|
1
|
Zhang ZN, Hao L, Han S, Li SS, Lin SX, Miao YD. Harnessing the prognostic power of preoperative systemic immune-inflammation index/albumin ratio in hepatocellular carcinoma resection. World J Gastrointest Surg 2025; 17:102261. [DOI: 10.4240/wjgs.v17.i2.102261] [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: 10/13/2024] [Revised: 12/05/2024] [Accepted: 12/16/2024] [Indexed: 01/22/2025] Open
Abstract
The recent study by Chen et al, published in the World Journal of Gastroenterology, introduces a groundbreaking assessment tool-the preoperative systemic immune-inflammation index/albumin (SII/ALB) ratio-for patients with hepatocellular carcinoma (HCC) undergoing curative resection. This study not only establishes the independent prognostic significance of the SII/ALB ratio but also incorporates it into a predictive nomogram, enhancing its utility for clinical decision-making. The SII/ALB ratio, by integrating inflammatory and nutritional biomarkers, offers a novel lens through which the prognosis of HCC patients can be viewed, suggesting a more tailored approach to patient management. The development of the nomogram, validated for its accuracy in predicting patient outcomes, marks a pivotal advance, potentially guiding surgical decisions and postoperative care. However, the study's focus on a single-center cohort prompts the need for validation in a broader, more diverse patient population to ensure its applicability across various clinical settings. Moreover, longitudinal studies could elucidate the dynamic changes in SII/ALB post-surgery, offering insights into its potential as a continuous monitor for recurrence and long-term survival. This abstract aim to underscore the critical findings of Chen et al's study while calling for further research to explore the full potential of the SII/ALB ratio in the global management of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Zhao-Nan Zhang
- Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, Shandong Province, China
| | - Liang Hao
- Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, Shandong Province, China
| | - Shuang Han
- Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, Shandong Province, China
| | - Shan-Shan Li
- Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, Shandong Province, China
| | - Si-Xiang Lin
- Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, Shandong Province, China
| | - Yan-Dong Miao
- Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, Shandong Province, China
| |
Collapse
|
|
2
|
Woo HJ, Kwon TK, Heo ST, Yoo JR, Kim M, Oh J, Bae IG, Bae S, Yoon YR, Hyun M, Kim HA, Jung SI, Kwon KT, Hwang S, Kim UJ, Kang G, Kim YJ, Hwang JH, Kim MG. Prognostic nutritional index as an early predictor of mortality in patients with severe fever with thrombocytopenia syndrome: multicenter retrospective study in South Korea. BMC Infect Dis 2025; 25:274. [PMID: 40001073 PMCID: PMC11863440 DOI: 10.1186/s12879-025-10661-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/17/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND AND AIM Severe fever with thrombocytopenia syndrome (SFTS) is a fatal tick-borne infectious disease lacking effective treatments or vaccines. Early identification of prognostic factors is essential for optimizing clinical management. This study investigated the predictors for mortality in SFTS patients. METHODS We conducted a retrospective multicenter cohort study of 413 SFTS patients hospitalized in South Korea from 2013 to 2024. Clinical and laboratory data were comprehensively analyzed to evaluate associations between in-hospital mortality and various inflammatory, immune, and nutritional biomarkers. Cox regression and time-dependent receiver operating characteristic (ROC) analyses were performed to identify risk factors. RESULTS 413 patients diagnosed with SFTS were included and In-hospital mortality was 17% (70/413). Multivariate Cox regression identified older age (HR: 1.042; 95% CI: 1.014-1.071), elevated PT(INR) (HR: 109.57; 95% CI: 19.79-606.57), and lower prognostic nutritional index (PNI) (HR: 0.937; 95% CI: 0.886-0.990) as early predictors of mortality. Time-dependent ROC analysis demonstrated predictive accuracy, with AUCs of 0.512 for age, 0.857 for PT(INR), and 0.694 for PNI at 30 days. Kaplan-Meier analysis revealed significant survival differences for patients stratified by PNI (< 40.75), PT(INR) (≥ 0.97), and age (≥ 59 years). CONCLUSIONS PNI, PT(INR), and age were identified as key early predictors of mortality in SFTS. PNI, as a novel biomarker, was found to be a useful index for risk level and treatment strategies in SFTS patients. CLINICAL TRIAL NUMBER Not applicable.
Collapse
Affiliation(s)
- Hyun Ji Woo
- Department of Healthcare Engineering, Graduate School, Jeonbuk National University, Jeonju, Republic of Korea
- Nanum Space Co., Ltd, Jeonju, Jeonbuk, Republic of Korea
| | - Tae-Kyu Kwon
- Division of Biomedical Engineering, College of Engineering, Jeonbuk National University, Jeonju, Republic of Korea
| | - Sang Taek Heo
- Division of Infectious Diseases, Department of Internal Medicine, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Jeong Rae Yoo
- Division of Infectious Diseases, Department of Internal Medicine, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Misun Kim
- Division of Infectious Diseases, Department of Internal Medicine, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Jaeseong Oh
- Department of Pharmacology, Jeju National University School of Medicine, Jeju National University Hospital, Jeju, Republic of Korea
| | - In-Gyu Bae
- Division of Infectious Diseases, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Sohyun Bae
- Division of Infectious Diseases, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Young-Ran Yoon
- Department of Clinical Pharmacology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Miri Hyun
- Division of Infectious Diseases, Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hyun Ah Kim
- Division of Infectious Diseases, Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Sook In Jung
- Division of Infectious Diseases, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Ki Tae Kwon
- Division of Infectious Diseases, Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Soyoon Hwang
- Division of Infectious Diseases, Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Uh Jin Kim
- Division of Infectious Diseases, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University School of Medicine, Gwangju, Republic of Korea
| | - Gaeun Kang
- Division of Clinical Pharmacology, Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Young Jun Kim
- Division of Infectious Diseases, Department of Internal Medicine, Wonkwang University Hospital, Iksan, Republic of Korea
| | - Jeong-Hwan Hwang
- Division of Infectious Diseases, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Republic of Korea.
| | - Min-Gul Kim
- Nanum Space Co., Ltd, Jeonju, Jeonbuk, Republic of Korea.
- Department of Pharmacology, Jeonbuk National University Medical School, Jeonju, Republic of Korea.
| |
Collapse
|
|
3
|
Chen J, Fang Y, Tang Z, Dong E, Gao J, Zhu G, Kwangwari P, Feng S, Qu W, Wu X, Mao S, Zhao Q, Wang Y, Yang R, Guan Z, Chu T, Bu Y, Zhou J, Fan J, Fu X, Liu W, Ding Z, Shi Y. Predictive value of neutrophil-to-lymphocyte ratio in recurrent HCC after repeat hepatectomy or salvage liver transplantation. Hepatol Int 2025:10.1007/s12072-025-10786-7. [PMID: 39985654 DOI: 10.1007/s12072-025-10786-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/26/2025] [Indexed: 02/24/2025]
Abstract
BACKGROUNDS AND AIMS Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer, characterized by a high rate of recurrence. This study aims to compare the efficacy and safety of repeat hepatectomy (RH) and salvage liver transplantation (sLT) for recurrent hepatocellular carcinoma (rHCC) and explores the predictive value of neutrophil-to-lymphocyte ratio (NLR) and neutrophil extracellular traps (NETs). METHODS In this study, consecutive patients receiving RH (n = 637) or sLT (n = 53) for rHCC within the University of California San Francisco (UCSF) Criteria were recruited. After propensity score matching (PSM), disease-free survival (DFS) and overall survival (OS) were compared utilizing the Kaplan-Meier method. Additionally, the level of neutrophil infiltration and NETs were analyzed by multiplex immunofluorescence. RESULTS After PSM, the sLT group demonstrated superior 5-year DFS and OS compared to the RH group (p < 0.001 and p = 0.014). Subgroup analysis demonstrated that NLR > 2.3 was associated with poorer OS (p < 0.001 in the RH group and p = 0.024 in the sLT group) and DFS (p = 0.002 in both groups). Furthermore, we identified that patients in the sLT group are more susceptible to extrahepatic metastasis. In addition, our results revealed that higher infiltration of intratumoral neutrophils was negatively correlated with OS and DFS (p = 0.002 and p = 0.001, respectively), especially in cases with higher NETs level. CONCLUSIONS This study indicates that sLT achieves better long-term outcomes than RH for rHCC. NLR and NETs formation are promising prognostic factors for HCC.
Collapse
Affiliation(s)
- Jiafeng Chen
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Yuan Fang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Zheng Tang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Enfu Dong
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Jun Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Guiqi Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Pascal Kwangwari
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Shanru Feng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Weifeng Qu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Xiaoling Wu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Shengwei Mao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Qianfu Zhao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Yi Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Rui Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Zhiqi Guan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Tianhao Chu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Yichao Bu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Xiutao Fu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
| | - Weiren Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
| | - Zhenbin Ding
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
- Department of Liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.
| | - Yinghong Shi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
| |
Collapse
|
|
4
|
Cai Q, Pang C, Wang Z, Li J, Dai Y, Fan FY, Wang ZQ, Hu X, Li L, Chen XW, Ji R, Mei Q, Zhang C, Liang P, Yu X, Liu FY, Cheng Z, Yu J. Relationship between postablation fever and prognosis in initial hepatocellular carcinoma: a 15-year multicenter, retrospective cohort study. Int J Surg 2025; 111:962-971. [PMID: 39291970 PMCID: PMC11745605 DOI: 10.1097/js9.0000000000002066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 08/25/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Fever is a common side effect following thermal ablation in patients with hepatocellular carcinoma (HCC), yet its impact on prognosis remains unclear. MATERIALS AND METHODS This retrospective study included initial HCC patients who underwent US-guided percutaneous microwave ablation at 13 hospitals between January 2006 and February 2021. All patients were categorized into afebrile, transient low-grade fever (TLF), and prolonged or high-grade fever (PHF) groups. Primary outcomes included very early recurrence (VER) and early recurrence (ER), secondary outcomes were disease-free survival (DFS) and overall survival (OS). Fever cut-offs for VER/ER were established using restrictive cubic splines and an adjusted Cox model. Survival analyses used the Kaplan-Meier method. RESULTS A total of 1458 initial HCC patients (mean age, 59±11[SD]; 1146 men). Compared to afebrile individuals, patients with TLF (temperatures ranging 37.0-38.8°C for 1-2 days), showed independent protective effects against VER (HR, 0.73; 95% CI: 0.57-0.95; P =0.02) and ER (HR, 0.66; 95% CI: 0.54-0.81; P <0.001), however, PHF showed no differences in VER (HR, 0.99; 95% CI: 0.76-1.30; P =0.96) and ER (HR, 0.86; 95% CI: 0.69-1.07; P =0.17). With a median follow-up of 47 months (IQR: 26-79), the median DFS for TLF patients was 40 months, superior to afebrile (30 months, P =0.019) and PHF patients (33 months, P =0.049). The 5-year OS rate for TLF patients was 73.2%, higher than afebrile (69.3%, P =0.02) and PHF patients (66.7%, P =0.03). No significant difference was found in DFS and OS between afebrile and PHF patients ( P =0.90 and 0.71). Notably, TLF patients exhibited the highest lymphocyte counts increasing median 7 days after ablation ( P <0.001 vs. afebrile and P =0.01 vs. PHF). CONCLUSION Transient low-grade fever following percutaneous microwave ablation in hepatocellular carcinoma patients demonstrated protection against early recurrence, possibly attributed to the short-term activation of lymphocytes.
Collapse
Affiliation(s)
- Qian Cai
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Chuan Pang
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Zhen Wang
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Jianming Li
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Yuqing Dai
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Fang-ying Fan
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Zhong-qi Wang
- Department of Orthopedics, Fourth Medical Center of Chinese PLA General Hospital and Chinese PLA Medical College, Beijing, People’s Republic of China
| | - Xin Hu
- Departments of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Lijuan Li
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Xu-wei Chen
- Department of Breast and Thyroid Surgery, Qingdao Women and Children’s Hospital, Qingdao University, Qingdao, People’s Republic of China
| | - Ran Ji
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Qian Mei
- Department of Bio-Therapeutic, The First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Chao Zhang
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Ping Liang
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Xiaoling Yu
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Fang-yi Liu
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Zhigang Cheng
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Jie Yu
- Senior Department of Oncology, Department of Interventional Ultrasound, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| |
Collapse
|
|
5
|
Jin Z, Zhou J, Chen J, Ding R, Scheiner B, Wang S, Li H, Shen Q, Lu Q, Liu Y, Zhang W, Luo B, Shi H, Huang M, Wu Y, Yuan C, Huang M, Li J, Wu J, Zhu X, Zhong B, Zhou H, Wang Y, Gu S, Peng Z, Zheng C, Liu R, Xu G, Yang W, Xu A, Liu D, Qi X, Yeo Y, Zhu H, Zhao Y, Pinato D, Ji F, Teng G. Longitudinal Body Composition Identifies Hepatocellular Carcinoma With Cachexia Following Combined Immunotherapy and Target Therapy (CHANCE2213). J Cachexia Sarcopenia Muscle 2024; 15:2705-2716. [PMID: 39604073 PMCID: PMC11634469 DOI: 10.1002/jcsm.13615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 08/09/2024] [Accepted: 09/18/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Cancer cachexia can impact prognosis, cause resistance to anticancer treatments and affect the tolerability of treatments. This study aims to identify hepatocellular carcinoma (HCC) with cachexia by characterizing longitudinal body composition (BC) trajectories. METHODS This longitudinal, multicentre cohort study included unresectable HCC patients treated with first-line programmed death-(ligand)1 inhibitors plus anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors between 01/2018-12/2022. BC measurements including skeletal muscle mass (SMM) and total adipose tissue area (TATA) were evaluated by computed tomography at the third lumbar vertebra at baseline and follow-up imaging. Unsupervised latent class growth mixed models were applied to distinguish potential longitudinal SMM and TATA trajectories for identifying cachexia. The primary study endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), objective response rate (ORR) and safety. Multiple Cox proportional hazards models were used to calculate adjusted hazard ratios (HRs) for survival. RESULTS A total of 411 patients with 2138 time-point measurements were included. The median age was 56 years, and 50 (12.2%) patients were female. Two distinct trajectories were identified for SMM and TATA: sharp-falling and stable. SMM sharply declined in 58 patients (14.1%) and TATA in 71 of 406 patients (17.5%) with significant worse OS (for SMM, 17.0 vs. 24.9 months; p < 0.001; HR = 0.59; for TATA, 15.3 vs. 25.1 months; p < 0.001; HR = 0.44). Patients were categorized into three phases based on trajectories: pre-cachexia (SMM and TATA stable, n = 299, 73.6%), cachexia (SMM or TATA sharp-falling, n = 86, 21.2%) and refractory cachexia (SMM and TATA sharp-falling, n = 21, 5.2%). Patients with refractory cachexia exhibited the worst OS, PFS and ORR, followed by those with cachexia. The median OS was 11.5 months for refractory cachexia, 17.7 for cachexia and 26.0 for pre-cachexia; median PFS was 6.0, 7.9 and 10.9 months, respectively, with ORR of 4.8%, 39.5% and 54.2%, respectively (all ps < 0.001). Multivariable Cox analysis identified refractory cachexia as an independent risk factor for both OS (HR = 3.31; p < 0.001) and PFS (HR = 2.94; p < 0.001), with cachexia also showing significant impacts. Grade 3-4 adverse events were higher in patients with refractory cachexia (23.8%) and cachexia (8.1%) compared with pre-cachexia (6.0%; p = 0.010). CONCLUSIONS HCC patients with cachexia and refractory cachexia were identified by longitudinal BC trajectories. Falling trajectories of BC identified refractory cachexia patients with worst response, survival and poor tolerability from systemic therapy combinations. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT05278195.
Collapse
Affiliation(s)
- Zhi‐Cheng Jin
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
- Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical EngineeringSoutheast UniversityNanjingChina
| | - Jia‐Wei Zhou
- Department of Health Statistics, School of Public HealthChongqing Medical UniversityChongqingChina
- Department of Biostatistics, School of Public HealthNanjing Medical UniversityNanjingChina
| | - Jian‐Jian Chen
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
- Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical EngineeringSoutheast UniversityNanjingChina
| | - Rong Ding
- Department of Minimally Invasive Interventional MedicineYunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical UniversityKunmingChina
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
- Department of Surgery and Cancer, Imperial College LondonHammersmith HospitalLondonUK
| | - Si‐Na Wang
- Department of Biostatistics, School of Public HealthNanjing Medical UniversityNanjingChina
| | - Hai‐Liang Li
- Department of Minimally Invasive InterventionThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
| | - Qing‐Xia Shen
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
| | - Qing‐Yun Lu
- Department of Oncology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
| | - Yi Liu
- Department of Infectious DiseasesThe Second Affiliated Hospital of Xi'an Jiaotong University, Xi'anChina
| | - Wei‐Hua Zhang
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
- Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical EngineeringSoutheast UniversityNanjingChina
| | - Biao Luo
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
| | - Hai‐Bin Shi
- Department of Interventional RadiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ming Huang
- Department of Minimally Invasive Interventional MedicineYunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical UniversityKunmingChina
| | - Ye‐Ming Wu
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
- Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical EngineeringSoutheast UniversityNanjingChina
| | - Chun‐Wang Yuan
- Center of Interventional Oncology and Liver DiseasesBeijing Youan Hospital, Capital Medical UniversityBeijingChina
| | - Ming‐Sheng Huang
- Department of Interventional Radiology, the Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Jia‐Ping Li
- Department of Interventional OncologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jian‐Bing Wu
- Department of OncologyThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Xiao‐Li Zhu
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouChina
| | - Bin‐Yan Zhong
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouChina
| | - Hai‐Feng Zhou
- Department of Interventional RadiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Yu‐Qing Wang
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
- Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical EngineeringSoutheast UniversityNanjingChina
| | - Shan‐Zhi Gu
- Interventional DepartmentHunan Provincial Tumor HospitalChangshaChina
| | - Zhi‐Yi Peng
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Chuan‐Sheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Rui‐Bao Liu
- Department of Interventional RadiologyThe Tumor Hospital of Harbin Medical UniversityHarbinChina
| | - Guo‐Hui Xu
- Department of Interventional RadiologySichuan Cancer Hospital and InstituteChengduChina
| | - Wei‐Zhu Yang
- Department of Interventional RadiologyUnion Hospital of Fujian Medical UniversityFuzhouChina
| | - Ai‐Bing Xu
- Department of Interventional TherapyNantong Tumor HospitalNantongChina
| | - Dong‐Fang Liu
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
- Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical EngineeringSoutheast UniversityNanjingChina
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
| | - Yee Hui Yeo
- Karsh Division of Gastroenterology and Hepatology, Department of MedicineCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Hai‐Dong Zhu
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
- Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical EngineeringSoutheast UniversityNanjingChina
| | - Yang Zhao
- Department of Biostatistics, School of Public HealthNanjing Medical UniversityNanjingChina
| | - David J. Pinato
- Department of Surgery and Cancer, Imperial College LondonHammersmith HospitalLondonUK
- Division of Oncology, Department of Translational MedicineUniversity of Piemonte Orientale “A. Avogadro”NovaraItaly
| | - Fanpu Ji
- Department of Infectious DiseasesThe Second Affiliated Hospital of Xi'an Jiaotong University, Xi'anChina
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong UniversityMinistry of Education of ChinaXi'anChina
| | - Gao‐Jun Teng
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
- Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical EngineeringSoutheast UniversityNanjingChina
| |
Collapse
|
|
6
|
Shen X, Niu X. Gamma-Glutamyl Transpeptidase to Neutrophil Ratio as Prognostic Indicator for Hepatocellular Carcinoma Patients Post-Curative Resection. J Hepatocell Carcinoma 2024; 11:2077-2085. [PMID: 39483455 PMCID: PMC11526730 DOI: 10.2147/jhc.s478186] [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: 07/09/2024] [Accepted: 10/23/2024] [Indexed: 11/03/2024] Open
Abstract
Background The close association between inflammation and the clinical outcomes of hepatocellular carcinoma (HCC) has been extensively documented. This study aims to analyze the association between a novel inflammatory indicator, the gamma-glutamyl transpeptidase to neutrophil ratio (GNR), and HCC prognosis following curative resection. Methods A cohort of 204 eligible HCC cases were included. Based on an optimal cut-off value determined utilizing the X-tile software, patients were categorized into low- and high-GNR groups. The overall survival (OS) and recurrence-free survival (RFS) rates were assessed using the Kaplan-Meier analysis method with Log rank tests. Multivariate Cox proportional hazard regression was used to investigate the independent association between GNR and HCC prognosis. Restricted cubic splines were used to explore the nonlinear relationship between GNR and the risk of death or recurrence. Results The low GNR group exhibited significantly higher 3-year OS and RFS rates than the high GNR group. Multivariate Cox analysis indicated that a high GNR level was independently associated with poor OS and RFS. A linear correlation between GNR and the risk of death, as well as a nonlinear inverted "U" shape correlation between GNR and the risk of recurrence, were observed. Conclusion The findings provide evidence supporting the independent association of GNR with HCC prognosis. These results offer promise for enhancing prognosis assessments and guiding active monitoring strategies for patients with HCC post-curative resection.
Collapse
Affiliation(s)
- Xueqin Shen
- Department of Clinical Nutrition, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
| | - Xiaoping Niu
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
| |
Collapse
|
|
7
|
Wang F, Qin Y, Wang ZM, Yan CY, He Y, Liu D, Wen L, Zhang D. A Dynamic Online Nomogram Based on Gd-EOB-DTPA-Enhanced MRI and Inflammatory Biomarkers for Preoperative Prediction of Pathological Grade and Stratification in Solitary Hepatocellular Carcinoma: A Multicenter Study. Acad Radiol 2024; 31:4021-4033. [PMID: 38494348 DOI: 10.1016/j.acra.2024.02.035] [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: 11/19/2023] [Revised: 12/24/2023] [Accepted: 02/22/2024] [Indexed: 03/19/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an inflammatory cancer. We aimed to explore whether preoperative inflammation biomarkers compared to the gadoxetic acid disodium (Gd-EOB-DTPA) enhanced MRI can add complementary value for predicting HCC pathological grade, and to develop a dynamic nomogram to predict solitary HCC pathological grade. METHODS 331 patients from the Institution A were divided chronologically into the training cohort (n = 231) and internal validation cohort (n = 100), and recurrence-free survival (RFS) was determined to follow up after surgery. 79 patients from the Institution B served as the external validation cohort. Overall, 410 patients were analyzed as the complete dataset cohort. Least absolute shrinkage and selection operator (LASSO) and multivariate Logistic regression were used to gradually filter features for model construction. The area under the receiver operating characteristic curve (AUC) and decision curve analysis were used to evaluate model's performance. RESULTS Five models of the inflammation, imaging, inflammation+AFP, inflammation+imaging and nomogram were developed. Adding inflammation to imaging model can improve the AUC in training cohort (from 0.802 to 0.869), internal validation cohort (0.827 to 0.870), external validation cohort (0.740 to 0.802) and complete dataset cohort (0.739 to 0.788), and obtain more net benefit. The nomogram had excellent performance for predicting high-grade HCC in four cohorts (AUCs: 0.882 vs. 0.869 vs. 0.829 vs. 0.806) with a good calibration, and accessed at https://predict-solitaryhccgrade.shinyapps.io/DynNomapp/. Additionally, the nomogram obtained an AUC of 0.863 (95% CI 0.797-0.913) for predicting high-grade HCC in the HCC≤ 3 cm. Kaplan-Meier survival curves demonstrated that the nomogram owned excellent stratification for HCC grade (P < 0.0001). CONCLUSION This easy-to-use dynamic online nomogram hold promise for use as a noninvasive tool in prediction HCC grade with high accuracy and robustness.
Collapse
Affiliation(s)
- Fei Wang
- Department of Radiology, XinQiao Hospital of Army Medical University, No.83, Xinqiao Central Street, Shapingba District, Chongqing 400037, China
| | - Yuan Qin
- Department of Radiology, Chongqing University Three Gorges Hospital, No.165, Xincheng Road, Wanzhou District, Chongqing 404031, China
| | - Zheng Ming Wang
- Department of Radiology, XinQiao Hospital of Army Medical University, No.83, Xinqiao Central Street, Shapingba District, Chongqing 400037, China
| | - Chun Yue Yan
- Department of gynaecology and obstetrics, Luzhou People's Hospital, No.316, Jiugu Avenue, Jiangyang District, Luzhou 646000, China
| | - Ying He
- Department of Radiology, XinQiao Hospital of Army Medical University, No.83, Xinqiao Central Street, Shapingba District, Chongqing 400037, China
| | - Dan Liu
- Department of Radiology, XinQiao Hospital of Army Medical University, No.83, Xinqiao Central Street, Shapingba District, Chongqing 400037, China
| | - Li Wen
- Department of Radiology, XinQiao Hospital of Army Medical University, No.83, Xinqiao Central Street, Shapingba District, Chongqing 400037, China
| | - Dong Zhang
- Department of Radiology, XinQiao Hospital of Army Medical University, No.83, Xinqiao Central Street, Shapingba District, Chongqing 400037, China.
| |
Collapse
|
|
8
|
Du J, Huang Z. NLR stability predicts response to immune checkpoint inhibitors in advanced hepatocellular carcinoma. Sci Rep 2024; 14:19583. [PMID: 39179639 PMCID: PMC11344071 DOI: 10.1038/s41598-024-68048-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 07/18/2024] [Indexed: 08/26/2024] Open
Abstract
A high baseline NLR is associated with a poor prognosis of immunotherapy in patients with advanced HCC. As anti-tumour immune activation takes time, early dynamic changes in NLR may serve as a biomarker for predicting immunotherapy response. We conducted a retrospective study in which we enrolled 209 patients with aHCC who received ICIs (training cohort: N = 121, validation cohort: N = 88). In the training cohort, we categorized the patients based on the early changes in their NLR. Specifically, we defined patients as NLR Stable-Responder, NLR Responder and NLR Non-Responder. We compared the outcomes of these three patient groups using survival analysis. Additionally, we shortened the observation period to 6 weeks and validated the findings in the validation cohort. In the training cohort, early dynamic changes in NLR (HR 0.14, 95%CI 0.03-0.65, p = 0.012, HR 0.19, 95%CI 0.07-0.54, p = 0.002; HR 0.21, 95%CI 0.10-0.42, p < 0.001, HR 0.40, 95%CI 0.23-0.69, p = 0.001), PD-L1 < 1% (HR 5.36, 95%CI 1.12-25.66, p = 0.036; HR 2.98, 95%CI 1.51-5.91, p = 0.002) and MVI (HR 3.52, 95%CI 1.28-9.69, p = 0.015; HR 1.99, 95%CI 1.14-3.47, p = 0.015) were identified as independent predictors of OS and PFS. In the validation cohort, when the observation period was reduced to 6 weeks, early NLR changes still have predictive value. Early dynamic changes in NLR may be an easily defined, cost-effective, non-invasive biomarker to predict aHCC response to ICIs.
Collapse
Affiliation(s)
- Jiajia Du
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, Hubei, China.
| |
Collapse
|
|
9
|
Galasso L, Cerrito L, Maccauro V, Termite F, Mignini I, Esposto G, Borriello R, Ainora ME, Gasbarrini A, Zocco MA. Inflammatory Response in the Pathogenesis and Treatment of Hepatocellular Carcinoma: A Double-Edged Weapon. Int J Mol Sci 2024; 25:7191. [PMID: 39000296 PMCID: PMC11241080 DOI: 10.3390/ijms25137191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.
Collapse
Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Irene Mignini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Giorgio Esposto
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| |
Collapse
|
|
10
|
Asoka AS, Kolikkandy A, Nair B, Kamath AJ, Sethi G, Nath LR. Role of Culinary Indian Spices in the Regulation of TGF-β Signaling Pathway in Inflammation-Induced Liver Cancer. Mol Nutr Food Res 2024; 68:e2300793. [PMID: 38766929 DOI: 10.1002/mnfr.202300793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/29/2023] [Indexed: 05/22/2024]
Abstract
SCOPE Hepatocellular carcinoma (HCC) results from various etiologies, such as Hepatitis B and C, Alcoholic and Non-alcoholic fatty liver disorders, fibrosis, and cirrhosis. About 80 to 90% of HCC cases possess cirrhosis, which is brought on by persistent liver inflammation. TGF-β is a multifunctional polypeptide molecule that acts as a pro-fibrogenic marker, inflammatory cytokine, immunosuppressive agent, and pro-carcinogenic growth factor during the progression of HCC. The preclinical and clinical evidence illustrates that TGF-β can induce epithelial-to-mesenchymal transition, promoting progression and hepatocyte immune evasion. Therefore, targeting the TGF-β pathway can be a promising therapeutic option against HCC. METHODS AND RESULTS We carry out a systemic analysis of eight potentially selected culinary Indian spices: Turmeric, Black pepper, Ginger, Garlic, Fenugreek, Red pepper, Clove, Cinnamon, and their bioactives in regulation of the TGF-β pathway against liver cancer. CONCLUSION Turmeric and its active constituent, curcumin, possess the highest therapeutic potential in treating inflammation-induced HCC and they also have the maximum number of ongoing in-vivo and in-vitro studies.
Collapse
Affiliation(s)
- Ajay Sarija Asoka
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
| | - Anusha Kolikkandy
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
| | - Adithya J Kamath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
| |
Collapse
|
|
11
|
Guerra F, Ponziani FR, Cardone F, Bucci C, Marzetti E, Picca A. Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders? Int J Mol Sci 2024; 25:4783. [PMID: 38732000 PMCID: PMC11084658 DOI: 10.3390/ijms25094783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/24/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.
Collapse
Affiliation(s)
- Flora Guerra
- Department of Biological and Environmental Sciences and Technologies, Università del Salento, Via Provinciale Lecce–Moteroni 165, 73100 Lecce, Italy;
| | - Francesca Romana Ponziani
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (F.R.P.); (F.C.); (E.M.)
| | - Ferdinando Cardone
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (F.R.P.); (F.C.); (E.M.)
| | - Cecilia Bucci
- Department of Experimental Medicine, Università del Salento, Via Provinciale Lecce–Moteroni 165, 73100 Lecce, Italy;
| | - Emanuele Marzetti
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (F.R.P.); (F.C.); (E.M.)
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00618 Rome, Italy
| | - Anna Picca
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (F.R.P.); (F.C.); (E.M.)
- Department of Medicine and Surgery, LUM University, SS100 km 18, 70010 Casamassima, Italy
| |
Collapse
|
|
12
|
Wang ZY, Xu B, Wang LN, Zhu XD, Huang C, Shen YH, Li H, Li ML, Zhou J, Fan J, Sun HC. Platelet-to-lymphocyte ratio predicts tumor response and survival of patients with hepatocellular carcinoma undergoing immunotherapies. Int Immunopharmacol 2024; 131:111863. [PMID: 38492340 DOI: 10.1016/j.intimp.2024.111863] [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: 12/22/2023] [Revised: 03/05/2024] [Accepted: 03/11/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND Lymphocyte-related factors were associated with survival outcome of different types of cancers. Nevertheless, the association between lymphocytes-related factors and tumor response of immunotherapy remains unclear. METHODS This is a retrospective study. Eligible participants included patients with unresectable or advanced hepatocellular carcinoma (HCC) who underwent immunotherapy as their first-line treatment. Radiological assessment of tumor response adhered to RECIST 1.1 and HCC-specific modified RECIST (mRECIST) criteria. Univariate and multivariate logistic analyses were employed to analyze clinical factors associated with tumor response. Kaplan-Meier survivial analysis were employed to compare progression-free survival (PFS) and overall survival (OS) across different clinical factors. Furthermore, patients who received treatment with either a combination of bevacizumab and anti-PD-1(L1) antibody (Beva group) or tyrosine-kinase inhibitor (TKI) and anti-PD-1 antibody (TKI group) were examined to explore the relation between clinical factors and tumor response. RESULTS A total of 208 patients were enrolled in this study. The median PFS and OS were 9.84 months and 24.44 months,respectively. An independent factor associated with a more favorable tumor response to immunotherapy was identified when PLR<100. Patients with PLR<100 had longer PFS than other patients, while OS showed no significant difference. Further analysis revealed that PLR exhibited superior prognostic value in patients of the Beva group as compared to those in the TKI group. CONCLUSIONS There exisits an association between PLR and tumor response as well as survival outcomes in patients receiving immunotherapy, particularly those treated with the combination of bevacizumab and anti-PD-1.
Collapse
Affiliation(s)
- Zi-Yi Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bin Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lu-Na Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Dong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying-Hao Shen
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hui Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mei-Ling Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
13
|
Li ZC, Wang J, Liu HB, Zheng YM, Huang JH, Cai JB, Zhang L, Liu X, Du L, Yang XT, Chai XQ, Jiang YH, Ren ZG, Zhou J, Fan J, Yu DC, Sun HC, Huang C, Liu F. Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy. Cell Rep 2024; 43:113877. [PMID: 38421869 DOI: 10.1016/j.celrep.2024.113877] [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: 06/07/2023] [Revised: 12/16/2023] [Accepted: 02/13/2024] [Indexed: 03/02/2024] Open
Abstract
Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.
Collapse
Affiliation(s)
- Zhong-Chen Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - He-Bin Liu
- Shanghai Omicsolution Co., Ltd., 28 Yuanwen Road, Shanghai 201199, China
| | - Yi-Min Zheng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - Jian-Hang Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - Jia-Bin Cai
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Institutes of Biomedical of Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
| | - Xin Liu
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Road, Shanghai 200071, China
| | - Ling Du
- Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - Xue-Ting Yang
- Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - Xiao-Qiang Chai
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - Ying-Hua Jiang
- Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - Zheng-Gang Ren
- Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - De-Cai Yu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Cheng Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Feng Liu
- Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China.
| |
Collapse
|
|
14
|
Wang F, Yan CY, Qin Y, Wang ZM, Liu D, He Y, Yang M, Wen L, Zhang D. Multiple Machine-Learning Fusion Model Based on Gd-EOB-DTPA-Enhanced MRI and Aminotransferase-to-Platelet Ratio and Gamma-Glutamyl Transferase-to-Platelet Ratio to Predict Microvascular Invasion in Solitary Hepatocellular Carcinoma: A Multicenter Study. J Hepatocell Carcinoma 2024; 11:427-442. [PMID: 38440051 PMCID: PMC10911084 DOI: 10.2147/jhc.s449737] [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: 12/05/2023] [Accepted: 02/20/2024] [Indexed: 03/06/2024] Open
Abstract
Background Currently, it is still confused whether preoperative aminotransferase-to-platelet ratio (APRI) and gamma-glutamyl transferase-to-platelet ratio (GPR) can predict microvascular invasion (MVI) in solitary hepatocellular carcinoma (HCC). We aimed to develop and validate a machine-learning integration model for predicting MVI using APRI, GPR and gadoxetic acid disodium (Gd-EOB-DTPA) enhanced MRI. Methods A total of 314 patients from XinQiao Hospital of Army Medical University were divided chronologically into training set (n = 220) and internal validation set (n = 94), and recurrence-free survival was determined to follow up after surgery. Seventy-three patients from Chongqing University Three Gorges Hospital and Luzhou People's Hospital served as external validation set. Overall, 387 patients with solitary HCC were analyzed as whole dataset set. Least absolute shrinkage and selection operator, tenfold cross-validation and multivariate logistic regression were used to gradually filter features. Six machine-learning models and an ensemble of the all models (ENS) were built. The area under the receiver operating characteristic curve (AUC) and decision curve analysis were used to evaluate model's performance. Results APRI, GPR, HBPratio3 ([liver SI‒tumor SI]/liver SI), PLT, peritumoral enhancement, non-smooth margin and peritumoral hypointensity were independent risk factors for MVI. Six machine-learning models showed good performance for predicting MVI in training set (AUCs range, 0.793-0.875), internal validation set (0.715-0.832), external validation set (0.636-0.746) and whole dataset set (0.756-0.850). The ENS achieved the highest AUCs (0.879 vs 0.858 vs 0.839 vs 0.851) in four cohorts with excellent calibration and more net benefit. Subgroup analysis indicated that ENS obtained excellent AUCs (0.900 vs 0.809 vs 0.865 vs 0.908) in HCC >5cm, ≤5cm, ≤3cm and ≤2cm cohorts. Kaplan‒Meier survival curves indicated that ENS achieved excellent stratification for MVI status. Conclusion The APRI and GPR may be new potential biomarkers for predicting MVI of HCC. The ENS achieved optimal performance for predicting MVI in different sizes HCC and may aid in the individualized selection of surgical procedures.
Collapse
Affiliation(s)
- Fei Wang
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
- Department of Medical Imaging, Luzhou People’s Hospital, Luzhou, 646000, People’s Republic of China
| | - Chun Yue Yan
- Department of Emergency Medicine, Luzhou People’s Hospital, Luzhou, 646000, People’s Republic of China
| | - Yuan Qin
- Department of Radiology, Chongqing University Three Gorges Hospital, Chongqing, 404031, People’s Republic of China
| | - Zheng Ming Wang
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Dan Liu
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Ying He
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Ming Yang
- Department of Medical Imaging, Luzhou People’s Hospital, Luzhou, 646000, People’s Republic of China
| | - Li Wen
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Dong Zhang
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| |
Collapse
|
|
15
|
She S, Shi J, Zhu J, Yang F, Yu J, Dai K. Impact of inflammation and the immune system on hepatocellular carcinoma recurrence after hepatectomy. Cancer Med 2024; 13:e7018. [PMID: 38457189 PMCID: PMC10922023 DOI: 10.1002/cam4.7018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 11/22/2023] [Accepted: 01/31/2024] [Indexed: 03/09/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Hepatectomy remains the first-line treatment for patients with resectable HCC. However, the reported recurrence rate of HCC at 5 years after surgery is between 50% and 70%. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease are well-known risk factors for recurrence after treatment. In addition to tumor-related factors, ever-increasing amounts of studies are finding that the tumor microenvironment also plays an important role in the recurrence of HCC, including systemic inflammatory response and immune regulation. Based on this, some inflammatory and immune markers were used in predicting postoperative cancer recurrence. These include neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, cytotoxic T cells, and regulatory T cells, among others. In this review, we summarized the inflammatory and immune markers that affect recurrence after HCC resection in order to provide direction for adjuvant therapy after HCC resection and ultimately achieve the goal of reducing recurrence.
Collapse
Affiliation(s)
- Sha She
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Jinzhi Shi
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Jiling Zhu
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Fan Yang
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Jia Yu
- Department of Hepatobiliary surgeryRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Kai Dai
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| |
Collapse
|
|
16
|
Chen X, Mohammed AF, Li C. Assessment of the Clinical Value of Platelet-to-Lymphocyte Ratio in Patients with Hepatocellular Carcinoma. Clin Appl Thromb Hemost 2024; 30:10760296231221535. [PMID: 38591958 PMCID: PMC11005495 DOI: 10.1177/10760296231221535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/30/2023] [Accepted: 12/03/2023] [Indexed: 04/10/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is associated with higher mortality as a result of poor prognosis and unavailability of effective treatment options. This study retrospectively analyzed the clinical value of platelet-to-lymphocyte ratio (PLR) to aid in differentiating early hepatocellular carcinoma from liver cirrhosis patients. Three hundred and nine (309) patients including 155 patients with hepatocellular carcinoma (HCC) and 154 patients with liver cirrhosis were enrolled in this study. General clinical characteristics and blood parameters of each patient were collected, calculated, and retrospectively analyzed. Mann-Whitney U test was calculated to compare the two groups. Receiver operating characteristics (ROC) curve was performed to investigate the diagnostic potential of PLR in the prediction of HCC at a cut-off with high accuracy (area under the curve [AUC]) > 0.80. Hemoglobin (HB) concentration, red blood cell (RBC) count, neutrophil (NEU) count, platelet count, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were significantly higher in the HCC patients than in the liver cirrhosis patients (p < 0.05). ROC curve analysis showed that the AUC, optimal cut-off value, sensitivity, and specificity of PLR to predict HCC patients were 0.912, 98.7, 81.2%, and 80.6% respectively. The results suggest that PLR is a potential biomarker that can be used to predict early HCC.
Collapse
Affiliation(s)
- Xu Chen
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
| | - Abdul Fatawu Mohammed
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
| | - Chengbin Li
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
| |
Collapse
|
|
17
|
Aida T, Haruki K, Akaoka M, Furukawa K, Onda S, Shirai Y, Shiozaki H, Takahashi K, Oikawa T, Ikegami T. A novel combined C-reactive protein-albumin ratio and modified albumin-bilirubin score can predict long-term outcomes in patients with hepatocellular carcinoma after hepatic resection. Ann Gastroenterol Surg 2024; 8:143-150. [PMID: 38250682 PMCID: PMC10797842 DOI: 10.1002/ags3.12727] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 07/15/2023] [Accepted: 07/27/2023] [Indexed: 01/23/2024] Open
Abstract
Background Systemic inflammatory response represented by C-reactive protein and albumin ratio (CAR) and modified albumin-bilirubin (mALBI) grade both have been associated with long-term outcome in patients with hepatocellular carcinoma (HCC). In this study, we investigated the prognostic utility of combined score of CAR and mALBI score to predict the prognosis of HCC patients after hepatic resection. Methods This study included 214 patients who had undergone primary hepatic resection for HCC between 2008 and 2018. Systemic inflammatory response and mALBI were evaluated preoperatively and patients were classified into three groups based on the combination of CAR and mALBI score: low CAR and low mALBI grade (score 0), either high CAR or high mALBI grade (score 1), and both high CAR and high mALBI grade ≥2b (score 2). Multivariate Cox proportional hazard models were conducted to assess disease-free and overall survival. Results In multivariate analysis, sex (p < 0.01), HBsAg positivity (p < 0.01), serum AFP level ≥20 ng/mL (p < 0.01), microvascular invasion (p = 0.02), multiple tumors (p < 0.01), type of resection (p < 0.01), and CAR-mALBI score ≥2 (HR 2.19, 95% CI 1.39-3.44, p < 0.01) were independent prognostic factors of disease-free survival, while sex (p = 0.01), HBsAg positivity (p < 0.01), poor tumor differentiation (p = 0.03), multiple tumors (p < 0.01), CAR-mALBI score ≥2 (HR 2.70, 95% CI 1.51-4.83, p < 0.01) were independent prognostic factors of overall survival. Conclusions CAR-mALBI score is associated with disease-free and overall survival in patients with HCC after hepatic resection, suggesting the importance of evaluating both hepatic functional reserve and host-inflammatory state in the risk assessment of HCC patients.
Collapse
Affiliation(s)
- Takashi Aida
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Koichiro Haruki
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Munetoshi Akaoka
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Kenei Furukawa
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Shinji Onda
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Yoshihiro Shirai
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Hironori Shiozaki
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Keita Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| |
Collapse
|
|
18
|
Zhou H, Zheng H, Wang Y, Lao M, Shu H, Huang M, Ou C. Nomogram for Predicting Postoperative Pulmonary Metastasis in Hepatocellular Carcinoma Based on Inflammatory Markers. Cancer Control 2024; 31:10732748241236333. [PMID: 38425007 PMCID: PMC10908236 DOI: 10.1177/10732748241236333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 01/14/2024] [Accepted: 02/08/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Uncertainty surrounds the usefulness of inflammatory markers in hepatocellular carcinoma (HCC) patients for predicting postoperative pulmonary metastasis (PM). The purpose of this study was to assess the predictive value of inflammatory markers as well as to create a new nomogram model for predicting PM. METHODS Cox regression was utilized to identify independent prognostic variables and to create a nomogram that predicted PM for comparison with a validation cohort and other prediction systems. We retrospectively analyzed a total of 1109 cases with HCC were included. RESULTS The systemic inflammatory response index (SIRI) and aspartate aminotransferase-to-platelet ratio index (APRI) were independent risk factors for PM, with a concordance index of .78 (95% CI: .74-.81) for the nomogram. The areas under the curve of the nomograms for PM predicted at 1-, 3-, and 5-year were .82 (95% CI: .77-.87), .82 (95% CI: .78-.87) and .81 (95% CI: .75-.86), respectively, which were better than those of Barcelona Clinic Liver Cancer and China liver cancer stage. Decision curve analyses demonstrated a broader range of nomogram threshold probabilities. CONCLUSION A nomogram based on SIRI and APRI can accurately predict postoperative PM in HCC.
Collapse
Affiliation(s)
- Huanjie Zhou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
| | - Haiping Zheng
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Ying Wang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
| | - Ming Lao
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
| | - Hong Shu
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
| | - Meifang Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
| | - Chao Ou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
| |
Collapse
|
|
19
|
Lin KY, Chen QJ, Tang SC, Lin ZW, Zhang JX, Zheng SM, Li YT, Wang XM, Lu Q, Fu J, Guo LB, Zheng LF, You PH, Wu MM, Lin KC, Zhou WP, Yang T, Zeng YY. Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients. BMC Cancer 2023; 23:1190. [PMID: 38053048 PMCID: PMC10696803 DOI: 10.1186/s12885-023-11693-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/28/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP). METHODS Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging. RESULTS Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages. CONCLUSION The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system.
Collapse
Affiliation(s)
- Kong-Ying Lin
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Qing-Jing Chen
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Shi-Chuan Tang
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Zhi-Wen Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Jian-Xi Zhang
- Department of Hepatobiliary Surgery, Xiamen Hospital, Beijing University of Chinese Medicine, Xiamen, 361000, China
| | - Si-Ming Zheng
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Ningbo University, Ningbo, 315000, China
| | - Yun-Tong Li
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, 361000, China
| | - Xian-Ming Wang
- Department of General Surgery, First Affiliated Hospital of Shandong First Medical University, Shandong, 250014, China
| | - Qiang Lu
- Department of Hepatopancreatobiliary Surgery, Third Hospital of Zhangzhou, Zhangzhou, 363000, China
| | - Jun Fu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Luo-Bin Guo
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Li-Fang Zheng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Peng-Hui You
- Biobank in Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Meng-Meng Wu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Ke-Can Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Wei-Ping Zhou
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, 200000, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, 200000, China.
| | - Yong-Yi Zeng
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China.
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China.
- Liver Disease Research Center of Fujian Province, Fuzhou, 350000, China.
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China.
| |
Collapse
|
|
20
|
Qin Q, Kou X, Zheng Y, Zhou F, Zhang X, Liu H. Early C-reactive Protein Kinetics Predict Response to Immune Checkpoint Blockade in Unresectable Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:2009-2019. [PMID: 37954495 PMCID: PMC10637213 DOI: 10.2147/jhc.s432054] [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: 08/24/2023] [Accepted: 10/24/2023] [Indexed: 11/14/2023] Open
Abstract
Purpose In recent years, a new therapeutic approach, known as immune checkpoint blockade (ICB), has been proposed as approach to improve outcomes in patients with intermediate stage (Barcelona Clinic Liver Cancer, BCLC B) or advanced stage (BCLC C) hepatocellular carcinoma (HCC). Unfortunately, only a select patients can benefit from ICB. Hence, biomarkers that can predict the success and survival of treatment are still necessary. Patients and Methods Between 2018 to 2021, 132 patients received ICB treatment for intermediate or advanced stage HCC. Based on the early kinetics of C-reactive protein (CRP), the patients were classified into three groups. The study endpoints were progression-free survival (PFS) and overall survival (OS). Results Our findings support the predictive power of early CRP kinetics in determining immunotherapy response for intermediate or advanced HCC. Objective response rates (ORR) were found in 41.2% of CRP flare-responders, 13.3% of CRP responders, and 3.5% of CRP non-responders (p<0.001). Disease control rates (DCR) in the three groups were substantially different (p<0.001). The improved PFS and OS were strongly correlated with the early kinetics of CRP. Compared to CRP non-responders, CRP responders, especially CRP flare-responders, had significantly longer PFS (median PFS: CRP flare-responders: 11.6 months vs CRP responders: 5.2 months vs CRP non-responders: 2.3 months, p<0.001). Conclusion The CRP flare response robustly predicts the immunotherapy response and outcomes in patients with HCC. Early CRP kinetics may be an inexpensive, easily implemented and non-invasive biomarker to anticipate response to ICB therapy in intermediate or advanced HCC, with the potential to optimize treatment monitoring.
Collapse
Affiliation(s)
- Qiuying Qin
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, People’s Republic of China
| | - Xiaoxuan Kou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, People’s Republic of China
| | - Yuanyuan Zheng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, People’s Republic of China
| | - Fei Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, People’s Republic of China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, People’s Republic of China
| | - Hongyan Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, People’s Republic of China
| |
Collapse
|
|
21
|
Xu Q, Ying H, Xie C, Lin R, Huang Y, Zhu R, Liao Y, Zeng Y, Yu F. Characterization of neutrophil extracellular traps related gene pair for predicting prognosis in hepatocellular carcinoma. J Gene Med 2023; 25:e3551. [PMID: 37401256 DOI: 10.1002/jgm.3551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/26/2023] [Accepted: 05/24/2023] [Indexed: 07/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a malignant disease with a high incidence rate, high mortality and poor prognosis. Neutrophil extracellular traps (NETs), as an extracellular reticular structure, promote the development and progression of cancer in the tumor microenvironment, and have a promising prospect as a prognostic indicator. In the present study, we elucidated the prognostic value of NET-related genes. METHODS The NETs gene pair of The Cancer Genome Atlas cohort was constructed by least absolute shrinkage and selection operator analysis. Samples from the International Cancer Genome Consortium were performed to verify its feasibility. Kaplan-Meier analysis was used to compare the overall survival (OS) rate of the two subgroups. The independent predictors of OS were determined by univariate and multivariate Cox analysis. Furthermore, Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway were analyzed by gene set enrichment analysis. The single sample gene set enrichment analysis method was performed to deplore the relationship of risk score with tumor immune microenvironment. The GSE149614 dataset was applied as single cell RNA level validation. PCR was performed to the detect mRNA expression profiles of NETs-related genes. RESULTS Our analysis of the NETs-related model provides a promising prospect as a prognostic indicator. The OS of high-risk group patients was significantly reduced. The risk score was an important independent predictor of HCC prognosis. The Nomogram model suggested a favorable classification performance. The drug resistance and sensitivity of tumor cells to chemotherapeutics was significantly correlated with the prognostic gene expression. The immune status of the two risk groups showed a marked difference. CONCLUSIONS The novel prognostic gene pair and immune landscape could predict the prognosis of HCC patients and provide a new understanding of immunotherapy in HCC.
Collapse
Affiliation(s)
- Qian Xu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huiya Ying
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chunming Xie
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rong Lin
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yangjin Huang
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ruhuang Zhu
- Department of Neurology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuejuan Liao
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuan Zeng
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fujun Yu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| |
Collapse
|
|
22
|
Li J, Su X, Xu X, Zhao C, Liu A, Yang L, Song B, Song H, Li Z, Hao X. Preoperative prediction and risk assessment of microvascular invasion in hepatocellular carcinoma. Crit Rev Oncol Hematol 2023; 190:104107. [PMID: 37633349 DOI: 10.1016/j.critrevonc.2023.104107] [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: 05/24/2023] [Accepted: 08/22/2023] [Indexed: 08/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and highly lethal tumors worldwide. Microvascular invasion (MVI) is a significant risk factor for recurrence and poor prognosis after surgical resection for HCC patients. Accurately predicting the status of MVI preoperatively is critical for clinicians to select treatment modalities and improve overall survival. However, MVI can only be diagnosed by pathological analysis of postoperative specimens. Currently, numerous indicators in serology (including liquid biopsies) and imaging have been identified to effective in predicting the occurrence of MVI, and the multi-indicator model based on deep learning greatly improves accuracy of prediction. Moreover, several genes and proteins have been identified as risk factors that are strictly associated with the occurrence of MVI. Therefore, this review evaluates various predictors and risk factors, and provides guidance for subsequent efforts to explore more accurate predictive methods and to facilitate the conversion of risk factors into reliable predictors.
Collapse
Affiliation(s)
- Jian Li
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China; Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Xin Su
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China; Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Xiao Xu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China; Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Changchun Zhao
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China; Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Ang Liu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China; Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Liwen Yang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China
| | - Baoling Song
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China
| | - Hao Song
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China
| | - Zihan Li
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou 730000, China
| | - Xiangyong Hao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China.
| |
Collapse
|
|
23
|
Baima G, Ribaldone DG, Romano F, Aimetti M, Romandini M. The Gum-Gut Axis: Periodontitis and the Risk of Gastrointestinal Cancers. Cancers (Basel) 2023; 15:4594. [PMID: 37760563 PMCID: PMC10526746 DOI: 10.3390/cancers15184594] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/01/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Periodontitis has been linked to an increased risk of various chronic non-communicable diseases, including gastrointestinal cancers. Indeed, dysbiosis of the oral microbiome and immune-inflammatory pathways related to periodontitis may impact the pathophysiology of the gastrointestinal tract and its accessory organs through the so-called "gum-gut axis". In addition to the hematogenous spread of periodontal pathogens and inflammatory cytokines, recent research suggests that oral pathobionts may translocate to the gastrointestinal tract through saliva, possibly impacting neoplastic processes in the gastrointestinal, liver, and pancreatic systems. The exact mechanisms by which oral pathogens contribute to the development of digestive tract cancers are not fully understood but may involve dysbiosis of the gut microbiome, chronic inflammation, and immune modulation/evasion, mainly through the interaction with T-helper and monocytic cells. Specifically, keystone periodontal pathogens, including Porphyromonas gingivalis and Fusobacterium nucleatum, are known to interact with the molecular hallmarks of gastrointestinal cancers, inducing genomic mutations, and promote a permissive immune microenvironment by impairing anti-tumor checkpoints. The evidence gathered here suggests a possible role of periodontitis and oral dysbiosis in the carcinogenesis of the enteral tract. The "gum-gut axis" may therefore represent a promising target for the development of strategies for the prevention and treatment of gastrointestinal cancers.
Collapse
Affiliation(s)
- Giacomo Baima
- Department of Surgical Sciences, University of Turin, 10125 Torino, Italy; (G.B.); (F.R.); (M.A.)
| | | | - Federica Romano
- Department of Surgical Sciences, University of Turin, 10125 Torino, Italy; (G.B.); (F.R.); (M.A.)
| | - Mario Aimetti
- Department of Surgical Sciences, University of Turin, 10125 Torino, Italy; (G.B.); (F.R.); (M.A.)
| | - Mario Romandini
- Department of Periodontology, Faculty of Dentistry, University of Oslo, 0313 Oslo, Norway
| |
Collapse
|
|
24
|
Chen S, Shen B, Wu Y, Shen L, Qi H, Cao F, Huang T, Tan H, Wen C, Fan W. The relationship between the efficacy of thermal ablation and inflammatory response and immune status in early hepatocellular carcinoma and the progress of postoperative adjuvant therapy. Int Immunopharmacol 2023; 119:110228. [PMID: 37121111 DOI: 10.1016/j.intimp.2023.110228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/10/2023] [Accepted: 04/20/2023] [Indexed: 05/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease. Thermal ablation has the advantages of being equivalent to surgical resection, minimally invasive, low cost and significantly reducing hospital stay. Therefore, it is recommended as one of the first-line radical treatment for early HCC. However, with the deepening of research on early HCC, more and more studies have found that not all patients with early HCC can obtain similar efficacy after radical thermal ablation, which may be related to the heterogeneity of HCC. Previous studies have shown that inflammation and immunity play an extremely important role in the prognostic heterogeneity of patients with HCC. Therefore, the inflammatory response and immune status of patients may be closely related to the efficacy of early HCC after curative thermal ablation. This article elaborates the mechanism of high inflammatory response and poor immune status in the poor prognosis after radical thermal ablation of early HCC, and clarifies the population who may benefit from adjuvant therapy after radical thermal ablation in patients with early HCC, which provides a new idea for the precise adjuvant treatment after radical ablation of early HCC in the future.
Collapse
Affiliation(s)
- Shuanggang Chen
- Department of Oncology, Yuebei People's Hospital, Shantou University Medical College, Shaoguan 512025, Guangdong, People's Republic of China; Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.
| | - Binyan Shen
- Department of Nursing, Medical College of Shaoguan University, Shaoguan 512026, People's Republic of China
| | - Ying Wu
- Department of Interventional Therapy, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Lujun Shen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Han Qi
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Fei Cao
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Tao Huang
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Hongtong Tan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Chunyong Wen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Weijun Fan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China.
| |
Collapse
|
|
25
|
Yang M, Pan Y, Wang W. Prognostic significance of the CRAFITY score in hepatocellular carcinoma treated with immunotherapy: a systematic review and meta-analysis. BMC Cancer 2023; 23:236. [PMID: 36915049 PMCID: PMC10012550 DOI: 10.1186/s12885-023-10686-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 02/28/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND This meta-analysis aimed to assess the performance of the CRAFITY (CRP and AFP in immunotherapy) score as a prognostic factor in hepatocellular carcinoma (HCC) treated with immunotherapy. METHODS The PubMed, Cochrane Library, and Web of Science databases were searched for published studies. Hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) outcomes were pooled using fixed- and random-effects models. Odds ratios (ORs) with 95% CI were used to measure the association of individual CRAFITY scores with the disease control rate (DCR). RESULTS Four eligible studies comprising 786 patients were included. The results indicate that a lower CRAFITY score is a significant predictor of better OS (HR = 0.22, 95% CI: 0.10-0.50) and PFS (HR = 0.36, 95% CI: 0.23-0.55) outcomes. In addition, the DCR was significantly higher in patients with lower CRAFITY scores (OR = 3.16, 95% CI: 2.00-4.99). A significant positive association between low CRAFITY scores and favorable prognoses was also observed in Barcelona Clinic Liver Cancer stage B/C/D patients. CONCLUSION In this study, a low CRAFITY score was associated with better overall outcomes in HCC patients treated with immunotherapy. However, this finding requires further investigation.
Collapse
Affiliation(s)
- Ming Yang
- Department of Liver Surgery, West China Hospital, Sichuan University, 610000, Chengdu, P. R. China
| | - Yilin Pan
- Department of Liver Surgery, West China Hospital, Sichuan University, 610000, Chengdu, P. R. China
| | - Wentao Wang
- Department of Liver Surgery, West China Hospital, Sichuan University, 610000, Chengdu, P. R. China.
| |
Collapse
|
|
26
|
Ait-Ahmed Y, Lafdil F. Novel insights into the impact of liver inflammatory responses on primary liver cancer development. LIVER RESEARCH 2023; 7:26-34. [PMID: 39959704 PMCID: PMC11791919 DOI: 10.1016/j.livres.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/05/2022] [Accepted: 01/27/2023] [Indexed: 03/10/2023]
Abstract
Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.
Collapse
Affiliation(s)
- Yeni Ait-Ahmed
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
| | - Fouad Lafdil
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
- Institut Universitaire de France (IUF), Paris, France
| |
Collapse
|
|
27
|
Lv Z, Li H, Yuan Y, Wu Q. A novel inflammasome-related gene nomogram predicts survival in hepatocellular carcinoma. Medicine (Baltimore) 2023; 102:e33121. [PMID: 36827012 PMCID: PMC11309600 DOI: 10.1097/md.0000000000033121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 02/04/2023] [Accepted: 02/08/2023] [Indexed: 02/25/2023] Open
Abstract
Inflammasomes are closely associated with the progression of multiple cancers. We established an inflammasome-related gene (IRG)-based model to predict the survival of patients with hepatocellular carcinoma (HCC). The RNA-sequencing data and clinical information of HCC patients were downloaded from the cancer genome atlas-liver hepatocellular carcinoma database, and the differentially expressed inflammasome-related gene were screened. Seven prognostic differentially expressed inflammasome-related genes were identified by univariate Cox analysis and incorporated into the risk model using least absolute shrinkage and selection operator-Cox algorithm. The predictive accuracy of the risk model was evaluated through the Kaplan-Meier, receiver operating characteristic and Cox regression analyses. The performance of the model was verified in the International Cancer Genome Consortium-Liver Cancer - RIKEN, JP cohort. A nomogram was constructed to predict the 1-, 2-, 3- ,and 5-year survival of HCC patients, and its performance was evaluated using calibration curves. The significantly enriched gene ontology terms, Kyoto encyclopedia of genes and genomes pathways and infiltrating immune cell populations associated with the IRG model were also analyzed to explore of the potential molecular mechanisms and immunotherapeutic targets. An independent and highly accurate prognostic model consisting of 7 IRGs was established and verified in 2 independent HCC cohorts. The IRG model was significantly associated with cell division and cell cycle. In addition, the high-risk group was more likely to have greater infiltration of immune cells and higher expression of immune checkpoint-related genes compared to the low-risk group. An IRG-based model was established to predict 1-, 2-, 3-, and 5-year survival rate in individual HCC patients, which provides new insights into the role of inflammasomes in HCC.
Collapse
Affiliation(s)
- Zhengqi Lv
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, P.R. China
| | - Heng Li
- Guizhou Medical University, Guiyang, Guizhou, P.R. China
| | - Yiwen Yuan
- Guizhou Medical University, Guiyang, Guizhou, P.R. China
| | - Qinghua Wu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, P.R. China
- Department of Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, P.R. China
| |
Collapse
|
|
28
|
Haruki K, Taniai T, Yanagaki M, Furukawa K, Tsunematsu M, Onda S, Shirai Y, Matsumoto M, Okui N, Ikegami T. Sustained Systemic Inflammatory Response Predicts Survival in Patients with Hepatocellular Carcinoma After Hepatic Resection. Ann Surg Oncol 2023; 30:604-613. [PMID: 36059035 DOI: 10.1245/s10434-022-12464-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/08/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Preoperative systematic inflammatory response, represented by neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein-albumin ratio (CAR), has been associated with long-term outcomes in patients with hepatocellular carcinoma (HCC). However, the impact of sustained systematic inflammatory response after resection remains unclear. METHODS This study comprised 210 patients who had undergone primary hepatic resection for HCC between 2008 and 2018. Preoperative and postoperative NLR, LMR, and CAR were evaluated, and patients were then classified into three groups according to the status of each marker: persistently high inflammatory state (elevated group), preoperatively low inflammatory state (normal group), and preoperatively high but postoperatively low inflammatory state (normalized group). Multivariate Cox proportional hazard models were conducted to assess disease-free and overall survival, adjusting for potential confounders. RESULTS In multivariate analysis, sex (p = 0.002), hepatitis B surface antigen (HBsAg) positivity (p = 0.002), serum α-fetoprotein (AFP) level ≥ 20 ng/mL (p < 0.001), multiple tumors (p < 0.001), microvascular invasion (p = 0.003), type of resection (p = 0.007), and elevated CAR (hazard ratio [HR] 2.40, 95% confidence interval [CI] 1.55-3.73; p < 0.001) were independent and significant predictors of cancer recurrence, while sex (p = 0.05), HBsAg positivity (p = 0.03), serum AFP level ≥20 ng/mL (p = 0.009), multiple tumors (p = 0.03), microvascular invasion (p = 0.006), and elevated CAR (HR 2.10, 95% CI 1.13-3.91; p = 0.02) were independent predictors of overall survival. CONCLUSIONS Sustained elevated CAR may be an independent and significant indicator of poor long-term outcomes in patients with HCC after hepatic resection, suggesting the interplay of the host's inflammatory state and tumor recurrence and progression in HCC.
Collapse
Affiliation(s)
- Koichiro Haruki
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
| | - Tomohiko Taniai
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Mitsuru Yanagaki
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kenei Furukawa
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Masashi Tsunematsu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Shinji Onda
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshihiro Shirai
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Michinori Matsumoto
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Norimitsu Okui
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
29
|
Yassine M, Hassan SA, Sommer S, Yücel LA, Bellert H, Hallenberger J, Sohn D, Korf HW, von Gall C, Ali AAH. Radiotherapy of the Hepatocellular Carcinoma in Mice Has a Time-Of-Day-Dependent Impact on the Mouse Hippocampus. Cells 2022; 12:cells12010061. [PMID: 36611854 PMCID: PMC9818790 DOI: 10.3390/cells12010061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/18/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Chronic liver diseases including hepatocellular carcinoma (HCC) create a state of chronic inflammation that affects the brain via the liver-brain axis leading to an alteration of neurotransmission and cognition. However, little is known about the effects of HCC on the hippocampus, the key brain region for learning and memory. Moreover, radiotherapy used to treat HCC has severe side effects that impair patients' life quality. Thus, designing optimal strategies, such as chronotherapy, to enhance the efficacy and reduce the side effects of HCC treatment is critically important. We addressed the effects of HCC and the timed administration of radiotherapy in mice on the expression of pro-inflammatory cytokines, clock genes, markers for glial activation, oxidative stress, neuronal activity and proliferation in the hippocampal neurogenic niche. Our data showed that HCC induced the upregulation of genes encoding for pro-inflammatory cytokines, altered clock gene expressions and reduced proliferation in the hippocampus. Radiotherapy, in particular when applied during the light/inactive phase enhanced all these effects in addition to glial activation, increased oxidative stress, decreased neuronal activity and increased levels of phospho(p)-ERK. Our results suggested an interaction of the circadian molecular clockwork and the brain's innate immune system as key players in liver-brain crosstalk in HCC and that radiotherapy when applied during the light/inactive phase induced the most profound alterations in the hippocampus.
Collapse
Affiliation(s)
- Mona Yassine
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Soha A. Hassan
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
- Zoology Department, Faculty of Science, Suez University, Cairo-Suez Road, Suez 43533, Egypt
| | - Simon Sommer
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Lea Aylin Yücel
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Hanna Bellert
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Johanna Hallenberger
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Dennis Sohn
- Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty, Heinrich-Heine-University, Universität Strasse 1, 40225 Düsseldorf, Germany
| | - Horst-Werner Korf
- Institute of Anatomy I, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Charlotte von Gall
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
- Correspondence: ; Tel.: +49-21-1811-5046
| | - Amira A. H. Ali
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
- Department of Human Anatomy and Embryology, Medical Faculty, Mansoura University, El-Gomhoria St. 1, Mansoura 35516, Egypt
| |
Collapse
|
|
30
|
Wu YL, Fulgenzi CAM, D’Alessio A, Cheon J, Nishida N, Saeed A, Wietharn B, Cammarota A, Pressiani T, Personeni N, Pinter M, Scheiner B, Balcar L, Huang YH, Phen S, Naqash AR, Vivaldi C, Salani F, Masi G, Bettinger D, Vogel A, Schönlein M, von Felden J, Schulze K, Wege H, Galle PR, Kudo M, Rimassa L, Singal AG, Sharma R, Cortellini A, Gaillard VE, Chon HJ, Pinato DJ, Ang C. Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Prognostic Biomarkers in Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab. Cancers (Basel) 2022; 14:5834. [PMID: 36497316 PMCID: PMC9737420 DOI: 10.3390/cancers14235834] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22−3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation.
Collapse
Affiliation(s)
- Yue Linda Wu
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Claudia Angela Maria Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
- Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Antonio D’Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Jaekyung Cheon
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 46371, Republic of Korea
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan
| | - Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66160, USA
| | - Brooke Wietharn
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66160, USA
| | - Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 71150, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
| | - Samuel Phen
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Abdul Rafeh Naqash
- Medical Oncology/TSET Phase 1 Program, Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA
| | - Caterina Vivaldi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56124 Pisa, Italy
| | - Francesca Salani
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Sant’Anna School of Advanced Studies, 56127 Pisa, Italy
| | - Gianluca Masi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56124 Pisa, Italy
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Dominik Bettinger
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
| | - Martin Schönlein
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Johann von Felden
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Kornelius Schulze
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Henning Wege
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Peter R. Galle
- I. Department of Internal Medicine, University Medical Center Mainz, 55131 Mainz, Germany
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Amit G. Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Rohini Sharma
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
| | - Alessio Cortellini
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
| | | | - Hong Jae Chon
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 46371, Republic of Korea
| | - David J. Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
| | - Celina Ang
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| |
Collapse
|
|
31
|
Yang Z, Zhang D, Zeng H, Fu Y, Hu Z, Pan Y, Chen J, Wang J, Zhang Y, Zhou Z, Xu L, Hu D, Chen M. Inflammation-Based Scores Predict Responses to PD-1 Inhibitor Treatment in Intrahepatic Cholangiocarcinoma. J Inflamm Res 2022; 15:5721-5731. [PMID: 36238770 PMCID: PMC9553318 DOI: 10.2147/jir.s385921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Purpose Inflammatory response is related to tumor progression and patient survival. We aimed to clarify the prognostic value of the inflammation-based scores in intrahepatic cholangiocarcinoma (ICC) patients receiving anti-PD1 therapy. Patients and Methods A total of 73 patients who received anti-PD-1 therapy from February 2019 to February 2021 were included in the study. Representative inflammation-based prognostic scores, including C-reactive protein (CRP), the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-CRP ratio (LCR), lymphocyte-to-monocyte ratio (LMR), systemic immune inflammation index (SII), CRP-to-albumin ratio (CAR), prognostic nutritional index (PNI), Glasgow Prognostic Score (GPS), and prognostic index (PI), were assessed for prediction accuracy using Kaplan–Meier survival curves and time-dependent receiver operating characteristic (ROC). All the ten inflammation-based prognostic scores were measured before receiving anti-PD1 therapy. Results All the ten inflammation-based prognostic scores showed good discriminatory ability in terms of overall survival (OS) (all P < 0.01), the higher the score, the worse the prognosis, while the CRP score was a remarkable independent predictor for OS in multivariate analysis (hazard ratio, 6.032; confidence interval, 2.467–14.752; P < 0.001). The area under the ROC curve at 6 months, 12 months, 18 months and 24 months consistently demonstrated that the predictive value of the CRP score was superior to other inflammation-based scores. Conclusion Inflammation-based scores predict the efficacy of anti-PD-1 therapy in patients with ICC and CRP score superior to the other inflammation-based prognostic scores in terms of predictive ability.
Collapse
Affiliation(s)
- Zhenyun Yang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Deyao Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Huilan Zeng
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Yizhen Fu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Zili Hu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Yangxun Pan
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Jinbin Chen
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Juncheng Wang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Yaojun Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Zhongguo Zhou
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Li Xu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| | - Dandan Hu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China,Correspondence: Dandan Hu; Minshan Chen, Tel +86-20-87343828; +86-20-87343117, Fax +86-20-87343585, Email ;
| | - Minshan Chen
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China
| |
Collapse
|
|
32
|
Kaprin AD, Sergeeva NS, Shegai PV, Alekseev BY. Oncology during the New Coronavirus Infection Pandemic. HERALD OF THE RUSSIAN ACADEMY OF SCIENCES 2022; 92:456-463. [PMID: 36091860 PMCID: PMC9447986 DOI: 10.1134/s1019331622040141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 06/15/2023]
Abstract
The COVID-19 pandemic has served as a catalyst for a whole layer of scientific research, including in Russia, where, since 2020, international multicenter studies have been conducted on the impact of the coronavirus infection on the course of oncological diseases, as well as on the development and application of new clinical methods in oncology. In the years 2020-2022, new methods of nuclear medicine based on the targeted effect of ionizing radiation of radiopharmaceuticals began to be actively developed, in particular, new domestic radiopharmaceuticals (RPs) for diagnostics and therapy and methods of intra-arterial radioembolization developed by RPs with 90Y and 188Re of primary and metastatic tumors of various localization. New methods of radiation therapy have been introduced into clinical practice, including remote radiation therapy with "fast" neutrons, which makes it possible to overcome the resistance of a tumor to radiation and drug treatment. In addition, the search for and introduction into clinical practice of new approaches in the field of gene therapy and the use of oncolytic viruses continues. Platforms for complex pharmacogenomic analysis based on global knowledge and deep machine learning are being used in Russia, allowing for the precise selection of the most effective therapy. New multidisciplinary technologies are being developed.
Collapse
Affiliation(s)
- A. D. Kaprin
- National Medical Research Radiological Center (NMRRC), Ministry of Health of the Russian Federation, Obninsk, Russia
| | - N. S. Sergeeva
- National Medical Research Radiological Center (NMRRC), Ministry of Health of the Russian Federation, Obninsk, Russia
| | - P. V. Shegai
- National Medical Research Radiological Center (NMRRC), Ministry of Health of the Russian Federation, Obninsk, Russia
| | - B. Ya. Alekseev
- National Medical Research Radiological Center (NMRRC), Ministry of Health of the Russian Federation, Obninsk, Russia
| |
Collapse
|
|
33
|
Zhao Y, Jia Y, Qi S, Wu C, Wu J, Zhang R, Li J, Guo Z. Comparison of Postoperative Prognosis Among HBV-Related, HCV-Related, and Non-HBV Non-HCV Hepatocellular Carcinomas: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2022; 22. [DOI: 10.5812/hepatmon-121820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 01/03/2025]
Abstract
Context: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and different hepatitis viruses might affect the prognosis of patients with HCC. Objectives: This study aimed to reveal the differences in the postoperative prognosis of patients with hepatitis B virus-related HCC (HBV-HCC), hepatitis C virus-related HCC (HCV-HCC), and non-HBV non-HCV hepatocellular carcinoma (NBNC-HCC). Methods: The databases PubMed, Embase, Cochrane, Web of Science, and Scopus were searched for articles published until April 2022. Stata software version 12 and Review Manager version 5.4 were used to conduct the meta-analysis, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was adopted in this study. Results: In the present study, 26 papers on a total of 20381 participants who met the inclusion criteria were analyzed. The 5-year overall survival in the HBV-HCC and HCV-HCC groups was lower than in the NBNC-HCC group (HBV-HCC vs. NBNC-HCC, P = 0.005; HCV-HCC vs. NBNC-HCC, P = 0.001). Patients with HBV-HCC and HCV-HCC had worse 5-year recurrence-free survival than patients with NBNC-HCC (HBV-HCC vs. NBNC-HCC, P = 0; HCV-HCC vs. NBNC-HCC, P = 0). In addition, the 5-year recurrence-free rate in the HCV-HCC group was lower than in the HBV-HCC group (P = 0). The observed association between serum alpha-fetoprotein levels and the postoperative prognosis was inconsistent in different subgroups. Conclusions: Patients with NBNC-HCC had a significantly better postoperative prognosis than those with virus-related HCC. The alpha-fetoprotein levels significantly correlated with the postoperative prognosis of patients with HCC.
Collapse
|
|
34
|
Kornberg A, Kaschny L, Kornberg J, Friess H. Preoperative Prognostic Nutritional Index May Be a Strong Predictor of Hepatocellular Carcinoma Recurrence Following Liver Transplantation. J Hepatocell Carcinoma 2022; 9:649-660. [PMID: 35923612 PMCID: PMC9342250 DOI: 10.2147/jhc.s366107] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/23/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose Malnutrition is a major risk factor of immune dysfunction and poor outcome in cancer patients. The prognostic nutritional index (PNI), which is established by serum albumin level and peripheral lymphocyte count, was shown to correlate with prognosis of hepatocellular carcinoma (HCC) patients following liver resection and non-surgical interventions. The aim of this study was to analyze the predictive value of preoperative PNI in liver transplantation (LT) patients with HCC. Patients and Methods A total of 123 HCC patients that underwent LT were included in the analysis. The prognostic impact of preoperatively assessed clinical factors including the PNI on post-LT outcome was analyzed by uni- and multivariate analysis. Results Post-transplant tumor recurrence rates were 5.1% in high-PNI (> 42) and 55.6% in low-PNI (≤ 42) patients (p < 0.001). Preoperative high-PNI could be identified as a significant and independent promoter of both recurrence-free survival (hazard ratio [HR] = 10.12, 95% CI: 3.40–30.10; p < 0.001) and overall survival (HR = 1.69, 95% CI: 1.02–2.79; p = 0.004) following LT. Apart from that low-PNI proved to be a significant and independent predictor of microvascular tumor invasion (OR = 7.71, 95% CI: 3.17–18.76; p < 0.001). In contrast, no tumor morphology features including the Milan criteria revealed an independent prognostic value. Conclusion Our data indicate that preoperative PNI correlates with biological tumor aggressiveness and outcome following LT in HCC patients and may therefore be useful for refining oncologic risk stratification.
Collapse
Affiliation(s)
- Arno Kornberg
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
- Correspondence: Arno Kornberg, Technical University of Munich, Medical School, Klinikum rechts der Isar, Department of Surgery, Ismaningerstr. 22, Munich, D-81675, Germany, Tel +49 89 41405087, Fax +49 89 41404884, Email
| | - Linda Kaschny
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Jennifer Kornberg
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Helmut Friess
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| |
Collapse
|
|
35
|
A novel epithelial-mesenchymal transition gene signature for the immune status and prognosis of hepatocellular carcinoma. Hepatol Int 2022; 16:906-917. [PMID: 35699863 PMCID: PMC9349121 DOI: 10.1007/s12072-022-10354-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/06/2022] [Indexed: 12/11/2022]
Abstract
Background This study clarified whether EMT-related genes can predict immunotherapy efficacy and overall survival in patients with HCC. Methods The RNA-sequencing profiles and patient information of 370 samples were derived from the Cancer Genome Atlas (TCGA) dataset, and EMT-related genes were obtained from the Molecular Signatures database. The signature model was constructed using the least absolute shrinkage and selection operator Cox regression analysis in TCGA cohort. Validation data were obtained from the International Cancer Genome Consortium (ICGC) dataset of patients with HCC. Kaplan–Meier analysis and multivariate Cox analyses were employed to estimate the prognostic value. Immune status and tumor microenvironment were estimated using a single-sample gene set enrichment analysis (ssGSEA). The expression of prognostic genes was verified using qRT-PCR analysis of HCC cell lines. Results A signature model was constructed using EMT-related genes to determine HCC prognosis, based on which patients were divided into high-risk and low-risk groups. The risk score, as an independent factor, was related to tumor stage, grade, and immune cells infiltration. The results indicated that the most prognostic genes were highly expressed in the HCC cell lines, but GADD45B was down-regulated. Enrichment analysis suggested that immunoglobulin receptor binding and material metabolism were essential in the prognostic signature. Conclusion Our novel prognostic signature model has a vital impact on immune status and prognosis, significantly helping the decision-making related to the diagnosis and treatment of patients with HCC. Supplementary Information The online version contains supplementary material available at 10.1007/s12072-022-10354-3.
Collapse
|
|
36
|
Llovet JM, Singal AG, Villanueva A, Finn RS, Kudo M, Galle PR, Ikeda M, Callies S, McGrath LM, Wang C, Abada P, Widau RC, Gonzalez-Gugel E, Zhu AX. Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials. Clin Cancer Res 2022; 28:2297-2305. [PMID: 35247922 PMCID: PMC9662930 DOI: 10.1158/1078-0432.ccr-21-4000] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/19/2022] [Accepted: 03/02/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Ramucirumab is an effective treatment for patients with advanced hepatocellular carcinoma (aHCC) and baseline alpha-fetoprotein (AFP) ≥400 ng/mL. We aimed to identify prognostic and predictive factors of response to ramucirumab in patients with aHCC with AFP ≥400 ng/mL from the phase III REACH and REACH-2 randomized trials. PATIENTS AND METHODS Patients with aHCC, Child-Pugh class A with prior sorafenib treatment were randomized in REACH and REACH-2 (ramucirumab 8 mg/kg or placebo, biweekly). Meta-analysis of individual patient-level data (pooled population) from REACH (AFP ≥400 ng/mL) and REACH-2 was performed. A drug exposure analysis was conducted for those with evaluable pharmacokinetic data. To identify potential prognostic factors for overall survival (OS), multivariate analyses were performed using a Cox proportional hazards regression model. To define predictors of ramucirumab benefit, subgroup-by-treatment interaction terms were evaluated. RESULTS Of 542 patients (316 ramucirumab, 226 placebo) analyzed, eight variables had independent prognostic value associated with poor outcome (geographical region, Eastern Cooperative Oncology Group performance score ≥1, AFP >1,000 ng/mL, Child-Pugh >A5, extrahepatic spread, high neutrophil-to-lymphocyte ratio, high alkaline phosphatase and aspartate aminotransferase). Ramucirumab survival benefit was present across all subgroups, including patients with very aggressive HCC [above median AFP; HR: 0.64; 95% confidence interval (CI): 0.49-0.84] and nonviral aHCC (HR: 0.56; 95% CI: 0.40-0.79). While no baseline factor was predictive of a differential OS benefit with ramucirumab, analyses demonstrated an association between high drug exposure, treatment-emergent hypertension (grade ≥3), and increased ramucirumab benefit. CONCLUSIONS Ramucirumab provided a survival benefit irrespective of baseline prognostic covariates, and this benefit was greatest in patients with high ramucirumab drug exposure and/or those with treatment-related hypertension.
Collapse
Affiliation(s)
- Josep M. Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Catalonia, Spain
- Institució Catalana d'Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Richard S. Finn
- Division of Hematology/Oncology, University of California, Los Angeles, California
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Peter R. Galle
- Department of Internal Medicine, Mainz University Medical Center, Mainz, Germany
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | | | | | | | - Paolo Abada
- Eli Lilly and Company, Indianapolis, Indiana
| | | | | | - Andrew X. Zhu
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
- Jiahui International Cancer Center, Jiahui Health, Shanghai, P.R. China
| |
Collapse
|
|
37
|
A New Inflammation-Related Risk Model for Predicting Hepatocellular Carcinoma Prognosis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5396128. [PMID: 35572724 PMCID: PMC9098315 DOI: 10.1155/2022/5396128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 04/20/2022] [Indexed: 01/15/2023]
Abstract
Background Hepatocellular carcinoma (HCC) is characterized by a poor prognosis. Inflammation has a vital role in the formation and development of HCC. However, the prediction of HCC prognosis using inflammation-related genes (IRGs) remains elusive. In this study, we constructed a new IRG risk model to predict the HCC prognosis. Results HCC-related RNA expression profiles and their corresponding clinical data were downloaded from TCGA and ICGC databases to explore the IRGs' predicting ability. Seven hundred thirty-seven IRGs from GeneCards were used as candidate genes to construct the model. The associations of overall survival (OS) with IRGs were evaluated using the log-rank test and univariate Cox analysis, and 32 out of 737 IRGs showed predicting the potential for HCC prognosis. These IRGs were further analyzed using the least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses. Finally, 6 IRGs were included in an IRG risk model. Based on the cut-off of the risk score calculated according to the IRG risk model, HCC samples were divided into the high-risk and the low-risk groups. The OS of patients was lower in the high-risk group than in the low-risk group (P < 0.05). The area under the receiver operating characteristic curve (AUC) of the risk score was 0.78 for 3-year survival. Univariate Cox and multivariate Cox analyses revealed that the risk score was an independent risk factor for HCC prognosis. The KEGG and GO enrichment analysis results further showed that the risk scores were closely related to inflammatory and immune pathways. In addition, the ssGSEA demonstrated that several immune cells and some immune-related pathways were negatively correlated with the risk score. Conclusions The new IRG risk score was an independent risk factor for HCC prognosis and could be used to assess the immune status of the HCC microenvironment.
Collapse
|
|
38
|
Li Z, Liang L, Duan W, Zhou C, Yang JJ. Non-linear relationship of gamma-glutamyl transpeptidase to lymphocyte count ratio with the recurrence of hepatocellular carcinoma with staging I-II: a retrospective cohort study. Infect Agent Cancer 2022; 17:16. [PMID: 35395799 PMCID: PMC8991940 DOI: 10.1186/s13027-022-00428-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 03/22/2022] [Indexed: 12/24/2022] Open
Abstract
Background High recurrence rate was a major factor for the poor postoperative prognosis of hepatocellular carcinoma (HCC) patients. The present study was intended to evaluate the association of gamma-glutamyl transpeptidase to lymphocyte count ratio (GLR) and the recurrence of HCC with staging I–II in Chinese. Methods The retrospective cohort data was derived from the First Affiliated Hospital of Zhengzhou University from January 2014 to December 2018 on 496 patients who underwent radical resection of HCC with staging I–II. Multivariable Cox regression models were used to determine hazard ratios (HR) and 95% confidence interval (CI) for the recurrence of HCC with staging I–II of each GLR tertile category. The restricted cubic spline model was used to find out the threshold effect. Results With the low tertile of GLR as the reference, multivariable-adjusted HR and 95% CI of the middle and high tertile categories were 1.748 (1.170–2.612) and 2.078 (1.339–3.227). In addition, there was a positive correlation (HR 1.002; 95% CI 1.001–1.004) and a non-liner relationship was found, whose point was 27.5. When the GLR was less than 27.5, the risk of recurrence increased, obviously with the increase in GLR levels (HR 1.041; 95% CI 1.014–1.068). Conclusions The GLR was independently associated with the recurrence of HCC patients with staging I–II. Furthermore, the relationship was positive and no-linear.
Collapse
Affiliation(s)
- Zeping Li
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Lili Liang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Wen Duan
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Chengmao Zhou
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
| | - Jian-Jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
| |
Collapse
|
|
39
|
Li S, Zeng Q, Liang R, Long J, Liu Y, Xiao H, Sun K. Using Systemic Inflammatory Markers to Predict Microvascular Invasion Before Surgery in Patients With Hepatocellular Carcinoma. Front Surg 2022; 9:833779. [PMID: 35310437 PMCID: PMC8931769 DOI: 10.3389/fsurg.2022.833779] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Background Mounting studies reveal the relationship between inflammatory markers and post-therapy prognosis. Yet, the role of the systemic inflammatory indices in preoperative microvascular invasion (MVI) prediction for hepatocellular carcinoma (HCC) remains unclear. Patients and Methods In this study, data of 1,058 cases of patients with HCC treated in the First Affiliated Hospital of Sun Yat-sen University from February 2002 to May 2018 were collected. Inflammatory factors related to MVI diagnosis in patients with HCC were selected by least absolute shrinkage and selection operator (LASSO) regression analysis and were integrated into an “Inflammatory Score.” A prognostic nomogram model was established by combining the inflammatory score and other independent factors determined by multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to evaluate the predictive efficacy of the model. Results Sixteen inflammatory factors, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, etc., were selected by LASSO regression analysis to establish an inflammatory score. Multivariate logistic regression analysis showed that inflammatory score (OR = 2.14, 95% CI: 1.63–2.88, p < 0.001), alpha fetoprotein (OR = 2.02, 95% CI: 1.46–2.82, p < 0.001), and tumor size (OR = 2.37, 95% CI: 1.70–3.30, p < 0.001) were independent factors for MVI. These three factors were then used to establish a nomogram for MVI prediction. The AUC for the training and validation group was 0.72 (95% CI: 0.68–0.76) and 0.72 (95% CI: 0.66–0.78), respectively. Conclusion These findings indicated that the model drawn in this study has a high predictive value which is capable to assist the diagnosis of MVI in patients with HCC.
Collapse
Affiliation(s)
- Shumin Li
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qianwen Zeng
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ruiming Liang
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianyan Long
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yihao Liu
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Han Xiao
- Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Han Xiao
| | - Kaiyu Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Kaiyu Sun
| |
Collapse
|
|
40
|
Muhammed A, D'Alessio A, Enica A, Talbot T, Fulgenzi CAM, Nteliopoulos G, Goldin RD, Cortellini A, Pinato DJ. Predictive biomarkers of response to immune checkpoint inhibitors in hepatocellular carcinoma. Expert Rev Mol Diagn 2022; 22:253-264. [PMID: 35236211 DOI: 10.1080/14737159.2022.2049244] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the most common primary liver cancer and fourth leading cause of cancer death. While drug discovery to improve disease survival was historically poor, there is now evidence of significant potential for immune checkpoint inhibitors (ICPIs) in treatment of the disease, and indeed such drug approvals are beginning to emerge. AREAS COVERED HCC typically arises in the context of cirrhosis and chronic liver disease (CLD), and HCC exhibits significant biological heterogeneity, in part reflecting the broad range of aetiologies of CLD. Different classes and combinations of ICPI-based therapy exist, but not all patients will respond and predictive biomarkers are not yet available to guide clinician decision making, unlike some other cancer types. In this review, we discuss the emerging biomarkers for ICPI sensitivity in HCC, including tumour genomic features, perturbation of the gut microbiome and systemic inflammatory markers. EXPERT OPINION Additional profiling studies are required to appreciate existing trends with clinical outcome and to further drive clinical studies in disease stratification by response. This will only be possible within collaborative and international efforts, especially regarding biopsy collection. A close collaboration between basic scientists and clinicians will be the key to shape the next future of HCC biomarker research.
Collapse
Affiliation(s)
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, UK.,Department of Biomedical Sciences, Humanitas University, Italy
| | - Andrei Enica
- Department of Surgery & Cancer, Imperial College London, UK
| | - Thomas Talbot
- Department of Surgery & Cancer, Imperial College London, UK
| | - Claudia Angela Maria Fulgenzi
- Department of Surgery & Cancer, Imperial College London, UK.,Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | | | | | | | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, UK.,Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| |
Collapse
|
|
41
|
Gu Y, Zheng F, Zhang Y, Qiao S. Novel Nomogram Based on Inflammatory Markers for the Preoperative Prediction of Microvascular Invasion in Solitary Primary Hepatocellular Carcinoma. Cancer Manag Res 2022; 14:895-907. [PMID: 35256861 PMCID: PMC8898018 DOI: 10.2147/cmar.s346976] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 02/15/2022] [Indexed: 01/01/2023] Open
Abstract
Purpose We aimed to develop and to validate a novel nomogram based on inflammatory markers to preoperatively predict microvascular invasion (MVI) in patients with solitary primary hepatocellular carcinoma (HCC). Patients and Methods Data from 658 patients with solitary primary HCC who underwent hepatectomy at the First Affiliated Hospital of Zhengzhou University from June 2018 to October 2021 were retrospectively analyzed. Patients were divided into training (n=441) and validation (n=217) cohorts according to surgical data. Independent risk factors for MVI were identified via univariate and multivariate logistic regression analyses in the training cohort. A novel nomogram was developed based on the independent risk factors identified. Its accuracy was evaluated using a calibration curve and concordance index (C-index). The predictive value was evaluated using the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Results Preoperative alpha-fetoprotein >969 µg/L (P<0.001), tumor size (P=0.002), neutrophil >1.8×109/L (P=0.002), gamma-glutamyl transpeptidase-to-platelet ratio (GPR) >0.32 (P=0.001), aspartate aminotransferase-to-platelet ratio (APR) >0.18 (P<0.001), gamma-glutamyl transpeptidase-to-albumin ratio (GAR) >2.30 (P=0.001), and gamma-glutamyl transpeptidase-to-lymphocyte ratio >29.58 (P<0.001) were identified as preoperative independent risk factors for MVI and were used to establish the nomogram. The C-index of the training and validation cohorts were 0.788 (95% confidence interval [CI]: 0.744–0.831) and 0.735 (95% CI: 0.668–0.802), respectively. The calibration curve analysis revealed that the standard curve fit well with the predicted curve. ROC curve analysis demonstrated high efficiency of the nomogram. DCA verified that the nomogram had notable clinical value. Conclusion Preoperative GPR >0.32, APR >0.18, and GAR >2.30 were independent risk factors for MVI in patients with solitary primary HCC, suggesting their utility as preoperative predictors of MVI. The novel nomogram developed and validated in this study may aid in determining optimal therapeutic approaches for patients with solitary HCC at risk for MVI.
Collapse
Affiliation(s)
- Yufei Gu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People’s Republic of China
| | - Fengyu Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People’s Republic of China
| | - Yingxuan Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People’s Republic of China
| | - Shishi Qiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People’s Republic of China
- Correspondence: Shishi Qiao, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, No. 50 Jianshe East Road, Erqi District, Zhengzhou City, Henan Province, People’s Republic of China, Tel +86 18595811956, Email
| |
Collapse
|
|
42
|
Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, Himmelsbach V, Schulze K, von Felden J, Fründt TW, Stadler M, Heinzl H, Shmanko K, Spahn S, Radu P, Siebenhüner AR, Mertens JC, Rahbari NN, Kütting F, Waldschmidt DT, Ebert MP, Teufel A, De Dosso S, Pinato DJ, Pressiani T, Meischl T, Balcar L, Müller C, Mandorfer M, Reiberger T, Trauner M, Personeni N, Rimassa L, Bitzer M, Trojan J, Weinmann A, Wege H, Dufour JF, Peck-Radosavljevic M, Vogel A, Pinter M. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol 2022; 76:353-363. [PMID: 34648895 DOI: 10.1016/j.jhep.2021.09.035] [Citation(s) in RCA: 159] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 09/20/2021] [Accepted: 09/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.
Collapse
Affiliation(s)
- Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Katharina Pomej
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Medicine I, University Medical Center Schleswig-Holstein, Lübeck, Germany
| | - Florian Hucke
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Fabian Finkelmeier
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Oliver Waidmann
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Vera Himmelsbach
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Kornelius Schulze
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johann von Felden
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorben W Fründt
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marc Stadler
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria; Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Harald Heinzl
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Kateryna Shmanko
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Stephan Spahn
- Department of Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany
| | - Pompilia Radu
- Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Alexander R Siebenhüner
- Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Zurich, Switzerland; Department of Medical Oncology and Hematology, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland
| | - Joachim C Mertens
- Department of Hepatology and Gastroenterology, University Hospital Zurich and University Zurich, Zurich, Switzerland
| | - Nuh N Rahbari
- Department of Surgery at University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Fabian Kütting
- Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany
| | | | - Matthias P Ebert
- Department of Internal Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Internal Medicine II, Division of Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sara De Dosso
- Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy
| | - Tobias Meischl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Christian Müller
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy
| | - Michael Bitzer
- Department of Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany
| | - Jörg Trojan
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Arndt Weinmann
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Henning Wege
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cancer Center Esslingen, Klinikum Esslingen, 73730 Esslingen am Neckar, Germany
| | - Jean-François Dufour
- Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Markus Peck-Radosavljevic
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
43
|
The Systemic Inflammatory Response Identifies Patients with Adverse Clinical Outcome from Immunotherapy in Hepatocellular Carcinoma. Cancers (Basel) 2021; 14:cancers14010186. [PMID: 35008350 PMCID: PMC8750517 DOI: 10.3390/cancers14010186] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/23/2021] [Accepted: 12/13/2021] [Indexed: 12/24/2022] Open
Abstract
Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45-2.64, p < 0.001; HR 1.73, 95%CI 1.23-2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6-2.40, p = 0.020; HR 1.99, 95%CI 1.11-3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.
Collapse
|
|
44
|
Sun Z, Shi Z, Xin Y, Zhao S, Jiang H, Wang D, Zhang L, Wang Z, Dai Y, Jiang H. Artificial Intelligent Multi-Modal Point-of-Care System for Predicting Response of Transarterial Chemoembolization in Hepatocellular Carcinoma. Front Bioeng Biotechnol 2021; 9:761548. [PMID: 34869272 PMCID: PMC8634755 DOI: 10.3389/fbioe.2021.761548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/22/2021] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks the second most lethal tumor globally and is the fourth leading cause of cancer-related death worldwide. Unfortunately, HCC is commonly at intermediate tumor stage or advanced tumor stage, in which only some palliative treatment can be used to offer a limited overall survival. Due to the high heterogeneity of the genetic, molecular, and histological levels, HCC makes the prediction of preoperative transarterial chemoembolization (TACE) efficacy and the development of personalized regimens challenging. In this study, a new multi-modal point-of-care system is employed to predict the response of TACE in HCC by a concept of integrating multi-modal large-scale data of clinical index and computed tomography (CT) images. This multi-modal point-of-care predicting system opens new possibilities for predicting the response of TACE treatment and can help clinicians select the optimal patients with HCC who can benefit from the interventional therapy.
Collapse
Affiliation(s)
- Zhongqi Sun
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongxing Shi
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanjie Xin
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Sheng Zhao
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hao Jiang
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dandan Wang
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Linhan Zhang
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ziao Wang
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanmei Dai
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huijie Jiang
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| |
Collapse
|
|
45
|
Yanhan W, Lianfang L, Hao L, Yunfeng D, Nannan S, Fanfan L, Chengzhan Z, Meilong W, Chuandong S. Effect of Microvascular Invasion on the Prognosis in Hepatocellular Carcinoma and Analysis of Related Risk Factors: A Two-Center Study. Front Surg 2021; 8:733343. [PMID: 34869551 PMCID: PMC8637807 DOI: 10.3389/fsurg.2021.733343] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/13/2021] [Indexed: 01/05/2023] Open
Abstract
Objective: Microvascular invasion is considered to initiate intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). We aimed to analyze the effect of MVI on the prognosis in HCC and identify related risk factors for microvascular invasion (MVI). Methods: The clinical data of 553 HCC patients who underwent liver surgery at Qingdao University from January 2014 to December 2018 and 89 patients at Beijing Tsinghua Changgung Hospital treated between October 2014 and October 2019 were collected retrospectively. We explored the impact of MVI on the prognosis of patients with HCC using Kaplan-Meier analysis. We conducted logistic regression analysis to identify variables significantly related to MVI. Results: Pathological examination confirmed the presence of MVI in 265 patients (41.3%). Six factors independently correlated with MVI were incorporated into the multivariate logistic regression analysis: Edmondson-Steiner grade [odds ratio (OR) = 3.244, 95%CI: 2.243–4.692; p < 0.001], liver capsule invasion (OR = 1.755; 95%CI: 1.215–2.535; p = 0.003), bile duct tumor thrombi (OR = 20.926; 95%CI: 2.552–171.553; p = 0.005), α-fetoprotein (> 400 vs. < 400 ng/ml; OR = 1.530; 95%CI: 1.017–2.303; p = 0.041), tumor size (OR = 1.095; 95%CI: 1.027–1.166; p = 0.005), and neutrophil-lymphocyte ratio (OR = 1.086; 95%CI: 1.016–1.162; p = 0.015). The area under the receiver operating characteristic curve (AUC) was 0.743 (95%CI: 0.704–0.781; p < 0.001), indicating that our logistic regression model had significant clinical usefulness. Conclusions: We analyzed the effect of MVI on the prognosis in HCC and evaluated the risk factors for MVI, which could be helpful in making decisions regarding patients with a high risk of recurrence.
Collapse
Affiliation(s)
- Wang Yanhan
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lu Lianfang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liu Hao
- Department of Operation Room, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ding Yunfeng
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Song Nannan
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lin Fanfan
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhu Chengzhan
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.,Shandong Key Laboratory of Digital Medicine and Computer Assisted Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wu Meilong
- School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Sun Chuandong
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
46
|
Rimassa L, Kelley RK, Meyer T, Ryoo BY, Merle P, Park JW, Blanc JF, Lim HY, Tran A, Chan YW, McAdam P, Wang E, Cheng AL, El-Khoueiry AB, Abou-Alfa GK. Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma. Liver Cancer 2021; 11:38-47. [PMID: 35222506 PMCID: PMC8820164 DOI: 10.1159/000519867] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 09/24/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. METHODS Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. RESULTS In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. CONCLUSION Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.
Collapse
Affiliation(s)
- Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy,*Lorenza Rimassa,
| | - Robin Kate Kelley
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA
| | - Tim Meyer
- Royal Free Hospital and UCL Cancer Institute, London, United Kingdom
| | - Baek-Yeol Ryoo
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | | | | | - Ho Yeong Lim
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Albert Tran
- Université Côte d'Azur, Nice, France,CHU de Nice, Digestive Center, Nice, France,INSERM, U1065, C3M, Team 8, Nice, France
| | - Yi-Wah Chan
- Fios Genomics Ltd, Edinburgh, United Kingdom
| | - Paul McAdam
- Fios Genomics Ltd, Edinburgh, United Kingdom
| | | | - Ann-Lii Cheng
- National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, New York, USA,Weill Medical College at Cornell University, New York, New York, USA
| |
Collapse
|
|
47
|
Han JW, Sung PS, Jang JW, Choi JY, Yoon SK. Whole blood viscosity is associated with extrahepatic metastases and survival in patients with hepatocellular carcinoma. PLoS One 2021; 16:e0260311. [PMID: 34855786 PMCID: PMC8638904 DOI: 10.1371/journal.pone.0260311] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Whole blood viscosity (WBV) is increased in cancer patients and associated with the advanced stage with systemic metastases. However, relevance of WBV in hepatocellular carcinoma (HCC) remains unclear. This pilot study included a discovery cohort of 148 treatment-naïve HCC patients with preserved liver function, and a validation cohort of 33 treatment-experienced HCC patients with nivolumab. Systolic and diastolic WBV was measured using an automated scanning capillary tube viscometer at diagnosis or before the nivolumab treatment. Extrahepatic metastases were observed in 15 treatment-naïve patients (11.3%) at diagnosis. Portal vein tumor thrombosis (PVTT), tumor size, number of tumors, and systolic/diastolic WBV were factors associated with extrahepatic metastases. Systolic WBV and diastolic WBV were significantly increased in patients with metastases compared with patients without metastases. Multivariate logistic regression showed that high diastolic WBV > 16 cP was an independent factor associated with metastases. Notably, patients who developed extrahepatic metastases during the observation period among patients without metastases at diagnosis had higher diastolic WBV initially. Patients with high diastolic WBV had poor survival, and multivariate Cox regression analyses showed high diastolic WBV was an independent risk factor for poor survival with the Child-Pugh B7 and PVTT. High diastolic WBV also predicted poor survival in patients with low alpha-fetoprotein (AFP) and proteins induced by vitamin K antagonist-II (PIVKA-II) levels. In 33 nivolumab-treated patients, high diastolic WBV before the treatment was also tended to be associated with overall and progression-free survival. Our study is the first in which high WBV is associated with the distant metastases and survival in patients with HCC, but future prospective, large cohort studies are necessary to validate the results.
Collapse
Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pil Soo Sung
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| |
Collapse
|
|
48
|
Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis. Microorganisms 2021; 9:microorganisms9061179. [PMID: 34070716 PMCID: PMC8227491 DOI: 10.3390/microorganisms9061179] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15–20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host’s epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.
Collapse
|
|
49
|
Brief Report: Accuracy of FIB-4 for Cirrhosis in People Living With HIV and Hepatocellular Carcinoma. J Acquir Immune Defic Syndr 2021; 85:530-534. [PMID: 33185999 DOI: 10.1097/qai.0000000000002510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) may develop in the absence of cirrhosis in HIV, and determining how often this occurs can provide insights into mechanisms of carcinogenesis. Studies evaluating the prevalence of cirrhosis in the setting of HCC among people living with HIV (PLWH) often rely on noninvasive markers, such as the Fibrosis-4 Index for Hepatic Fibrosis (FIB-4). However, the accuracy of FIB-4 for cirrhosis in the setting of HCC has not been determined among PLWH. METHODS We conducted a cross-sectional study among PLWH in the Veterans Aging Cohort Study with VA cancer registry-confirmed HCC diagnosed between 1999 and 2015. FIB-4 was calculated using the age, alanine aminotransferase, aspartate aminotransferase, and platelet count obtained closest to, but within 1 year before, HCC diagnosis. Medical records were reviewed within 1 year before HCC diagnosis to determine the cirrhosis status. We evaluated the area under the receiver-operating characteristic curve and performance characteristics of FIB-4 for confirmed cirrhosis. RESULTS Incident HCC was diagnosed in 302 PLWH. After medical record review, 203 (67.2%, 95% confidence interval: 61.6% to 72.5%) had evidence of cirrhosis. FIB-4 identified patients with cirrhosis with an area under the receiver-operating characteristic curve of 0.67 (95% confidence interval: 0.60 to 0.73). FIB-4 scores >5.0 had a positive predictive value >80% and specificity of >77%, negative predictive value of <41%, and sensitivity of <45%. CONCLUSION The accuracy of FIB-4 for cirrhosis in the setting of HIV and HCC is modest and may result in misclassification of cirrhosis in this population.
Collapse
|
|
50
|
Liao C, Li G, Bai Y, Zhou S, Huang L, Yan M, Qiu F, Chen J, Wang Y, Tian Y, Chen S. Prognostic value and association of sarcopenic obesity and systemic inflammatory indexes in patients with hepatocellular carcinoma following hepatectomy and the establishment of novel predictive nomograms. J Gastrointest Oncol 2021; 12:669-693. [PMID: 34012658 DOI: 10.21037/jgo-20-341] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Background The specific impacts of sarcopenic obesity (SO) on hepatocellular carcinoma (HCC) and the association between SO and systemic inflammation remain unclear. This study aimed to investigate the prognostic value and association of SO and systemic inflammation with outcomes after hepatectomy for HCC and develop novel nomograms based on SO and inflammatory indexes for survival prediction. Methods We retrospectively enrolled 452 patients with HCC who underwent radical hepatectomy between January 2012 and March 2015 in Fujian Provincial Hospital as the training cohort. In addition, 275 patients during the same period were enrolled as the external validation cohort. Patients were classified into different groups according to the presence of sarcopenia and obesity. Different inflammation indexes were evaluated to select the best predictor of overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate logistic regression were performed to investigate the associations between inflammatory indexes and SO. The inflammatory indexes with the highest predictive values and SO were selected for subgroup analyses to establish a novel classification system: the SOLMR grade. SOLMR grades identified in the multivariate Cox analysis were selected to construct novel nomograms for OS and RFS. Results SO (P<0.001) was an independent risk factor for OS and RFS. The lymphocyte-monocyte ratio (LMR) had the highest areas under the receiver operating characteristic (ROC) curves (AUCs) for OS (P<0.001) and RFS (P<0.001) and was identified as an independent factor of SO (P=0.001). SO and the LMR were selected to establish the SOLMR grade. Multivariate Cox analysis revealed that SOLMR grade was a significant independent predictor of OS (P<0.001) and RFS (P<0.001). Nomograms based on SOLMR grades were generated and accurately predicted 1-, 3- and 5-year OS and RFS in HCC patients. The C-index of the novel nomograms was higher than those of the other conventional staging systems (P<0.001). Conclusions Both SO and the LMR were independent risk factors for OS and RFS in HCC patients after hepatectomy. The LMR was an independent factor of SO. The novel nomograms developed from the SOLMR grading system combining SO with the LMR provide good prognostic estimates of the outcomes of HCC patients.
Collapse
Affiliation(s)
- Chengyu Liao
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| | - Ge Li
- Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yannan Bai
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| | - Songqiang Zhou
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| | - Long Huang
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| | - Maolin Yan
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| | - Funan Qiu
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| | - Jiangzhi Chen
- Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yaodong Wang
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| | - Yifeng Tian
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| | - Shi Chen
- Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provinvial Hospital, Fuzhou, China
| |
Collapse
|