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Sun L, Li X, Xiao Y, Yu W, Chen X, Wang Z, Xia N, Chen X, Chen M, Zhu H, Li J, Wei J, Han S, Pu L. Mfsd2a suppresses colorectal cancer progression and liver metastasis via the S100A14/STAT3 axis. J Transl Med 2025; 23:59. [PMID: 39806334 PMCID: PMC11726956 DOI: 10.1186/s12967-024-05994-y] [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: 09/22/2024] [Accepted: 12/13/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) exhibits a high incidence globally, with the liver being the most common site of distant metastasis. At the time of diagnosis, 20-30% of CRC patients already present with liver metastases. Colorectal liver metastasis (CRLM) is a major cause of mortality among CRC patients. The pathogenesis of CRLM involves complex molecular mechanisms and the hepatic immune microenvironment, but current clinical prevention and treatment are significantly limited. Recent studies have revealed that the major facilitator superfamily domain containing protein-2a (Mfsd2a) plays a pivotal role in the development and metastasis of various cancers. For instance, Mfsd2a inhibits gastric cancer initiation and progression and may impact angiogenesis. However, the mechanisms by which Mfsd2a influences CRC progression and liver metastasis remain unclear. METHODS In this study, we conducted a survival analysis of Mfsd2a in colorectal cancer using data from the GEPIA and GEO databases, and examined the expression differences between primary tumor (PT) and liver metastasis (LM). We further assessed the clinical significance and prognostic relevance of Mfsd2a through immunohistochemical analysis of tissue samples from 70 CRLM patients. Moreover, Kaplan-Meier analysis was used to perform survival analysis on these patients. The biological function of Mfsd2a in CRLM was confirmed by a series of experiments conducted both in vitro and in vivo. Additionally, we investigated downstream molecular pathways using western blot, Co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques. RESULTS We observed that Mfsd2a expression is reduced in LM compared to PT, and higher Mfsd2a levels are associated with better prognosis in CRLM patients. Furthermore, function assays demonstrated that Mfsd2a suppresses CRC cells proliferation, migration, invasion, and EMT in vitro, while also delaying tumor growth and liver metastasis in vivo. Mechanistically, Mfsd2a interacts with S100A14, enhancing its expression and inhibiting phosphorylation of STAT3. In addition, the STAT3 activator colivelin partially reversed the inhibitory effect of Mfsd2a overexpression on the progression of colorectal cancer and liver metastasis. CONCLUSION In summary, Mfsd2a inhibits colorectal cancer progression and liver metastasis by interacting with S100A14, thereby suppressing the phosphorylation of STAT3. Mfsd2a functions as a tumor suppressor in CRLM and could be a promising therapeutic target for treating CRC patients with liver metastasis.
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Affiliation(s)
- Linfeng Sun
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Xiangdong Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Yuhao Xiao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Wenjie Yu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Xuyang Chen
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Ziyi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Nan Xia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Xuejiao Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Minhao Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Haoliang Zhu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Jie Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Jie Wei
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Sheng Han
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China.
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China.
| | - Liyong Pu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China.
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China.
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Dai S, Zhuang H, Li Z, Chen Z, Chai Y, Zhou Q. miR-122/NEGR1 axis contributes colorectal cancer liver metastasis by PI3K/AKT pathway and macrophage modulation. J Transl Med 2024; 22:1060. [PMID: 39587606 PMCID: PMC11590399 DOI: 10.1186/s12967-024-05901-5] [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: 08/28/2024] [Accepted: 11/18/2024] [Indexed: 11/27/2024] Open
Abstract
Colorectal cancer (CRC) is a prevalent malignant tumor in the gastrointestinal tract, with around 50% of patients experiencing distant metastases, predominantly to the liver. Colorectal cancer liver metastasis (CRLM) is a leading cause of CRC-related death, and effective treatments remain limited. This study aims to identify new targets for predicting and treating CRLM. Bioinformatics analysis highlighted the miR-122/NEGR1 axis as crucial in CRLM. In vitro assays (Colony formation, Wound healing, Transwell) explored the impact of this axis on CRC cell proliferation, invasion, and migration. Dual-Luciferase Reporter Gene Assay and RNA-pulldown confirmed miR-122/NEGR1 interaction. In vivo, CRLM model mice were used to investigate the axis's effects on tumor metastasis and macrophage polarization. Immunofluorescence (IF), Quantitative Real-time PCR (qRT-PCR), Enzyme-linked Immunosorbent Assay (ELISA), and Western Blot (WB) analyzed macrophage polarization markers and cytokine/protein/RNA expression. Results showed increased miR-122 and decreased NEGR1 in liver metastases compared to primary tumors. The miR-122/NEGR1 axis enhanced CRC cell proliferation, migration, invasion, and affected the PI3K/AKT pathway. Furthermore, reduced NEGR1 promoted M2 macrophage polarization and accelerated liver metastasis in CRLM model mice. In conclusion, the miR-122/NEGR1 axis drives CRC progression and liver metastasis through the PI3K/AKT pathway and M2 macrophage polarization, representing a potential target for the therapy of CRLM.
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Affiliation(s)
- Shipeng Dai
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China
- Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Haiwen Zhuang
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an Second People's Hospital, Huai'an, Jiangsu Province, China
| | - Zhuozheng Li
- School of Life Science and Technology, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Zhongda Chen
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Yue Chai
- Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Qing Zhou
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China.
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Hou S, Li L, Hou H, Zhou T, Zhou H. Establishment of nomogram to predict overall survival and cancer-specific survival of local tumor resection in patients with colorectal cancer liver metastasis with unresectable metastases: a large population-based analysis. Discov Oncol 2024; 15:315. [PMID: 39073708 PMCID: PMC11286894 DOI: 10.1007/s12672-024-01182-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 07/20/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND AND PURPOSE The tumour-node metastasis (TNM) classification is a common model for evaluating the prognostic value of tumour patients. However, few models have been used to predict the survival outcomes of patients with colorectal cancer liver metastasis (CRLM) with unresectable metastases who received the primary local surgery. Thus, we utilized the Surveillance, Epidemiology, and End Results (SEER) database to establish novel nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) of these patients. METHODS Extracted primary data on CRLM patients by local surgery from SEER database. All prognostic factors of OS and CSS were determined by Cox regression analysis. The concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves were used to further evaluate the accuracy and discrimination of these nomograms. Decision curve analysis (DCA) was executed to evaluate the nomograms for the clinical net benefit. Risk stratification analysis (RSA) was used to evaluate the reliability of them in clinical. RESULTS 3622 eligible patients were screened and assigned to training cohort (1812) or validation cohort (1810). The age, chemotherapy, tumour grade, primary tumour site, tumour size, lymph node positive rate (LNR), marital status, and carcinoembryonic antigen (CEA) were independent prognostic factors of OS. Additionally, the age, chemotherapy, tumour grade, primary tumour site, tumour size, LNR, and CEA were independent prognostic factors of CSS. The results of C-indexes and ROC curves indicated that the established nomograms exhibited better discrimination power than TNM classification. The calibration curves demonstrated excellent agreement between the predicted and actual survival rates for 1-, 3-, and 5 year OS and CSS. Meanwhile, the validation cohort demonstrated similar results. Background the clinic context, the DCA showed that these nomograms have higher net benefits, and the RSA showed that patients were further divided into low risk, medium risk, and high risk groups according to the predicted scores from nomograms. And, the Kaplan-Meier curve and log-rank test showed that the survival differences among the three groups are statistically significant. CONCLUSIONS The prognostic nomograms showed very high accuracy, identifiability, and clinical practicality in predicting the OS and CSS of CRLM patients with unresectable metastases treated by local surgery at 1-, 3-, and 5 years, which might improve individualized predictions of survival risks and help clinicians formulate treatment plans.
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Affiliation(s)
- Songlin Hou
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, 1 Maoyuan South Road, Nanchong, 637000, Sichuan, People's Republic of China
- Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China
| | - Lifa Li
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, 1 Maoyuan South Road, Nanchong, 637000, Sichuan, People's Republic of China
- Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China
| | - Huafang Hou
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, 1 Maoyuan South Road, Nanchong, 637000, Sichuan, People's Republic of China
| | - Tong Zhou
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, 1 Maoyuan South Road, Nanchong, 637000, Sichuan, People's Republic of China
- Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China
| | - He Zhou
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, 1 Maoyuan South Road, Nanchong, 637000, Sichuan, People's Republic of China.
- Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China.
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Dai S, Xu F, Xu X, Huang T, Wang Y, Wang H, Xie Y, Yue L, Zhao W, Xia Y, Gu J, Qian X. miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. Cancer Cell Int 2024; 24:235. [PMID: 38970064 PMCID: PMC11225248 DOI: 10.1186/s12935-024-03422-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 06/25/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Colorectal cancer is among the most common malignant tumors affecting the gastrointestinal tract. Liver metastases, a complication present in approximately 50% of colorectal cancer patients, are a considerable concern. Recently, studies have revealed the crucial role of miR-455 in tumor pathogenesis. However, the effect of miR-455 on the progression of liver metastases in colorectal cancer remains controversial. As an antagonist of bone morphogenetic protein(BMP), Gremlin 1 (GREM1) may impact organogenesis, body patterning, and tissue differentiation. Nevertheless, the role of miR-455 in regulating GREM1 in colorectal cancer liver metastases and how miR-455/GREM1 axis influences tumour immune microenvironment is unclear. METHODS Bioinformatics analysis shows that miR-455/GREM1 axis plays crucial role in liver metastasis of intestinal cancer and predicts its possible mechanism. To investigate the impact of miR-455/GREM1 axis on the proliferation, invasion, and migration of colorectal cancer cells, colony formation assay, wound healing and transwell assay were examined in vitro. The Dual-Luciferase reporter gene assay and RNA pull-down assay confirmed a possible regulatory effect between miR-455 and GREM1. In vivo, colorectal cancer liver metastasis(CRLM) model mice was established to inquiry the effect of miR-455/GREM1 axis on tumor growth and macrophage polarization. The marker of macrophage polarization was tested using immunofluorescence(IF) and quantitative real-time polymerase chain reaction(qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), cytokines were detected in culture medium supernatants. RESULTS We found that miR-455 and BMP6 expression was increased and GREM1 expression was decreased in liver metastase compared with primary tumor. miR-455/GREM1 axis promotes colorectal cancer cells proliferation, migration, invasion via affected PI3K/AKT pathway. Moreover, downregulating GREM1 augmented BMP6 expression in MC38 cell lines, inducing M2 polarization of macrophages, and promoting liver metastasis growth in CRLM model mice. CONCLUSION These data suggest that miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. These results offer valuable insights and direction for future research and treatment of CRLM.
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Affiliation(s)
- Shipeng Dai
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Fan Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Xiaozhang Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Tian Huang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Yiming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Hongyu Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Yucheng Xie
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Lei Yue
- Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Wenhu Zhao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Yongxiang Xia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
| | - Jian Gu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
| | - Xiaofeng Qian
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
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Xu X, Zhang M, Liu X, Chai M, Diao L, Ma L, Nie S, Xu M, Wang Y, Mo F, Liu M. Probiotics formulation and cancer nanovaccines show synergistic effect in immunotherapy and prevention of colon cancer. iScience 2023; 26:107167. [PMID: 37456845 PMCID: PMC10338235 DOI: 10.1016/j.isci.2023.107167] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/26/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023] Open
Abstract
Probiotics play essential roles in immune modulation. Combining probiotics with cancer vaccines potentially can achieve a synergistic effect. To maximize the efficacy of probiotics, proper probiotics formulation is necessary. Herein, Lactobacillus rhamnosus and Bifidobacterium longum are coated with lipid membrane to achieve the goal of losing less activity and bettering colonization in colon. In the subcutaneous transplanted colon cancer mouse model, probiotics formulation showed potent preventive and therapeutic efficacy, and the efficacy could be further improved by combining with cancer nanovaccines. Probiotics formulation can perform as immune adjuvants to enhance the innate immune response or as in-situ cancer vaccines. In the study of preventing chemical-induced orthotopic colon cancer model, probiotics formulation alone efficiently reduced tumor number in colon and the efficacy is improved by combining with cancer nanovaccines. All in all, the studies demonstrated that probiotics formulation can assist to maximize the efficacy of cancer nanovaccines.
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Affiliation(s)
- Xiangxiang Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
- Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, People’s Republic of China
- Suzhou Ersheng Biopharmaceutical Co., Ltd, Suzhou 215123, People’s Republic of China
| | - Meng Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
| | - Xiaoyan Liu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
| | - Mingze Chai
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
| | - Lu Diao
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
- Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, People’s Republic of China
- Suzhou Ersheng Biopharmaceutical Co., Ltd, Suzhou 215123, People’s Republic of China
| | - Lin Ma
- Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, People’s Republic of China
| | - Shuang Nie
- Department of Nutrition and Food Hygiene, Faculty of Naval Medicine, Naval Medical University, 800 Xiangyin Rd, Shanghai 200433, People’s Republic of China
| | - Minghao Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
- Suzhou Ersheng Biopharmaceutical Co., Ltd, Suzhou 215123, People’s Republic of China
| | - Yipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
| | - Fengfeng Mo
- Department of Nutrition and Food Hygiene, Faculty of Naval Medicine, Naval Medical University, 800 Xiangyin Rd, Shanghai 200433, People’s Republic of China
| | - Mi Liu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
- Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu 215300, People’s Republic of China
- Suzhou Ersheng Biopharmaceutical Co., Ltd, Suzhou 215123, People’s Republic of China
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Kim SK, Lee NH, Son CG. A Review of Herbal Resources Inducing Anti-Liver Metastasis Effects in Gastrointestinal Tumors via Modulation of Tumor Microenvironments in Animal Models. Cancers (Basel) 2023; 15:3415. [PMID: 37444525 PMCID: PMC10340630 DOI: 10.3390/cancers15133415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/22/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Liver metastases remain a major obstacle for the management of all types of tumors arising from digestive organs, and the tumor microenvironment has been regarded as an important factor in metastasis. To discover herbal candidates inhibiting the liver metastasis of tumors originating from the digestive system via the modulation of the tumor microenvironment and liver environment, we searched three representative public databases and conducted a systematic review. A total of 21 studies that employed experimental models for pancreatic (9), colon (8), and stomach cancers (4) were selected. The herbal agents included single-herb extracts (5), single compounds (12), and multiherbal decoctions (4). Curcuma longa Linn was most frequently studied for its anti-colon-liver metastatic effects, and its possible mechanisms involved the modulation of tumor microenvironment components such as vascular endothelial cells and immunity in both tumor tissues and circulating cells. The list of herbal agents and their mechanisms produced in this study is helpful for the development of anti-liver metastasis drugs in the future.
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Affiliation(s)
- Sul-Ki Kim
- Liver and Immunology Research Center, Collage of Korean Medicine, Daejeon University, Daejeon 35235, Republic of Korea;
| | - Nam-Hun Lee
- East-West Cancer Center, Cheonan Korean Medicine Hospital, Daejeon University, Cheonan 31099, Republic of Korea;
| | - Chang-Gue Son
- Liver and Immunology Research Center, Collage of Korean Medicine, Daejeon University, Daejeon 35235, Republic of Korea;
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Nygaard V, Ree AH, Dagenborg VJ, Børresen-Dale AL, Edwin B, Fretland ÅA, Grzyb K, Haugen MH, Mælandsmo GM, Flatmark K. A PRRX1 Signature Identifies TIM-3 and VISTA as Potential Immune Checkpoint Targets in a Subgroup of Microsatellite Stable Colorectal Cancer Liver Metastases. CANCER RESEARCH COMMUNICATIONS 2023; 3:235-244. [PMID: 36968142 PMCID: PMC10035516 DOI: 10.1158/2767-9764.crc-22-0295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/21/2022] [Accepted: 01/27/2023] [Indexed: 02/04/2023]
Abstract
Disease recurrence and drug resistance are major challenges in the clinical management of patients with colorectal cancer liver metastases (CLM), and because tumors are generally microsatellite stable (MSS), responses to immune therapies are poor. The mesenchymal phenotype is overrepresented in treatment-resistant cancers and is associated with an immunosuppressed microenvironment. The aim of this work was to molecularly identify and characterize a mesenchymal subgroup of MSS CLM to identify novel therapeutic approaches. We here generated a mesenchymal gene expression signature by analysis of resection specimens from 38 patients with CLM using ranked expression level of the epithelial-to-mesenchymal transition-related transcription factor PRRX1. Downstream pathway analysis based on the resulting gene signature was performed and independent, publicly available datasets were used to validate the findings. A subgroup comprising 16% of the analyzed CLM samples were classified as mesenchymal, or belonging to the PRRX1 high group. Analysis of the PRRX1 signature genes revealed a distinct immunosuppressive phenotype with high expression of immune checkpoints HAVCR2/TIM-3 and VISTA, in addition to the M2 macrophage marker CD163. The findings were convincingly validated in datasets from three external CLM cohorts. Upregulation of immune checkpoints HAVCR2/TIM-3 and VISTA in the PRRX1 high subgroup is a novel finding, and suggests immune evasion beyond the PD-1/PD-L1 axis, which may contribute to poor response to PD-1/PD-L1-directed immune therapy in MSS colorectal cancer. Importantly, these checkpoints represent potential novel opportunities for immune-based therapy approaches in a subset of MSS CLM. Significance CLM is an important cause of colorectal cancer mortality where the majority of patients have yet to benefit from immunotherapies. In this study of gene expression profiling analyses, we uncovered novel immune checkpoint targets in a subgroup of patients with MSS CLMs harboring a mesenchymal phenotype.
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Affiliation(s)
- Vigdis Nygaard
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Anne Hansen Ree
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Vegar Johansen Dagenborg
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - Anne-Lise Børresen-Dale
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Bjørn Edwin
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
- The Intervention Center, Oslo University Hospital, Oslo, Norway
| | - Åsmund Avdem Fretland
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
- The Intervention Center, Oslo University Hospital, Oslo, Norway
| | - Krzysztof Grzyb
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Mads H. Haugen
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Gunhild M. Mælandsmo
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute for Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Kjersti Flatmark
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
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8
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Zhai Y, Bai W, Zhou J, Dong Q, Zhang J. Effect of tumour size ratio on liver recurrence-free survival of patients undergoing hepatic resection for colorectal liver metastases. BMC Cancer 2022; 22:103. [PMID: 35078439 PMCID: PMC8788127 DOI: 10.1186/s12885-022-09199-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 01/14/2022] [Indexed: 11/10/2022] Open
Abstract
Background The study aimed to assess the impact of size differences of multiple liver metastases on liver recurrence-free survival (RFS) in patients undergoing hepatic resection for colorectal liver metastases (CRLMs). Methods Overall, 147 patients with CRLMs who underwent hepatic resection between January 2010 and December 2016 were retrospectively analysed. Tumour size ratio (TSR) was defined as the maximum diameter of the largest liver lesion over the maximum diameter of the smallest liver lesion. The univariate and multivariate analyses were performed to determine independent prognostic risk factors. The prognostic value of the TSR was further explored in each Tumour Burden Score (TBS) zone. Log-rank survival analyses were used to compare liver RFS in the new clinical score and the Fong clinical score. Results Based on the TSR, patients were classified into three groups: TSR < 2, 2 ≤ TSR < 4, and TSR ≥ 4. According to the multivariate analysis, TSR of 2–4 (hazard ratio [HR], 2.580; 95% confidence interval [CI] 1.543–4.312; P < 0.001) and TSR < 2 (HR, 4.435; 95% CI 2.499–7.872; P < 0.001) were associated with worse liver RFS. As TSR decreased, liver RFS worsened. TSR could further stratify patients in zones 1 and 2 into different risk groups according to the TBS criteria (zone 1: median liver RFS, 3.2 and 8.9 months for groups 1 and 2, respectively, P = 0.003; zone 2: median liver RFS, 3.5, 5.0, and 10.9 months for groups 1, 2, and 3, respectively, P < 0.05). The predictive ability of the new clinical score, which includes TSR, was superior to that of the Fong clinical score. Conclusions TSR, as a prognostic tool, could accurately assess the effect of size differences across multiple liver metastases on liver RFS in patients undergoing hepatectomy for CRLMs. Trial registration Retrospectively registered
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9
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Cui X, Geng XP, Zhou DC, Yang MH, Hou H. Advances in liver transplantation for unresectable colon cancer liver metastasis. World J Gastrointest Surg 2021; 13:1615-1627. [PMID: 35070067 PMCID: PMC8727191 DOI: 10.4240/wjgs.v13.i12.1615] [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: 07/03/2021] [Revised: 09/19/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
It is estimated that 50% of patients with colorectal cancer will develop liver metastasis. Surgical resection significantly improves survival and provides a chance of cure for patients with colorectal cancer liver metastasis (CRLM). Increasing the resectability of primary unresectable liver metastasis provides more survival benefit for those patients. Considerable surgical innovations have been made to increase the resection rate and decrease the potential risk of hepatic failure postoperation. Liver transplantation (LT) has been explored as a potential curative treatment for unresectable CRLM. However, candidate selection criteria, chemotherapy strategies, refined immunity regimens and resolution for the shortage of grafts are lacking. This manuscript discusses views on surgical indication, peritransplantation anti-tumor and anti-immunity therapy and updated advances in LT for unresectable CRLM. A literature review of published articles and registered clinical trials in PubMed, Google Scholar, and Clinicaltrials.gov was performed to identify studies related to LT for CRLM. Some research topics were identified, including indications for LT for CRLM, oncological risk, antitumor regimens, graft loss, administration of anti-immunity drugs and solutions for graft deficiency. The main candidate selection criteria are good patient performance, good tumor biological behavior and chemosensitivity. Chemotherapy should be administered before transplantation but is not commonly administered posttransplantation for preventive purposes. Mammalian target of rapamycin regimens are recommended for their potential oncological benefit, although there are limited cases. In addition to extended criterion grafts, living donor grafts and small grafts combined with two-stage hepatectomy are efficient means to resolve organ deficiency. LT has been proven to be an effective treatment for selected patients with liver-only CRLM. Due to limited donor grafts, high cost and poorly clarified oncological risks, LT for unresectable CRLM should be strictly performed under a well-organized study plan in selected patients. Some vital factors, like LT indication and anti-tumor and anti-immune treatment, remain to be confirmed. Ongoing clinical trials are expected to delineate these topics.
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Affiliation(s)
- Xiao Cui
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Xiao-Ping Geng
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Da-Chen Zhou
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Ming-Hao Yang
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Hui Hou
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
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10
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Tasoudis PT, Ziogas IA, Alexopoulos SP, Fung JJ, Tsoulfas G. Role of liver transplantation in the management of colorectal liver metastases: Challenges and opportunities. World J Clin Oncol 2021; 12:1193-1201. [PMID: 35070738 PMCID: PMC8716993 DOI: 10.5306/wjco.v12.i12.1193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 06/27/2021] [Accepted: 11/26/2021] [Indexed: 02/06/2023] Open
Abstract
The liver is the most common site of colorectal cancer metastasis. Complete resection of the metastatic tumor is currently the only treatment modality available with a potential for cure. However, only 20% of colorectal liver metastases (CRLM) are considered resectable at the time of presentation. Liver transplantation (LT) has been proposed as an alternative oncologic treatment for patients with unresectable CRLM. This review summarizes the published experiences of LT in the setting of unresectable CRLM from the previous decades and discusses the challenges and future horizons in the field. Contemporary experiences that come mostly from countries with broader access to liver grafts are also explored and their promising findings in terms of overall survival (OS) and disease-free survival (DFS) are outlined along with their study design and methods. The rationale of establishing specific patient selection criteria and the dilemmas around immunosuppressive regimens in patients undergoing LT for CRLM are also highlighted. Additionally, this review describes the findings of studies comparing LT vs chemotherapy alone and LT vs portal vein embolization plus resection for CRLM in terms of OS and DFS. Last but not least, we present current perspectives and ongoing prospective trials that try to elucidate the role of LT for CRLM.
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Affiliation(s)
| | - Ioannis A Ziogas
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Sophoclis P Alexopoulos
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - John J Fung
- Department of Surgery, University of Chicago Medicine Transplant Institute, Chicago, IL 60637, United States
| | - Georgios Tsoulfas
- Department of Transplant Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
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11
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Missing colorectal liver metastases: the surgical challenge. Langenbecks Arch Surg 2021; 406:2163-2175. [PMID: 34590190 DOI: 10.1007/s00423-021-02297-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 08/04/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND New chemotherapy schemes have allowed for a better radiological response of unresectable colorectal liver metastases, leading to an interesting scenario known as a complete radiological response. The aim of this study was to review the current management of missing liver metastases (MLM) from the liver surgeon's point of view. METHODS A systematic search was conducted on all publications of PubMed and Embase between 2003 and 2018. Meta-analysis was performed on MLM resected/unresected. Residual tumor or regrowth and relapse-free survival were used as evaluation indices. RESULTS After literature search, 18 original articles were included for analysis. The predictive factors for MLM are type and duration of chemotherapy and size and number of lesions. Magnetic resonance is the most sensitive preoperative technique. Regarding clinical management, liver surgery is deemed the fundamental pillar in the therapeutic strategy of these patients. Meta-analysis due to data heterogeneity was inconclusive. CONCLUSIONS Depending on the clinical context, MLM monitoring appears to be a valid therapeutic alternative. Nevertheless, prospective randomized clinical studies are needed.
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12
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Kelm M, Schollbach J, Anger F, Wiegering A, Klein I, Germer CT, Schlegel N, Kunzmann V, Löb S. Prognostic impact of additive chemotherapy after curative resection of metachronous colorectal liver metastasis: a single-centre retrospective study. BMC Cancer 2021; 21:490. [PMID: 33941104 PMCID: PMC8091534 DOI: 10.1186/s12885-021-07941-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 02/21/2021] [Indexed: 01/05/2023] Open
Abstract
Background A prognostic benefit of additive chemotherapy in patients following resection of metachronous colorectal liver metastases (CRLM) remains controversial. Therefore, the goal of this retrospective study was to investigate the impact of perioperative chemotherapy on disease-free survival (DFS) and overall survival (OS) of patients after curative resection of metachronous CRLM. Methods In a retrospective single-centre study, patients after curative resection of metachronous CRLM were included and analysed for DFS and OS with regard to the administration of additive chemotherapy. The Kaplan-Meier method was applied to compare DFS and OS while Cox regression models were used to identify independent prognostic variables. Results Thirty-four of 75 patients were treated with additive 5-FU based chemotherapy. OS was significantly prolonged in this patient subgroup (62 vs 57 months; p = 0.032). Additive chemotherapy significantly improved 10-year survival rates (42% vs 0%, p = 0.023), but not 5-year survival (58% vs 42%, p = 0.24). Multivariate analysis identified additive chemotherapy (p = 0.016, HR 0.44, 95% CI 0.23–0.86), more than five CRLM (p = 0.026, HR 2.46, 95% CI 1.16–10.32) and disease recurrence (0.009, HR 2.70, 95% CI 1.29–5.65) as independent risk factors for OS. Conclusion Additive chemotherapy significantly prolonged OS and 10-year survival in patients after curative resection of metachronous CRLM. Randomized clinical trials are needed in the future to identify optimal chemotherapy regimens for those patients.
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Affiliation(s)
- Matthias Kelm
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.
| | - Julia Schollbach
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany
| | - Friedrich Anger
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany
| | - Armin Wiegering
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.,Theodor-Boveri-Institute, Biocenter, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.,Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany
| | - Ingo Klein
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.,Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany
| | - Christoph-Thomas Germer
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.,Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany
| | - Nicolas Schlegel
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany
| | - Volker Kunzmann
- Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany.,Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
| | - Stefan Löb
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.,Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany
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13
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Chu KKW, Wong KHC, Chok KSH. Expanding Indications for Liver Transplant: Tumor and Patient Factors. Gut Liver 2021; 15:19-30. [PMID: 32102130 PMCID: PMC7817931 DOI: 10.5009/gnl19265] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 11/29/2019] [Accepted: 11/29/2019] [Indexed: 12/16/2022] Open
Abstract
During the past few decades, liver transplant has developed from a high-mortality procedure to an almost routine procedure with good survival outcomes. The development of living donor liver transplant has increased the availability of liver grafts, and the scope of indications for liver transplant has been expanding ever since. The aim of this review is to provide an overview of such an expansion of scope. Various criteria have been proposed to expand the eligibility of patients with hepatocellular carcinoma exceeding the Milan criteria for liver transplant. Furthermore, liver transplant is increasingly performed as a treatment modality for cholangiocarcinoma, neuroendocrine liver metastasis and colorectal liver metastasis. The number of elderly patients receiving liver transplant is on the rise. Combined organ transplantation has also been adopted to treat patients with multiple organ failure. Going forward, further development of preoperative noninvasive predictors in tumor, patient and even donor factors is needed to identify patients at risk of poor outcomes and hence optimize patient management.
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Affiliation(s)
- Kevin Ka-Wan Chu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | | | - Kenneth Siu-Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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14
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Ruzzenente A, Bagante F, Ratti F, Beal EW, Alexandrescu S, Merath K, Makris EA, Poultsides GA, Margonis GA, Weiss MJ, Popescu I, Aldrighetti L, Guglielmi A, Pawlik TM. Response to preoperative chemotherapy: impact of change in total burden score and mutational tumor status on prognosis of patients undergoing resection for colorectal liver metastases. HPB (Oxford) 2019; 21:1230-1239. [PMID: 30792047 DOI: 10.1016/j.hpb.2019.01.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/29/2018] [Accepted: 01/18/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Progression of colorectal liver metastasis (CRLM) on preoperative chemotherapy has been associated with a worse prognosis compared with patients who have responsive disease. Defining response can be challenging as traditional criteria largely assess only tumor size. METHODS Patients who underwent hepatectomy between 2010 and 2017 were identified using a multi-centric database. This study aimed to define the impact of preoperative chemotherapy response relative to initial tumor burden score (TBS) and determine impact of clinico-pathological variables on overall survival (OS). RESULTS Among 784 patients who received preoperative chemotherapy, the regimen was oxaliplatin- (66%) or irinotecan-based (34%). Among patients with a TBS<6 at diagnosis, genetic status was the most important prognostic variable. Patients with a TBS<6, 5-year OS was 55%, 35%, and 0% for patients with KRAS/NRAS/BRAF wild-type, KRAS/NRAS, and BRAF mutations, respectively. Among patients who presented with CRLM with a TBS≥6, only Δ-TBS was prognostically important and patients with a Δ-TBS ≥ -10% had a 5-year OS of 27% compared with 49% for patients with a Δ-TBS < -10%. CONCLUSIONS Prognostic stratification of patients with CRLM receiving preoperative chemotherapy should be multi-faceted and include consideration of initial tumor burden, change in tumor burden due to chemotherapy, and tumor genetic status.
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Affiliation(s)
| | - Fabio Bagante
- Department of Surgery, University of Verona, Verona, Italy; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | - Eliza W Beal
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | - Katiuscha Merath
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | | | - Georgios A Margonis
- Department of Surgery, The Johns Hopkins University Hospital, Baltimore, MD, USA
| | - Matthew J Weiss
- Department of Surgery, The Johns Hopkins University Hospital, Baltimore, MD, USA
| | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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15
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Radioembolization treatment for liver metastases. Contemp Oncol (Pozn) 2018; 21:274-278. [PMID: 29416432 PMCID: PMC5798416 DOI: 10.5114/wo.2017.72153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 08/26/2017] [Indexed: 12/17/2022] Open
Abstract
The liver is an organ that, due to vascularisation and functions, is prone to metastases. Most liver metastases are observed in cases of gastrointestinal cancers in: stomach, colon, gallbladder, and bile ducts. Metastatic lesions are also observed in lung, breast, thyroid, kidney, and pancreatic cancer. One of the best known and most effective ways of liver lesion treatment is Metastasectomy. Unfortunately, lesions are frequently inoperable. Apart from chemotherapy, it is possible to apply local treatment such as TACE (trans-arterial chemoembolisation), RFA (Radio Frequency Ablation), and SBRT (Stereotactic Body Radiation Therapy). One of the newest methods of inoperable lesion treatment is radioembolisation (SIRT). Intravascular administration of microspheres containing radioisotope 90Y allows delivery of a higher dose of radiation directly to the tumour than traditional radiation with an external beam, while maintaining a small dose to healthy liver methods. Conducted clinical studies confirm the efficacy and safety of SIRT. It is an interesting alternative to other ways of treatment.
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16
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Line PD, Hagness M, Dueland S. The Potential Role of Liver Transplantation as a Treatment Option in Colorectal Liver Metastases. Can J Gastroenterol Hepatol 2018; 2018:8547940. [PMID: 29623266 PMCID: PMC5829437 DOI: 10.1155/2018/8547940] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 12/19/2017] [Indexed: 12/29/2022] Open
Abstract
Liver resection is the only potentially curative treatment option in patients with liver metastases from colorectal cancer, but only about 20% of the patients are resectable. Liver transplantation of patients with unresectable liver metastases was attempted in the early era but it was abandoned due to poor survival. During the last decade, several case reports, a controlled pilot study, and a retrospective cohort study indicated that prolonged disease-free survival and overall survival can be obtained in a proportion of these patients. Strict selection criteria have not yet been well defined, but tumor load, response to chemotherapy, pretransplant carcinoembryonic antigen level, and time interval from resection of the primary tumor to transplant are all factors related to outcome. Carefully selected patients may obtain 5-year overall survival that approaches conventional indications for liver transplant. The scarcity of liver grafts is a significant problem, but this can possibly to some extent be addressed by use of extended criteria grafts and novel surgical techniques. There is an increasing interest in liver transplantation in these patients in the transplant community, and currently 4 clinical trials are active and are recruiting.
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Affiliation(s)
- Pål-Dag Line
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Morten Hagness
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Svein Dueland
- Department of Oncology, Oslo University Hospital, Oslo, Norway
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17
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Østrup O, Dagenborg VJ, Rødland EA, Skarpeteig V, Silwal-Pandit L, Grzyb K, Berstad AE, Fretland ÅA, Mælandsmo GM, Børresen-Dale AL, Ree AH, Edwin B, Nygaard V, Flatmark K. Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. Oncotarget 2017; 8:76290-76304. [PMID: 29100312 PMCID: PMC5652706 DOI: 10.18632/oncotarget.19350] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 06/26/2017] [Indexed: 01/05/2023] Open
Abstract
Background Metastatic colorectal cancer (CRC) is associated with highly variable clinical outcome and response to therapy. The recently identified consensus molecular subtypes (CMS1-4) have prognostic and therapeutic implications in primary CRC, but whether these subtypes are valid for metastatic disease is unclear. We performed multi-level analyses of resectable CRC liver metastases (CLM) to identify molecular characteristics of metastatic disease and evaluate the clinical relevance. Methods In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent liver tissue from 46 patients were analyzed by profiling mutations (targeted sequencing), genome-wide copy number alteration (CNAs), and gene expression. Results Somatic mutations and CNAs detected in CLM were similar to reported primary CRC profiles, while CNA profiles of eight metastatic pairs suggested intra-patient divergence. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of genes with highly variable expression identified two subgroups separated by high or low expression of 55 genes with immune-related and metabolic functions. Importantly, induction of genes and pathways associated with immunogenic cell death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy (NACT). Conclusions The uniform classification of CLM by CMS subtyping may indicate that novel class discovery approaches need to be explored to uncover clinically useful stratification of CLM. Detected gene expression signatures support the role of metabolism and chemotherapy in shaping the immune microenvironment of CLM. Furthermore, the results point to rational exploration of immune modulating strategies in CLM, particularly by exploiting NACT-induced ICD.
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Affiliation(s)
- Olga Østrup
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Vegar Johansen Dagenborg
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Einar Andreas Rødland
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Veronica Skarpeteig
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Laxmi Silwal-Pandit
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Krzysztof Grzyb
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Audun Elnæs Berstad
- Department of Radiology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Åsmund Avdem Fretland
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- The Intervention Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Gunhild Mari Mælandsmo
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Department of Pharmacy, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Anne-Lise Børresen-Dale
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Anne Hansen Ree
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Bjørn Edwin
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- The Intervention Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Vigdis Nygaard
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Kjersti Flatmark
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Department of Gastroenterological Surgery, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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18
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Moris D, Tsilimigras DI, Chakedis J, Beal EW, Felekouras E, Vernadakis S, Schizas D, Fung JJ, Pawlik TM. Liver transplantation for unresectable colorectal liver metastases: A systematic review. J Surg Oncol 2017; 116:288-297. [PMID: 28513862 DOI: 10.1002/jso.24671] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023]
Abstract
The use of liver transplantation (LT) for liver metastases attempted in the early 1990's was associated with poor perioperative outcomes and unacceptably low overall survival. Recently, there has been renewed interest in LT as a treatment option for colorectal liver metastases (CLM) in countries where organ supply is high. To date, no meticulous analysis about the efficacy, safety and outcomes of LT in CLM patients has been published. We present the first systematic review on the subject.
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Affiliation(s)
- Dimitrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
| | - Diamantis I Tsilimigras
- First Department of Surgery, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Jeffery Chakedis
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
| | - Eliza W Beal
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
| | - Evangelos Felekouras
- First Department of Surgery, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Spiridon Vernadakis
- Transplantation Unit, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - John J Fung
- Department of Surgery, University of Chicago Medicine Transplant Institute, University of Chicago, Chicago, Illinois
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
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Moris D, Pawlik TM. Personalized treatment in patients with colorectal liver metastases. J Surg Res 2017; 216:26-29. [PMID: 28807210 DOI: 10.1016/j.jss.2017.04.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 02/19/2017] [Accepted: 04/11/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND Precision Medicine Initiative is a new research effort aiming to offer personalized treatment in many diseases, including cancer. The aim of the present article is to offer novel insights about the role of personalized treatment in patients with colorectal liver metastases (CRLM). METHODS A review of the literature regarding personalized medicine and colorectal liver metastases was performed mainly in the MEDLINE/PubMed database. RESULTS Surgical resection remains the only hope for cure of CRLM. Improved surgical strategies to optimize remnant liver volume are recently introduced and gaining ground. Following resection of CRLM scoring systems have been developed by combining certain preoperative factors such as microsatellite instability KRAS expression and sensitivity to immunotherapy with Programmed Death-1 inhibitor. CONCLUSIONS Multidisciplinary management of patients with CRLM has markedly contributed to increased survival. While the last several decades have been characterized by these important developments, future advances for patients with CRLM will depend on a better understanding of genomics and molecular biology to facilitate characterization of a specific tumor "identity" so that individualized treatment for each CRLM patient becomes the rule, and not the exception.
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Affiliation(s)
- Dimitrios Moris
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio.
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
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Schneider C, Johnson SP, Gurusamy K, Cook RJ, Desjardins AE, Hawkes DJ, Davidson BR, Walker-Samuel S. Identification of liver metastases with probe-based confocal laser endomicroscopy at two excitation wavelengths. Lasers Surg Med 2017; 49:280-292. [PMID: 27990658 PMCID: PMC5396307 DOI: 10.1002/lsm.22617] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Metastasis of colorectal cancer to the liver is the most common indication for hepatic resection in a western population. Incomplete excision of malignancy due to residual microscopic disease normally results in worse patient outcome. Therefore, a method aiding in the real time discrimination of normal and malignant tissue on a microscopic level would be of benefit. MATERIAL AND METHODS The ability of fluorescent probe-based confocal laser endomicroscopy (pCLE) to identify normal and malignant liver tissue was evaluated in an orthotopic murine model of colorectal cancer liver metastasis (CRLM). To maximise information yield, two clinical fluorophores, fluorescein and indocyanine green (ICG) were injected and imaged in a dual wavelength approach (488 and 660 nm, respectively). Visual tissue characteristics on pCLE examination were compared with histological features. Fluorescence intensity in both tissues was statistically analysed to elucidate if this can be used to differentiate between normal and malignant tissue. RESULTS Fluorescein (488 nm) enabled good visualisation of normal and CRLM tissue, whereas ICG (660 nm) visualisation was limited to normal liver tissue only. Fluorescence intensity in areas of CRLM was typically 53-100% lower than normal hepatic parenchyma. Using general linear mixed modelling and receiver operating characteristic analysis, high fluorescence intensity was found to be statistically more likely in normal hepatic tissue. CONCLUSION Real time discrimination between normal liver parenchyma and metastatic tissue with pCLE examination of fluorescein and ICG is feasible. Employing two (rather than a single) fluorophores allows a combination of qualitative and quantitative characteristics to be used to distinguish between hepatic parenchyma and CRLM. Lasers Surg. Med. 49:280-292, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Crispin Schneider
- Division of Surgery & Interventional Science, University College London, Floor 9, Royal Free Hospital, London, NW3 2QG, UK
| | - Sean P Johnson
- UCL Centre for Advanced Biomedical Imaging, Paul O'Gorman Building, University College London, 72 Huntley Street, London, WC1E 6DD, UK
| | - Kurinchi Gurusamy
- Division of Surgery & Interventional Science, University College London, Floor 9, Royal Free Hospital, London, NW3 2QG, UK
| | - Richard J Cook
- Department of Tissue Engineering and Biophotonics, King's College London, Dental Institute-Central Office, Floor 18, Guy's Tower, Guy's Hospital, London, SE1 9RT, UK
| | - Adrien E Desjardins
- Department of Medical Physics and Biomedical Engineering, University College London, Malet Place Engineering Building, Gower Street, London, WC1E 6BT, UK
| | - David J Hawkes
- Centre for Medical Image Computing, University College London, The Front Engineering Building, Floor 3, Malet Place, London, WC1E 7JE, UK
| | - Brian R Davidson
- Division of Surgery & Interventional Science, University College London, Floor 9, Royal Free Hospital, London, NW3 2QG, UK
| | - Simon Walker-Samuel
- UCL Centre for Advanced Biomedical Imaging, Paul O'Gorman Building, University College London, 72 Huntley Street, London, WC1E 6DD, UK
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21
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Røhrl K, Guren MG, Miaskowski C, Cooper BA, Diep LM, Rustøen T. No Differences in Symptom Burden Between Colorectal Cancer Patients Receiving Curative Versus Palliative Chemotherapy. J Pain Symptom Manage 2016; 52:539-547. [PMID: 27470003 DOI: 10.1016/j.jpainsymman.2016.04.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 03/08/2016] [Accepted: 04/29/2016] [Indexed: 11/23/2022]
Abstract
CONTEXT Colorectal cancer (CRC) is one of the most common cancers worldwide. Patients with CRC may have multiple cooccurring symptoms as a result of their disease or its treatment. Little is known about potential differences in symptom burden in CRC patients scheduled to receive curative versus palliative chemotherapy (CTX). OBJECTIVES The purposes of this study were to investigate the overall symptom burden of patients with CRC before their first CTX treatment or before the initiation of a new CTX regimen and to evaluate for differences in symptom occurrence, severity, and distress between patients with CRC who were scheduled to receive curative versus palliative CTX. METHODS Consecutive patients with CRC were recruited (n = 120), and symptoms were assessed using the Memorial Symptom Assessment Scale before the initiation of the CTX. The most common symptoms that occurred in ≥30% of the patients were evaluated. Differences in occurrence rates and severity and distress scores between the curative (n = 68) and palliative (n = 52) patient groups were evaluated using binary logistic regression and ordinal logistic regression analyses, respectively. RESULTS In both groups, patients reported an average of 10 cooccurring symptoms. Worrying (65%), lack of energy (59%), feeling drowsy (54%), feeling bloated (53%), pain (51%), and difficulty sleeping (50%) were the most prevalent symptoms. Problems with sexual interest had the highest severity and distress scores in both groups. For the 13 most common symptoms, no significant differences were found between the two patient groups on any of the Memorial Symptom Assessment Scale dimensions (i.e., occurrence, severity, distress). CONCLUSION Regardless of the reason for CTX, CRC patients experience a large number of cooccurring symptoms.
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Affiliation(s)
- Kari Røhrl
- Institute for Health and Society, University of Oslo, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway.
| | - Marianne Grønlie Guren
- Department of Oncology, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | | | - Bruce A Cooper
- School of Nursing, University of California, San Francisco, California, USA
| | - Lien My Diep
- Department for Biostatistics, Epidemiology, and Health Economics, Oslo University, Oslo, Norway
| | - Tone Rustøen
- Institute for Health and Society, University of Oslo, Oslo, Norway; Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
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Chen KN. Radiofrequency ablation is one of safe and effective local control alternative for colorectal pulmonary metastases. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:315. [PMID: 27668235 DOI: 10.21037/atm.2016.07.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Ke-Neng Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, China
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Matos AP, Altun E, Ramalho M, Velloni F, AlObaidy M, Semelka RC. An overview of imaging techniques for liver metastases management. Expert Rev Gastroenterol Hepatol 2016; 9:1561-76. [PMID: 26414180 DOI: 10.1586/17474124.2015.1092873] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Evaluation of liver metastases is one of the most common indications for liver imaging. Imaging plays a key role in the of assessment liver metastases. A variety of imaging techniques, including ultrasonography, computed tomography, MRI and PET combined with CT scan are available for diagnosis, planning treatment, and follow-up treatment response. In this paper, the authors present the role of imaging for the assessment of liver metastases and the contribution of each of the different imaging techniques for their evaluation and management. Following recent developments in the field of oncology, the authors also present the importance of imaging for the assessment of liver metastases response to therapy. Finally, future perspectives on imaging of liver metastases are presented.
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Affiliation(s)
- António P Matos
- a University of North Carolina, Department of Radiology, Chapel Hill, NC, USA
| | - Ersan Altun
- a University of North Carolina, Department of Radiology, Chapel Hill, NC, USA
| | - Miguel Ramalho
- a University of North Carolina, Department of Radiology, Chapel Hill, NC, USA
| | - Fernanda Velloni
- a University of North Carolina, Department of Radiology, Chapel Hill, NC, USA
| | - Mamdoh AlObaidy
- a University of North Carolina, Department of Radiology, Chapel Hill, NC, USA
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Pouillon L, Bossuyt P, Peyrin-Biroulet L. Considerations, challenges and future of anti-TNF therapy in treating inflammatory bowel disease. Expert Opin Biol Ther 2016; 16:1277-90. [PMID: 27329436 DOI: 10.1080/14712598.2016.1203897] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Crohn's disease (CD) and ulcerative colitis (UC) are chronic disabling conditions. Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNF) has revolutionized the care of patients with inflammatory bowel disease (IBD). AREAS COVERED Considerations before starting anti-TNF therapy are highlighted: the best time to start with anti-TNF therapy, either alone or in combination with an immunomodulator, the choice of an anti-TNF agent and the contra-indications to anti-TNF therapy. Primary nonresponse and secondary loss of response are discussed. De-escalating therapy, the role of therapeutic drug monitoring and the use of biosimilars, are handled. Finally, the future directions of anti-TNF therapy are emphasized. EXPERT OPINION Anti-TNF therapy remains the cornerstone in the treatment of IBD. When initiating long-term therapy, safety and cost issues are of great importance. The therapeutic armamentarium in the treatment of IBD is rapidly growing. Therefore, the challenge is to optimize the use and refine the exact position of anti-TNF therapy in the near future, with personalized medicine as the ultimate goal.
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Affiliation(s)
- Lieven Pouillon
- a Department of Hepato-Gastroenterology , University Hospitals Leuven, Uz Gasthuisberg , Leuven , Belgium
| | - Peter Bossuyt
- b Imelda GI Clinical Research Centre , Imeldaziekenhuis Bonheiden , Bonheiden , Belgium
| | - Laurent Peyrin-Biroulet
- c Inserm U954 and Department of Gastroenterology , Nancy University Hospital, Université de Lorraine , Vandœuvre-lès-Nancy , France
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25
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Bleckmann A, Conradi LC, Menck K, Schmick NA, Schubert A, Rietkötter E, Arackal J, Middel P, Schambony A, Liersch T, Homayounfar K, Beißbarth T, Klemm F, Binder C, Pukrop T. β-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases. Clin Exp Metastasis 2016; 33:309-23. [PMID: 26862065 PMCID: PMC4799797 DOI: 10.1007/s10585-016-9780-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 02/01/2016] [Indexed: 12/18/2022]
Abstract
Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01–0.56) and high Ki67 (HR 3.68, 95 % CI 1.12–12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11–5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02–4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.
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Affiliation(s)
- Annalen Bleckmann
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.,Department of Medical Statistics, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Kerstin Menck
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Nadine Annette Schmick
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Antonia Schubert
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Eva Rietkötter
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Jetcy Arackal
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Peter Middel
- Institute of Pathology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Alexandra Schambony
- Department Biology, Developmental Biology, Friedrich-Alexander University Erlangen-Nürnberg, 91058, Erlangen, Germany
| | - Torsten Liersch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Kia Homayounfar
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Tim Beißbarth
- Department of Medical Statistics, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Florian Klemm
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Claudia Binder
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Tobias Pukrop
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany. .,Clinic for Internal Medicine III, Hematology and Medical Oncology, University Regensburg, 93053, Regensburg, Germany.
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