David Schaub
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Joseph Gunderson
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Sierra Thompson
- Department of Surgery, A.T. Still University School of Osteopathic Medicine, Mesa, Arizona, USA
| | - Sabina Saeed
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Elisabeth Batzli
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Rohan Mittal
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Daniom Tecle
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Katherine Pavleszek
- Department of Surgery, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA, USA
| | - Valentine Nfonsam
- Department of Surgery, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA, USA
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11
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Su CC, Su YC, Wu CC, Lee PT. Explanatory Role of Conversion Surgery as a Mediator of the Mortality Risk Difference Between Patients With Unresectable Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR Agents Versus Bevacizumab. Clin Colorectal Cancer 2024; 23:364-371. [PMID: 38879376 DOI: 10.1016/j.clcc.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 12/01/2024]
Abstract
INTRODUCTION Bevacizumab and antiepidermal growth factor receptor-blocking (anti-EGFR) agents plus chemotherapy are first-line therapies for metastatic colorectal cancer (mCRC). Conversion surgery may improve outcomes; however, the extent to which it explains the difference in mortality rates among treatments is unclear. Herein, we aimed to assess the effects of conversion surgery on survival outcomes of patients with unresectable mCRC treated with bevacizumab and anti-EGFR agents. MATERIALS AND METHODS This retrospective cohort study included patients with mCRC treated with bevacizumab and anti-EGFR agents as first-line therapy. We estimated the direct and indirect effects of treatments by comparing the mortality risk associated with targeted therapy type. Hazard ratios (HR) and the corresponding confidence intervals (CI) were estimated. Mediation analysis was used to estimate hazard ratio differences, and the proportion mediated. RESULTS A total of 5,106 patients were included. The natural indirect effect of conversion surgery reduced mortality risk (HR: 0.95; 95% CI, 0.93-0.97), with a mediated proportion of 42% after propensity score adjustment. In subgroup analyses, KRAS wild-type (HR: 0.94; 95% CI: 0.91-0.97), left tumor sidedness (HR: 0.94; 95% CI, 0.91-0.96), and liver resection (HR: 0.95; 95% CI, 0.93-0.98) were associated with reduced risks of mortality. The controlled and total direct effects of targeted therapy were associated with reduced mortality risk in the anti-EGFR-treated group compared to those in the bevacizumab-treated group; however, this effect was not statistically significant. CONCLUSION Conversion surgery may account for the difference in survival outcomes between users of the anti-EGFR agents and bevacizumab.
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Affiliation(s)
- Chien-Chou Su
- Clinical Innovation and Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Chia Su
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Chih-Chien Wu
- Department of Surgery, Division of Colorectal Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Pei-Ting Lee
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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12
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Sawano H, Matsuoka H, Mizuno T, Kamiya T, Chong Y, Iwama H, Takahara T, Hiro J, Otsuka K, Ishihara T, Hayashi T, Suda K. Risk factors for residual liver recurrence of colorectal cancer after resection of liver metastases and significance of adjuvant chemotherapy. Asian J Surg 2024; 47:5124-5130. [PMID: 39034242 DOI: 10.1016/j.asjsur.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 04/05/2024] [Accepted: 07/04/2024] [Indexed: 07/23/2024] Open
Abstract
OBJECTIVE The risk factors for residual liver recurrence after resection of colorectal cancer liver metastases were analyzed separately for synchronous and metachronous metastases. METHODS This retrospective study included 236 patients (139 with synchronous and 97 with metachronous lesions) who underwent initial surgery for colorectal cancer liver metastases from April 2010 to December 2021 at the Fujita Health University Hospital. We performed univariate and multivariate analyses of risk factors for recurrence based on clinical background. RESULTS Univariate analysis of synchronous liver metastases identified three risk factors: positive lymph nodes (p = 0.018, HR = 2.067), ≥3 liver metastases (p < 0.001, HR = 2.382), and use of adjuvant chemotherapy (p = 0.013, HR = 0.560). Multivariate analysis identified the same three factors. For metachronous liver metastases, univariate and multivariate analysis identified ≥3 liver metastases as a risk factor (p = 0.002, HR = 2.988); however, use of adjuvant chemotherapy after hepatic resection was not associated with a lower risk of recurrence for metachronous lesions. Inverse probability of treatment weighting analysis of patients with these lesions with or without adjuvant chemotherapy after primary resection showed that patients with metachronous liver metastases who did not receive this treatment had fewer recurrences when adjuvant therapy was administered after subsequent liver resection, although the difference was not significant. Patients who received adjuvant chemotherapy after hepatic resection had less recurrence but less benefit from this treatment. CONCLUSION Risk factors for liver recurrence after resection of synchronous liver metastases were positive lymph nodes, ≥3 liver metastases, and no postoperative adjuvant chemotherapy. Adjuvant chemotherapy is recommended after hepatic resection of synchronous liver metastases.
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Affiliation(s)
- Hiroko Sawano
- College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan
| | - Hiroshi Matsuoka
- Department of Surgery, Fujita Health University School of Medicine, Toyoake, Japan.
| | - Tomohiro Mizuno
- Department of Pharmacotherapeutics and Informatics, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tadahiro Kamiya
- Department of Surgery, Fujita Health University School of Medicine, Toyoake, Japan
| | - Yongchol Chong
- Department of Surgery, Fujita Health University School of Medicine, Toyoake, Japan
| | - Hideaki Iwama
- Department of Surgery, Fujita Health University School of Medicine, Toyoake, Japan
| | - Takeshi Takahara
- Department of Surgery, Fujita Health University School of Medicine, Toyoake, Japan
| | - Junichiro Hiro
- Department of Surgery, Fujita Health University School of Medicine, Toyoake, Japan
| | - Koki Otsuka
- Department of Surgery, Fujita Health University School of Medicine, Toyoake, Japan
| | - Takuma Ishihara
- Innovative and Clinical Research Promotion Center, Gifu University Hospital, Yanagido, Gifu, Japan
| | | | - Kouichi Suda
- Department of Surgery, Fujita Health University School of Medicine, Toyoake, Japan
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13
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Lee CJ, Jang TY, Jeon SE, Yun HJ, Cho YH, Lim DY, Nam JS. The dysadherin/MMP9 axis modifies the extracellular matrix to accelerate colorectal cancer progression. Nat Commun 2024; 15:10422. [PMID: 39613801 PMCID: PMC11607440 DOI: 10.1038/s41467-024-54920-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 11/26/2024] [Indexed: 12/01/2024] Open
Abstract
The dynamic alteration of the tumor microenvironment (TME) serves as a driving force behind the progression and metastasis of colorectal cancer (CRC). Within the intricate TME, a pivotal player is the extracellular matrix (ECM), where modifications in components, degradation, and stiffness are considered critical factors in tumor development. In this study, we find that the membrane glycoprotein dysadherin directly targets matrix metalloprotease 9 (MMP9), initiating ECM remodeling within the TME and amplifying cancer progression. Mechanistically, the dysadherin/MMP9 axis not only enhances CRC cell invasiveness and ECM proteolytic activity but also activates cancer-associated fibroblasts, orchestrating the restructuring of the ECM through the synthesis of its components in human CRC cells, patient samples, and mouse models. Notably, disruption of ECM reorganization by dysadherin knockout results in a discernible reduction in the immunosuppressive and proangiogenic milieu in a humanized mouse model. Intriguingly, these effects are reversed upon the overexpression of MMP9, highlighting the intricate and pivotal role of the dysadherin/MMP9 axis in shaping the development of a malignant TME. Therefore, our findings not only highlight that dysadherin contributes to CRC progression by influencing the TME through ECM remodeling but also suggest that dysadherin may be a potential therapeutic target for CRC.
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Affiliation(s)
- Choong-Jae Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Tae-Young Jang
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - So-El Jeon
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Hyeon-Ji Yun
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Yeong-Hoon Cho
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Da-Ye Lim
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Jeong-Seok Nam
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
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14
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Kryczka J, Bachorz RA, Kryczka J, Boncela J. Radial Data Visualization-Based Step-by-Step Eliminative Algorithm to Predict Colorectal Cancer Patients' Response to FOLFOX Therapy. Int J Mol Sci 2024; 25:12149. [PMID: 39596218 PMCID: PMC11595261 DOI: 10.3390/ijms252212149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/04/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Application of the FOLFOX scheme to colorectal cancer (CRC) patients often results in the development of chemo-resistance, leading to therapy failure. This study aimed to develop a functional and easy-to-use algorithm to predict patients' response to FOLFOX treatment. Transcriptomic data of CRC patient's samples treated with FOLFOX were downloaded from the Gene Expression Omnibus database (GSE83129, GSE28702, GSE69657, GSE19860 and GSE41568). Comparing the expression of top up- and downregulated genes in FOLFOX responder and non-responder patients' groups, we selected 30 potential markers that were used to create a step-by-step eliminative procedure based on modified radial data visualization, which depicts the interplay between the expression level of chosen attributes (genes) to locate data points in low-dimensional space. Our analysis proved that FOLFOX-resistant CRC samples are predominantly characterized by upregulated expression levels of TMEM182 and MCM9 and downregulated LRRFIP1. Additionally, the procedure developed based on expression levels of TMEM182, MCM9, LRRFIP1, LAMP1, FAM161A, KLHL36, ETV5, RNF168, SRSF11, NCKAP5, CRTAP, VAMP2, ZBTB49 and RIMBP2 proved to be capable in predicting FOLFOX therapy response. In conclusion, our approach can give a unique insight into clinical decision-making regarding therapy scheme administration, potentially increasing patients' survival and, consequently, medical futility due to incorrect therapy application.
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Affiliation(s)
- Jakub Kryczka
- Laboratory of Cell Signaling, Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa St., 93-232 Lodz, Poland;
| | - Rafał Adam Bachorz
- Laboratory of Molecular Modeling, Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa St., 93-232 Lodz, Poland;
| | - Jolanta Kryczka
- Department of Biomedicine and Genetics, Medical University of Lodz, 92-213 Lodz, Poland;
| | - Joanna Boncela
- Laboratory of Cell Signaling, Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa St., 93-232 Lodz, Poland;
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15
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Chen HH, Luo CW, Chen YL, Chiang JY, Huang CR, Wang YT, Chen CH, Guo J, Yip HK. Probiotic-facilitated cytokine-induced killer cells suppress peritoneal carcinomatosis and liver metastasis in colorectal cancer cells. Int J Biol Sci 2024; 20:6162-6180. [PMID: 39664585 PMCID: PMC11628340 DOI: 10.7150/ijbs.101051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/19/2024] [Indexed: 12/13/2024] Open
Abstract
Background: This study tested the hypothesis that combined therapy with probiotics and cytokine-induced killer (CIK) cells was superior to merely one on suppressing the peritoneal carcinomatosis and liver metastasis of colorectal cancer (CRC) cells in nude mice. Methods and Results: The in vitro study revealed that in HCT 116/SW620 CRC cell lines, cell viability, proliferation, colony formation, migratory ability, wound healing, and protein expression of PD-L1 and FAK were significantly and comparably suppressed and that apoptosis was significantly and comparably increased by probiotics and CIK cells, and these effects were further significantly enhanced by combined probiotics + CIK cell therapy (all p<0.001). Nude mice were categorized into Groups 1 (SC), 2 (HCT 116), 3 (HCT 116 + probiotics), 4 (HCT 116 + CIK cells), and 5 (HCT 116 + probiotics + CIK cells). CRC cells were intraperitoneally implanted into Groups 2 to 5, and the animals were euthanized by Day 28. The results demonstrated that the abdominal dissemination of CRC cells, tumor numbers, tumor weights, liver weights, liver necrosis areas and the expression of γ-H2AX/PD-L1/FAK in harvested liver tumors were lowest in Group 1, highest in Group 2, and significantly and progressively decreased in Groups 3 to 5 (all p<0.0001). The protein expression levels of apoptotic and DNA damage biomarkers (Bax/c-caspase 3/c-PARP/γ-H2AX), a metastatic biomarker (FAK) and three tumor proliferation and survival signaling biomarkers (JAK-STAT1, PI3K/Akt/m-TOR and Ras/Raf/MEK/ERK) exhibited identical patterns to that of a tumor immune escape biomarker (PD-L1) among the groups (all p<0.0001). Conclusion: The combination of probiotics and CIK cells was superior to either therapy alone in suppressing CRC cell growth, proliferation, liver metastasis and survival, mainly through downregulating cell proliferation and survival signaling pathways.
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Affiliation(s)
- Hong-Hwa Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Chi-Wen Luo
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
- Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Yi-Ling Chen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - John Y. Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Chi-Ruei Huang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital Kaohsiung 833401, Taiwan
| | - Yi-Ting Wang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Chih-Hung Chen
- Divisions of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Jun Guo
- Department of Cardiology, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital Kaohsiung 833401, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
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16
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Lu CC, Lu CT, Chang KY, Chun-Li W, Wu CY. Robot-assisted vs. laparoscopic right hemicolectomy in octogenarians and nonagenarians: an analysis of the US nationwide inpatient sample 2005-2018. Aging Clin Exp Res 2024; 36:193. [PMID: 39311977 PMCID: PMC11420325 DOI: 10.1007/s40520-024-02833-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 08/09/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is a significant health concern, particularly among older adults. Outcomes between laparoscopic and robot-assisted surgeries for right-sided colon cancers in the oldest old population have yet to be evaluated despite increased use of these surgeries. AIM This study aimed to compare clinical outcomes after robot-assisted right hemicolectomy (RARH) versus laparoscopic right hemicolectomy (LRH) in octogenarian and nonagenarian patients. METHODS This population-based, retrospective and observational study analyzed the data of adults ≥ 80 years old diagnosed with right-side colon cancer who received RARH or LRH. All data were extracted from the US National Inpatient Sample (NIS) database 2005-2018. Associations between type of surgery and in-hospital outcomes were determined using univariate and multivariable logistic regression and linear regression analysis. RESULTS Data of 7,550 patients (representing 37,126 hospitalized patients in the U.S.) were analyzed. Mean age of the study population was 84.8 years, 61.4% were females, and 79.1% were non-smokers. After adjusting for relevant confounders, regression analysis showed that patients undergoing RARH had a significantly shorter LOS (adjusted Beta (aBeta), -0.24, 95% CI: -0.32, -0.15) but greater total hospital costs (aBeta, 26.54, 95% CI: 24.64, 28.44) than patients undergoing LRH. No significant differences in mortality, perioperative complications, and risk of unfavorable discharge were observed between the two procedures (p > 0.05). Stratified analyses by frailty status revealed consistent results. CONCLUSIONS RARH is associated with a significantly shorter LOS but higher total hospital costs than LRH among octogenarians and nonagenarians. Other short-term outcomes for this population are similar between the two procedures, including in-hospital mortality, perioperative complications, and unfavorable discharge. These findings also apply to frail patients.
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Affiliation(s)
- Chien-Chang Lu
- Department of Colorectal Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 123, Dapi Road, Niaosong District, Kaohsiung City, Taiwan.
| | - Chi-Tung Lu
- Department of Colorectal Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 123, Dapi Road, Niaosong District, Kaohsiung City, Taiwan
| | - Kai-Yen Chang
- Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Wang Chun-Li
- Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chien-Ying Wu
- Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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17
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Lund M, Bjerre TA, Grønbæk H, Mortensen FV, Andersen PK. CEUS compared with CECT, MRI, and FDG-PET/CT for diagnosing CRC liver metastases: a diagnostic test accuracy systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2024; 18:541-549. [PMID: 39315472 DOI: 10.1080/17474124.2024.2407973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 08/15/2024] [Accepted: 09/08/2024] [Indexed: 09/25/2024]
Abstract
OBJECTIVE To determine the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) compared with contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI), and Fluorine-18-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for diagnosing suspected liver metastases in patients with newly diagnosed colorectal cancer (CRC). METHODS The meta-analysis using the bivariate model included studies on patients with newly diagnosed CRC only and excluded patients with non-CRC liver metastases, known liver metastases, patients treated with chemotherapy and local treatments, e.g. hepatic resection or radiofrequency ablation. We used QUADAS-2 to assess the methodological quality of the studies. RESULTS We included 32 studies, 6 studies evaluated the accuracy of CEUS (n = 937 participants), 26 studies evaluated CECT (n = 2,582), 8 studies evaluated MRI (n = 564) and 6 studies evaluated FDG-PET/CT (n = 813). Sensitivity: FDG-PET/CT 94.4% [95% CI: 90.7-98.1%], MRI 92.9% [95% CI: 88.8-97.0%], CEUS 86.1% [95% CI: 78.0-94.3%] and CECT 84.6% [95% CI: 79.3-89.9%]. Specificity FDG-PET/CT 97.9% [95% CI: 95.9-99.9%], CEUS 96.1% [95% CI: 93.6-98.6%], MRI 94.4% [95% CI: 90.5-98.3%], and CECT 94.3% [95% CI: 91.8-96.8%]. CONCLUSION FDG-PET/CT had significantly higher sensitivity and specificity than CECT, and significantly higher sensitivity than CEUS. MRI had a significantly higher sensitivity than CEUS, but a lower non-significant specificity. CECT had the lowest sensitivity and specificity. PROSPERO REGISTRATION DETAILS CRD42017055015 and CRD42017082996.
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Affiliation(s)
- Martin Lund
- Department of Radiology, Randers Regional Hospital, Randers, Denmark
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Thomas A Bjerre
- Department of Radiology, Randers Regional Hospital, Randers, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Frank V Mortensen
- Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Per Kragh Andersen
- Department of Biostatistics, University of Copenhagen Faculty of Health Sciences, Institute of Public Health, Copenhagen K, Denmark
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18
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Bayat M, Sadri Nahand J. Exosomal miRNAs: the tumor's trojan horse in selective metastasis. Mol Cancer 2024; 23:167. [PMID: 39164756 PMCID: PMC11334467 DOI: 10.1186/s12943-024-02081-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 08/12/2024] [Indexed: 08/22/2024] Open
Abstract
Organs of future metastasis are not passive receivers of circulating tumor cells, but are instead selectively and actively modified by the primary tumor before metastatic spread has even occurred. Tumors orchestrate a pre-metastatic program by conditioning distant organs to create microenvironments that foster the survival and proliferation of tumor cells before their arrival, thereby establishing pre-metastatic niches. Primary tumor-derived exosomes modulate these pre-metastatic niches, generating a permissive environment that facilitates the homing and expansion of tumor cells. Moreover, microRNAs have emerged as a key component of exosomal cargo, serving not only to induce the formation of pre-metastatic niches but also to prime these sites for the arrival and colonization of specific secondary tumor populations. Against this backdrop, this review endeavors to elucidate the impact of tumor-derived exosomal microRNAs on the genesis of their individualized pre-metastatic niches, with a view towards identifying novel means of specifying cancer metastasis and exploiting this phenomenon for cancer immunotherapy.
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Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran.
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19
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Swierz MJ, Storman D, Mitus JW, Hetnal M, Kukielka A, Szlauer-Stefanska A, Pedziwiatr M, Wolff R, Kleijnen J, Bala MM. Transarterial (chemo)embolisation versus systemic chemotherapy for colorectal cancer liver metastases. Cochrane Database Syst Rev 2024; 8:CD012757. [PMID: 39119869 PMCID: PMC11311242 DOI: 10.1002/14651858.cd012757.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
BACKGROUND The liver is affected by two groups of malignant tumours: primary liver cancers and liver metastases. Liver metastases are significantly more common than primary liver cancer, and five-year survival after radical surgical treatment of liver metastases ranges from 28% to 50%, depending on primary cancer site. However, R0 resection (resection for cure) is not feasible in most people; therefore, other treatments have to be considered in the case of non-resectability. One possible option is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Transarterial chemoembolisation (TACE) of the peripheral branches of the hepatic artery can be achieved by administering a chemotherapeutic drug followed by vascular occlusive agents and can lead to selective necrosis of the cancer tissue while leaving normal liver parenchyma virtually unaffected. The entire procedure can be performed without infusion of chemotherapy and is then called bland transarterial embolisation (TAE). These procedures are usually applied over a few sessions. Another possible treatment option is systemic chemotherapy which, in the case of colorectal cancer metastases, is most commonly performed using FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) regimens applied in multiple sessions over a long period of time. These therapies disrupt the cell cycle, leading to death of rapidly dividing malignant cells. Current guidelines determine the role of TAE and TACE as non-curative treatment options applicable in people with liver-only or liver-dominant metastatic disease that is unresectable or non-ablatable, and in people who have failed systemic chemotherapy. Regarding the treatment modalities in people with colorectal cancer liver metastases, we found no systematic reviews comparing the efficacy of TAE or TACE versus systemic chemotherapy. OBJECTIVES To evaluate the beneficial and harmful effects of transarterial embolisation (TAE) or transarterial chemoembolisation (TACE) compared with systemic chemotherapy in people with liver-dominant unresectable colorectal cancer liver metastases. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three additional databases up to 4 April 2024. We also searched two trials registers and the European Medicines Agency database and checked reference lists of retrieved publications. SELECTION CRITERIA We included randomised clinical trials assessing beneficial and harmful effects of TAE or TACE versus systemic chemotherapy in adults (aged 18 years or older) with colorectal cancer liver metastases. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were all-cause mortality; overall survival (time to mortality); and any adverse events or complications. Our secondary outcomes were cancer mortality; health-related quality of life; progression-free survival; proportion of participants dying or surviving with progression of the disease; time to progression of liver metastases; recurrence of liver metastases; and tumour response measures (complete response, partial response, stable disease, and progressive disease). For the purpose of the review and to perform necessary analyses, whenever possible, we converted survival rates to mortality rates, as this was our primary outcome. For the analysis of dichotomous outcomes, we used the risk ratio (RR); for continuous outcomes, we used the mean difference; and for time to event outcomes, we calculated hazard ratios (HRs), all with 95% confidence intervals (CI). We used the standardised mean difference with 95% CIs when the trials used different instruments. We used GRADE to assess the certainty of evidence for each outcome. We based our conclusions on outcomes analysed at the longest follow-up. MAIN RESULTS We included three trials with 118 participants randomised to TACE versus 120 participants to systemic chemotherapy. Four participants were excluded; one due to disease progression prior to treatment and three due to decline in health. The trials reported data on one or more outcomes. Two trials were performed in China and one in Italy. The trials differed in terms of embolisation techniques and chemotherapeutic agents. Follow-up ranged from 12 months to 50 months. TACE may reduce mortality at longest follow-up (RR 0.86, 95% CI 0.79 to 0.94; 3 trials, 234 participants; very low-certainty evidence), but the evidence is very uncertain. TACE may have little to no effect on overall survival (time to mortality) (HR 0.61, 95% CI 0.37 to 1.01; 1 trial, 70 participants; very low-certainty evidence), any adverse events or complications (3 trials, 234 participants; very low-certainty evidence), health-related quality of life (2 trials, 154 participants; very low-certainty evidence), progression-free survival (1 trial, 70 participants; very low-certainty evidence), and tumour response measures (presented as the overall response rate) (RR 1.81, 95% CI 1.11 to 2.96; 3 trials, 234 participants; very low-certainty evidence), but the evidence is very uncertain. No trials reported cancer mortality, proportion of participants dying or surviving with progression of the disease, and recurrence of liver metastases. We found no trials comparing the effects of TAE versus systemic chemotherapy in people with colorectal cancer liver metastases. AUTHORS' CONCLUSIONS The evidence regarding effectiveness of TACE versus systemic chemotherapy in people with colorectal cancer liver metastases is of very low certainty and is based on three trials. Our confidence in the results is limited due to the risk of bias, inconsistency, indirectness, and imprecision. It is very uncertain whether TACE confers benefits with regard to reduction in mortality, overall survival (time to mortality), reduction in adverse events or complications, improvement in health-related quality of life, improvement in progression-free survival, and tumour response measures (presented as the overall response rate). Data on cancer mortality, proportion of participants dying or surviving with progression of the disease, and recurrence of liver metastases are lacking. We found no trials assessing TAE versus systemic chemotherapy. More randomised clinical trials are needed to strengthen the body of evidence and provide insight into the benefits and harms of TACE or TAE in comparison with systemic chemotherapy in people with liver metastases from colorectal cancer.
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Affiliation(s)
- Mateusz J Swierz
- Chair of Epidemiology and Preventive Medicine, Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland
| | - Dawid Storman
- Chair of Epidemiology and Preventive Medicine, Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland
| | - Jerzy W Mitus
- Department of Surgical Oncology, The Maria Sklodowska-Curie National Research Institute of Oncology, Krakow Branch; Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland
| | - Marcin Hetnal
- Faculty of Medicine & Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland
- Radiotherapy Centre Amethyst, Rydygier Memorial Hospital, Krakow, Poland
| | - Andrzej Kukielka
- Center for Oncology Diagnosis and Therapy, NU-MED, Zamosc, Poland
- Brachytherapy Department, University Hospital, Krakow, Poland
| | - Anastazja Szlauer-Stefanska
- Bone Marrow Transplantation and Oncohematology Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Michal Pedziwiatr
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland
| | | | | | - Malgorzata M Bala
- Chair of Epidemiology and Preventive Medicine, Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland
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Jeong JU, Rim CH, Yoo GS, Cho WK, Chie EK, Ahn YC, Lee JH, on behalf of Korean Oligometastasis Working Group, Korean Cancer Association. The Clinical Efficacy of Colorectal Cancer Patients with Pulmonary Oligometastases by Sterotactic Body Ablative Radiotherapy: A Meta-Analysis. Cancer Res Treat 2024; 56:809-824. [PMID: 38097919 PMCID: PMC11261202 DOI: 10.4143/crt.2023.920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 12/13/2023] [Indexed: 07/18/2024] Open
Abstract
PURPOSE There is increasing interest in the efficacy of stereotactic ablative radiotherapy (SABR) for treating colorectal cancer (CRC) patients with oligometastases (OM), recently. The purpose of this meta-analysis was to evaluate local control (LC), progression-free survival (PFS), and overall survival (OS) of CRC patients with pulmonary OM treated with SABR and toxicities. MATERIALS AND METHODS Studies that reported SABR for CRC patients with pulmonary OM were searched from MEDLINE and Embase. Treatment outcomes including LC, PFS, OS, and toxicities of grade 3 or higher were assessed. RESULTS A total of 19 studies with 1,668 patients were chosen for this meta-analysis. Pooled 1-, 2-, and 3-year LC rates were 83.1%, 69.3%, and 63.9%, respectively. PFS rates were 44.8%, 26.5%, and 21.5% at 1, 2, and 3 years, respectively. OS rates at 1-, 2-, and 3-year were 87.5%, 69.9%, and 60.5%, respectively. The toxicity rate of grade 3 or higher was 3.6%. The effect of dose escalation was meta-analyzed using available studies. CONCLUSION Application of SABR to CRC patients with pulmonary OM achieved modest local control with acceptable toxicity according to the present meta-analysis. Further studies establishing the clinical efficacy of SABR are guaranteed.
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Affiliation(s)
- Jae-Uk Jeong
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, Korea
| | - Chai Hong Rim
- Department of Radiation Oncology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Gyu Sang Yoo
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Kyung Cho
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eui Kyu Chie
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Chan Ahn
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Hoon Lee
- Department of Radiation Oncology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - on behalf of Korean Oligometastasis Working Group, Korean Cancer Association
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, Korea
- Department of Radiation Oncology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
- Department of Radiation Oncology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
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Lee YS, Mun JG, Park SY, Hong DY, Kim HY, Kim SJ, Lee SB, Jang JH, Han YH, Kee JY. Saikosaponin D Inhibits Lung Metastasis of Colorectal Cancer Cells by Inducing Autophagy and Apoptosis. Nutrients 2024; 16:1844. [PMID: 38931199 PMCID: PMC11206761 DOI: 10.3390/nu16121844] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Saikosaponin D (SSD), derived from Bupleurum falcatum L., has various pharmacological properties, including immunoregulatory, anti-inflammatory, and anti-allergic effects. Several studies have investigated the anti-tumor effects of SSD on cancer in multiple organs. However, its role in colorectal cancer (CRC) remains unclear. Therefore, this study aimed to elucidate the suppressive effects of SSD on CRC cell survival and metastasis. SSD reduced the survival and colony formation ability of CRC cells. SSD-induced autophagy and apoptosis in CRC cells were measured using flow cytometry. SSD treatment increased LC3B and p62 autophagic factor levels in CRC cells. Moreover, SSD-induced apoptosis occurred through the cleavage of caspase-9, caspase-3, and PARP, along with the downregulation of the Bcl-2 family. In the in vivo experiment, a reduction in the number of metastatic tumor nodules in the lungs was observed after the oral administration of SSD. Based on these results, SSD inhibits the metastasis of CRC cells to the lungs by inducing autophagy and apoptosis. In conclusion, SSD suppressed the proliferation and metastasis of CRC cells, suggesting its potential as a novel substance for the metastatic CRC treatment.
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Affiliation(s)
- Yoon-Seung Lee
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
| | - Jeong-Geon Mun
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
| | - Shin-Young Park
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
| | - Dah Yun Hong
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
| | - Ho-Yoon Kim
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
| | - Su-Jin Kim
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
| | - Sun-Bin Lee
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
| | - Jeong-Ho Jang
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
| | - Yo-Han Han
- Department of Microbiology, Wonkwang University School of Medicine, Iksan 54538, Jeonbuk, Republic of Korea
| | - Ji-Ye Kee
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, 460 Iksandae-ro, Iksan 54538, Jeonbuk, Republic of Korea
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Singla S, Jena G. Studies on the mechanism of local and extra-intestinal tissue manifestations in AOM-DSS-induced carcinogenesis in BALB/c mice: role of PARP-1, NLRP3, and autophagy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4321-4337. [PMID: 38091080 DOI: 10.1007/s00210-023-02878-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/28/2023] [Indexed: 05/23/2024]
Abstract
Colitis-associated colorectal cancer (CACC) is one of the devastating complications of long-term inflammatory bowel disease and is associated with substantial morbidity and mortality. Combination of azoxymethane (AOM) and dextran sulfate sodium (DSS) has been extensively used for inflammation-mediated colon tumor development due to its reproducibility, potency, histological and molecular changes, and resemblance to human CACC. In the tumor microenvironment and extra-intestinal tissues, PARP-1, NLRP3 inflammasome, and autophagy's biological functions are complicated and encompass intricate interactions between these molecular components. The focus of the present investigation is to determine the colonic and extra-intestinal tissue damage induced by AOM-DSS and related molecular mechanisms. Azoxymethane (10 mg/kg, i.p.; single injection) followed by DSS (3 cycles, 7 days per cycle) over a period of 10 weeks induced colitis-associated colon cancer in male BALB/c mice. By initiating carcinogenesis with a single injection of azoxymethane (AOM) and then establishing inflammation with dextran sulfate sodium (DSS), a two-stage murine model for CACC was developed. Biochemical parameters, ELISA, histopathological and immunohistochemical analysis, and western blotting have been performed to evaluate the colonic, hepatic, testicular and pancreatic damage. In addition, the AOM/DSS-induced damage has been assessed by analyzing the expression of a variety of molecular targets, including proliferating cell nuclear antigen (PCNA), interleukin-10 (IL-10), AMP-activated protein kinase (AMPK), poly (ADP-ribose) polymerase-1 (PARP-1), cysteine-associated protein kinase-1 (caspase-1), NLR family pyrin domain containing 3 (NLRP3), beclin-1, and interleukin-1β (IL-1β). Present findings revealed that AOM/DSS developed tumors in colon tissue followed by extra-intestinal hepatic, testicular, and pancreatic damages.
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Affiliation(s)
- Shivani Singla
- Facility for Risk Assessment and Intervention Studies, Dept. of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S, Nagar, Punjab, 160062, India
| | - Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Dept. of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S, Nagar, Punjab, 160062, India.
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Kyrochristou I, Giannakodimos I, Tolia M, Georgakopoulos I, Pararas N, Mulita F, Machairas N, Schizas D. Robotic Stereotactic Body Radiation Therapy for Oligometastatic Liver Metastases: A Systematic Review of the Literature and Evidence Quality Assessment. Diagnostics (Basel) 2024; 14:1055. [PMID: 38786353 PMCID: PMC11487420 DOI: 10.3390/diagnostics14101055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 05/25/2024] Open
Abstract
INTRODUCTION The role of stereotactic body radiation therapy (SBRT) as a locally effective therapeutic approach for liver oligometastases from tumors of various origin is well established. We investigated the role of robotic SBRT (rSBRT) treatment on oligometastatic patients with liver lesions. MATERIAL AND METHODS This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The PubMed and Scopus databases were accessed by two independent investigators concerning robotic rSBRT for liver metastases, up to 3 October 2023. RESULTS In total, 15 studies, including 646 patients with 847 lesions that underwent rSBRT, were included in our systematic review. Complete response (CR) after rSBRT was achieved in 40.5% (95% CI, 36.66-44.46%), partial response (PR) in 19.01% (95% CI, 16.07-22.33%), whereas stable disease (SD) was recorded in 14.38% (95% CI, 11.8-17.41%) and progressive disease (PD) in 13.22% (95% CI, 10.74-16.17%) of patients. Progression-free survival (PFS) rates at 12 and 24 months were estimated at 61.49% (95% CI, 57.01-65.78%) and 32.55% (95% CI, 28.47-36.92%), respectively, while the overall survival (OS) rates at 12 and 24 months were estimated at 58.59% (95% CI, 53.67-63.33%) and 44.19% (95% CI, 39.38-49.12%), respectively. Grade 1 toxicity was reported in 13.81% (95% CI, 11.01-17.18%), Grade 2 toxicity in 5.57% (95% CI, 3.82-8.01%), and Grade 3 toxicity in 2.27% (955 CI, 1.22-4.07%) of included patients. CONCLUSIONS rSBRT represents a promising method achieving local control with minimal toxicity in a significant proportion of patients. Further studies are needed to evaluate the role of rSBRT in the management of metastatic liver lesions.
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Affiliation(s)
- Ilektra Kyrochristou
- Second Department of Surgery, General Hospital of Nikaia, 18454 Athens, Greece; (I.K.); (I.G.)
| | - Ilias Giannakodimos
- Second Department of Surgery, General Hospital of Nikaia, 18454 Athens, Greece; (I.K.); (I.G.)
| | - Maria Tolia
- Department of Radiation Oncology, School of Medicine, University of Crete, 71300 Heraklion, Greece;
| | - Ioannis Georgakopoulos
- Radiation Oncology Unit, First Department of Radiology, Medical School, Aretaieion Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolaos Pararas
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Francesk Mulita
- Department of General Surgery, University General Hospital of Patras, 26504 Patras, Greece;
| | - Nikolaos Machairas
- Second Department of Propaedeutic Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Song J, Zhang Y, Zhou C, Zhan J, Cheng X, Huang H, Mao S, Zong Z. The dawn of a new Era: mRNA vaccines in colorectal cancer immunotherapy. Int Immunopharmacol 2024; 132:112037. [PMID: 38599100 DOI: 10.1016/j.intimp.2024.112037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/24/2024] [Accepted: 04/05/2024] [Indexed: 04/12/2024]
Abstract
Colorectal cancer (CRC) is a typical cancer that accounts for 10% of all new cancer cases annually and nearly 10% of all cancer deaths. Despite significant progress in current classical interventions for CRC, these traditional strategies could be invasive and with numerous adverse effects. The poor prognosis of CRC patients highlights the evident and pressing need for more efficient and targeted treatment. Novel strategies regarding mRNA vaccines for anti-tumor therapy have also been well-developed since the successful application for the prevention of COVID-19. mRNA vaccine technology won the 2023 Nobel Prize in Physiology or Medicine, signaling a new direction in human anti-cancer treatment: mRNA medicine. As a promising new immunotherapy in CRC and other multiple cancer treatments, the mRNA vaccine has higher specificity, better efficacy, and fewer side effects than traditional strategies. The present review outlines the basics of mRNA vaccines and their advantages over other vaccines and informs an available strategy for developing efficient mRNA vaccines for CRC precise treatment. In the future, more exploration of mRNA vaccines for CRC shall be attached, fostering innovation to address existing limitations.
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Affiliation(s)
- Jingjing Song
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; School of Ophthalmology and Optometry, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Yujun Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; Huankui Academy, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Chulin Zhou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; The Second Clinical Medical College, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Jianhao Zhan
- Huankui Academy, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Xifu Cheng
- School of Ophthalmology and Optometry, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Haoyu Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China
| | - Shengxun Mao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China.
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China.
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Laenger JG, Rooney EF, Dial PF, Le CT, Tan SA. Colon Cancer Metastasis to Spermatic Cord Presenting as an Inguinal Hernia. HCA HEALTHCARE JOURNAL OF MEDICINE 2024; 5:133-138. [PMID: 38984220 PMCID: PMC11229589 DOI: 10.36518/2689-0216.1593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2024]
Abstract
Introduction Inguinal hernias are very common. Their pathology and treatment are typically strait forward. Metastatic cancer can sometimes present as an inguinal hernia, but this presentation is often local metastasis. Case Presentation Herein we describe the case of a 68-year-old man who presented with a 2-month history of an inguinal hernia. Intraoperatively, the hernia sac was found to contain a mass attached to the spermatic cord, which was later determined to be a metastatic lesion from a locally advanced proximal transverse colon adenocarcinoma. Conclusion A spermatic cord mass can be a rare presentation of colon cancer metastasis. Colon cancer should be considered a rare but possible primary lesion when evaluating tumors of the spermatic cord.
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Affiliation(s)
| | - Eamon Ff Rooney
- General Surgery Residency, University of Central Florida, Orlando, FL
- HCA Florida West Hospital, Pensacola, FL
| | | | | | - Sanda A Tan
- Florida State University College of Medicine, Pensacola, FL
- General Surgery Residency, University of Central Florida, Orlando, FL
- HCA Florida West Hospital, Pensacola, FL
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Su YC, Wu CC, Chen YH, Su CC, Chang YC, Hsieh MC, Kao Yang YH. Assessing the effectiveness of targeted agents in adjuvant therapy for patients with metastatic colorectal cancer undergoing surgical resection: a retrospective cohort study. Ther Adv Med Oncol 2024; 16:17588359241246427. [PMID: 38655393 PMCID: PMC11036930 DOI: 10.1177/17588359241246427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Background Primary tumor resection and metastasectomy may be beneficial for many patients with metastatic colorectal cancer (mCRC). Objective To assess the differences in postoperative survival outcomes between adjuvant therapy with chemotherapy alone and chemotherapy plus targeted agents (TAs). Design Retrospective cohort study. Methods Patients with mCRC who underwent surgical resection for primary colorectal tumor and distant metastases and received adjuvant therapy from 1 January 2010 to 31 December 2017 were enrolled in the Taiwan Cancer Registry. We analyzed the overall survival of patients with resectable or initially unresectable mCRC who received adjuvant chemotherapy alone and chemotherapy plus TAs. Results We enrolled 1124 and 542 patients with resectable and initially unresectable mCRC, respectively. Adjuvant chemotherapy plus TAs and chemotherapy alone resulted in similar mortality rates among patients with resectable mCRC [adjusted hazard ratio (aHR) = 1.13; 95% confidence interval (CI), 0.93-1.36]; however, it marginally reduced the mortality rate among patients with initially unresectable mCRC who underwent conversion surgery after neoadjuvant therapy (aHR = 0.81; 95% CI, 0.62-1.06). The subgroup analysis of patients who received more than nine cycles of TAs preoperatively and anti-epidermal growth factor receptor agents revealed aHRs of 0.48 (95% CI, 0.27-0.87) and 0.33 (95% CI, 0.18-0.60), respectively. Conclusion Adjuvant chemotherapy plus TAs may improve survival in patients with initially unresectable tumors who underwent conversion surgery following neoadjuvant therapy with TAs, especially in those who respond well to the targeted therapy. Our study underscores the importance of stratifying patients with mCRC based on tumor resectability when selecting the adjuvant therapy regimen.
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Affiliation(s)
- Yi-Chia Su
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
- Department of Nursing, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan
| | - Chih-Chien Wu
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Hsun Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chien-Chou Su
- Clinical Innovation Center, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Ching Chang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Meng-Che Hsieh
- Department of Hematology and Oncology, E-Da Cancer Hospital, Kaohsiung, Taiwan
- College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Yea-Huei Kao Yang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan
- Health Outcome Research Center, National Cheng Kung University, Tainan, Taiwan
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Tivadar BM, Dumitrascu T, Vasilescu C. A Glimpse into the Role and Effectiveness of Splenectomy for Isolated Metachronous Spleen Metastasis of Colorectal Cancer Origin: Long-Term Survivals Can Be Achieved. J Clin Med 2024; 13:2362. [PMID: 38673636 PMCID: PMC11050850 DOI: 10.3390/jcm13082362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/15/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024] Open
Abstract
Background: Many papers exploring the role of resectioning metastases in colorectal cancer (CRC) have focused mainly on liver and lung sites, showing improved survival compared with non-resectional therapies. However, data about exceptional metastatic sites such as splenic metastases (SMs) are scarce. This paper aims to assess the role and effectiveness of splenectomy in the case of isolated metachronous SM of CRC origin. Methods: The patients' data were extracted after a comprehensive literature search through public databases for articles reporting patients with splenectomies for isolated metachronous SM of CRC origin. Potential predictors of survival were explored, along with demographic, diagnostic, pathology, and treatment data for each patient. Results: A total of 83 patients with splenectomies for isolated metachronous SM of CRC origin were identified. The primary CRC was at an advanced stage (Duke's C-70.3%) and on the left colon (45.5%) for most patients, while the median interval between CRC resection and SM was 24 months. The median overall survival after splenectomy was 84 months, and patients younger than 62 years presented statistically significantly worse overall survival rates than those ≥62 years old (p = 0.011). There was no significant impact on the long-term outcomes for factors including primary tumor location or adjuvant chemotherapy (p values ≥ 0.070, ns). Laparoscopic splenectomy was increasingly used in the last 20 years from 2002 (33.3% vs. 0%, p < 0.001). Conclusions: Splenectomy is the optimal treatment for patients with isolated metachronous SM of CRC, with the laparoscopic approach being increasingly used and having the potential to become a standard of care. Encouraging long-term survival rates were reported in the context of a multidisciplinary approach. Younger ages are associated with worse survival. Perioperative chemotherapy in the context of a patient diagnosed with SM of CRC origin appears to be a reasonable option, although the present study failed to show any significant impact on long-term survival.
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Affiliation(s)
| | - Traian Dumitrascu
- Department of General Surgery, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Fundeni Street No. 258, 022328 Bucharest, Romania; (B.M.T.); (C.V.)
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Luther L, McGlone PJ, Hardacker KD, Alsoof D, Hayda RA, Terek RM. Distal Fibular Metastasis of Colorectal Carcinoma: A Case Report. Orthop Rev (Pavia) 2024; 16:91505. [PMID: 38469575 PMCID: PMC10927312 DOI: 10.52965/001c.91505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 12/03/2023] [Indexed: 03/13/2024] Open
Abstract
Case A 62-year-old woman presenting with ankle pain was initially treated for a non-displaced fracture. Persistent pain despite months of conservative management for her presumed injury prompted repeat radiographs which demonstrated the progression of a lytic lesion and led to an orthopedic oncology referral. Following a complete work-up, including biopsy and staging, she was diagnosed with colorectal carcinoma metastatic to the distal fibula. Conclusion Secondary tumors of the fibula are uncommon but an important diagnosis to consider for intractable lower extremity pain especially in patients with history of malignancy or lack of age-appropriate cancer screening.
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Affiliation(s)
| | | | | | - Daniel Alsoof
- Corresponding Author: Daniel Alsoof Department of Orthopaedic Surgery Brown University, Warren Alpert School of Medicine 1 Kettle Point Avenue Providence, RI 02906
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Sommerhäuser G, Karthaus M, Kurreck A, Ballhausen A, Meyer-Knees JW, Fruehauf S, Graeven U, Mueller L, Koenig AO, Weikersthal LFV, Goekkurt E, Haas S, Stahler A, Heinemann V, Held S, Alig AHS, Kasper-Virchow S, Stintzing S, Trarbach T, Modest DP. Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic colorectal cancer: Subgroup analysis of patients treated within the PanaMa trial (AIO KRK 0212). Int J Cancer 2024; 154:863-872. [PMID: 37840339 DOI: 10.1002/ijc.34760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/16/2023] [Accepted: 07/25/2023] [Indexed: 10/17/2023]
Abstract
Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered.
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Affiliation(s)
- Greta Sommerhäuser
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Meinolf Karthaus
- Department of Hematology, Oncology, and Palliative Care, Klinikum Neuperlach/Klinikum Harlaching, Munich, Germany
| | - Annika Kurreck
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alexej Ballhausen
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Johanna W Meyer-Knees
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Stefan Fruehauf
- Department of Hematology, Oncology, and Palliative Care, Klinik Dr. Hancken GmbH, Stade, Germany
| | - Ullrich Graeven
- Department of Hematology, Oncology, and Gastroenterology, Kliniken Maria Hilf GmbH, Moenchengladbach, Germany
| | | | - Alexander O Koenig
- Department of Gastroenterology and Gastrointestinal Oncology Goettingen, University Medical Center Goettingen, Germany
| | | | - Eray Goekkurt
- Practice of Hematology and Oncology (HOPE), Hamburg, Germany
| | - Siegfried Haas
- Department of Hematology and Oncology, Friedrich-Ebert-Hospital, Neumuenster, Germany
| | - Arndt Stahler
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Volker Heinemann
- Department of Hematology/Oncology, and Comprehensive Cancer Center Munich, LMU Klinikum, University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | | | - Annabel H S Alig
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Stefan Kasper-Virchow
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
- West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany
| | - Sebastian Stintzing
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Tanja Trarbach
- West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany
- Reha-Zentrum am Meer, Bad Zwischenahn, Germany
| | - Dominik P Modest
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
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Zhao H, Song G, Wang R, Guan N, Yun C, Yang J, Ma JB, Li H, Xiao W, Peng L. Primary tumor resection improves prognosis of unresectable carcinomas of the transverse colon including flexures with pulmonary metastasis: a cohort study. Eur J Cancer Prev 2024; 33:95-104. [PMID: 37823436 PMCID: PMC10833197 DOI: 10.1097/cej.0000000000000841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/15/2023] [Indexed: 10/13/2023]
Abstract
PURPOSE Studies of unresectable colorectal cancer pulmonary metastasis (CRPM) have rarely analyzed patient prognosis from the perspective of colonic subsites. This study aimed to evaluate the effects of primary tumor resection (PTR) on the prognosis of patients with unresectable pulmonary metastases of transverse colon cancer pulmonary metastasis (UTCPM), hepatic flexure cancer pulmonary metastasis (UHFPM), and splenic flexure cancer pulmonary metastasis (USFPM). METHODS Patients were identified from the Surveillance, Epidemiology, and End Results database between 2000 and 2018. The Cox proportional hazards regression models were used to identify prognostic factors of overall survival (OS) and cause-specific survival (CSS). The Kaplan-Meier analyses and log-rank tests were conducted to assess the effectiveness of PTR on survival. RESULTS This study included 1294 patients: 419 with UHFPM, 636 with UTCPM, and 239 with USFPM. Survival analysis for OS and CSS in the PTR groups, showed that there were no statistical differences in the the UHFPM, UTCPM, and USFPM patients. There were statistical differences in the UHFPM, UTCPM, and USFPM patients for OS and CSS. Three non-PTR subgroups showed significant statistical differences for OS and CSS. CONCLUSION We confirmed the different survival rates of patients with UTCPM, UHFPM, and USFPM and proved for the first time that PTR could provide survival benefits for patients with unresectable CRPM from the perspective of the colonic subsites of the transverse colon, hepatic flexure, and splenic flexure.
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Affiliation(s)
- Huixia Zhao
- Department of Oncology, The Fourth Medical Center of PLA General Hospital
| | - Guangze Song
- Department of Orthopedics, Aerospace Center Hospital, Beijing
| | - Ruliang Wang
- Department of Oncology, Haihe Hospital, Tianjin University, Tianjin
| | - Na Guan
- Jinzhou Medical University, Shenyang
| | - Chao Yun
- Department of Oncology, The Fourth Medical Center of PLA General Hospital
| | - Jingwen Yang
- Department of Oncology, The Fourth Medical Center of PLA General Hospital
| | - Jin-Bao Ma
- Department of Drug-resistance Tuberculosis, West Section of HangTian Avenue, Xi’an Chest Hospital, Xi’an, Shanxi Province, China
| | - Hui Li
- Department of Oncology, The Fourth Medical Center of PLA General Hospital
| | - Wenhua Xiao
- Department of Oncology, The Fourth Medical Center of PLA General Hospital
| | - Liang Peng
- Department of Oncology, The Fourth Medical Center of PLA General Hospital
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Papavassiliou AG, Delle Cave D. Novel Therapeutic Approaches for Colorectal Cancer Treatment. Int J Mol Sci 2024; 25:2228. [PMID: 38396903 PMCID: PMC10889277 DOI: 10.3390/ijms25042228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
According to GLOBOCAN 2020 data, colorectal cancer (CRC) represents the third most common malignancy and the second most deadly cancer worldwide [...].
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Affiliation(s)
- Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Donatella Delle Cave
- Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, CNR, 80131 Naples, Italy
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Alfonsín G, Berral-González A, Rodríguez-Alonso A, Quiroga M, De Las Rivas J, Figueroa A. Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours. Int J Mol Sci 2024; 25:1919. [PMID: 38339195 PMCID: PMC10856263 DOI: 10.3390/ijms25031919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/17/2024] [Accepted: 01/27/2024] [Indexed: 02/12/2024] Open
Abstract
The consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin-ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelial-to-mesenchymal transition (EMT), tumour progression and metastasis. Using bioinformatic methods, we have analysed CBLL1 expression on a large integrated cohort of primary tumour samples from CRC patients. The cohort included survival data and was divided into consensus molecular subtypes. Colon cancer tumourspheres were used to analyse the expression of stem cancer cells markers via RT-PCR and Western blotting. We show that CBLL1 gene expression is specifically associated with canonical subtype CMS2. WNT target genes LGR5 and c-MYC show a similar association with CMS2 as CBLL1. These mRNA levels are highly upregulated in cancer tumourspheres, while CBLL1 silencing shows a clear reduction in tumoursphere size and in stem cell biomarkers. Importantly, CMS2 patients with high CBLL1 expression displayed worse overall survival (OS), which is similar to that associated with CMS4 tumours. Our findings reveal CBLL1 as a specific biomarker for CMS2 and the potential of using CMS2 with high CBLL1 expression to stratify patients with poor OS.
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Affiliation(s)
- Gloria Alfonsín
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (G.A.); (A.R.-A.); (M.Q.)
| | - Alberto Berral-González
- Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL & IBSAL), Consejo Superior de Investigaciones Cientificas (CSIC), University of Salamanca (USAL) and Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Andrea Rodríguez-Alonso
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (G.A.); (A.R.-A.); (M.Q.)
| | - Macarena Quiroga
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (G.A.); (A.R.-A.); (M.Q.)
| | - Javier De Las Rivas
- Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL & IBSAL), Consejo Superior de Investigaciones Cientificas (CSIC), University of Salamanca (USAL) and Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Angélica Figueroa
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (G.A.); (A.R.-A.); (M.Q.)
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Huang CR, Chu YT, Chang CL, Yip HK, Chen HH. ZNF746 plays cardinal roles on colorectal cancer (CRC) cell invasion and migration and regulates mitochondrial dynamics and morphological changes of CRC cells-Role of combined melatonin and 5-FU regimen. J Cell Biochem 2024; 125:e30507. [PMID: 38047497 DOI: 10.1002/jcb.30507] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 11/10/2023] [Accepted: 11/20/2023] [Indexed: 12/05/2023]
Abstract
The underlying mechanism of colorectal cells developing into cancer cells has been extensively investigated, yet is still not fully delineated, resulting in the treatment of advanced colorectal cancer (CRC) remains regrettably an unmet need. Zinc Finger Protein 746/Parkin-interacting substrate (ZNF746/PARIS) has previously been identified to play a fundamental role on bladder cancer cell proliferation and metastasis that were effectively inhibited by melatonin (Mel). In this study, we utilized ex vivo/in vivo studies to verify whether the ZNF746 signaling was also crucial in CRC growth/invasion/migration. Tissue-bank specimens showed that the protein expression of ZNF746 was significantly increased in CRC than that of healthy colorectal tissues (p < 0.001). Additionally, in vitro study demonstrated that excessive expression of ZNF746 significantly inhibited mitochondrial activity via (1) interfering with the dynamic balance of mitochondrial fusion/fission and (2) inhibiting the protein expression of MFN1/MFN2/PGC1a (all p < 0.001). Furthermore, we identified that inhibition of ZNF746 protein expression significantly reduced the resistance of CRC cell lines to the anticancer drug of 5-FU (p < 0.001), whereas overexpression of ZNF746 significantly augmented resistance of CRC cells to 5-FU (all p < 0.001). Finally, using the cell culture method, we found that combined Mel and 5-FU was superior to merely one on promoting the CRC cell apoptosis (p < 0.001). Our results confirmed that ZNF746 signaling played a cardinal role of CRC cell proliferation/survival and combined Mel and 5-FU treatment attenuated the resistance of CRC cells to the drug mainly through suppressing this signaling.
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Affiliation(s)
- Chi-Ruei Huang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital Kaohsiung, Kaohsiung, Taiwan
| | - Yu-Ting Chu
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital Kaohsiung, Kaohsiung, Taiwan
| | - Chia-Lo Chang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital Kaohsiung, Kaohsiung, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital Kaohsiung, Kaohsiung, Taiwan
- Department of Nursing, Asia University Taichung, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Hong-Hwa Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Lan YZ, Wu Z, Chen WJ, Fang ZX, Yu XN, Wu HT, Liu J. Small nucleolar RNA and its potential role in the oncogenesis and development of colorectal cancer. World J Gastroenterol 2024; 30:115-127. [PMID: 38312115 PMCID: PMC10835520 DOI: 10.3748/wjg.v30.i2.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/21/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Small nucleolar RNAs (snoRNAs) represent a class of non-coding RNAs that play pivotal roles in post-transcriptional RNA processing and modification, thereby contributing significantly to the maintenance of cellular functions related to protein synthesis. SnoRNAs have been discovered to possess the ability to influence cell fate and alter disease progression, holding immense potential in controlling human diseases. It is suggested that the dysregulation of snoRNAs in cancer exhibits differential expression across various cancer types, stages, metastasis, treatment response and/or prognosis in patients. On the other hand, colorectal cancer (CRC), a prevalent malignancy of the digestive system, is characterized by high incidence and mortality rates, ranking as the third most common cancer type. Recent research indicates that snoRNA dysregulation is associated with CRC, as snoRNA expression significantly differs between normal and cancerous conditions. Consequently, assessing snoRNA expression level and function holds promise for the prognosis and diagnosis of CRC. Nevertheless, current comprehension of the potential roles of snoRNAs in CRC remains limited. This review offers a comprehensive survey of the aberrant regulation of snoRNAs in CRC, providing valuable insights into the discovery of novel biomarkers, therapeutic targets, and potential tools for the diagnosis and treatment of CRC and furnishing critical cues for advancing research into CRC and the judicious selection of therapeutic targets.
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Affiliation(s)
- Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xin-Ning Yu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Khorasani M. Role of cGAS-STING in colorectal cancer: A new window for treatment strategies. Cytokine 2024; 173:156422. [PMID: 37948979 DOI: 10.1016/j.cyto.2023.156422] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 10/29/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023]
Abstract
Colorectal cancer (CRC) is a common and deadly form of cancer, leading to the need for new therapeutic targets and strategies for treatment. Recent studies have shown the cGAS-STING pathway to be a promising target for cancer therapy. The cGAS-STING pathway is a part of the innate immune system and serves to identify DNA damage and viral infection, promoting an immune response. Activation of this pathway leads to the production of immune mediators, such as type I interferons, that activate immune cells to attack cancer cells. Research has identified the cGAS-STING pathway as a frequently dysregulated component in CRC, promoting tumor growth and metastasis, or leading to chronic inflammation and tissue damage. The modulation of this pathway presents a potential therapeutic approach, either activating or inhibiting the pathway to enhance the immune response and prevent inflammation, respectively. Developing drugs that can modulate the cGAS-STING pathway offers promise for improving treatment outcomes for CRC patients. The present review explores recent research on the role of cGAS-STING in CRC and highlights the potential therapeutic benefits of targeting this pathway.
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Affiliation(s)
- Milad Khorasani
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran; Department of Biochemistry and Nutrition, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Wang J, Zhang S, He Y, Sun W, Zhu X, Xi Z, Ma Q, Ye Y, Song Z, Zhang Y, Shao G. A Comparative Study of DC Beads, Callispheres and Multimodal Imaging Nano-Assembled Microspheres Loaded with Irinotecan in Vitro. Technol Cancer Res Treat 2024; 23:15330338241274289. [PMID: 39149935 PMCID: PMC11456700 DOI: 10.1177/15330338241274289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/02/2024] [Accepted: 07/12/2024] [Indexed: 08/17/2024] Open
Abstract
Introduction: In recent years, the development of drug-eluting embolization beads that can be imaged has become a hot research topic in regard to meeting clinical needs. In our previous study, we successfully developed nano-assembled microspheres (NAMs) for multimodal imaging purposes. NAMs can not only be visualized under CT/MR/Raman imaging but can also load clinically required doses of doxorubicin. It is important to systematically compare the pharmacokinetics of NAMs with those of commercially available DC Beads and CalliSpheres to evaluate the clinical application potential of NAMs. Methods: In our study, we compared NAMs with two types of drug-eluting beads (DEBs) in terms of irinotecan, drug-loading capacity, release profiles, microsphere diameter variation, and morphological characteristics. Results: Our results indicate that NAMs had an irinotecan loading capacity similar to those of DC Beads and CalliSpheres but exhibited better sustained release in vitro. Conclusion: NAMs have great potential for application in transcatheter arterial chemoembolization for the treatment of colorectal cancer liver metastases.
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Affiliation(s)
- Jieyu Wang
- Wenzhou Medical University, Wenzhou, China
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Shaoya Zhang
- Zhejiang University of Technology, Hangzhou, China
| | - Yiwei He
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Wan Sun
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Xiaoyang Zhu
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Zihan Xi
- Wenzhou Medical University, Wenzhou, China
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Qian Ma
- Wenzhou Medical University, Wenzhou, China
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yuanxin Ye
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ziyang Song
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yuqing Zhang
- School of Automation, Hangzhou Dianzi University, Hangzhou, China
| | - Guoliang Shao
- Wenzhou Medical University, Wenzhou, China
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
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Tang F, Huang CW, Tang ZH, Lu SL, Bai T, Huang Q, Li XZ, Zhang B, Wu FX. Prognostic role of serum carcinoembryonic antigen in patients receiving liver resection for colorectal cancer liver metastasis: A meta-analysis. World J Gastrointest Surg 2023; 15:2890-2906. [PMID: 38222018 PMCID: PMC10784827 DOI: 10.4240/wjgs.v15.i12.2890] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 11/03/2023] [Accepted: 11/28/2023] [Indexed: 12/27/2023] Open
Abstract
BACKGROUND Carcinoembryonic antigen (CEA) is a broad-spectrum tumor marker for differential diagnosis, monitoring, and response assessment of a variety of malignancies. AIM To evaluate whether serum CEA could predict the prognosis in patients with colorectal cancer liver metastasis (CRCLM) before and after liver resection (LR). METHODS PubMed, Embase, Cochrane, and Web of Science were systematically searched to retrieve literature, with a search cut-off date of February 27, 2023. Articles were strictly screened for inclusion according to pre-specified inclusion and exclusion criteria. Data were pooled and analyzed using Stata 16.0. RESULTS This meta-analysis included 36 studies involving a total of 11143 CRCLM patients. The results showed that a high pre-LR serum CEA level was correlated with poor overall survival (OS) [hazard ratio (HR) = 1.61, 95% confidence interval (CI): 1.49-1.75, P < 0.001] and recurrence-free survival (HR = 1.27, 95%CI: 1.11-1.45, P < 0.001) in CRCLM patients. A high post-LR serum CEA level predicted poor OS (HR = 2.66, 95%CI: 2.10-3.38, P < 0.001). A comparison by treatment modality, analysis modality, patient source, and cutoff-value showed that overall, high preoperative and postoperative serum CEA levels remained correlated with a poor prognosis. CONCLUSION This study concluded that high pre-LR and post-LR serum CEA levels were significantly correlated with a poor prognosis in CRCLM patients.
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Affiliation(s)
- Fan Tang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Cheng-Wen Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Hong Tang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shao-Long Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Bai
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Qing Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xing-Zhi Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Bin Zhang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fei-Xiang Wu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Tom CK, Placone N, Yung E, Shaker A. The Travels of Signet-Ring Cell Carcinoma: From Colon to Stomach and Duodenum. ACG Case Rep J 2023; 10:e01239. [PMID: 38130481 PMCID: PMC10735161 DOI: 10.14309/crj.0000000000001239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 11/16/2023] [Indexed: 12/23/2023] Open
Abstract
Colorectal cancer (CRC) metastasizing to the stomach and duodenum is rare. Even rarer is when the CRC subtype is signet-ring cell carcinoma (SRCC). Endoscopic findings of CRC metastasis to the stomach have been described as solitary and submucosal while duodenal metastasis has been observed to be exophytic. In this report, we describe a case of a middle-aged man with colon SRCC presenting with oral intolerance. He was found to have concurrent metastases to the stomach and duodenum and died 8 months after his SRCC diagnosis.
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Affiliation(s)
- Chloe K. Tom
- Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA
| | - Nicholas Placone
- Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA
| | - Evan Yung
- Department of Pathology, University of Southern California, Los Angeles, CA
| | - Anisa Shaker
- Division of Gastrointestinal and Liver Diseases and Swallowing and Esophageal Disorders Center, University of Southern California, Los Angeles, CA
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39
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Fu MX, Carvalho C, Milan-Chhatrisha B, Gadi N. Stereotactic Body Radiotherapy for Management of Pulmonary Oligometastases in Stage IV Colorectal Cancer: A Perspective. Clin Colorectal Cancer 2023; 22:402-410. [PMID: 37748936 DOI: 10.1016/j.clcc.2023.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 02/05/2023] [Accepted: 09/05/2023] [Indexed: 09/27/2023]
Abstract
In pulmonary oligometastases from colorectal cancer (POM-CRC), metastasectomy is the primarily recommended treatment. Stereotactic body radiotherapy (SBRT) has been suggested as a viable alternative therapy. SBRT efficacy for POM-CRC is poorly delineated compared to selected non-CRC primaries. This perspective article aims to critically summarize the existing evidence regarding efficacy of SBRT in terms of overall survival (OS) and local control (LC), and factors modulating this, in the treatment of POM-CRC. Overall, reasonable LC and OS rates were observed. The wide range of expansions in planning target volume margins introduced variation in pretreatment protocols. Dose-fractionation schedules varied according to patient and tumor characteristics, though leverage of BED10 in select studies enabled standardization. An association between SBRT dose and improved OS and LC was observed across multiple studies. Prognostic factors that were associated with improved LC included: fewer oligometastases, absence of extra-pulmonary metastases, primary tumor histology, and smaller gross tumor volume. Differences in SBRT modality and techniques over time further confounded results. Many studies included patients receiving additional systemic therapies; preprotocol and adjuvant chemotherapies were identified as prognostic factors for LC. SBRT compared with metastasectomy showed no differences in short-term OS and LC outcomes. In conclusion, SBRT is an efficacious treatment for POM-CRC, in terms of OS and LC. Heterogeneity in study design, particularly pertaining to dose protocols, patient selection, and additional therapies should be controlled for future randomized studies to further validate SBRT efficacy.
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Affiliation(s)
- Michael X Fu
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.
| | - Catarina Carvalho
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Bella Milan-Chhatrisha
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Nishita Gadi
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
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40
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Lu Y, Chen QM, An L. Semi-reference based cell type deconvolution with application to human metastatic cancers. NAR Genom Bioinform 2023; 5:lqad109. [PMID: 38143958 PMCID: PMC10748484 DOI: 10.1093/nargab/lqad109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 11/01/2023] [Accepted: 12/13/2023] [Indexed: 12/26/2023] Open
Abstract
Bulk RNA-seq experiments, commonly used to discern gene expression changes across conditions, often neglect critical cell type-specific information due to their focus on average transcript abundance. Recognizing cell type contribution is crucial to understanding phenotype and disease variations. The advent of single-cell RNA sequencing has allowed detailed examination of cellular heterogeneity; however, the cost and analytic caveat prohibits such sequencing for a large number of samples. We introduce a novel deconvolution approach, SECRET, that employs cell type-specific gene expression profiles from single-cell RNA-seq to accurately estimate cell type proportions from bulk RNA-seq data. Notably, SECRET can adapt to scenarios where the cell type present in the bulk data is unrepresented in the reference, thereby offering increased flexibility in reference selection. SECRET has demonstrated superior accuracy compared to existing methods using synthetic data and has identified unknown tissue-specific cell types in real human metastatic cancers. Its versatility makes it broadly applicable across various human cancer studies.
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Affiliation(s)
- Yingying Lu
- Interdisciplinary Program in Statistics and Data Science, University of Arizona, Tucson, AZ, USA
| | - Qin M Chen
- College of Pharmacy, University of Arizona, Tucson, AZ, USA
- Cancer Biology Program, University of Arizona, Tucson, AZ, USA
| | - Lingling An
- Interdisciplinary Program in Statistics and Data Science, University of Arizona, Tucson, AZ, USA
- Department of Biosystems Engineering, University of Arizona, Tucson, AZ, USA
- Department of Epidemiology and Biostatistics, University of Arizona, Tucson, AZ, USA
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41
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Brandt VP, Holland H, Wallenborn M, Koschny R, Frydrychowicz C, Richter M, Holland L, Nestler U, Sander C. SNP array genomic analysis of matched pairs of brain and liver metastases in primary colorectal cancer. J Cancer Res Clin Oncol 2023; 149:18173-18183. [PMID: 38010391 PMCID: PMC10725338 DOI: 10.1007/s00432-023-05505-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/31/2023] [Indexed: 11/29/2023]
Abstract
PURPOSE Brain metastasis formation is a rare and late event in colorectal cancer (CRC) patients and associated with poor survival. In contrast to other metastatic sites, the knowledge on chromosomal aberrations in brain metastases is very limited. METHODS Therefore, we carried out single nucleotide polymorphism (SNP) array analyses on matched primary CRC and brain metastases of four patients as well as on liver metastases of three patients. RESULTS Brain metastases showed more chromosomal aberrations than primary tumors or liver metastases. Commonly occurring aberrations were gain of 8q11.1-q24.3 (primary CRC), gain of 13q12.13-q12.3 (liver metastases), and gain of 20q11.1-q13.33 (brain metastases). Furthermore, we found one copy-neutral loss of heterozygosity (cn-LOH) region on chromosome 3 in primary CRC, three cn-LOH regions in liver metastases and 23 cn-LOH regions in brain metastases, comprising 26 previously undescribed sites. CONCLUSION The more frequent occurrence of cn-LOHs and subsequently affected genes in brain metastases shed light on the pathophysiology of brain metastasis formation. Further pairwise genetic analyses between primary tumors and their metastases will help to define the role of affected genes in cn-LOH regions.
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Affiliation(s)
- Vivian-Pascal Brandt
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany.
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany.
| | - Heidrun Holland
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Marco Wallenborn
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Ronald Koschny
- Interdisciplinary Endoscopy Center (IEZ), Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany
| | - Clara Frydrychowicz
- Paul Flechsig Institute of Neuropathology, University Medicine Leipzig, Leipzig, Saxony, Germany
| | - Mandy Richter
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Lydia Holland
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Ulf Nestler
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
| | - Caroline Sander
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
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42
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Sun BJ, Daniel SK, Lee B. The Role of Prophylactic and Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Prevention of Peritoneal Metastases in Advanced Colorectal Cancer. J Clin Med 2023; 12:6443. [PMID: 37892582 PMCID: PMC10607874 DOI: 10.3390/jcm12206443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/28/2023] [Accepted: 10/08/2023] [Indexed: 10/29/2023] Open
Abstract
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a locoregional therapy that may be combined with cytoreductive surgery (CRS) to treat patients with colorectal cancer and peritoneal metastases (PM). In recent years, three randomized controlled trials (RCTs) have investigated the role of prophylactic or adjuvant HIPEC in preventing the development of PM in patients with high-risk colorectal cancer: PROPHYLOCHIP and COLOPEC evaluated adjuvant HIPEC, and HIPECT4 studied concurrent HIPEC and CRS. Although PROPHYLOCHIP and COLOPEC were negative trials, a great deal may be learned from their methodology, outcome measures, and patient selection criteria. HIPECT4 is the first RCT to show a clinical benefit of HIPEC in high-risk T4 colorectal cancer, demonstrating improved locoregional disease control with the addition of HIPEC to CRS with no increase in the rate of complications. This review critically examines the strengths and limitations of each major trial and discusses their potential impact on the practice of HIPEC. Several additional ongoing clinical trials also seek to investigate the role of HIPEC in preventing PM in advanced colorectal cancer.
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Affiliation(s)
| | | | - Byrne Lee
- Section of Surgical Oncology, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; (B.J.S.); (S.K.D.)
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43
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Houssein EH, Oliva D, Samee NA, Mahmoud NF, Emam MM. Liver Cancer Algorithm: A novel bio-inspired optimizer. Comput Biol Med 2023; 165:107389. [PMID: 37678138 DOI: 10.1016/j.compbiomed.2023.107389] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/04/2023] [Accepted: 08/25/2023] [Indexed: 09/09/2023]
Abstract
This paper introduces a new bio-inspired optimization algorithm named the Liver Cancer Algorithm (LCA), which mimics the liver tumor growth and takeover process. It uses an evolutionary search approach that simulates the behavior of liver tumors when taking over the liver organ. The tumor's ability to replicate and spread to other organs inspires the algorithm. LCA algorithm is developed using genetic operators and a Random Opposition-Based Learning (ROBL) strategy to efficiently balance local and global searches and explore the search space. The algorithm's efficiency is tested on the IEEE Congress of Evolutionary Computation in 2020 (CEC'2020) benchmark functions and compared to seven widely used metaheuristic algorithms, including Genetic Algorithm (GA), particle swarm optimization (PSO), Differential Evolution (DE), Adaptive Guided Differential Evolution Algorithm (AGDE), Improved Multi-Operator Differential Evolution (IMODE), Harris Hawks Optimization (HHO), Runge-Kutta Optimization Algorithm (RUN), weIghted meaN oF vectOrs (INFO), and Coronavirus Herd Immunity Optimizer (CHIO). The statistical results of the convergence curve, boxplot, parameter space, and qualitative metrics show that the LCA algorithm performs competitively compared to well-known algorithms. Moreover, the versatility of the LCA algorithm extends beyond mathematical benchmark problems. It was also successfully applied to tackle the feature selection problem and optimize the support vector machine for various biomedical data classifications, resulting in the creation of the LCA-SVM model. The LCA-SVM model was evaluated in a total of twelve datasets, among which the MonoAmine Oxidase (MAO) dataset stood out, showing the highest performance compared to the other datasets. In particular, the LCA-SVM model achieved an impressive accuracy of 98.704% on the MAO dataset. This outstanding result demonstrates the efficacy and potential of the LCA-SVM approach in handling complex datasets and producing highly accurate predictions. The experimental results indicate that the LCA algorithm surpasses other methods to solve mathematical benchmark problems and feature selection.
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Affiliation(s)
- Essam H Houssein
- Faculty of Computers and Information, Minia University, Minia, Egypt.
| | - Diego Oliva
- Depto. Innovación Basada en la Información y el Conocimiento, Universidad de Guadalajara, CUCEI, Guadalajara, Jal, Mexico.
| | - Nagwan Abdel Samee
- Department of Information Technology, College of Computer and Information Sciences, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Noha F Mahmoud
- Rehabilitation Sciences Department, Health and Rehabilitation Sciences College, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Marwa M Emam
- Faculty of Computers and Information, Minia University, Minia, Egypt.
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44
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Kang AR, Kim JL, Kim Y, Kang S, Oh SC, Park JK. A novel RIP1-mediated canonical WNT signaling pathway that promotes colorectal cancer metastasis via β -catenin stabilization-induced EMT. Cancer Gene Ther 2023; 30:1403-1413. [PMID: 37500894 PMCID: PMC10581897 DOI: 10.1038/s41417-023-00647-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 06/02/2023] [Accepted: 07/12/2023] [Indexed: 07/29/2023]
Abstract
RIP1 (receptor-interacting protein kinase 1) is an important component of TNF-α signaling that contributes to various pathological effects. Here, we revealed new potential roles of RIP1 in controlling WNT/β-catenin canonical signaling to enhance metastasis of colorectal cancer (CRC). First, we showed that WNT3A treatment sequentially increased the expression of RIP1 and β-catenin. Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary, and metastatic cancers indicated that elevated RIP1 expression might be related to β-catenin expression, carcinogenesis, and metastasis. Intravenous injection of RIP1 over-expressed CRC cells into mice has demonstrated that RIP1 may promote metastasis. Immunoprecipitation (IP) results indicated that WNT3A treatment induces direct binding between RIP1 and β-catenin, and that this stabilizes the β-catenin protein in a manner that depends on the regulation of RIP1 ubiquitination via downregulation of the E3 ligase, cIAP1/2. Elimination of cIAP1/2 expression and inhibition of its ubiquitinase activity enhance WNT3A-induced RIP1 and β-catenin protein expression and binding, which stimulates endothelial-mesenchymal transition (EMT) induction to enhance the migration and invasion of CRC cells in vitro. The results of the in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally verified the direct binding of RIP1 and β-catenin. RIP1 expression can destroy the β-catenin-β-TrCP complex. Taken together, these results suggest a novel EMT-enhancing role of RIP1 in the WNT pathway and suggest a new canonical WNT3A-RIP1-β-catenin pathway that contributes to CRC malignancy by promoting EMT.
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Affiliation(s)
- A-Ram Kang
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Jung-Lim Kim
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - YoungHa Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Sanghee Kang
- Division of Colon and Rectal Surgery, Department of Surgery, Guro Hospital, Korea University College of Medicine, Korea University, Seoul, Republic of Korea
| | - Sang-Cheul Oh
- Division of Colon and Rectal Surgery, Department of Surgery, Guro Hospital, Korea University College of Medicine, Korea University, Seoul, Republic of Korea
| | - Jong Kuk Park
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
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Oliveira-Silveira J, Filippi-Chiela E, Saffi J. Laterality influence on gene expression of DNA damage repair in colorectal cancer. Sci Rep 2023; 13:15963. [PMID: 37749112 PMCID: PMC10519976 DOI: 10.1038/s41598-023-42890-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 09/15/2023] [Indexed: 09/27/2023] Open
Abstract
Colorectal carcinoma (CRC) is the third most common malignancy worldwide, and second in number of deaths in the world. The molecular pathogenesis of CRC is heterogeneous and can affect several genes. Moreover, genomic instability is recognized as an important part of CRC carcinogenesis and is tightly connected to DNA damage response. DNA damage repair (DDR) pathways are intrinsically associated with cancer development and establishment. Traditionally, CRC is considered as one coherent disease, however, new evidence shows that left and right-sided CRC present differences observed in clinical settings, as well as in pre-clinical studies. Therefore, this study aimed to investigate the impact of DDR transcriptional profiles on survival in different sublocations of the colon and rectum using Cox regression, survival analysis and differential gene expression. Right side colon (RSC) has DDR genes' expression associated only with higher risk of death, while left side colon (LSC) and Rectum have most genes' expression associated with lower risk. The pattern is the same with survival analysis. All significant DDR genes had lower expression associated with better survival in RSC, as opposed to LSC and Rectum. Our results demonstrate that RSC is distinctively different from LSC and Rectum. LSC and Rectum have similar DDR expression profiles.
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Affiliation(s)
- Juliano Oliveira-Silveira
- Centro de Biotecnologia, PPGBCM, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
- Departamento de Ciências Básicas da Saúde, Laboratório de Genética Toxicológica, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Eduardo Filippi-Chiela
- Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Jenifer Saffi
- Departamento de Ciências Básicas da Saúde, Laboratório de Genética Toxicológica, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil.
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Li D, Wang X, Miao H, Liu H, Pang M, Guo H, Ge M, Glass SE, Emmrich S, Ji S, Zhou Y, Ye X, Mao H, Wang J, Liu Q, Kim T, Klusmann JH, Li C, Liu Z, Jin H, Nie Y, Wu K, Fan D, Song X, Wang X, Li L, Lu Y, Zhao X. The lncRNA MIR99AHG directs alternative splicing of SMARCA1 by PTBP1 to enable invadopodia formation in colorectal cancer cells. Sci Signal 2023; 16:eadh4210. [PMID: 37725664 DOI: 10.1126/scisignal.adh4210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 08/31/2023] [Indexed: 09/21/2023]
Abstract
Alternative splicing regulates gene expression and functional diversity and is often dysregulated in human cancers. Here, we discovered that the long noncoding RNA (lncRNA) MIR99AHG regulated alternative splicing to alter the activity of a chromatin remodeler and promote metastatic behaviors in colorectal cancer (CRC). MIR99AHG was abundant in invasive CRC cells and metastatic tumors from patients and promoted motility and invasion in cultured CRC cells. MIR99AHG bound to and stabilized the RNA splicing factor PTBP1, and this complex increased cassette exon inclusion in the mRNA encoding the chromatin remodeling gene SMARCA1. Specifically, MIR99AHG altered the nature of PTBP1 binding to the splice sites on intron 12 of SMARCA1 pre-mRNA, thereby triggering a splicing switch from skipping to including exon 13 to produce the long isoform, SMARCA1-L. SMARCA1, but not SMARCA1-L, suppressed invadopodia formation, cell migration, and invasion. Analysis of CRC samples revealed that the abundance of MIR99AHG transcript positively correlated with that of SMARCA1-L mRNA and PTBP1 protein and with poor prognosis in patients with CRC. Furthermore, TGF-β1 secretion from cancer-associated fibroblasts increased MIR99AHG expression in CRC cells. Our findings identify an lncRNA that is induced by cues from the tumor microenvironment and that interacts with PTBP1 to regulate alternative splicing, potentially providing a therapeutic target and predictive biomarker for metastatic CRC.
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Affiliation(s)
- Danxiu Li
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xin Wang
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Hui Miao
- Center for Functional Genomics and Bioinformatics, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan 610065, China
| | - Hao Liu
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Maogui Pang
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Hao Guo
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co. Ltd., Nanjing, Jiangsu 210042, China
| | - Minghui Ge
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co. Ltd., Nanjing, Jiangsu 210042, China
| | - Sarah E Glass
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Stephan Emmrich
- Department of Biology, University of Rochester, Rochester, NY 14627, USA
| | - Songtao Ji
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Yun Zhou
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xiaoni Ye
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Huajie Mao
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jing Wang
- Department of Biomedical Informatics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Qi Liu
- Department of Biomedical Informatics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Taewan Kim
- Department of Anatomy, Histology & Developmental Biology, Base for International Science and Technology Cooperation, Carson Cancer Stem Cell Vaccines R&D Center, International Cancer Center, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Jan-Henning Klusmann
- Pediatric Hematology and Oncology, Department of Pediatrics, Goethe University Frankfurt, Frankfurt (Main) 60590, Germany
| | - Cunxi Li
- Jiaen Genetics Laboratory, Beijing Jiaen Hospital, Beijing 100191, China
| | - Zhenxiong Liu
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Haifeng Jin
- Center for Functional Genomics and Bioinformatics, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan 610065, China
| | - Yongzhan Nie
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Kaichun Wu
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Daiming Fan
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xu Song
- Center for Functional Genomics and Bioinformatics, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan 610065, China
| | - Xin Wang
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Ling Li
- Center for Functional Genomics and Bioinformatics, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan 610065, China
| | - Yuanyuan Lu
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xiaodi Zhao
- Department of Gastroenterology, Tangdu Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
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Qiu QS, Zhu K, Wang JH, Chen XS, Wang WT, Dong SY, Sun W, Rao SX. Diagnostic Performance of Contrast Enhanced CT Alone or in Combination with (Non-)Enhanced MRI for Colorectal Liver Metastasis. Acad Radiol 2023; 30:1856-1865. [PMID: 36481127 DOI: 10.1016/j.acra.2022.11.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 11/02/2022] [Accepted: 11/13/2022] [Indexed: 12/12/2022]
Abstract
RATIONALE AND OBJECTIVES To compare the diagnostic performance of contrast enhanced CT (CE-CT), CE-CT combined with non-enhanced MRI (NE-MRI) or contrast enhanced MRI (CE-MRI) for colorectal liver metastasis (CRLM). MATERIALS AND METHODS Sixty-six colorectal cancer patients with 198 focal liver lesions who underwent preoperative abdominal CE-CT and MRI examinations were included respectively. The images were assessed independently by two readers in three protocols (1: CE-CT, 2: CE-CT+NE-MRI, 3: CE-CT+CE-MRI). The diagnostic performance of each protocol was analyzed by receiver operating characteristic (ROC) curve and the areas under ROC (AUCs) were calculated and compared. RESULTS The detection rates of protocol 2 were 90.9%-92.9% for liver lesions and 86.4%-89.6% for CRLM, and both significantly higher than protocol 1 of 82.8%-85.4% and 76.8%-80.8% (p<0.001-0.001), whereas similar to protocol 3 of 91.9%-94.4% and 87.2%-91.2% (p 0.250-1.000). The AUCs of protocol 2 were greater than protocol 1 for all lesions (0.914-0.934 vs. 0.779-0.799, p<0.001) and lesions < 10mm (0.726-0.776 vs. 0.528-0.561, p<0.001), and were not inferior to that of protocol 3 (0.929-0.949 in all lesions and 0.754-0.821 in lesion < 10mm, p 0.053-0.162). CONCLUSION CE-CT combined with NE-MRI offered superior diagnostic performance for CRLM compared to CE-CT alone and showed comparable performance to CE-CT combined with CE-MRI.
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Affiliation(s)
- Qian-Sai Qiu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai 200032, P. R. China; Department of Radiology, Affiliated Tumor Hospital of Nantong University, Nantong University, Nantong, P. R. China
| | - Kai Zhu
- Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai P. R. China
| | - Jia-Hui Wang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai 200032, P. R. China
| | - Xiao-Shan Chen
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai 200032, P. R. China
| | - Wen-Tao Wang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai 200032, P. R. China; Department of Cancer Center, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - San-Yuan Dong
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai 200032, P. R. China
| | - Wei Sun
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai 200032, P. R. China; Department of Cancer Center, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Sheng-Xiang Rao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai 200032, P. R. China; Department of Cancer Center, Zhongshan Hospital Fudan University, Shanghai, 200032, China.
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Yearley AG, McNulty JJ, Chalif EJ, Chalif JI, Lee SJ, Klinger NV, Zaidi HA. Spinal Metastases from Colorectal Cancer at Mass General Brigham: A Twenty-Year Case Series With Literature Review. World Neurosurg 2023; 176:e246-e253. [PMID: 37207725 DOI: 10.1016/j.wneu.2023.05.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/21/2023]
Abstract
OBJECTIVE We present an institutional case series of patients treated for colorectal carcinoma (CRC) spinal metastases to investigate the outcomes between no treatment, radiation, surgery, and surgery/radiation. METHODS A retrospective cohort of patients with CRC spinal metastases presenting to affiliated institutions between 2001 and 2021 wereidentified. Information related to patient demographics, treatment modality, treatment outcomes, symptom improvement, and survival was collected by chart review. Overall survival (OS) was compared between treatments by log-rank significance testing. A literature review was conducted to identify other cases series of CRC patients with spinal metastases. RESULTS Eighty-nine patients (mean age 58.5) with CRC spinal metastases across a mean of 3.3 levels met inclusion criteria: 14 (15.7%) received no treatment, 11 (12.4%) received surgery alone, 37 (41.6%) received radiation alone, and 27 (30.3%) received both radiation and surgery. Patients treated with combination therapy had the longest median OS of 24.7 months (range 0.6-85.9), which did not significantly differ from the median OS of 8.9 months (range 0.2-42.6) observed in patients who received no treatment (P = 0.075). Combination therapy provided objectively longer survival time in comparison to other treatment modalities but failed to reach statistical significance. The majority of patients that received treatment (n = 51/75, 68.0%) experienced some degree of symptomatic or functional improvement. CONCLUSIONS Therapeutic intervention has the potential to improve the quality of life in patients with CRC spinal metastases. We demonstrate that surgery and radiation are useful options for these patients, despite their lack of objective improvement in OS.
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Affiliation(s)
- Alexander G Yearley
- Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Jack J McNulty
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
| | - Eric J Chalif
- George Washington University, School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Joshua I Chalif
- Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Suk Joon Lee
- Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Neil V Klinger
- Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Hasan A Zaidi
- Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
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49
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Yang M, Yang C, Ma D, Li Z, Zhao W, Yang D. Single-cell analysis reveals cellular reprogramming in advanced colon cancer following FOLFOX-bevacizumab treatment. Front Oncol 2023; 13:1219642. [PMID: 37576892 PMCID: PMC10421721 DOI: 10.3389/fonc.2023.1219642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 07/10/2023] [Indexed: 08/15/2023] Open
Abstract
Introduction The combination of FOLFOX and bevacizumab (FOLFOX-Bev) is a promising treatment for advanced colorectal cancer (CRC). However, the response of the tumor microenvironment to FOLFOX-Bev is still largely unexplored. Methods We conducted single-cell transcriptomic analysis of CRC samples derived from a patient before and after treatment to gain insights into the cellular changes associated with FOLFOX-Bev treatment. Results We found that cancer cells with high proliferative, metastatic, and pro-angiogenic properties respond better to FOLFOX-Bev treatment. Moreover, FOLFOX-Bev enhances CD8+ T cell cytotoxicity, thereby boosting the anti-tumor immune response. Conversely, FOLFOX-Bev impairs the functionality of tumor-associated macrophages, plasma cells, and cancer-associated fibroblasts, leading to a decrease in VEGFB-mediated angiogenesis. Furthermore, FOLFOX-Bev treatment reset intercellular communication, which could potentially affect the function of non-cancer cells. Discussion Our findings provide valuable insights into the molecular mechanisms underlying the response of advanced CRC to FOLFOX-Bev treatment and highlight potential targets for improving the efficacy of this treatment strategy.
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Affiliation(s)
- Meiling Yang
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Ciqiu Yang
- Department of Breast Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Dong Ma
- Medical Oncology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zijun Li
- Guangdong Provincial Institute of Geriatrics, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Wei Zhao
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Dongyang Yang
- Medical Oncology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
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50
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Rodger EJ, Gimenez G, Ajithkumar P, Stockwell PA, Almomani S, Bowden SA, Leichter AL, Ahn A, Pattison S, McCall JL, Schmeier S, Frizelle FA, Eccles MR, Purcell RV, Chatterjee A. An epigenetic signature of advanced colorectal cancer metastasis. iScience 2023; 26:106986. [PMID: 37378317 PMCID: PMC10291510 DOI: 10.1016/j.isci.2023.106986] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/12/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide. The majority of CRC deaths are caused by tumor metastasis, even following treatment. There is strong evidence for epigenetic changes, such as DNA methylation, accompanying CRC metastasis and poorer patient survival. Earlier detection and a better understanding of molecular drivers for CRC metastasis are of critical clinical importance. Here, we identify a signature of advanced CRC metastasis by performing whole genome-scale DNA methylation and full transcriptome analyses of paired primary cancers and liver metastases from CRC patients. We observed striking methylation differences between primary and metastatic pairs. A subset of loci showed coordinated methylation-expression changes, suggesting these are potentially epigenetic drivers that control the expression of critical genes in the metastatic cascade. The identification of CRC epigenomic markers of metastasis has the potential to enable better outcome prediction and lead to the discovery of new therapeutic targets.
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Affiliation(s)
- Euan J. Rodger
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Gregory Gimenez
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | | | - Peter A. Stockwell
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Suzan Almomani
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Sarah A. Bowden
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Anna L. Leichter
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Antonio Ahn
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- The Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - Sharon Pattison
- Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - John L. McCall
- Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | | | - Frank A. Frizelle
- Department of Surgery, University of Otago, Christchurch, New Zealand
| | - Michael R. Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Rachel V. Purcell
- Department of Surgery, University of Otago, Christchurch, New Zealand
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- Honorary Professor, School of Health Sciences and Technology, UPES University, India
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