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Soliman N, Maqsood A, Connor AA. Role of genomics in liver transplantation for cholangiocarcinoma. Curr Opin Organ Transplant 2025; 30:158-170. [PMID: 39917813 DOI: 10.1097/mot.0000000000001209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize the current knowledge of cholangiocarcinoma molecular biology and to suggest a framework for implementation of next-generation sequencing in all stages of liver transplantation. This is timely as recent guidelines recommend increased use of these technologies with promising results. RECENT FINDINGS The main themes covered here address germline and somatic genetic alterations recently discovered in cholangiocarcinoma, particularly those associated with prognosis and treatment responses, and nascent efforts to translate these into contemporary practice in the peri-liver transplantation period. SUMMARY Early efforts to translate molecular profiling to cholangiocarcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking is a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care with the ambition of increasing the number of patients eligible for liver transplantation and improving their long-term outcomes.
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Affiliation(s)
- Nadine Soliman
- Department of Surgery
- J. C. Walter Jr. Transplant Center, Houston Methodist Hospital
- Houston Methodist Academic Institute
| | - Anaum Maqsood
- Department of Medicine
- Neill Cancer Center, Houston Methodist Hospital, Houston, Texas
| | - Ashton A Connor
- Department of Surgery
- J. C. Walter Jr. Transplant Center, Houston Methodist Hospital
- Houston Methodist Academic Institute
- Neill Cancer Center, Houston Methodist Hospital, Houston, Texas
- Department of Surgery, Weill Cornell Medicine, Cornell University, New York, New York, USA
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Luo G, Zhu S, He L, Liu Q, Xu C, Yao Q, Hu H, Wang Q, Zou S. Platelets promote metastasis of intrahepatic cholangiocarcinoma through activation of TGF-β/Smad2 pathway. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167734. [PMID: 39978442 DOI: 10.1016/j.bbadis.2025.167734] [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: 04/27/2024] [Revised: 01/11/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
Intrahepatic cholangiocarcinoma (ICC), an aggressive liver cancer, lacks simple and accurate clinical tests, which poses challenges to postoperative diagnosis and treatment. Recent studies have indicated that platelet levels might be relevant to the postoperative prognosis of ICC. However, their prognostic significance in ICC remains unclarified. This study included 218 ICC patients who underwent hepatic resection. Comprehensive analyses of patients' postoperative prognosis were conducted primarily focusing on their platelet levels associated with prognostic traits. To further investigate the underlying mechanism between platelet levels and patients' postoperative prognosis, we elucidated the association between platelets and tumor metastasis using HCCC-9810 and HUCC-T1 cells as well as mouse models. In the retrospective cohort study, elevated serum platelet levels (≥300 × 109/L) or tumoral platelet levels (≥0.23) individually indicated an unfavorable postoperative prognosis in individuals with ICC. Multivariate analysis showed that tumoral platelet levels can be an independent prognostic factor, while the loss of prognostic superiority of serum platelet levels in the analysis may be attributed to the influence of confounding inclusion variables. Epithelial/mesenchymal transition (EMT) marker expression changes in HCCC-9810 and HUCC-T1 cells with platelet treatment were analyzed to understand how platelets contribute to ICC malignant recurring progression. The significant role of the TGF-β/Smad2 pathway in ICC metastasis was identified. In addition, aspirin was found to have the potential to reduce ICC metastasis by inhibiting platelet function. In conclusion, this study indicated that ICC patients with postoperative serum platelet levels ≥300 × 109/L or tumoral platelet levels ≥0.23 have significantly higher risk of poor postoperative prognosis. This is due to platelet-derived TGFβ1 leading to EMT in ICC cells, thus promoting tumor metastasis.
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Affiliation(s)
- Guijuan Luo
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Shuyang Zhu
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Liujie He
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Qiang Liu
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Chao Xu
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Xinhua Hospital of Zhejiang Province, Hangzhou 310005, China; Integrated Traditional Chinese and Western Medicine Oncology Laboratory, Key Laboratory of Traditional Chinese Medicine of Zhejiang Province, Hangzhou 310022, China
| | - Qinghua Yao
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Xinhua Hospital of Zhejiang Province, Hangzhou 310005, China; Integrated Traditional Chinese and Western Medicine Oncology Laboratory, Key Laboratory of Traditional Chinese Medicine of Zhejiang Province, Hangzhou 310022, China
| | - Heping Hu
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
| | - Qiang Wang
- Department of Urology, Peking University People's Hospital, Beijing 100044, China.
| | - Shanshan Zou
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
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Cao XR, Xu YL, Chai JW, Zheng K, Kong JJ, Liu J, Zheng SZ. Pretreatment red blood cell distribution width as a predictive marker for postoperative complications after laparoscopic pancreatoduodenectomy. World J Gastrointest Oncol 2025; 17:98168. [PMID: 39817125 PMCID: PMC11664621 DOI: 10.4251/wjgo.v17.i1.98168] [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: 06/19/2024] [Revised: 09/10/2024] [Accepted: 10/29/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Red blood cell distribution width (RDW) is associated with the development and progression of various diseases. AIM To explore the association between pretreatment RDW and short-term outcomes after laparoscopic pancreatoduodenectomy (LPD). METHODS A total of 804 consecutive patients who underwent LPD at our hospital between March 2017 and November 2021 were retrospectively analyzed. Correlations between pretreatment RDW and clinicopathological characteristics and short-term outcomes were investigated. RESULTS Patients with higher pretreatment RDW were older, had higher Eastern Cooperative Oncology Group scores and were associated with poorer short-term outcomes than those with normal RDW. High pretreatment RDW was an independent risk factor for postoperative complications (POCs) (hazard ratio = 2.973, 95% confidence interval: 2.032-4.350, P < 0.001) and severe POCs of grade IIIa or higher (hazard ratio = 3.138, 95% confidence interval: 2.042-4.824, P < 0.001) based on the Clavien-Dino classification system. Subgroup analysis showed that high pretreatment RDW was an independent risk factor for Clavien-Dino classification grade IIIb or higher POCs, a comprehensive complication index score ≥ 26.2, severe postoperative pancreatic fistula, severe bile leakage and severe hemorrhage. High pretreatment RDW was positively associated with the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and was negatively associated with albumin and the prognostic nutritional index. CONCLUSION Pretreatment RDW was a special parameter for patients who underwent LPD. It was associated with malnutrition, severe inflammatory status and poorer short-term outcomes. RDW could be a surrogate marker for nutritional and inflammatory status in identifying patients who were at high risk of developing POCs after LPD.
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Affiliation(s)
- Xian-Rang Cao
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Yin-Long Xu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Jia-Wei Chai
- Department of Breast and Thyroid Surgery, Shandong Provincial Maternal and Child Health Care Hospital, Jinan 250014, Shandong Province, China
| | - Kai Zheng
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Jun-Jie Kong
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Shun-Zhen Zheng
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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Suzuki H, Kuwano A, Takahira J, Tanaka K, Yada M, Motomura K. Prognostic Significance of Lymphocyte-to-Monocyte Ratio in Patients With Unresectable Biliary Tract Cancer Undergoing Systemic Chemotherapy. CANCER DIAGNOSIS & PROGNOSIS 2025; 5:132-137. [PMID: 39758246 PMCID: PMC11696337 DOI: 10.21873/cdp.10422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 11/23/2024] [Accepted: 11/25/2024] [Indexed: 01/07/2025]
Abstract
Background/Aim The incidence of biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, has been increasing worldwide. Approximately 70% of BTC patients have advanced disease at diagnosis, leading to a poor survival rate. Recent clinical trials have demonstrated that the addition of immune checkpoint inhibitors, such as durvalumab or pembrolizumab, to gemcitabine plus cisplatin chemotherapy significantly improves survival rates, making triple therapy the current standard for first-line treatment of BTC. Few models with predictive value exist for BTC. Lymphocyte-to-monocyte ratio (LMR) is a relatively new inflammation-related score and translational biomarker and has prognostic value for survival of patients with other cancers. This study assessed the prognostic value of LMR in patients with advanced BTC and analyzed the risk factors associated with overall survival (OS). Patients and Methods This prospective study enrolled 75 patients with advanced BTC who were treated with gemcitabine-based chemotherapies at Aso Iizuka Hospital, Japan. The cutoff value of LMR for predicting 6-month survival was 3.27. Results OS was longer for patients with high LMR compared with low LMR (median 32.4 months and 8.6 months, respectively; p=0.0069). Multivariate analysis identified LMR >3.27 [hazard ratio (HR)=0.427, p=0.0339] and objective response rate (HR=0.210, p=0.0116) as independent factors associated with OS. Conclusion Despite some limitations, such as the single-center design and small sample size, the results of this study suggest a potential role for LMR in predicting survival outcomes for BTC patients treated with gemcitabine-based chemotherapies.
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Affiliation(s)
- Hideo Suzuki
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
| | - Akifumi Kuwano
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
| | - Junro Takahira
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
| | - Kosuke Tanaka
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
| | - Masayoshi Yada
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
- Department of Gastroenterology, Ichinomiyanishi Hospital, Ichinomiya, Japan
| | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
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Bai S, Shi X, Dai Y, Wang H, Xia Y, Liu J, Wang K. The preoperative scoring system combining neutrophil/lymphocyte ratio and CA19-9 predicts the long-term prognosis of intrahepatic cholangiocarcinoma patients undergoing curative liver resection. BMC Cancer 2024; 24:1106. [PMID: 39237882 PMCID: PMC11378368 DOI: 10.1186/s12885-024-12819-0] [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: 06/20/2024] [Accepted: 08/16/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND This study aims to investigate preoperative prognostic factors available for intrahepatic cholangiocarcinoma (ICC) patients and propose a new preoperative prognostic scoring system for ICC that combines CA19-9 and neutrophil/lymphocyte ratio (NLR). METHODS In this retrospective analysis, 1728 patients diagnosed with ICC and undergoing curative liver resections were studied. This study employed univariate and multivariate Cox regression to find factors affecting recurrence and overall survival (OS), and furthermore assessed how preoperative models influenced tumor traits and postoperative recurrence. RESULTS The results of the multivariate Cox regression analysis indicated that two preoperative variables, NLR and Ca19-9, were independent risk factors affecting postoperative recurrence and OS in ICC patients. Based on this data, assigning a score of 0 (NLR ≤ 2.4 and Ca19-9 ≤ 37U/ml) or 1 (NLR > 2.4 and Ca19-9 > 37U/ml) to these two factors, a preoperative prognostic score was derived. According to the scoring model, patients were divided into three groups: 0 points (low-risk group), 1 point (intermediate-risk group), and 2 points (high-risk group). The 5-year recurrence and OS rates for the three groups were 56.6%, 68.2%, 77.8%, and 56.8%, 40.6%, 27.6%, respectively, with all P values < 0.001. Furthermore, high-risk group patients were more prone to early recurrence (early recurrence rates for high-, intermediate-, and low-risk groups were 56.8%, 51.5%, and 37.1%, respectively, P < 0.001) and extrahepatic metastasis (extrahepatic metastasis rates for high-, intermediate-, and low-risk groups were 31.7%, 26.4%, and 15.4%, respectively, P < 0.001). In terms of tumor characteristics, high-risk group patients had larger tumor diameters and were more likely to experience microvascular invasion, lymph node metastasis, and perineural invasion. CONCLUSIONS The predictive capacity of postoperative recurrence and OS rates in ICC patients is effectively captured by the preoperative scoring system incorporating NLR and CA19-9 levels.
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Affiliation(s)
- Shilei Bai
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), No. 225, Changhai Road, Yangpu District, Shanghai, 200438, People's Republic of China
| | - Xiaodong Shi
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), No. 225, Changhai Road, Yangpu District, Shanghai, 200438, People's Republic of China
| | - Yizhe Dai
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, People's Republic of China
| | - Huifeng Wang
- Department of Hepatic Surgery, the Fifth Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, People's Republic of China
| | - Yong Xia
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, People's Republic of China
| | - Jian Liu
- Department of Biliary Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, People's Republic of China.
| | - Kui Wang
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), No. 225, Changhai Road, Yangpu District, Shanghai, 200438, People's Republic of China.
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Cai W, Li Z, Liu B, Cao Y. A predictive model for colorectal cancer complicated with intestinal obstruction based on specific inflammation score. BMC Cancer 2024; 24:1035. [PMID: 39169325 PMCID: PMC11340113 DOI: 10.1186/s12885-024-12806-5] [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: 08/29/2023] [Accepted: 08/13/2024] [Indexed: 08/23/2024] Open
Abstract
PURPOSE Inflammatory factors play an important role in the onset and progression of colorectal cancer (CRC). This study aimed to develop and validate a novel scoring system that utilizes specific inflammatory factor indicators to predict intestinal obstruction in CRC patients. METHODS This study conducted a retrospective analysis of 1,470 CRC patients who underwent surgical resection between January 2013 and July 2018. These patients were randomly allocated to the training group (n = 1060) and the validation group (n = 410). Univariate and multivariate logistic regression analyses were performed to identify independent predictive factors for intestinal obstruction. The CRC peculiar inflammation score (CPIS), comprising lymphocyte-to-monocyte ratio (LMR), prognostic nutrition index (PNI), and alanine transaminase-to-lymphocyte ratio index (ALRI) scores, was significantly associated with the occurrence of intestinal obstruction. A nomogram combining CPIS with other clinical features was developed to predict this occurrence. Model accuracy was assessed by determining the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS The CPIS generated by multi-factor logistic regression was as follows: - 1.576 × LMR - 0.067 × PNI + 0.018 × ALRI. Using CPIS cutoff values of 50% (- 7.188) and 85% (- 6.144), three predictive groups were established. Patients with a high CPIS had a significantly higher risk of intestinal obstruction than those with a low CPIS (odds ratio [OR]: 10.0, confidence interval [CI]: 5.85-17.08, P < 0.001). The predictive nomogram demonstrated good calibration and discrimination abilities. The AUC of the ROC curve for the obstruction nomogram was 0.813 (95% CI: 0.777-0.850) in the training set and 0.806 (95% CI: 0.752-0.860) in the validation set. The calibration curve exhibited neither bias nor high credibility. Decision curve analysis indicated the utility of this predictive model. CONCLUSION CRC-associated intestinal obstruction is closely linked to inflammatory markers in patients. CPIS is a CRC-specific inflammatory predictive score based on a combination of inflammatory-related indicators. A high CPIS serves as a strong indicator of intestinal obstruction. Its integration with other clinical factors and preoperative inflammatory-specific indicators significantly enhances the diagnosis and treatment of CRC patients with intestinal obstruction.
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Affiliation(s)
- Wentai Cai
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- The First Clinical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zhenzhou Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- The First Clinical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Bo Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Rd, Wuhan, 430022, Hubei Province, China.
| | - Yinghao Cao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Precision Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Xie H, Hong T, Liu W, Jia X, Wang L, Zhang H, Xu C, Zhang X, Li WL, Wang Q, Yin C, Lv X. Interpretable machine learning-based clinical prediction model for predicting lymph node metastasis in patients with intrahepatic cholangiocarcinoma. BMC Gastroenterol 2024; 24:137. [PMID: 38641789 PMCID: PMC11031954 DOI: 10.1186/s12876-024-03223-w] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 04/05/2024] [Indexed: 04/21/2024] Open
Abstract
OBJECTIVE Prediction of lymph node metastasis (LNM) for intrahepatic cholangiocarcinoma (ICC) is critical for the treatment regimen and prognosis. We aim to develop and validate machine learning (ML)-based predictive models for LNM in patients with ICC. METHODS A total of 345 patients with clinicopathological characteristics confirmed ICC from Jan 2007 to Jan 2019 were enrolled. The predictors of LNM were identified by the least absolute shrinkage and selection operator (LASSO) and logistic analysis. The selected variables were used for developing prediction models for LNM by six ML algorithms, including Logistic regression (LR), Gradient boosting machine (GBM), Extreme gradient boosting (XGB), Random Forest (RF), Decision tree (DT), Multilayer perceptron (MLP). We applied 10-fold cross validation as internal validation and calculated the average of the areas under the receiver operating characteristic (ROC) curve to measure the performance of all models. A feature selection approach was applied to identify importance of predictors in each model. The heat map was used to investigate the correlation of features. Finally, we established a web calculator using the best-performing model. RESULTS In multivariate logistic regression analysis, factors including alcoholic liver disease (ALD), smoking, boundary, diameter, and white blood cell (WBC) were identified as independent predictors for LNM in patients with ICC. In internal validation, the average values of AUC of six models ranged from 0.820 to 0.908. The XGB model was identified as the best model, the average AUC was 0.908. Finally, we established a web calculator by XGB model, which was useful for clinicians to calculate the likelihood of LNM. CONCLUSION The proposed ML-based predicted models had a good performance to predict LNM of patients with ICC. XGB performed best. A web calculator based on the ML algorithm showed promise in assisting clinicians to predict LNM and developed individualized medical plans.
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Affiliation(s)
- Hui Xie
- Department of General Surgery, Yan 'an People's Hospital, Yan 'an, China
| | - Tao Hong
- Department of Cardiac Surgery, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China
| | - Wencai Liu
- Department of Orthopaedic Surgery, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaodong Jia
- Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Le Wang
- Department of thoracic surgery, the first affiliated hospital of Dalian Medical University, Dalian, China
| | - Huan Zhang
- Graduate School of Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Chan Xu
- State Key Laboratory of MolecularVaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Xiaoke Zhang
- Graduate School of Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Wen-Le Li
- State Key Laboratory of MolecularVaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China.
| | - Quan Wang
- Radiation Oncology Department, Fifth Medical Center of PLA General Hospital, Beijing, China.
| | - Chengliang Yin
- Faculty of Medicine, Macau University of Science and Technology, Macau, China.
| | - Xu Lv
- Department of General Surgery, Yixing Cancer Hospital, Yixing, Jiangsu, 214200, China.
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Saeheng T, Karbwang J, Na-Bangchang K. Interleukin-6 and Lymphocyte-to-Monocyte Ratio Indices Identify Patients with Intrahepatic Cholangiocarcinoma. Biomedicines 2024; 12:844. [PMID: 38672199 PMCID: PMC11047984 DOI: 10.3390/biomedicines12040844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/21/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND AND AIMS Intrahepatic cholangiocarcinoma (iCCA) is a fatal biliary tract cancer with a dismal prognosis due to ineffective diagnostic tools with limited clinical utility. This study investigated peripheral blood indices and cytokine levels to diagnose iCCA. METHODS Blood samples were collected from healthy subjects (n = 48) and patients with advanced-stage iCCA (n = 47) during a phase I and then phase II trial, respectively. Serum cytokines were measured using a flow cytometer. The peripheral blood indices were estimated based on laboratory data. Multi-linear regression analysis was applied, followed by a probability transformation. The cut-off value and model accuracy were determined using the receiver operating curve (ROC) and the area under the curve (AUC). RESULTS The interleukin-6 (IL6) and lymphocyte-to-monocyte ratio (LMR) were potential predictors of iCCA [AUC = 0.91 (0.85-0.97) and 0.81 (0.68-0.93); sensitivity = 0.70 and 0.91; specificity = 0.91 and 0.85, respectively]. Patients with IL6 concentrations higher than 11.635 pg/mL (OR = 23.33, p < 0.001) or LMR lower than 7.2 (OR = 58.08, p < 0.001) are at risk of iCCA development. Patients with IL6 levels higher than 21.83 pg/mL, between 15.95 and 21.83 pg/mL, between 8.8 and 15.94 pg/mL, and lower than 8.8 pg/mL were classified as very high-, high-, intermediate-, and low-risk, respectively. Patients with an LMR between 1 and 3.37, 3.38 and 5.76, 5.77 and 7.18, and higher than 7.18 were classified as very high-, high-, intermediate-, and low-risk, respectively. CONCLUSIONS LMR is recommended for iCCA screening since the estimation is based on a routine laboratory test, which is available in most hospitals.
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Affiliation(s)
- Teerachat Saeheng
- Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), 99, moo 18, Phaholyothin Road, Klongneung Sub-District, Klongluang District, Pathum Thani 12121, Thailand;
| | - Juntra Karbwang
- Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University (Rangsit Campus), Pathum Thani 12121, Thailand;
| | - Kesara Na-Bangchang
- Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), 99, moo 18, Phaholyothin Road, Klongneung Sub-District, Klongluang District, Pathum Thani 12121, Thailand;
- Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University (Rangsit Campus), Pathum Thani 12121, Thailand;
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Xu B, Zhu J, Wang R, Pang X, Wang X, Lian J, Lu H. Clinical Implications of Naples Prognostic Score for Patients with Resected Cholangiocarcinoma: A Real-World Experience. J Inflamm Res 2024; 17:655-667. [PMID: 38328562 PMCID: PMC10849881 DOI: 10.2147/jir.s446735] [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: 10/26/2023] [Accepted: 01/16/2024] [Indexed: 02/09/2024] Open
Abstract
Purpose The Nutritional Prognostic Score (NPS) is a composite indicator that effectively reflects the preoperative nutritional and inflammation status of patients. Its prognostic value has been extensively confirmed in various types of tumors. Our study aims to investigate the clinical implications of the NPS in the postoperative patients with cholangiocarcinoma (CCA). Patients and Methods Data on clinicopathological characteristics were collected from CCA patients who underwent radical surgery between 2014 and 2019 at Harbin Medical University Cancer Hospital. NPS was calculated using relevant indicators to categorize the patients, and association of NPS with clinicopathological characteristics and survival outcomes were analyzed. To assess differences in survival rates between different groups, we utilized the Kaplan-Meier method. Independent prognostic risk factors were identified by Cox regression analysis. A CONomogram was created, and its accuracy in survival prediction was evaluated using receiver operating characteristic (ROC) curves. Independent verification was conducted in the validation group. Results For this study, a cohort of 232 patients was enlisted and subsequently divided into training group (N=162) and validation group (N=70). An evident correlation was detected between NPS and preoperative malnutrition. Patients with higher NPS exhibited a worse overall survival (OS), with 5-year OS rates of 79.1%, 33.1%, and 10.6%. Multivariate analysis revealed that NPS was an independent risk factor for OS in resected CCA patients (P<0.001). The NPS-based Nomogram was developed to accurately assess the risk of patients. Conclusion The NPS was identified as a significant risk factor that impacts the prognosis of patients with resected CCA. In order to improve prognosis management, the NPS-based Nomogram has been demonstrated to be a precise and efficient tool.
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Affiliation(s)
- Benjie Xu
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Jiahao Zhu
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Ren Wang
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Xiangyi Pang
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Xin Wang
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Jie Lian
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Haibo Lu
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
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Tomlinson JL, Valle JW, Ilyas SI. Immunobiology of cholangiocarcinoma. J Hepatol 2023; 79:867-875. [PMID: 37201670 PMCID: PMC10524996 DOI: 10.1016/j.jhep.2023.05.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/18/2023] [Accepted: 05/03/2023] [Indexed: 05/20/2023]
Abstract
Recent literature has significantly advanced our knowledge and understanding of the tumour immune microenvironment of cholangiocarcinoma. Detailed characterisation of the immune landscape has defined new patient subtypes. While not utilised in clinical practice yet, these novel classifications will help inform decisions regarding immunotherapeutic approaches. Suppressive immune cells, such as tumour-associated macrophages and myeloid-derived suppressor cells, form a barrier that shields tumour cells from immune surveillance. The presence of this immunosuppressive barrier in combination with a variety of immune escape mechanisms employed by tumour cells leads to poor tumour immunogenicity. Broad strategies to re-equip the immune system include blockade of suppressive immune cell recruitment to priming cytotoxic effector cells against tumour antigens. While immunotherapeutic strategies are gaining traction for the treatment of cholangiocarcinoma, there is a long road of discovery ahead in order to make meaningful contributions to patient therapy and survival.
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Affiliation(s)
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester & Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA.
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11
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Ilyas SI, Affo S, Goyal L, Lamarca A, Sapisochin G, Yang JD, Gores GJ. Cholangiocarcinoma - novel biological insights and therapeutic strategies. Nat Rev Clin Oncol 2023; 20:470-486. [PMID: 37188899 PMCID: PMC10601496 DOI: 10.1038/s41571-023-00770-1] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2023] [Indexed: 05/17/2023]
Abstract
In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of 'immune-desert' tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2) fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1) obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for early stage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.
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Affiliation(s)
- Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Silvia Affo
- Liver, Digestive System and Metabolism Research, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Lipika Goyal
- Department of Medicine, Mass General Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Angela Lamarca
- Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gonzalo Sapisochin
- Ajmera Transplant Program and HPB Surgical Oncology, Toronto General Hospital, University of Toronto, Toronto, Canada
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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12
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Zhu J, Wang D, Liu C, Huang R, Gao F, Feng X, Lan T, Li H, Wu H. Development and validation of a new prognostic immune–inflammatory–nutritional score for predicting outcomes after curative resection for intrahepatic cholangiocarcinoma: A multicenter study. Front Immunol 2023; 14:1165510. [PMID: 37063918 PMCID: PMC10102611 DOI: 10.3389/fimmu.2023.1165510] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/21/2023] [Indexed: 04/03/2023] Open
Abstract
BackgroundImmune function, nutrition status, and inflammation influence tumor initiation and progression. This was a retrospective multicenter cohort study that investigated the prognostic value and clinical relevance of immune-, inflammatory-, and nutritional-related biomarkers to develop a novel prognostic immune–inflammatory–nutritional score (PIIN score) for patients with intrahepatic cholangiocarcinoma (ICC).MethodsThe clinical data of 571 patients (406 in the training set and 165 in the validation set) were collected from four large hepato-pancreatico-biliary centers of patients with ICC who underwent surgical resection between January 2011 and September 2017. Twelve blood biomarkers were collected to develop the PIIN score using the LASSO Cox regression model. The predictive value was further assessed using validation datasets. Afterward, nomograms combining the PIIN score and other clinicopathological parameters were developed and validated based on the calibration curve, time-dependent AUC curves, and decision curve analysis (DCA). The primary outcomes evaluated were overall survival (OS) and recurrence-free survival (RFS) from the day of primary resection of ICC.ResultsBased on the albumin–bilirubin (ALBI) grade, neutrophil- to- lymphocyte ratio (NLR), prognostic nutritional index (PNI), and systemic immune- inflammation index (SII) biomarkers, the PIIN score that classified patients into high-risk and low-risk groups could be calculated. Patients with high-risk scores had shorter OS (training set, p < 0.001; validation set, p = 0.003) and RFS (training set, p < 0.001; validation set, p = 0.002) than patients with low-risk scores. The high PIIN score was also associated with larger tumors (≥5 cm), lymph node metastasis (N1 stage), multiple tumors, and high tumor grade or TNM (tumor (T), nodes (N), and metastases (M)) stage. Furthermore, the high PIIN score was a significant independent prognostic factor of OS and RFS in both the training (p < 0.001) and validation (p = 0.003) cohorts, respectively. A PIIN-nomogram for individualized prognostic prediction was constructed by integrating the PIIN score with the clinicopathological variables that yielded better predictive performance than the TNM stage.ConclusionThe PIIN score, a novel immune–inflammatory–nutritional-related prognostic biomarker, predicts the prognosis in patients with resected ICC and can be a reliable tool for ICC prognosis prediction after surgery. Our study findings provide novel insights into the role of cancer-related immune disorders, inflammation, and malnutrition.
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Affiliation(s)
- Jiang Zhu
- Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Denghui Wang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chang Liu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Hepatopancreatobiliary Minimal Invasive Surgery, Chengdu ShangJin NanFu Hospital, Chengdu, China
| | - Rui Huang
- Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fengwei Gao
- Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
- Department of Hepatobiliary Surgery, The People's Hospital of Leshan, Leshan, China
| | - Xuping Feng
- Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Lan
- Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Hong Wu, ; Hui Li, ; Tian Lan,
| | - Hui Li
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
- *Correspondence: Hong Wu, ; Hui Li, ; Tian Lan,
| | - Hong Wu
- Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Hong Wu, ; Hui Li, ; Tian Lan,
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13
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Vita F, Olaizola I, Amato F, Rae C, Marco S, Banales JM, Braconi C. Heterogeneity of Cholangiocarcinoma Immune Biology. Cells 2023; 12:cells12060846. [PMID: 36980187 PMCID: PMC10047186 DOI: 10.3390/cells12060846] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/04/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
Cholangiocarcinomas (CCAs) are aggressive tumors arising along the biliary tract epithelium, whose incidence and mortality are increasing. CCAs are highly desmoplastic cancers characterized by a dense tumor microenvironment (TME), in which each single component plays a fundamental role in shaping CCA initiation, progression and resistance to therapies. The crosstalk between cancer cells and TME can affect the recruitment, infiltration and differentiation of immune cells. According to the stage of the disease and to intra- and inter-patient heterogeneity, TME may contribute to either protumoral or antitumoral activities. Therefore, a better understanding of the effect of each immune cell subtype may open the path to new personalized immune therapeutic strategies for the management of CCA. In this review, we describe the role of immune cells in CCA initiation and progression, and their crosstalk with both cancer-associated fibroblasts (CAFs) and the cancer-stem-cell-like (CSC) niche.
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Affiliation(s)
- Francesca Vita
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
- Department of Oncology, University of Turin, 10043 Turin, Italy
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (I.O.); (J.M.B.)
| | - Francesco Amato
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Colin Rae
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Sergi Marco
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (I.O.); (J.M.B.)
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), 28029 Madrid, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
- Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
- Correspondence:
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14
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Alaimo L, Moazzam Z, Endo Y, Lima HA, Ruzzenente A, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Pawlik TM. Long-Term Recurrence-Free and Overall Survival Differ Based on Common, Proliferative, and Inflammatory Subtypes After Resection of Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2023; 30:1392-1403. [PMID: 36383331 DOI: 10.1245/s10434-022-12795-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/24/2022] [Indexed: 11/17/2022]
Abstract
INTRODUCTION While generally associated with poor prognosis, intrahepatic cholangiocarcinoma (ICC) can have a heterogeneous presentation and natural history. We sought to identify specific ICC subtypes that may be associated with varied long-term outcomes and patterns of recurrence after liver resection. METHODS Patients who underwent curative-intent resection for ICC from 2000 to 2020 were identified from a multi-institutional database. Hierarchical cluster analysis characterized three ICC subtypes based on morphology (i.e., tumor burden score [TBS]) and biology (i.e., preoperative neutrophil-to-lymphocyte ratio [NLR] and CA19-9 levels). RESULTS Among 598 patients, the cluster analysis identified three ICC subtypes: Common (n = 300, 50.2%) (median, TBS: 4.5; NLR: 2.4; CA19-9: 38.0 U/mL); Proliferative (n = 246, 41.1%) (median, TBS: 8.8; NLR: 2.9; CA19-9: 71.2 U/mL); Inflammatory (n = 52, 8.7%) (median, TBS: 5.4; NLR: 12.6; CA19-9: 26.7 U/mL). Median overall survival (OS) (Common: 72.0 months; Proliferative: 31.4 months; Inflammatory: 22.9 months) and recurrence-free survival (RFS) (Common: 21.5 months; Proliferative: 11.9 months; Inflammatory: 9.0 months) varied considerably among the different ICC subtypes (all p < 0.001). Even though patients with Inflammatory ICC had more favorable T-(T1/T2, Common: 84.4%; Proliferative: 80.6%; Inflammatory: 86.5%) and N-(N0, Common: 14.0%; Proliferative: 20.7%; Inflammatory: 26.9%) disease, the Inflammatory subtype was associated with a higher incidence of intra- and extrahepatic recurrence (Common: 15.8%; Proliferative: 24.2%; Inflammatory: 28.6%) (all p = 0.01). CONCLUSIONS Cluster analysis identified three distinct subtypes of ICC based on TBS, NLR, and CA19-9. ICC subtype was associated with RFS and OS and predicted worse outcomes among patients. Despite more favorable T- and N-disease, the Inflammatory ICC subtype was associated with worse outcomes ICC subtype should be considered in the prognostic stratification of patients.
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Affiliation(s)
- Laura Alaimo
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.,Department of Surgery, University of Verona, Verona, Italy
| | - Zorays Moazzam
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Yutaka Endo
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Henrique A Lima
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | | | | | | | - Matthew Weiss
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Todd W Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | | | | | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | | | - Carlo Pulitano
- Department of Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - François Cauchy
- Department of Hepatobiliopancreatic Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, Clichy, France
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA. .,Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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15
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Lv M, Wang K, Zhang Z, Zhang Z, Wan J. The predictive value of lymphocyte to monocyte ratio for overall survival in cholangiocarcinoma patients with hepatic resection. Cancer Med 2023; 12:9482-9495. [PMID: 36825605 PMCID: PMC10166960 DOI: 10.1002/cam4.5712] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 12/20/2022] [Accepted: 02/08/2023] [Indexed: 02/25/2023] Open
Abstract
BACKGROUND There is considerable heterogeneity in clinical behavior and survival outcomes in patients with cholangiocarcinoma (CCA), and the prognosis of CCA patients is poor. We proposed lymphocyte to monocyte ratio (LMR) as a novel prognostic element for CCA patients with hepatic resection in present study. METHODS By retrospectively analyzing the clinical data of 145 CCA patients with hepatic resection, we determined the optimal LMR cutoff value according to the receiver operating characteristic (ROC). We comparatively analyzed the clinical features of CAA patients between low LMR group and high LMR group, mainly including overall survival (OS) analysis by using the Kaplan-Meier method, univariate and multivariate Cox regression. RESULTS We found there was a longer OS in CCA patients of the high LMR group than the low LMR group. The total median OS of cholangiocarcinoma patients were 13.6 months, and the OS of low LMR group was markedly lower than the high LMR group. The 1-year, 3-year, and 5-year OS of high LMR group were respectively 62.9%, 32.4%, and 16.4%, and were significantly higher the cholangiocarcinoma patients of low LMR group (40.2%, 16.4%, and 0%). Multivariate regression analyses showed that preoperative cholangitis, elevated CEA level and nerve invasion were risk factors for the OS of cholangiocarcinoma patients, while the high LMR level and postoperative treatment were protective factors for the OS of cholangiocarcinoma patients. CONCLUSIONS Preoperative LMR was a vital prognostic factor to predict the prognosis of CCA patients with hepatic resection and provided additional prognostic value beyond standard clinicopathological parameters.
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Affiliation(s)
- Minghe Lv
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiotherapy Oncology Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Kun Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiotherapy Oncology Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Zhiyuan Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiotherapy Oncology Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiotherapy Oncology Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Juefeng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiotherapy Oncology Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
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16
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Munir MM, Endo Y, Lima HA, Alaimo L, Moazzam Z, Shaikh C, Poultsides GA, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Kitago M, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Pawlik TM. Albumin-Bilirubin Grade and Tumor Burden Score Predict Outcomes Among Patients with Intrahepatic Cholangiocarcinoma After Hepatic Resection: a Multi-Institutional Analysis. J Gastrointest Surg 2023; 27:544-554. [PMID: 36652178 DOI: 10.1007/s11605-023-05578-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/31/2022] [Indexed: 01/19/2023]
Abstract
BACKGROUND The prognostic role of tumor burden score (TBS) relative to albumin-bilirubin (ALBI) grade among patients undergoing curative-intent resection of ICC has not been examined. METHODS We identified patients who underwent curative-intent resection for ICC between 1990 and 2017 from a multi-institutional database. Multivariable analysis was performed to assess the effect of TBS relative to ALBI grade on both short- and long-term outcomes. RESULTS Among 724 patients, 360 (49.7%) patients had low TBS and low ALBI grade, 142 (19.6%) patients had low TBS and high ALBI grade, 138 (19.1%) patients had high TBS and low ALBI grade, and 84 patients (11.6%) had high TBS and high ALBI grade. Decreased tumor burden was associated with better long-term outcomes among patients with both low (5-year OS; low TBS vs. high TBS: 52.4% vs 21.4%; p < 0.001) and high ALBI grade (5-year OS; low TBS vs. high TBS: 40.7% vs 12.0%; p < 0.001). On multivariable analysis, higher ALBI grade was associated with greater odds of an extended hospital LOS (> 10 days) (OR 2.80, 95%CI 1.62-4.82; p < 0.001), perioperative transfusion (OR 2.04, 95%CI 1.25-3.36; p = 0.005), 90-day mortality (OR 2.56, 95%CI 1.12-5.81; p = 0.025), as well as a major complication (OR 1.99, 95%CI 1.13-3.49; p = 0.016) among patients with similar tumor burden. Of note, patients with high TBS and high ALBI grade had markedly worse overall survival compared with patients who had low TBS and low ALBI grade disease (HR 2.27; 95%CI 1.44-3.59; p < 0.001). Importantly, high TBS and high ALBI grade were strongly associated with both early recurrence (88.1%%) and 5-year risk of death (96.4%). CONCLUSION Both TBS (i.e., tumor morphology) and ALBI grade (i.e., hepatic function reserve) were strong predictors of outcomes among patients undergoing ICC resection. There was an interplay between TBS and ALBI grade relative to patient prognosis after hepatic resection of ICC with high ALBI grade predicting worse outcomes among ICC patients with different TBS.
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Affiliation(s)
- Muhammad Musaab Munir
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Yutaka Endo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Henrique A Lima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Laura Alaimo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Zorays Moazzam
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Chanza Shaikh
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | | | | | | | - Matthew Weiss
- Department of Surgery, John Hopkins Hospital, Baltimore, MA, USA
| | - Todd W Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | | | - Minoru Kitago
- Department of Surgery, Keio University, Tokyo, Japan
| | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | | | - Carlo Pulitano
- Department of Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - François Cauchy
- Department of Hepatibiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City, University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA. .,Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Columbus, OH, USA. .,Health Services Management and Policy, The Ohio State University, Wexner Medical Center, 395 W. 12Th Ave., Suite 670, Columbus, OH, USA.
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17
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Li J, Gao L, Liu T, Feng D. Association of systemic inflammation index with survival in patients with advanced perihilar cholangiocarcinoma treated with interventional therapy. Front Oncol 2022; 12:1038759. [PMID: 36620590 PMCID: PMC9815453 DOI: 10.3389/fonc.2022.1038759] [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: 09/07/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Immunity and inflammation are key mediators of carcinoma development, invasion and metastasis. However, it remains unknown whether the systemic immune-inflammation index (SII) can be used as a prognostic indicator for cholangiocarcinoma. In this study, we investigated the association and predictive value of the SII with the prognosis of advanced perihilar cholangiocarcinoma (pCCA) after interventional therapy. Methods A retrospective cohort of patients with advanced pCCA treated with interventional therapy at the First Hospital of Shanxi Medical University enrolled in this study from January 2019 through January 2021 was examined. Cox regression models were used to analyze the relationship between the SII and overall survival (OS) of patients with advanced pCCA. Receiver operating characteristic (ROC) analysis was used to evaluate the predictive power of SII. Results Preoperative SII was positively associated with poor OS of pCCA after interventional therapy, with corresponding hazard ratios (HR) of 1.57 (95% CI: 1.17 - 2.10) for an inter-quartile range increase. The predictive power of SII was higher than that of other inflammation indexes based on ROC analysis (AUC = 0.835 [95% CI (0.731 - 0.940)]). The optimal cut-off values, sensitivity, and specificity with SII were 700, 0.774 and 0.846, respectively. An SII ≥ 700 was significantly associated with lymph node metastasis and high carbohydrate antigen199 (CA199) level. In multivariate analyses, total bilirubin, carbohydrate antigen 199, vascular invasion, and SII independently predicted overall survival (P < 0.05). Conclusion This is the first study demonstrating that an increase in the SII is associated with poor advanced pCCA prognosis, and could serve as a reliable prognostic indicator of pCCA after interventional therapy.
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Affiliation(s)
- Jinyu Li
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Long Gao
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Tianci Liu
- College of Medical Imaging, Shanxi Medical University, Taiyuan, China
| | - Duiping Feng
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan, China,*Correspondence: Duiping Feng,
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18
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Liu D, Heij LR, Czigany Z, Dahl E, Dulk MD, Lang SA, Ulmer TF, Neumann UP, Bednarsch J. The prognostic value of neutrophil-to-lymphocyte ratio in cholangiocarcinoma: a systematic review and meta-analysis. Sci Rep 2022; 12:12691. [PMID: 35879385 PMCID: PMC9314341 DOI: 10.1038/s41598-022-16727-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 07/14/2022] [Indexed: 12/02/2022] Open
Abstract
The neutrophil-to-lymphocyte ratio (NLR) is used as biomarker in malignant diseases showing significant association with poor oncological outcomes. The main research question of the present study was whether NLR has also prognostic value in cholangiocarcinoma patients (CCA). A systematic review was carried out to identify studies related to NLR and clinical outcomes in CCA evaluating the literature from 01/2000 to 09/2021. A random-effects model, pooled hazard ratios (HR) and 95% confidence interval (CI) were used to investigate the statistical association between NLR and overall survival (OS) as well as disease-free survival (DFS). Subgroup analyses, evaluation of sensitivity and risk of bias were further carried out. 32 studies comprising 8572 patients were eligible for this systematic review and meta-analysis. The pooled outcomes revealed that high NLR prior to treatment is prognostic for poor OS (HR 1.28, 95% CI 1.18–1.38, p < 0.01) and DFS (HR 1.39, 95% CI 1.17–1.66, p < 0.01) with meaningful HR values. Subgroup analysis revealed that this association is not significantly affected by the treatment modality (surgical vs. non-surgical), NLR cut-off values, age and sample size of the included studies. Given the likelihood of NLR to be prognostic for reduced OS and DFS, pre-treatment NLR might serve as a useful biomarker for poor prognosis in patients with CCA and therefore facilitate clinical management.
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Affiliation(s)
- Dong Liu
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Lara R Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Edgar Dahl
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Marcel den Dulk
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Sven A Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom F Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Ulf P Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
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19
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Ruffolo LI, Jackson KM, Kuhlers PC, Dale BS, Figueroa Guilliani NM, Ullman NA, Burchard PR, Qin SS, Juviler PG, Keilson JM, Morrison AB, Georger M, Jewell R, Calvi LM, Nywening TM, O'Dell MR, Hezel AF, De Las Casas L, Lesinski GB, Yeh JJ, Hernandez-Alejandro R, Belt BA, Linehan DC. GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity. Gut 2022; 71:1386-1398. [PMID: 34413131 PMCID: PMC8857285 DOI: 10.1136/gutjnl-2021-324109] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 07/28/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Here, we show that tumour-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and the host bone marrow is central for monopoiesis and potentiation of TAMs, and abrogation of this signalling axis facilitates antitumour immunity in a novel model of iCCA. METHODS Blood and tumours were analysed from iCCA patients and controls. Treatment and correlative studies were performed in mice with autochthonous and established orthotopic iCCA tumours treated with anti-GM-CSF monoclonal antibody. RESULTS Systemic elevation in circulating myeloid cells correlates with poor prognosis in patients with iCCA, and patients who undergo resection have a worse overall survival if tumours are more infiltrated with CD68+ TAMs. Mice with spontaneous iCCA demonstrate significant elevation of monocytic myeloid cells in the tumour microenvironment and immune compartments, and tumours overexpress GM-CSF. Blockade of GM-CSF with a monoclonal antibody decreased tumour growth and spread. Mice bearing orthotopic tumours treated with anti-GM-CSF demonstrate repolarisation of immunosuppressive TAMs and MDSCs, facilitating T cell response and tumour regression. GM-CSF blockade dampened inflammatory gene networks in tumours and TAMs. Human tumours with decreased GM-CSF expression exhibit improved overall survival after resection. CONCLUSIONS iCCA uses the GM-CSF-bone marrow axis to establish an immunosuppressive tumour microenvironment. Blockade of the GM-CSF axis promotes antitumour T cell immunity.
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Affiliation(s)
- Luis I Ruffolo
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Katherine M Jackson
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Peyton C Kuhlers
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Benjamin S Dale
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | | | - Nicholas A Ullman
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Paul R Burchard
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Shuyang S Qin
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Peter G Juviler
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Jessica Millian Keilson
- Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA
| | - Ashley B Morrison
- Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Mary Georger
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Rachel Jewell
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Laura M Calvi
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Timothy M Nywening
- Division of Surgical Oncology, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Michael R O'Dell
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Aram F Hezel
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Luis De Las Casas
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Gregory B Lesinski
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Jen Jen Yeh
- Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA
| | | | - Brian A Belt
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - David C Linehan
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
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20
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The Value of Platelet-to-Lymphocyte Ratio as a Prognostic Marker in Cholangiocarcinoma: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:cancers14020438. [PMID: 35053599 PMCID: PMC8773915 DOI: 10.3390/cancers14020438] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Platelet-to-lymphocyte ratio has shown prognostic value in several malignancies; however, its role in cholangiocarcinoma remains to be determined. Therefore, we conducted a systematic review and meta-analysis of the currently available literature. Overall, our analysis revealed that a high platelet-to-lymphocyte ratio before treatment is associated with an impaired long-term oncological outcome. Further, our results indicate that this assumption was not influenced by the used treatment modality (surgical vs. non-surgical), PLR cut-off values, study population age, or sample size of the included studies. Thus, an elevated pretreatment platelet-to-lymphocyte ratio has valid prognostic value for cholangiocarcinoma patients. Abstract The platelet-to-lymphocyte ratio (PLR), an inflammatory parameter, has shown prognostic value in several malignancies. The aim of this meta-analysis was to determine the impact of pretreatment PLR on the oncological outcome in patients with cholangiocarcinoma (CCA). A systematic literature search has been carried out in the PubMed and Google Scholar databases for pertinent papers published between January 2000 and August 2021. Within a random-effects model, the pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated to investigate the relationships among the PLR, overall survival (OS), and disease-free survival (DFS). Subgroup analysis, sensitivity analysis, and publication bias were also conducted to further evaluate the relationship. A total of 20 articles comprising 5429 patients were included in this meta-analysis. Overall, the pooled outcomes revealed that a high PLR before treatment is associated with impaired OS (HR = 1.14; 95% CI = 1.06–1.24; p < 0.01) and DFS (HR = 1.57; 95% CI = 1.19–2.07; p < 0.01). Subgroup analysis revealed that this association is not influenced by the treatment modality (surgical vs. non-surgical), PLR cut-off values, or sample size of the included studies. An elevated pretreatment PLR is prognostic for the OS and DFS of CCA patients. More high-quality studies are required to investigate the pathophysiological basis of the observation and the prognostic value of the PLR in clinical management as well as for patient selection.
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21
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Filippi R, Montagnani F, Lombardi P, Fornaro L, Aprile G, Casadei-Gardini A, Faloppi L, Palloni A, Satolli MA, Scartozzi M, Citarella F, Lutrino SE, Vivaldi C, Silvestris N, Rovesti G, Rimini M, Aglietta M, Brandi G, Leone F. A prognostic model in patients with advanced biliary tract cancer receiving first-line chemotherapy. Acta Oncol 2021; 60:1317-1324. [PMID: 34282710 DOI: 10.1080/0284186x.2021.1953704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1. METHODS A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out. RESULTS Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS (p <0.01). The prognostic score could generate a highly significant stratification (all between-group p values ≤0.001) into groups of favorable (comprising 51.5% of the sample), intermediate (39.2%), and poor prognosis (9.3%): median OS was 12.7 (CI95% 11.0-14.4), 7.1 (CI95% 5.8-8.4), and 3.2 months (CI95% 1.7-4.7), respectively. This OS gradient was replicated in the validation set (129 patients), with median OS of 12.7 (CI95% 11.0-14.3), 7.5 (CI95% 6.1-8.9), and 1.4 months (CI95% 0.1-2.7), respectively (all between-group p values ≤0.05). CONCLUSION A prognostic score, derived from a limited set of easily-retrievable variables, efficiently stratified a large population of unselected aBTC patients undergoing CT1. This tool could be useful to clinicians, to ascertain the potential benefit from CT1 at the start of treatment.
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Affiliation(s)
- Roberto Filippi
- Department of Oncology, University of Turin, Torino, Italy
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Centro Oncologico Ematologico Subalpino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Francesco Montagnani
- Division of Medical Oncology, ASL BI, Nuovo Ospedale degli Infermi, Ponderano, Italy
| | - Pasquale Lombardi
- Department of Oncology, University of Turin, Torino, Italy
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Lorenzo Fornaro
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, University Hospital of Udine, Udine, Italy
- Department of Oncology, San Bortolo General Hospital, AULSS8, Vicenza, Italy
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy
- Department of Oncology and Haematology, University Hospital of Modena, Italy
| | - Luca Faloppi
- Medical Oncology Unit, Macerata General Hospital, Macerata, Italy
| | - Andrea Palloni
- Department of Experimental, Diagnostic and Specialty Medicine, University Hospital S. Orsola-Malpighi, Bologna, Italy
| | - Maria Antonietta Satolli
- Department of Oncology, University of Turin, Torino, Italy
- Centro Oncologico Ematologico Subalpino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital, Cagliari, Italy
| | - Fabrizio Citarella
- Department of Medical Oncology, Campus Bio-Medico University, Roma, Italy
| | | | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, IRCCS Cancer Institute “Giovanni Paolo II”, Bari, Italy
- Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, Italy
| | - Giulia Rovesti
- Department of Oncology and Haematology, University Hospital of Modena, Italy
| | - Margherita Rimini
- Department of Oncology and Haematology, University Hospital of Modena, Italy
| | - Massimo Aglietta
- Department of Oncology, University of Turin, Torino, Italy
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, University Hospital S. Orsola-Malpighi, Bologna, Italy
| | - Francesco Leone
- Division of Medical Oncology, ASL BI, Nuovo Ospedale degli Infermi, Ponderano, Italy
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22
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Role of Inflammatory and Immune-Nutritional Prognostic Markers in Patients Undergoing Surgical Resection for Biliary Tract Cancers. Cancers (Basel) 2021; 13:cancers13143594. [PMID: 34298807 PMCID: PMC8305862 DOI: 10.3390/cancers13143594] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/03/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Biliary tract cancers (BTCs) are a heterogeneous group of malignancies, which arise from the epithelial cells of the biliary tree, with a high rate of local invasion and metastatic spreading. Surgical resection remains the treatment which offers the best chance of long-term survival. However, new chemotherapy regimens and multimodal strategies have showed encouraging results, supporting the need for simple and readily available preoperative tools able to predict survival and guide the treatment strategy. Recently, the prognostic role of several nutritional and inflammatory indexes in growth, biological aggressiveness, and spread has been investigated in different types of cancers. Nevertheless, complete and conclusive results on BTCs are lacking. By identifying a preoperative immune and inflammatory prognostic index based on simple routine blood samples, we may have an additional element that is useful in guiding the treatment strategy by assigning selected patients to preoperative or postoperative treatments despite pathological results. Abstract The relationship between immune-nutritional status and tumor growth; biological aggressiveness and survival, is still debated. Therefore, this study aimed to evaluate the prognostic performance of different inflammatory and immune-nutritional markers in patients who underwent surgery for biliary tract cancer (BTC). The prognostic role of the following inflammatory and immune-nutritional markers were investigated: Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), Neutrophil to Lymphocyte ratio (NLR), Platelet to Lymphocyte ratio (PLR), Lymphocyte to Monocyte ratio (LMR), Prognostic Nutritional Index (PNI). A total of 282 patients undergoing surgery for BTC were included. According to Cox regression and ROC curves analysis for survival, LMR had the best prognostic performances, with hazard ratio (HR) of 1.656 (p = 0.005) and AUC of 0.652. Multivariable survival analysis identified the following independent prognostic factors: type of BTC (p = 0.002), T stage (p = 0.014), N stage (p < 0.001), histological grading (p = 0.045), and LMR (p = 0.025). Conversely, PNI was related to higher risk of severe morbidity (p < 0.001) and postoperative mortality (p = 0.005). In conclusion, LMR appears an independent prognostic factor of long-term survival, whilst PNI seems associated with worse short-term outcomes.
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23
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The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma. Vaccines (Basel) 2021; 9:vaccines9050422. [PMID: 33922362 PMCID: PMC8146949 DOI: 10.3390/vaccines9050422] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions.
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24
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Zhao J, Chen Y, Wang J, Wang J, Wang Y, Chai S, Zhang Y, Chen X, Zhang W. Preoperative risk grade predicts the long-term prognosis of intrahepatic cholangiocarcinoma: a retrospective cohort analysis. BMC Surg 2021; 21:113. [PMID: 33676467 PMCID: PMC7936481 DOI: 10.1186/s12893-020-00954-x] [Citation(s) in RCA: 4] [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] [Received: 05/23/2020] [Accepted: 11/12/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cumulating evidence indicates that the systemic inflammatory response (SIR) plays a crucial role in the prognosis of various cancers. We aimed to generate a preoperative risk grade (PRG) by integrating SIR markers to preoperatively predict the long-term prognosis of intrahepatic cholangiocarcinoma (ICC). METHODS 468 consecutive ICC patients who underwent hepatectomy between 2010 and 2017 were enrolled. The PRG and a nomogram were generated and their predictive accuracy was evaluated. RESULTS The PRG consisted of two non-tumor-specific SIR markers platelet-to-lymphocyte ratio (PLR) and albumin (ALB), which were both the independent predictors of overall survival (OS). Multivariate analysis showed that the PRG was significantly associated with OS (PRG = 1: hazard ratio (HR) = 3.800, p < 0.001; PRG = 2: HR = 7.585, p < 0.001). The C-index of the PRG for predicting survival was 0.685 (95% CI 0.655 to 0.716), which was statistically higher than that of the following systems: American Joint Committee on Cancer (AJCC) 8th edition (C-index 0.645), Liver Cancer Study Group of Japan (LCSGJ) (C-index 0.644) and Okabayashi (C-index 0.633) (p < 0.05). Besides, the C-index of the nomogram only consisting of the tumor-specific factors (serum carcinoembryonic antigen, carbohydrate antigen 19-9, tumor number) could be improved to 0.737 (95% CI 0.062-0.768) from 0.625 (95% CI 0.585-0.665) when the PRG was incorporated (p < 0.001). CONCLUSIONS The PRG integrating two non-tumor-specific SIR markers PLR and ALB was a novel method to preoperative predicting the prognosis of ICC.
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Affiliation(s)
- Jianping Zhao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Yao Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Jingjing Wang
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Wang
- Department of Hepatopancreatobiliary Surgery Treatment Center, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Ying Wang
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Songshan Chai
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Yuxin Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
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Shirono T, Niizeki T, Iwamoto H, Shimose S, Suzuki H, Kawaguchi T, Kamachi N, Noda Y, Okamura S, Nakano M, Kuromatu R, Koga H, Torimura T. Therapeutic Outcomes and Prognostic Factors of Unresectable Intrahepatic Cholangiocarcinoma: A Data Mining Analysis. J Clin Med 2021; 10:jcm10050987. [PMID: 33801202 PMCID: PMC7957874 DOI: 10.3390/jcm10050987] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/15/2022] Open
Abstract
Prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is unsatisfactory. Tumor, host, and treatment factors including hepatic arterial infusion chemotherapy (HAIC) are intricately involved in the progression of ICC. We aimed to identify profiles associated with disease control rate (DCR) and the prognosis of patients with unresectable ICC by decision tree analysis. We analyzed 31 consecutive patients with unresectable ICC (median age, 71 years; the male ratio was 58.1%). Stage IVB occupied 51.6% of patients, and 38.7% and 58.1% of patients were treated with gemcitabine plus cisplatin combination therapy and HAIC, respectively. Profiles associated with prognosis as well as DCR were investigated by decision tree analysis. The median survival time (MST) of the patients was 11.6 months, and the DCR was 70.9%. Multivariate correlation analysis showed that albumin levels and WBC levels were significantly correlated with survival time (albumin, ρ = 0.3572, p = 0.0485; WBC, ρ = -0.4008, p = 0.0280). In decision tree analysis, WBC level was selected as the initial split variable, and subjects with WBC levels of 6800/μL or less (45.1%) showed a long survival time (MST 476 days). We also demonstrated that the profile associated with the highest DCR was "less than 4.46 mg/dL of CRP levels and treatment with HAIC". We demonstrated a new prognostic profile for ICC patients, which consisted of WBC and CRP levels. Moreover, we demonstrated that HAIC was associated with better disease control in ICC patients with low CPR levels. Thus, these new profiles may be useful for the management of ICC patients.
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26
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Golse N, Nunez J, Mazzotta A, Cano L, Bergeat D, Sulpice L, Jeddou H, Abdelrafee A, Sa Cunha A, Cherqui D, Adam R, Boudjema K, Vibert E. Personalized Preoperative Nomograms Predicting Postoperative Risks after Resection of Perihilar Cholangiocarcinoma. World J Surg 2021; 44:3449-3460. [PMID: 32474628 DOI: 10.1007/s00268-020-05618-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Curative treatment of perihilar tumors requires major hepatectomy responsible for high morbidity and mortality. Current nomograms are based on definitive pathological analysis, not usable for patient selection. Our aim was to propose preoperative predictors for severe morbidity (Dindo-Clavien ≥3) and mortality at sixth month after resection of perihilar tumors. PATIENTS AND METHODS We reviewed perioperative data of 186 patients operated with major hepatectomy for perihilar tumors between 2012 and 2018 in two high-volume centers. Univariate and multivariate analysis were performed to determine the preoperative predictors of morbidity and mortality. A stepwise regression in forward direction was developed to select variables for definitive models. Hosmer-Lemeshow test, Akaike information criteria and area under the ROC curves were calculated to validate both nomograms. RESULTS Resections were indicated for perihilar and intrahepatic cholangiocarcinoma in 125 and 61 cases, respectively. Severe complications occurred in 76 patients (40.8%). Nineteen patients (10.2%) deceased before the sixth postoperative month. The predictors of severe morbidity were: male gender, portal vein embolization, planned biliary resection, low psoas muscle area/height2 and low hemoglobinemia. The predictors of early mortality were: age, high bilirubinemia, hypoalbuminemia, biliary drainage and long drainage-to-surgery interval. For both models, the p values of Hosmer-Lemeshow tests were of 0.9 and 0.99, respectively, the Akaike information criteria were of 35.5 and 37.7, respectively, and area under the curves was of 0.73 and 0.86, respectively. CONCLUSION We developed two accurate and practical nomograms based on exclusively preoperative data to predict early outcomes following the resection of perihilar tumors. If validated in larger series, these tools could be integrated in the decision-making process for patient selection.
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Affiliation(s)
- Nicolas Golse
- Department of Surgery, Assistance Publique Hôpitaux de Paris, Paul-Brousse Hospital, Centre Hépato-Biliaire, 94800, Villejuif, France.
- FHU Hepatinov, 94800, Villejuif, France.
- Physiopathogénèse et Traitement des Maladies du Foie, Inserm, Université Paris-Saclay, UMR-S 1193, Villejuif, France.
- Centre Hépato-Biliaire, Hôpital Paul Brousse, 12 Avenue Paul Vaillant Couturier, 94804, Villejuif, France.
| | - Julio Nunez
- Department of Surgery, Assistance Publique Hôpitaux de Paris, Paul-Brousse Hospital, Centre Hépato-Biliaire, 94800, Villejuif, France
| | - Alessandro Mazzotta
- Hepatobiliary and Digestive Surgery, Pontchaillou Hospital, Rennes 1 University, 35033, Rennes, France
| | - Luis Cano
- Nutrition Metabolism and Cancer, INRA, INSERM, Unit 991, CHU Rennes, Univ Rennes, Univ Bretagne Loire, Rennes, France
| | - Damien Bergeat
- Hepatobiliary and Digestive Surgery, Pontchaillou Hospital, Rennes 1 University, 35033, Rennes, France
| | - Laurent Sulpice
- Hepatobiliary and Digestive Surgery, Pontchaillou Hospital, Rennes 1 University, 35033, Rennes, France
| | - Heithem Jeddou
- Hepatobiliary and Digestive Surgery, Pontchaillou Hospital, Rennes 1 University, 35033, Rennes, France
| | - Ahmed Abdelrafee
- Department of Surgery, Assistance Publique Hôpitaux de Paris, Paul-Brousse Hospital, Centre Hépato-Biliaire, 94800, Villejuif, France
| | - Antonio Sa Cunha
- Department of Surgery, Assistance Publique Hôpitaux de Paris, Paul-Brousse Hospital, Centre Hépato-Biliaire, 94800, Villejuif, France
- FHU Hepatinov, 94800, Villejuif, France
- Physiopathogénèse et Traitement des Maladies du Foie, Inserm, Université Paris-Saclay, UMR-S 1193, Villejuif, France
| | - Daniel Cherqui
- Department of Surgery, Assistance Publique Hôpitaux de Paris, Paul-Brousse Hospital, Centre Hépato-Biliaire, 94800, Villejuif, France
- FHU Hepatinov, 94800, Villejuif, France
- Physiopathogénèse et Traitement des Maladies du Foie, Inserm, Université Paris-Saclay, UMR-S 1193, Villejuif, France
| | - René Adam
- Department of Surgery, Assistance Publique Hôpitaux de Paris, Paul-Brousse Hospital, Centre Hépato-Biliaire, 94800, Villejuif, France
- FHU Hepatinov, 94800, Villejuif, France
- INSERM, Unit 985, 94800, Villejuif, France
- Univ Paris-Sud, UMR-S 985, 94800, Villejuif, France
| | - Karim Boudjema
- Hepatobiliary and Digestive Surgery, Pontchaillou Hospital, Rennes 1 University, 35033, Rennes, France
| | - Eric Vibert
- Department of Surgery, Assistance Publique Hôpitaux de Paris, Paul-Brousse Hospital, Centre Hépato-Biliaire, 94800, Villejuif, France
- FHU Hepatinov, 94800, Villejuif, France
- Physiopathogénèse et Traitement des Maladies du Foie, Inserm, Université Paris-Saclay, UMR-S 1193, Villejuif, France
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Systemic Immune-Inflammation Index Is a Prognostic Predictor in Patients with Intrahepatic Cholangiocarcinoma Undergoing Liver Transplantation. Mediators Inflamm 2021; 2021:6656996. [PMID: 33628115 PMCID: PMC7899762 DOI: 10.1155/2021/6656996] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023] Open
Abstract
Background It was reported that systemic immune inflammation index (SII) was related to poor prognosis in a variety of cancers. We aimed to investigate the ability of the prognostic predictors of SII in patients with intrahepatic cholangiocarcinoma (iCCA) undergoing liver transplantation (LT). Methods The 28 iCCA patients who underwent LT at our hospital between 2013 and 2018 were reviewed. Kaplan–Meier survival curves and Cox regression analyses were used to evaluate the prognostic significance of SII. Patients were divided into the high and low SII groups according to the cut-off value. Results The 1-, 3-, and 5-year OS rates were significantly lower in the high SII group (85.7%, 28.6%, and 21.4%, respectively) than in the low SII group (92.9%, 71.4%, and 57.2%, respectively; P = 0.009). The 1-, 3-, and 5-year RFS rates were, respectively, 57.1%, 32.7%, and 21.8% in the high SII group and 85.7%, 61.1%, and 61.1% in the low SII group (P = 0.021). SII ≥ 447.48 × 109/L (HR 0.273, 95% CI 0.082–0.908; P = 0.034) was an independent prognostic factor for OS. Conclusions Our results showed that SII can be used to predict the survival of patients with iCCA who undergo LT.
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Fabris L, Sato K, Alpini G, Strazzabosco M. The Tumor Microenvironment in Cholangiocarcinoma Progression. Hepatology 2021; 73 Suppl 1:75-85. [PMID: 32500550 PMCID: PMC7714713 DOI: 10.1002/hep.31410] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 05/07/2020] [Accepted: 05/16/2020] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree. A typical hallmark of CCA is that cancer cells are embedded into a dense stroma containing fibrogenic cells, lymphatics and a variety of immune cells. Functional roles of the reactive tumor stroma are not fully elucidated; however, recent studies suggest that the tumor microenvironment plays a key role in the progression and invasiveness of CCA. CCA cells exchange autocrine/paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment. This crosstalk is under the control of signals mediated by various cytokines, chemokines, and growth factors. In addition, extracellular vesicles (EVs), exosomes and microvesicles, containing cargo mediators, such as proteins and RNAs, play a key role in cell-to-cell communication, and particularly in epigenetic regulation thanks to their content in miRNAs. Both cytokine- and EV-mediated communications between CCA cells and other liver cells provide a potential novel target for the management of CCA. This review summarizes current understandings of the tumor microenvironment and intercellular communications in CCA and their role in tumor progression.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padua, Italy,Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Keisaku Sato
- Hepatology and Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT,Correspondence: Mario Strazzabosco MD, PhD, Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA,
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Liu HT, Cheng SB, Lai CY, Chen YJ, Su TC, Wu CC. Locoregional therapies in patients with recurrent intrahepatic cholangiocarcinoma after curative resection. Therap Adv Gastroenterol 2020; 13:1756284820976974. [PMID: 33354228 PMCID: PMC7734491 DOI: 10.1177/1756284820976974] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/29/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Hepatectomy is one potential treatment for intrahepatic cholangiocarcinoma (IHCC). Recurrent rate is high after curative resection and most recurrences occur within residual liver parenchyma. The aim of this study was to elucidate the impact of different treatment modalities on recurrent diseases in patients with IHCC after primary liver resection. METHODS Between February 1999 and December 2015, we retrospectively identified patients who received curative resection for IHCC. Patients who experienced recurrences were included. Locoregional therapies included re-hepatectomy, radiofrequent ablation, and transhepatic arterial chemoembolization. These patients were categorized into three groups: intrahepatic recurrence without locoregional therapies (group A), intrahepatic recurrence with locoregional therapies (group B) and extrahepatic metastases (group C). RESULTS Forty-three patients were included and there were 12, 15, and 16 patients in groups A, B, and C, respectively. The median disease-free survival times were 8.3, 9.1, and 8.7 months in groups A, B, and C (p = 0.099). The median after-recurrence overall survival times (period between recurrence and death/censor) were 6.4, 34.0, and 8.3 months in groups A, B, and C (p = 0.001). Locoregional therapies showed favorable benefit in multivariant analysis (hazard ratio: 0.274, confidence interval: 0.083-0.908, p = 0.010). CONCLUSION Locoregional therapies offered favorable benefits for patients with recurrent intrahepatic cholangiocarcinoma.
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Affiliation(s)
| | - Shao-Bin Cheng
- Department of Surgery, Taichung Veterans General Hospital,School of Medicine, Chung Shan Medical University, Taichung
| | - Chia-Yu Lai
- Department of Surgery, Taichung Veterans General Hospital
| | - Yi-Ju Chen
- Department of Surgery, Taichung Veterans General Hospital
| | - Te-Cheng Su
- Department of Radiology, Taichung Veterans General Hospital
| | - Cheng-Chung Wu
- Department of Surgery, Taichung Veterans General Hospital School of Medicine, Chung Shan Medical University, Taichung
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Tsilimigras DI, Moris D, Mehta R, Paredes AZ, Sahara K, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Soubrane O, Koerkamp BG, Endo I, Pawlik TM. The systemic immune-inflammation index predicts prognosis in intrahepatic cholangiocarcinoma: an international multi-institutional analysis. HPB (Oxford) 2020; 22:1667-1674. [PMID: 32265108 DOI: 10.1016/j.hpb.2020.03.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The objective of this study was to examine whether the systemic immune inflammation index (SII) was associated with prognosis among patients following resection of intrahepatic cholangiocarcinoma (ICC). METHODS The impact of SII on overall (OS) and cancer-specific survival (CSS) following resection of ICC was assessed. The performance of the final multivariable models that incorporated inflammatory markers (i.e. neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR] and SII [platelets∗NLR]) was assessed using the Harrell's concordance index. RESULTS Patients with high SII had worse 5-year OS (37.7% vs 46.6%, p < 0.001) and CSS (46.1% vs 50.1%, p < 0.001) compared with patients with low SII. An elevated SII (HR = 1.70, 95% CI 1.23-2.34) and NLR (HR = 1.58, 95% CI 1.10-2.27) independently predicted worse OS, whereas high PLR (HR = 1.17, 95% CI 0.85-1.60) was no longer associated with prognosis. Only SII remained an independent predictor of CSS (HR = 1.55, 95% CI 1.09-2.21). The SII multivariable model outperformed models that incorporated PLR and NLR relative to OS (c-index; 0.696 vs 0.689 vs 0.692) and CSS (c-index; 0.697 vs 0.689 vs 0.690). CONCLUSION SII independently predicted OS and CSS among patients with resectable ICC. SII may be a better predictor of outcomes compared with other markers of inflammatory response among patients with resectable ICC.
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Affiliation(s)
- Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Dimitrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Rittal Mehta
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Anghela Z Paredes
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Kota Sahara
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | | | | | - Matthew Weiss
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Todd W Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | | | | | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | | | - Carlo Pulitano
- Department of Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Olivier Soubrane
- Department of Hepatobiliopancreatic Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, Clichy, France
| | - Bas G Koerkamp
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
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Tsilimigras DI, Hyer JM, Paredes AZ, Diaz A, Moris D, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Soubrane O, Koerkamp BG, Endo I, Pawlik TM. A Novel Classification of Intrahepatic Cholangiocarcinoma Phenotypes Using Machine Learning Techniques: An International Multi-Institutional Analysis. Ann Surg Oncol 2020; 27:5224-5232. [PMID: 32495285 DOI: 10.1245/s10434-020-08696-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Patients with intrahepatic cholangiocarcinoma (ICC) generally have a poor prognosis, yet there can be heterogeneity in the patterns of presentation and associated outcomes. We sought to identify clusters of ICC patients based on preoperative characteristics that may have distinct outcomes based on differing patterns of presentation. METHODS Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified using a multi-institutional database. A cluster analysis was performed based on preoperative variables to identify distinct patterns of presentation. A classification tree was built to prospectively assign patients into cluster assignments. RESULTS Among 826 patients with ICC, three distinct presentation patterns were noted. Specifically, Cluster 1 (common ICC, 58.9%) consisted of individuals who had a small-size ICC (median 4.6 cm) and median carbohydrate antigen (CA) 19-9 and neutrophil-to-lymphocyte ratio (NLR) levels of 40.3 UI/mL and 2.6, respectively; Cluster 2 (proliferative ICC, 34.9%) consisted of patients who had larger-size tumors (median 9.0 cm), higher CA19-9 levels (median 72.0 UI/mL), and similar NLR (median 2.7); Cluster 3 (inflammatory ICC, 6.2%) comprised of patients with a medium-size ICC (median 6.2 cm), the lowest range of CA19-9 (median 26.2 UI/mL), yet the highest NLR (median 13.5) (all p < 0.05). Median OS worsened incrementally among the three different clusters {Cluster 1 vs. 2 vs. 3; 60.4 months (95% confidence interval [CI] 43.0-77.8) vs. 27.2 months (95% CI 19.9-34.4) vs. 13.3 months (95% CI 7.2-19.3); p < 0.001}. The classification tree used to assign patients into different clusters had an excellent agreement with actual cluster assignment (κ = 0.93, 95% CI 0.90-0.96). CONCLUSION Machine learning analysis identified three distinct prognostic clusters based solely on preoperative characteristics among patients with ICC. Characterizing preoperative patient heterogeneity with machine learning tools can help physicians with preoperative selection and risk stratification of patients with ICC.
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Affiliation(s)
- Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - J Madison Hyer
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Anghela Z Paredes
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Adrian Diaz
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Dimitrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | | | | | - Matthew Weiss
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Todd W Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | | | | | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | | | - Carlo Pulitano
- Department of Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Olivier Soubrane
- Department of Hepatobiliopancreatic Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, Clichy, France
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
- Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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Ji F, Kang Q, Wang L, Liu L, Ke Y, Zhu Y, Zhang N, Xiong S, Li Y, Zou H. Prognostic significance of the neutrophil-to-lymphocyte ratio with distal cholangiocarcinoma patients. Medicine (Baltimore) 2020; 99:e22827. [PMID: 33120809 PMCID: PMC7581158 DOI: 10.1097/md.0000000000022827] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND The present study aimed to investigate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in distal cholangiocarcinoma (DCC) following radical surgery. METHODS The clinicopathological data of 59 patients with DCC were retrospectively reviewed. Patients were treated by radical surgery and diagnosed by postoperative pathology at the Second Affiliated Hospital of Kunming Medical University (Yunnan, China), between July 2015 and December 2017. The optimal cut-off value for the NLR was determined by generating receiver operating characteristic (ROC) curves. Kaplan-Meier survival analysis and Cox proportional hazards models were used to determine the risk factors and independent risk factors influencing the prognosis of patients with DCC. RESULTS According to the ROC curve, the optimal cut-off value for the NLR was 2.933. The results of Kaplan-Meier survival analysis and the Cox proportional hazards model showed that carbohydrate antigen 125, NLR, perineural, vascular and fat invasion, regional lymph node metastasis, and the American Joint Committee on Cancer stage were risk factors for DCC; the only independent risk factor to affect the prognosis of DCC patients was the NLR. CONCLUSIONS The preoperative NLR plays an important guiding role in evaluating the prognosis of patients with DCC, and an increase in the NLR is associated with poor patient prognosis.
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Affiliation(s)
- Fengming Ji
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
- Urology Department of The Affiliated Children's Hospital of Kunminng Medical University, Kunming Chlidren's Hospital, Key Laboratory of Children's Major Disease Research, Kunming Medical University
| | - Qiang Kang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
| | - Lianmin Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
| | - Lixin Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
| | - Yang Ke
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
| | - Ya Zhu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
| | - Naiqiang Zhang
- Department of General Surgery, Kunming Traditional Chinese Medicine Hospital, Kunming, Yunnan, PR China
| | - Shifeng Xiong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
| | - Yuehua Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
| | - Hao Zou
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital
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Huh G, Ryu JK, Chun JW, Kim JS, Park N, Cho IR, Paik WH, Lee SH, Kim YT. High platelet-to-lymphocyte ratio is associated with poor prognosis in patients with unresectable intrahepatic cholangiocarcinoma receiving gemcitabine plus cisplatin. BMC Cancer 2020; 20:907. [PMID: 32967632 PMCID: PMC7510111 DOI: 10.1186/s12885-020-07390-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 09/08/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Several systemic inflammatory response (SIR) markers, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and albumin-to-globulin ratio (AGR), have emerged as prognostic markers in various cancers. The aim of this study was to explore the impact of SIR markers on the survival outcomes of unresectable intrahepatic cholangiocarcinoma (IHC) patients. METHODS Patients with histologically confirmed, unresectable IHC treated with gemcitabine plus cisplatin (GP) chemotherapy in a single tertiary hospital from 2012 to 2016 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) were determined using unadjusted Kaplan-Meier and adjusted Cox-proportional-hazards analysis. Time-dependent receiver operating characteristic (ROC) analysis was performed to compare the performance of the SIR markers in predicting OS. RESULTS A total of 137 patients received a median of six cycles (interquartile range [IQR], 3-11) of GP chemotherapy with a median observation time of 9.9 months (range, 1.8-54.7 months). The median PFS and OS of all patients were 7.8 months and 9.9 months, respectively. Among the SIR markers, high PLR (> 148) and high NLR (> 5) were associated with a short PFS (Hazard ratio [HR] 1.828, P = 0.006; HR 1.738, P = 0.030, respectively) and short OS (HR 2.332, P < 0.001; HR 2.273, P < 0.001, respectively). Low LMR (< 3.5) and low AGR (< 1.2) were associated with a short OS (HR 2.423, P < 0.001; HR 1.768, P = 0.002, respectively). In multivariable cox-regression analysis, high PLR (HR 1.766, P = 0.009) and distant lymph node (LN) metastasis (HR 2.085, P = 0.001) were associated with a short PFS. High PLR (HR 1.856, P = 0.002) was an independent predictor of a short OS, along with distant LN metastasis (HR 1.929; P < 0.001), low LMR (HR 1.691; P = 0.041), and low level of serum albumin (< 3.5 g/dL) (HR 1.632; P = 0.043). Time-dependent ROC analysis revealed that the area under the curve of PLR for predicting overall survival was greater than that of NLR, LMR, and AGR at most time points. CONCLUSIONS High PLR was an independent prognostic factor of a short PFS and OS in patients with unresectable IHC receiving GP chemotherapy.
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Affiliation(s)
- Gunn Huh
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Ji Kon Ryu
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.
| | - Jung Won Chun
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Joo Seong Kim
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Namyoung Park
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - In Rae Cho
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Woo Hyun Paik
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Sang Hyub Lee
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Yong-Tae Kim
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
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Polidoro MA, Mikulak J, Cazzetta V, Lleo A, Mavilio D, Torzilli G, Donadon M. Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells. World J Gastroenterol 2020; 26:4900-4918. [PMID: 32952338 PMCID: PMC7476172 DOI: 10.3748/wjg.v26.i33.4900] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/24/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.
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Affiliation(s)
- Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Joanna Mikulak
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Valentina Cazzetta
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Ana Lleo
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Internal Medicine, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Domenico Mavilio
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Matteo Donadon
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
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Cao Y, Ke S, Gu J, Mao F, Yao S, Deng S, Yan L, Wu K, Liu L, Cai K. The Value of Haematological Parameters and Tumour Markers in the Prediction of Intestinal Obstruction in 1474 Chinese Colorectal Cancer Patients. DISEASE MARKERS 2020; 2020:8860328. [PMID: 32855747 PMCID: PMC7443225 DOI: 10.1155/2020/8860328] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 04/30/2020] [Accepted: 07/27/2020] [Indexed: 12/19/2022]
Abstract
Intestinal obstruction, a life-threatening problem, often occurs in patients with advanced colorectal cancer (CRC). However, the cause of obstruction is still unknown. Very few prediction models for intestinal obstruction in CRC exist, and their results are unreliable. Therefore, we investigated whether preoperative serum tumour markers (STMs) combined with haematological and biochemical markers could be used as predictors. We retrospectively analysed 1474 patients with CRC who underwent radical resection after admission. Several clinical features, STMs, and serum biochemical and haematological indicators were analysed. Predictors of intestinal obstruction were analysed with univariate and multivariate logistic regression. The accuracy of the multivariate predictors of obstruction was measured by the area under the receiver operating characteristic (ROC) curve (AUC). The Kaplan-Meier method was used to create survival curves. Obstruction was found more in males (62.18%), never-smokers (73.95%), the left colon (54.20%), the tumour diameter > 4.5 cm (55.88%), high differentiation (89.50%), and negative nerve invasion (70.17%). The serum tumour markers (STMs) and peripheral blood routine indexes (PBRI) were significantly associated with obstructive status (p < 0.05). Multivariate analysis demonstrated that the neutrophil and lymphocyte counts, carcinoembryonic antigen, carbohydrate antigen 19-9, carbohydrate antigen 125, albumin, alkaline phosphatase, gamma-glutamyl transpeptidase, total protein, and neutrophil-to-lymphocyte ratio were predictors of intestinal obstruction (p < 0.05). The AUC for the curve with all the eight factors was 0.715 (95% confidence interval: 0.673-0.758). The STMs and PBRI were related to the obstruction status of the patients, and they could be used in combination with other clinical factors to significantly improve diagnosis and management of intestinal obstruction in CRC patients.
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Affiliation(s)
- Yinghao Cao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Songqing Ke
- Department of Epidemiology and Biostatistics, The Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Junnan Gu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Fuwei Mao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Shuang Yao
- Department of Epidemiology and Biostatistics, The Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Shenghe Deng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Lizhao Yan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Ke Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, The Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
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Tsilimigras DI, Mehta R, Aldrighetti L, Poultsides GA, Maithel SK, Martel G, Shen F, Koerkamp BG, Endo I, Pawlik TM. Development and Validation of a Laboratory Risk Score (LabScore) to Predict Outcomes after Resection for Intrahepatic Cholangiocarcinoma. J Am Coll Surg 2020; 230:381-391.e2. [PMID: 32014569 DOI: 10.1016/j.jamcollsurg.2019.12.025] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 12/10/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Estimating prognosis in the preoperative setting is challenging, as most survival risk scores rely exclusively on postoperative factors. We sought to develop a composite score that incorporated preoperative liver, tumor, nutritional, and inflammatory markers to predict long-term outcomes after resection of intrahepatic cholangiocarcinoma (ICC). STUDY DESIGN Patients who underwent curative-intent hepatectomy for ICC between 2000 and 2017 were identified using an international multi-institutional database. Clinicopathologic factors were assessed using bivariate and multivariable analysis and a prognostic model to estimate overall survival (OS) based only on preoperative laboratory values (LabScore) was developed and validated. RESULTS Among 660 patients, median OS was 43.2 months and 5-year OS rate was 42.4%. On multivariable analysis, laboratory values associated with OS included carbohydrate antigen 19-9 (hazard ratio [HR] 1.16; 95% CI 1.05 to 1.27), neutrophil-to-lymphocyte ratio (HR 1.09; 95% CI, 1.05 to 1.13), platelet count (HR 1.01; 95% CI, 1.00 to 1.01), and albumin (HR 0.75; 95% CI, 0.62 to 0.92). A weighted LabScore was constructed based on the formula: (8.2 + 1.45 × natural logarithm of carbohydrate antigen 19-9 + 0.84 × neutrophil-to-lymphocyte ratio + 0.03 × platelets - 2.83 × albumin). Patients with a LabScore of 0 to 9 (n = 223), 10 to 19 (n = 353) and ≥20 (n = 88) had incrementally worse 5-year OS rates of 54.9%, 38.2% and 21.6%, respectively (p < 0.001). The model demonstrated good performance in both the test (c-index 0.70) and validation cohorts (c-index 0.67), as well as outperformed individual laboratory markers, the prognostic nutritional index (c-index 0.58), and American Joint Committee on Cancer staging system (c-index 0.60). CONCLUSIONS A preoperative LabScore was able to predict long-term outcomes of patients after resection for ICC better than American Joint Committee on Cancer staging system. The LabScore can be used to preoperatively identify patients who will benefit the most from upfront operation or alternative treatment options, including neoadjuvant chemotherapy before resection.
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Affiliation(s)
- Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH
| | - Rittal Mehta
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH
| | | | | | | | - Guillaume Martel
- Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH.
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Moro A, Mehta R, Sahara K, Tsilimigras DI, Paredes AZ, Farooq A, Hyer JM, Endo I, Shen F, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Maithel SK, Marques HP, Martel G, Pulitano C, Soubrane O, Koerkamp BG, Sasaki K, Pawlik TM. The Impact of Preoperative CA19-9 and CEA on Outcomes of Patients with Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2020; 27:2888-2901. [DOI: 10.1245/s10434-020-08350-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Indexed: 12/12/2022]
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Wang T, Kong J, Yang X, Shen S, Zhang M, Wang W. Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: A Propensity Score Matching analysis. J Surg Oncol 2019; 121:524-537. [PMID: 31867746 DOI: 10.1002/jso.25815] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 12/10/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma with sarcomatoid change (iCCA-SC) is a rare histological subtype of iCCA, the clinical features and outcomes after surgical resection on the prognosis is still unknown. METHODS We retrospectively reviewed the clinical data of patients with histologically proven iCCA who underwent curative liver resection at our hospital between January 2008 and December 2018. Propensity score matching analysis was used to match patients with and without sarcomatoid change at a ratio of 1:4. The nomogram integrating all significant independent factors for overall survival (OS) and recurrence-free survival (RFS) was constructed to predict prognosis for iCCA. The predictive accuracy ability of the nomogram was determined by Harrell's index (C-index). RESULTS A total of 40 iCCA-SC and 160 ordinary iCCA patients were included in this study. RFS and OS in the iCCA-SC group were significantly lower than those in the ordinary iCCA group (P<.001 and P = .002, respectively). The calibration curve for the probability of survival showed good agreement between the nomogram prediction and actual observation. CONCLUSION The histological sarcomatoid subtype is an independent predictor of tumor recurrence and shorter OS in iCCA patients. The nomogram we established could provide more accurate prognostic prediction for iCCA patients.
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Affiliation(s)
- Tao Wang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
| | - Junjie Kong
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xianwei Yang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
| | - Shu Shen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
| | - Menglan Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Wentao Wang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
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Akita M, Ajiki T, Ueno K, Tsugawa D, Hashimoto Y, Tanaka M, Kido M, Toyama H, Fukumoto T. Predictors of postoperative early recurrence of extrahepatic bile duct cancer. Surg Today 2019; 50:344-351. [PMID: 31549244 DOI: 10.1007/s00595-019-01880-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 09/04/2019] [Indexed: 12/20/2022]
Abstract
PURPOSES Resected bile duct cancers often relapse during postoperative follow-up. The aim of this study was to detect predictors of early recurrence in patients with extrahepatic bile duct cancer. METHODS Consecutive cases (n = 162) of extrahepatic bile duct cancer in which R0 or R1 resection was achieved in Kobe University Hospital between 2000 and 2016 were divided into three groups [early recurrence (ER), within 6 months of surgery, late recurrence (LR), and no recurrence (NR)] and their clinicopathological features were compared. RESULTS Twenty-two patients (14%) developed ER and 69 (43%) developed LR after surgery. The rates of lymph node metastasis and residual cancer status were similar in all three groups. Liver metastasis was more common in the ER group than in the LR group (59% vs. 32%, p = 0.02). ER had a significantly worse prognosis than LR and NR (7% vs. 44% vs. 85% at 1 year, p < 0.01, respectively). Multivariate analysis showed that age > 75 years, serum CA19-9 > 1008 U/ml and perineural invasion were independent predictors of early recurrence. CONCLUSIONS High serum CA19-9 values (> 1008 U/ml) were an independent predictor of early recurrence. Neoadjuvant therapy and aggressive adjuvant therapy may be beneficial for patients who show highly elevated CA19-9 values before surgery.
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Affiliation(s)
- Masayuki Akita
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Tetsuo Ajiki
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
| | - Kimihiko Ueno
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Daisuke Tsugawa
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Yu Hashimoto
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Motofumi Tanaka
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Masahiro Kido
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Hirochika Toyama
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Takumi Fukumoto
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
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Chen XQ, Xue CR, Hou P, Lin BQ, Zhang JR. Lymphocyte-to-monocyte ratio effectively predicts survival outcome of patients with obstructive colorectal cancer. World J Gastroenterol 2019; 25:4970-4984. [PMID: 31543687 PMCID: PMC6737316 DOI: 10.3748/wjg.v25.i33.4970] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 06/09/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obstructive colorectal cancer (OCC) is always accompanied by severe complications, and the optimal strategy for patients with OCC remains undetermined. Different from emergency surgery (ES), self-expandable metal stents (SEMS) as a bridge to surgery (BTS), could increase the likelihood of primary anastomosis. However, the stent failure and related complications might give rise to a high recurrence rate. Few studies have focused on the indications for either method, and the relationship between preoperative inflammation indexes and the prognosis of OCC is still underestimated.
AIM To explore the indications for ES and BTS in OCCs based on preoperative inflammation indexes.
METHODS One hundred and twenty-eight patients who underwent ES or BTS from 2008 to 2015 were enrolled. Receiver operating characteristic (ROC) curve analysis was used to define the optimal preoperative inflammation index and its cutoff point. Kaplan–Meier analyses and Cox proportional hazards models were applied to assess the association between the preoperative inflammation indexes and the survival outcomes [overall survival (OS) and disease-free survival (DFS)]. Stratification analysis was performed to identify the subgroups that would benefit from ES or BTS.
RESULTS OS and DFS were comparable between the ES and BTS groups (P > 0.05). ROC curve analysis showed derived neutrophil-to-lymphocyte ratio (dNLR) as the optimal biomarker for the prediction of DFS in ES (P < 0.05). Lymphocyte-to-monocyte ratio (LMR) was recommended for BTS with regard to OS and DFS (P < 0.05). dNLR was related to stoma construction (P = 0.001), pneumonia (P = 0.054), and DFS (P = 0.009) in ES. LMR was closely related to lymph node invasion (LVI) (P = 0.009), OS (P = 0.020), and DFS (P = 0.046) in the BTS group. dNLR was an independent risk factor for ES in both OS (P = 0.032) and DFS (P = 0.016). LMR affected OS (P = 0.053) and DFS (P = 0.052) in the BTS group. LMR could differentiate the OS between the ES and BTS groups (P < 0.05).
CONCLUSION Preoperative dNLR and LMR could predict OS and DFS in patients undergoing ES and BTS, respectively. For OCC, as the potential benefit group, patients with a low LMR might be preferred for BTS via SEMS insertion.
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Affiliation(s)
- Xian-Qiang Chen
- Department of General Surgery (Emergency Surgery), Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Chao-Rong Xue
- Department of General Surgery (Emergency Surgery), Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Ping Hou
- Immunotherapy Institute, Fujian Medical University, Fuzhou 350122, Fujian Province, China
| | - Bing-Qiang Lin
- Department of General Surgery (Emergency Surgery), Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Jun-Rong Zhang
- Department of General Surgery (Emergency Surgery), Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
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Predictive utility of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in intraductal papillary neoplasm of the bile duct. Clin Exp Hepatol 2019; 5:250-255. [PMID: 31598563 PMCID: PMC6781823 DOI: 10.5114/ceh.2019.87641] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 05/20/2019] [Indexed: 02/08/2023] Open
Abstract
Aim of the study Intraductal papillary neoplasm of the bile duct (IPNB) can present at various stages of the disease. Each stage needs different treatment. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have been described as predictive markers for several tumors. There has been no investigation on the role of NLR and PLR in IPNB. Material and methods We retrospectively reviewed the medical records of 112 patients who underwent curative-intent hepatic resection for IPNB between January 2007 and December 2011. All clinical parameters and survival were analyzed for their association with NLR and PLR. Results For prediction of malignancy, the best respective cut-off for NLR and PLR was 2.74 and 130, with area under the ROC curve being 0.662 and 0.763. For micro-papillary IPNB, both markers well predict malignancy and lymph node involvement. The respective area under the ROC curve of NLR and PLR for prediction of malignancy was 0.78 and 0.88. Both markers had an area under the ROC curve for prediction of lymph node involvement of 1.0. The median overall survival of those with PLR < 130 was 86.4 months compared with 45.0 months for those with PLR > 130 (p = 0.02). Conclusions NLR and PLR seem likely candidates for predicting malignancy, lymph node involvement, and survival of the patients. PLR performed better than NLR for all predictions. The markers worked very well for micro-papillary IPNB; however, we recommend using these markers in conjunction with the radiologic appearance of tumors.
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Moro A, Paredes AZ, Farooq A, Sahara K, Tsilimigras DI, Mehta R, Endo I, Guglielmi A, Aldrighetti L, Alexandrescu S, Marques HP, Shen F, Koerkamp BG, Sasaki K, Pawlik TM. Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: A preoperative vs postoperative perspective. J Surg Oncol 2019; 120:946-955. [DOI: 10.1002/jso.25671] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 08/04/2019] [Indexed: 12/25/2022]
Affiliation(s)
- Amika Moro
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Anghela Z. Paredes
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Ayesha Farooq
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Kota Sahara
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
- Department of Gastroenterological SurgeryYokohama City University School of Medicine Yokohama Japan
| | - Diamantis I. Tsilimigras
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Rittal Mehta
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
| | - Itaru Endo
- Department of Gastroenterological SurgeryYokohama City University School of Medicine Yokohama Japan
| | | | | | | | | | - Feng Shen
- Department of SurgeryEastern Hepatobiliary Surgery Hospital Shanghai China
| | - Bas G. Koerkamp
- Department of SurgeryErasmus University Medical Centre Rotterdam Netherlands
| | - Kazunari Sasaki
- Department of General SurgeryCleveland Clinic Foundation Cleveland Ohio
| | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical OncologyThe Ohio State University Wexner Medical Center and James Comprehensive Cancer Center Columbus Ohio
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Fabris L, Perugorria MJ, Mertens J, Björkström NK, Cramer T, Lleo A, Solinas A, Sänger H, Lukacs-Kornek V, Moncsek A, Siebenhüner A, Strazzabosco M. The tumour microenvironment and immune milieu of cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:63-78. [PMID: 30907492 PMCID: PMC10878127 DOI: 10.1111/liv.14098] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 12/11/2022]
Abstract
Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padova, Italy
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - María Jesús Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Niklas K. Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- ESCAM – European Surgery Center Aachen Maastricht, Germany and The Netherlands
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Antonio Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Hanna Sänger
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital, Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Veronika Lukacs-Kornek
- Institute of Experimental Immunology, University Hospital, Friedrich-Wilhelms-Universität Bonn, Germany
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Alexander Siebenhüner
- Department of Hematology and Medical Oncology, University Hospital Zürich, Zürich, Switzerland
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
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Abstract
Cholangiocarcinoma is a rare malignancy and accounts for 2% of all malignancies. Incidence is on the increase in the Western world. Cholangiocarcinoma arises from the malignant growth of the epithelial lining of the bile ducts and can be found all along the biliary tree. It can be classified into subtypes based on location: intrahepatic (arising from the intrahepatic biliary tract in the hepatic parenchyma), perihilar (at the hilum of the liver involving the biliary confluence) and distal (extrahepatic, often in the head of the pancreas). Margin status and locoregional lymph node metastases are the most important determinants of postsurgical outcomes.
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Affiliation(s)
- Adeel S Khan
- Section of Abdominal Transplant Surgery, Washington University St Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO 63110, USA.
| | - Leigh Anne Dageforde
- Division of Transplant Surgery, Massachusetts General Hospital, 55 Fruit Street, White 511, Boston, MA 02114, USA
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Prognostic Significance of Platelet-to-Lymphocyte Ratio in Cholangiocarcinoma: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7375169. [PMID: 30539019 PMCID: PMC6261069 DOI: 10.1155/2018/7375169] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/20/2018] [Accepted: 10/29/2018] [Indexed: 12/16/2022]
Abstract
Introduction Pretreatment platelet-to-lymphocyte ratio (PLR) has been considered a prognostic factor in various cancers. However, the application of PLR in the assessment of patients with cholangiocarcinoma remains controversial. This study aimed to evaluate the prognostic value of pretreatment PLR in cholangiocarcinoma. Methods A systematic search was performed in MEDLINE, EMBASE, and Cochrane Library to identify studies assessing the prognostic significance of the pretreatment PLR in cholangiocarcinoma. Three databases were searched from inception to August 5, 2018. The primary outcome was overall survival (OS), and the secondary outcomes were recurrence-free survival (RFS) and progression-free survival (PFS). Pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models. Results A total of 9 studies including 2395 patients were finally enrolled in the meta-analysis based on the inclusion and exclusion criteria. All of the included studies were retrospective observational cohorts. Elevated PLR predicted poor OS (HR: 1.38, 95% CI: 1.19-1.62, P < 0.001) and RFS or PFS (HR = 1.55; 95% CI = 1.27-1.88; P < 0.001). Moreover, elevated PLR was highly associated with male sex (male versus female OR = 0.59, 95% CI: 0.44-0.80, P < 0.001) and R1 resection margin (OR = 2.09, 95% CI: 1.24-3.54, P = 0.006). Conclusion The present meta-analysis demonstrated that pretreatment PLR might serve as a useful prognostic biomarker in cholangiocarcinoma.
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