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Kuang J, Li J, Zhou S, Li Y, Lin J, Huang W, Yuan X. Genomic and micro-environmental insights into drug resistance in colorectal cancer liver metastases. Discov Oncol 2025; 16:241. [PMID: 40009285 DOI: 10.1007/s12672-025-01976-8] [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: 12/01/2024] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is known for its high heterogeneity, with liver metastases significantly impairing survival outcomes. Understanding the tumor microenvironment (TME) and genomic alterations in metastatic sites is crucial for developing personalized therapies that overcome drug resistance and improve prognosis. METHODS We profiled 54 CRC liver metastases, comparing them with 198 other metastatic lesions and normal liver tissues. By analyzing immune cell infiltration, stromal interactions, and key genomic alterations, we constructed an 11-gene prognostic model to predict survival and immunotherapy outcomes. RESULTS CRC liver metastases with high-risk profiles demonstrated enriched follicular helper T cells, activated dendritic cells, and M2 macrophages in the TME. Frequent mutations in APC, TP53, KRAS, and PIK3CA were identified, alongside altered EGFR signaling. The 11-gene model effectively stratified patients by prognosis and predicted immunotherapy responses, emphasizing the therapeutic potential of targeting resistance mechanisms. CONCLUSIONS This study reveals how genomic and TME-driven factors contribute to drug resistance in CRC liver metastases. Integrating these insights with clinical data could advance precision therapies, addressing the evolving challenge of tumor drug resistance in CRC.
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Affiliation(s)
- Junjie Kuang
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Jun Li
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Siwei Zhou
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Yi Li
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Jinbo Lin
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Weizhen Huang
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China.
| | - Xia Yuan
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China.
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Xu N, Gao Z, Wu D, Chen H, Zhang Z, Zhang L, Wang Y, Lu X, Yao X, Liu X, Huang Y, Qiu M, Wang S, Liang J, Mao C, Zhang F, Xu H, Wang Y, Li X, Chen Z, Huang D, Shi J, Huang W, Lei F, Yang Z, Chen L, He C, Zhu H, Luo H, Gu J, Lin J. 5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target. Clin Transl Med 2025; 15:e70189. [PMID: 39956959 PMCID: PMC11830572 DOI: 10.1002/ctm2.70189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/24/2024] [Accepted: 01/08/2025] [Indexed: 02/18/2025] Open
Abstract
Metachronous liver metastases (MLM) are characterised by high incidence and high mortality in clinical colorectal cancer treatment. Currently traditional clinical methods cannot effectively predict and prevent the occurrence of metachronous liver metastasis in colorectal cancer. Based on 5hmC-Seal analysis of blood and tissue samples, this study found that portal venous blood was more relevant to tumour gDNA than peripheral blood. We performed a novel epigenetic liquid biopsy strategy using the 10 5hmC epigenetic alterations, to accurately distinguish MLM patients from patients without metastases. Among these epigenetic alterations, phosphodiesterase 4 (PDE4D) was highly increased in MLM patients and correlated with poor survival. Moreover, our studies demonstrated that PDE4D was a key metastasis-driven target for drug development. Interfering with the function of PDE4D significantly repressed liver metastases. Similarly, roflumilast, a PDE4 inhibitor for chronic obstructive pulmonary disease (COPD) therapy, also inhibits liver metastases. Further studies indicate that blocking the function of PDE4D can affect CRC invasion through the HIF-1α-CCN2 pathway. To develop a more efficient PDE4 inhibitor and reduce the occurrence of adverse events, we also designed several new compounds based on 2-arylbenzofurans and discovered lead L11 with potent affinity for PDE4D and significant suppression of liver metastases. In this work, our study provides a promising strategy for predicting metachronous liver metastasis and discovers L11 as a potential repurposed drug for inhibiting liver metastasis, which have the potential to benefit patients with CRC in the future. KEY POINTS: 5hmC epigenetic markers derived from portal venous blood could accurately predict metachronous metastasis of colorectal cancer. PDE4D was a key metastasis-driven target that promoted metachronous metastasis via the HIF-1α-CCN2 pathway. The newly synthesised compound L11 could specifically inhibit PDE4D and abolish metachronous metastasis of colorectal cancer without obvious toxic side effects.
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Paramythiotis D, Karlafti E, Tsavdaris D, Apostolidou Kiouti F, Haidich AB, Ioannidis A, Panidis S, Michalopoulos A. The Effect of Hepatic Surgical Margins of Colorectal Liver Metastases on Prognosis: A Systematic Review and Meta-Analysis. J Clin Med 2024; 13:7776. [PMID: 39768699 PMCID: PMC11727772 DOI: 10.3390/jcm13247776] [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: 11/13/2024] [Revised: 12/14/2024] [Accepted: 12/16/2024] [Indexed: 01/16/2025] Open
Abstract
Introduction: Colorectal cancer is the third most common malignancy, with around half of patients developing liver metastases. Hepatectomy is the preferred treatment, but its success depends on several factors, including surgical margins. Various surgical margins have been suggested to achieve optimal results. This systematic review and meta-analysis aim to explore the impact of negative surgical margins ranging from 1 to 10 mm, and >10 mm on survival, with the objective of identifying optimal surgical margins. Methods: A systematic literature search was conducted on the MEDLINE, Scopus, and Cochrane databases. The six included studies that examined the effect of surgical margins at the aforementioned distances on patient survival. Studies were assessed for risk of bias using the Quality in Prognosis Studies tool. Statistical analysis was performed using SPSS software. Results: The results of the meta-analysis revealed the superiority of wider surgical margins (>10) on overall survival compared to smaller margins (1-10 mm), as the HR was calculated to be 1.38 [1.10; 1.73]. Specifically, negative margins between 1 and 10 mm are linked to a 38% increased risk of mortality compared to margins larger than 10 mm. The low heterogeneity indicates consistent findings across studies, and the statistically significant hazard ratio underscores the importance of aiming for larger surgical margins to enhance patient outcomes. In the subgroup that included only studies in which patients received neoadjuvant therapy, the HR was 1.48 [1.06; 2.07], further emphasizing the importance of ensuring negative surgical margins in today's era. Conclusions: In summary, this systematic review and meta-analysis highlights the impact of surgical margin width on the survival of patients with colorectal liver metastases, as well as the importance of margin optimization in surgical management strategies.
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Affiliation(s)
- Daniel Paramythiotis
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
| | - Eleni Karlafti
- Emergency Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- First Propaedeutic Department of Internal Medicine, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Dimitrios Tsavdaris
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
| | - Fani Apostolidou Kiouti
- Department of Hygiene, Social-Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece (A.-B.H.)
| | - Anna-Bettina Haidich
- Department of Hygiene, Social-Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece (A.-B.H.)
| | - Aristeidis Ioannidis
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
| | - Stavros Panidis
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
| | - Antonios Michalopoulos
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
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Zhang C, Zhang L, Huang Q, Jiang S, Peng T, Wang S, Xu X. Diagnostic and screening potential of plasma exosome miR‑99b‑5p and its combination with other miRNAs for colorectal cancer. Oncol Lett 2024; 28:461. [PMID: 39119230 PMCID: PMC11307556 DOI: 10.3892/ol.2024.14594] [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: 07/21/2023] [Accepted: 02/15/2024] [Indexed: 08/10/2024] Open
Abstract
Extracellular vesicles (EVs) secreted by tumor cells have been documented to hold viable biomarker potential. Therefore, the present study evaluated the potential clinical value of EV-microRNAs (miRNAs or miRs) in the plasma exosomes of patients with colorectal cancer (CRC) for the early diagnosis and screening of CRC. In total, 95 plasma samples were collected at The Third Affiliated Hospital of Guangzhou Medical University (Guangzhou, China) between 2017 and 2019. Specifically, 68 samples were from patients with CRC and 27 were from healthy control (HC) donors. High-throughput sequencing was used to detect the expression of miRNAs in the isolated plasma EVs, which was subsequently verified by reverse transcription-quantitative PCR. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic potential of single and combined miRNAs for CRC. Bioinformatics analysis was employed to predict the target genes of candidate miRNAs. Compared with those in the HC group, the CRC group expressed higher levels of miR-99b-5p and miR-409-3p, especially during the early stages of CRC. Clinicopathological analysis confirmed the higher expression levels of miR-99b-5p during the early stages, as well as higher expression levels in the colon compared with those in the rectum. ROC curve analysis revealed that the area under the curve (AUC) of miR-99b-5p for the diagnosis of early CRC was 73.5% (P=0.007). The early diagnostic capability of miR-99b-5p combined with miR-409-3p for CRC was evaluated, and the AUC was found to be 74.1% (P=0.006). In addition, the AUC of the combination of miR-99b-5p, miR-409-3p and carcinoembryonic antigen was 81.2% (P<0.001), indicating that this three-parameter combination displayed higher diagnostic power compared with any single miRNA for early CRC screening. The results from the present study suggest that the expression of miR-99b-5p in plasma exosomes is significantly upregulated in CRC, which holds potential for the early diagnosis of this cancer type. Such potential can be enhanced further by combining it with other miRNAs. Therefore, the present study provides a comprehensive but preliminary insight for the viability of miR-99b-5p (alone or combined with other miRNAs) for CRC diagnosis, which requires further exploration in the future.
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Affiliation(s)
- Chang Zhang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi'an, Shanxi 710032, P.R. China
- Department of Aviation Medicine, The First Affiliated Hospital, Air Force Medical University, Xi'an, Shanxi 710032, P.R. China
| | - Limei Zhang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
| | - Qiyuan Huang
- Nursing School, Guangzhou Medical University, Guangzhou, Guangdong 510030, P.R. China
| | - Siyuan Jiang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
| | - Tao Peng
- Sino-French Hoffmann Institute, Guangzhou Hoffman Institute of Immunology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Shu Wang
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Republic of Singapore
| | - Xuehu Xu
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
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Ai XN, Zhang Q, Jin CG, Hu H, Zhang WX, Wu ZY, Xiu DR. Relationship between hepatic surgical margins of colorectal cancer liver metastases and prognosis: A review. Medicine (Baltimore) 2024; 103:e37038. [PMID: 38335431 PMCID: PMC10860945 DOI: 10.1097/md.0000000000037038] [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: 11/15/2023] [Revised: 12/17/2023] [Accepted: 01/03/2024] [Indexed: 02/12/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health concern, as characterized by its high mortality rate ranking second among all the leading causes of death. The liver serves as the primary site of CRC metastasis, and the occurrence of liver metastasis is a significant contributor to mortality among patients diagnosed with CRC. The survival rate of patients with colorectal liver metastasis has significantly increased with the advancement of comprehensive tumor therapy. However, radical surgery remains the key factor. Since there are frequently multiple liver metastases, which are prone to recurrence after surgery, it is crucial to preserve as much liver parenchyma as possible without affecting the prognosis. The issue of surgical margins plays a crucial role in this regard. In this review, we begin by examining the occurrence of positive surgical margins in liver metastases of patients diagnosed with CRC. We aim to define positive margins in hepatic surgery, examine the relationship between margins and prognosis and establish a foundation for future research in this field.
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Affiliation(s)
- Xiang-Nan Ai
- Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, China
| | - Qiang Zhang
- Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, China
| | - Chang-Guo Jin
- Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, China
| | - Hao Hu
- Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, China
| | - Wen-Xuan Zhang
- Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, China
| | - Zhen-Yu Wu
- Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, China
| | - Dian-Rong Xiu
- Department of General Surgery, Peking University Third Hospital, Beijing, China
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Liu M, Wang Y, Wang K, Bao Q, Wang H, Jin K, Liu W, Yan X, Xing B. Combined ablation and resection (CARe) for resectable colorectal cancer liver Metastases-A propensity score matching study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:106931. [PMID: 37183048 DOI: 10.1016/j.ejso.2023.05.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/28/2023] [Accepted: 05/06/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND The efficacy of combining ablation and resection (CARe) in treating unresectable colorectal cancer liver metastases (CRLM) was well established. This study aimed to investigate the surgical and oncological outcomes of CARe strategy focusing on initially resectable CRLM. PATIENTS AND METHODS A total of 971 patients with resectable CRLM from a retrospective database of 1414 CRLM patients were enrolled, including 120 in the CARe group and 851 in the hepatectomy alone group. Short- and long-term outcomes were compared between groups using propensity score matching analysis. RESULTS After propensity score matching, 96 matched pairs of patients from each group were included. General characteristics of primary tumour and liver metastases were not statistically different between the CARe group and hepatectomy alone group. Disease-free survival (p = 0.257), intrahepatic recurrence-free survival (p = 0.329), and overall survival (p = 0.358) were similar between the two groups. Patients in CARe group had significantly reduced rate of major hepatectomy (5.2% vs. 21.9%, p = 0.001), lower incidence of postoperative hepatic insufficiency (0.0% vs. 5.2%, p = 0.023), and shortened postoperative hospital stay (7 d vs. 8 d, p = 0.019). Multivariate analysis showed that surgical approach did not affect oncologic outcome; liver metastasis with diameter >3 cm was an independent prognostic factor for hepatic recurrence-free and disease-free survival, and RAS status and lymph node metastasis at the primary site were independent prognostic factors for overall survival. CONCLUSION For patients with resectable CRLM, CARe may be a better treatment strategy than hepatectomy alone, as it could avoid major hepatectomy and get better surgical outcomes, while providing the similar oncologic results.
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Affiliation(s)
- Ming Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China
| | - Yanyan Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China
| | - Kun Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China
| | - Quan Bao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China
| | - Hongwei Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China
| | - Kemin Jin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China
| | - Wei Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China
| | - Xiaoluan Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China
| | - Baocai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, China.
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Kim JS, Kim H, Lee SY, Han YD, Han K, Min BS, Kim MD, Won JY, Beom SH, Shin SJ, Kim HS, Han DH, Ahn JB. Hepatic arterial infusion in combination with systemic chemotherapy in patients with hepatic metastasis from colorectal cancer: a randomized phase II study - (NCT05103020) - study protocol. BMC Cancer 2023; 23:691. [PMID: 37481515 PMCID: PMC10363309 DOI: 10.1186/s12885-023-11085-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 06/16/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND Although 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis. METHODS This is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate. DISCUSSION This is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate. TRIAL REGISTRATION ClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.
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Affiliation(s)
- Ji Su Kim
- Division of Hepatobiliary and Pancreas Surgery, Incheon St. Mary's Hospital, The Catholic University College of Medicine, Incheon, Korea
| | - Hyunwook Kim
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Seo Young Lee
- Department of Medical Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Dae Han
- Department of Colorectal Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kichang Han
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byung Soh Min
- Department of Colorectal Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Man-Deuk Kim
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Yun Won
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seung-Hoon Beom
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Sang Joon Shin
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Han Sang Kim
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
- Graduate School of Medical Science, Brain Korea 21 Project, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
| | - Dai Hoon Han
- Department of Hepatobiliary and Pancreatic Surgery, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
| | - Joong Bae Ahn
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
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Kataoka K, Takahashi K, Takeuchi J, Ito K, Beppu N, Ceelen W, Kanemitsu Y, Ajioka Y, Endo I, Hasegawa K, Takahashi K, Ikeda M. Correlation between recurrence-free survival and overall survival after upfront surgery for resected colorectal liver metastases. Br J Surg 2023; 110:864-869. [PMID: 37196147 DOI: 10.1093/bjs/znad127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/11/2023] [Accepted: 04/28/2023] [Indexed: 05/19/2023]
Abstract
BACKGROUND The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis. METHODS Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated. RESULTS A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06). CONCLUSION In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required.
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Affiliation(s)
- Kozo Kataoka
- Division of Lower Gastrointestinal, Department of Gastroenterological Surgery, Hyogo Medical University, Nishinomiya, Japan
| | - Kanae Takahashi
- Department of Biostatistics, Hyogo Medical University, Nishinomiya, Japan
| | - Jiro Takeuchi
- Department of Clinical Epidemiology, Hyogo Medical University, Nishinomiya, Japan
| | - Kazuma Ito
- Division of Lower Gastrointestinal, Department of Gastroenterological Surgery, Hyogo Medical University, Nishinomiya, Japan
| | - Naohito Beppu
- Division of Lower Gastrointestinal, Department of Gastroenterological Surgery, Hyogo Medical University, Nishinomiya, Japan
| | - Wim Ceelen
- Department of Gastrointestinal Surgery, Ghent University Hospital, and Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
| | - Yukihide Kanemitsu
- Department of Colorectal Surgery, National Cancer Centre Hospital, Tokyo, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Niigata University, Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Yokohama, Japan
| | - Kiyoshi Hasegawa
- Department of Surgery, Hepato-Biliary-Pancreatic Surgery Division, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Keiichi Takahashi
- Department of Surgery, Tokyo Metropolitan Ohkubo Hospital, Tokyo, Japan
| | - Masataka Ikeda
- Division of Lower Gastrointestinal, Department of Gastroenterological Surgery, Hyogo Medical University, Nishinomiya, Japan
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Ai XN, Tao M, Wang HY, Li JL, Sun T, Xiu DR. Analysis of survival factors after hepatic resection for colorectal cancer liver metastases: Does the R1 margin matter? Front Surg 2023; 9:1020240. [PMID: 36684119 PMCID: PMC9852629 DOI: 10.3389/fsurg.2022.1020240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 11/28/2022] [Indexed: 01/07/2023] Open
Abstract
Introduction The effect of liver margin on colorectal cancer liver metastases (CRLM) after hepatectomy has been controversial. In this study, we conducted a postoperative follow-up study of 205 patients with CRLM to clarify whether a positive margin is significant and to define the risk factors affecting CRLM survival. Methods The data of 205 patients with CRLM who underwent surgical treatment at the Third Hospital of Peking University in the Department of General Surgery from January 2009 to December 2020 were retrospectively analyzed. The general data, surgical data and postoperative follow-up of the patients were statistically analyzed. Results There were 130 cases (63.4%) of R0 resection and 75 cases (36.6%) of R1 resection. There were 136 males and 69 females, age 61 ± 11 years, and body mass index (BMI 24.5 ± 3.3 kg/m2). The overall survival rates at 1, 3, and 5 years for the entire cohort were 93.4%, 68.4%, and 45.5% in the R0 resection group vs. 93.2%, 53.7%, and 42% in the R1 resection group, respectively, which were not statistically significant (P = 0.520). The 1-, 3-, and 5-year disease-free survival rates of 63.2%, 33.3%, and 29.7% were significantly better in the R0 resection group than in the R1 resection group of 47.9%, 22.7%, and 17.7% (P = 0.016), respectively. After multivariable analysis, carbohydrate antigen 19-9 (CA19-9) > 39 U/ml (HR = 2.29, 95% CI: 1.39-3.79, P = 0.001), primary tumor perineural invasion (HR = 1.78, 95% CI: 1.01-3.13, P = 0.047), and BMI > 24 kg/m2 (HR = 1.75, 95% CI: 1.05-2.93, P = 0.033) were independently associated with poorer overall patient survival. The number of liver metastases >2 (HR = 1.65, 95% CI: 1.10-2.47, P = 0.016), the maximum diameter of metastases ≥50 mm (HR = 1.67, 95% CI: 1.06-2.64, P = 0.026), and vascular invasion of the primary tumor (HR = 1.65, 95% CI: 1.03-2.64, P = 0.038) were also independently associated with poorer disease-free survival. Conclusion In patients undergoing hepatectomy for CRLM, the negative effect of the R1 margin should be downplayed, and although the disease-free survival of the R1 margin is shorter than that of the R0 margin, it has no impact on overall survival. To improve overall survival, extra attention should be given to the factors of preoperative BMI, preoperative CA19-9, and the presence of perineural invasion of the primary tumor.
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Affiliation(s)
- Xiang-nan Ai
- Department of General Surgery, Peking University Third Hospital, Beijing, China,Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, China
| | - Ming Tao
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Hang-yan Wang
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Jing-lin Li
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Tao Sun
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Dian-rong Xiu
- Department of General Surgery, Peking University Third Hospital, Beijing, China,Correspondence: Dian-rong Xiu
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10
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Sun R, Lin Z, Wang X, Liu L, Huo M, Zhang R, Lin J, Xiao C, Li Y, Zhu W, Lu L, Zhang J, Chen J. AADAC protects colorectal cancer liver colonization from ferroptosis through SLC7A11-dependent inhibition of lipid peroxidation. J Exp Clin Cancer Res 2022; 41:284. [PMID: 36163032 PMCID: PMC9511737 DOI: 10.1186/s13046-022-02493-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 09/11/2022] [Indexed: 12/04/2022] Open
Abstract
Background Oxidative stress is a highly active metabolic process in the liver, that poses great threats to disseminated tumor cells during their colonization. Here, we aimed to investigate how colorectal cancer (CRC) cells overcome lipid peroxidation to sustain their metastatic colonization in the liver. Methods Orthotopic colorectal liver metastasis (CRLM) and CRC liver colonization mouse models were constructed to determine the roles of lipid peroxidation and AADAC in CRC liver colonization. The levels of lipid peroxidation were detected in cells or tissues. AADAC overexpression in LMs and its clinical relevance were analyzed. The oncogenic role of AADAC in CRC liver colonization was evaluated in cell experiments. Results Compared with primary tumors (PTs), liver metastases (LMs) showed significantly lower glutathione to oxidized glutathione (GSH/GSSG) ratio and higher malondialdehyde (MDA) levels in CRLM patients and orthotopic mouse models. Inhibition of lipid peroxidation by liproxstatin-1 promoted CRC liver colonization in mouse models. RNA-seq results revealed AADAC as the most significantly upregulated lipid metabolism related gene in LMs compared with PTs. Analyses of datasets and patient and mouse model samples confirmed that AADAC was upregulated in LMs compared with PTs, and was correlated with poor prognosis. AADAC promoted cell proliferation, and facilitated liver colonization in a mouse model by reducing ROS accumulation, which led to lipid peroxidation and ferroptosis. Mechanistically, AADAC upregulated SLC7A11 by activating NRF2 to inhibit lipid peroxidation, thereby protecting metastatic cells from ferroptosis. Conclusions AADAC protects metastatic CRC cells from ferroptosis by inhibiting lipid peroxidation in an SLC7A11-dependent manner, thus effectively promoting their metastatic colonization and growth in the liver. Together, our findings suggest that AADAC can act as a prognostic indicator and potential therapeutic target for CRLM. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02493-0.
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11
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More Liver Metastases Detected Intraoperatively Indicates Worse Prognosis for Colorectal Liver Metastases Patients after Resection Combined with Microwave Ablation. JOURNAL OF ONCOLOGY 2022; 2022:3819564. [PMID: 35498543 PMCID: PMC9050310 DOI: 10.1155/2022/3819564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/26/2022] [Accepted: 03/28/2022] [Indexed: 11/26/2022]
Abstract
Background Whether more tumor numbers detected in surgery compared to preoperative image affecting survival of colorectal liver metastases (CRLM) patients after hepatectomy combined with microwave ablation (MWA) remains unclear. Methods From 2013 to 2018, 85 CRLM patients who underwent hepatectomy combined with MWA were retrospectively assessed. Compared to the tumor numbers in preoperative image, patients with equal intraoperative tumor numbers were defined as the equal number group (n = 45); patients detected more tumor numbers in surgery were defined as the more number group (n = 40). Clinicopathological factors and prognosis were compared between two groups. Results Compared to the equal number group, the more number group was characterized by more lymphatic metastasis, synchronous metastasis of liver lesion, and tumor numbers over 5 (all P < 0.05). Median survival time was 46.7 months and 26.8 months in the equal and more number group. Significantly worse overall survival (OS) was found in more number group to the equal number group (P = 0.027). In Cox analysis, more tumor number than image and high level of carbohydrate antigen 19-9 (CA19-9) were poor prognostic factors for OS. Conclusion In patients receiving hepatectomy combined with MWA, detecting more liver metastases in surgery than preoperative image indicates poor long-term survival. These patients were characterized by more lymphatic metastasis, synchronous metastasis of liver lesion, and tumor numbers over 5. Intensive follow-up to detect early recurrence and potent postoperative therapy to improve survival may be justified in patients detected more tumor numbers in surgery with a high CA19-9 level.
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12
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Pushing the limit of liver regeneration - Safety and survival after monosegment-ALPPS: systematic review and individual patient data meta-analysis. HPB (Oxford) 2022; 24:353-358. [PMID: 34330644 DOI: 10.1016/j.hpb.2021.06.427] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/20/2021] [Accepted: 06/25/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has expanded and spearheaded development in hepatobiliary surgery. Monosegment-ALPPS tests liver regeneration limits and may present as the last feasible curative treatment option. METHODS Electronic databases (MEDLINE, Web of Science, Google Scholar, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on mono-ALPPS using a predefined strategy without date or language restrictions. Individual patient data was extracted and analyzed. RESULTS 237 publications were identified. 19 patients were identified to have undergone mono-ALPPS. Primarily, mono-ALPPS has been utilized as curative treatment for CRLM (17 of 19 cases). Successful mono-ALPPS was possible in FLR above 8% SLV. All patients received either chemotherapy alone or in combination with radiotherapy prior to surgery. 8 of 19 patients experienced PHLF grade A or B. There was no in-hospital mortality described. Recurrent disease has occurred in 7 of 19 patients and 3 have died during follow-up. CONCLUSION Mono-ALPPS is an experimental procedure that provides a reasonably safe opportunity to curatively treat extensive liver malignancies in patients with FLR as low as 8% SLV. PHLF is the most prevalent complication in mono-ALPPS. Mono-ALPPS should be evaluated in a multicentral study setting.
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13
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Liu L, Liu J, Wang J, Yuan W. Machine learning revealed molecular classification of colorectal cancer with negative lymph node metastasis. Biomarkers 2021; 27:86-94. [PMID: 34894932 DOI: 10.1080/1354750x.2021.2016971] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Purpose: Accurate preoperative staging directly affects the treatment decision of patients with rectal cancer. However, our understanding of the immune subclasses of CRC without lymph node metastasis is still incomplete.Materials and methods: Here, we first analyzed the subclasses of CRC without lymph node metastasis on the Cancer Genome Atlas (TCGA) and verified its stability in the GSE39582 dataset. Four immune subclasses (C1-C4) were identified and verified by non-negative matrix factorization (NMF) of gene expression profiles. Then, ICI scores of six genes were constructed to characterize subclasses.Results: There were significant differences in metabolic and progression-associated signatures, immune characteristics, and clinical characteristics among subclasses. C3 represented a good prognosis with high TMB. C4 showed unique immune characteristics. We believe that C3 is the initial stage of CRC. After the C1 and C2 stages, it progresses to the C4 stage, and finally, lymph node metastasis occurs.Conclusions: This work may help to provide a basis for immunotherapy decision-making in early CRC and may guide personalized methods of cancer immunotherapy.
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Affiliation(s)
- Li Liu
- College of Data Science, Jiaxing University, Jiaxing, Zhejiang, China
| | - June Liu
- School of Economics and Management, Huaibei Normal University, Huaibei, Anhui, China
| | - Jiayao Wang
- College of Information Engineering, Yangzhou University, Yangzhou, Jiangsu, China
| | - Wenliang Yuan
- College of Data Science, Jiaxing University, Jiaxing, Zhejiang, China
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14
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BOZBIYIK O, ÇOKER A. Factors affecting survival in liver metastasis of colorectal cancer. EGE TIP DERGISI 2021. [DOI: 10.19161/etd.1036904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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15
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Kanemitsu Y, Shimizu Y, Mizusawa J, Inaba Y, Hamaguchi T, Shida D, Ohue M, Komori K, Shiomi A, Shiozawa M, Watanabe J, Suto T, Kinugasa Y, Takii Y, Bando H, Kobatake T, Inomata M, Shimada Y, Katayama H, Fukuda H. Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial. J Clin Oncol 2021; 39:3789-3799. [PMID: 34520230 DOI: 10.1200/jco.21.01032] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC. PATIENTS AND METHODS In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis. RESULTS Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration. CONCLUSION DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.
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Affiliation(s)
| | | | | | | | - Tetsuya Hamaguchi
- Saitama Medical University International Medical Center, Hidaka, Japan
| | - Dai Shida
- National Cancer Center Hospital, Tokyo, Japan
| | | | | | - Akio Shiomi
- Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | | | - Jun Watanabe
- Yokohama City University Medical Center, Yokohama, Japan
| | - Takeshi Suto
- Yamagata Prefectural Central Hospital, Yamagata, Japan
| | | | | | | | - Takaya Kobatake
- National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
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Sena G, Picciariello A, Marino F, Goglia M, Rocca A, Meniconi RL, Gallo G. One-Stage Total Laparoscopic Treatment for Colorectal Cancer With Synchronous Metastasis. Is It Safe and Feasible? Front Surg 2021; 8:752135. [PMID: 34869559 PMCID: PMC8637405 DOI: 10.3389/fsurg.2021.752135] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/18/2021] [Indexed: 12/28/2022] Open
Abstract
Liver is the main target organ for colorectal cancer (CRC) metastases. It is estimated that ~25% of CRC patients have synchronous metastases at diagnosis, and about 60% of CRC patients will develop metastases during the follow up. Although several teams have performed simultaneous laparoscopic resections (SLR) of liver and colorectal lesions, the feasibility and safety of this approach is still widely debated and few studies on this topic are present in the literature. The purpose of this literature review is to understand the state of the art of SLR and to clarify the potential benefits and limitations of this approach. Several studies have shown that SLR can be performed safely and with short-term outcomes similarly to the separated procedures. Simultaneous laparoscopic colorectal and hepatic resections combine the advantages of one stage surgery with those of laparoscopic surgery. Several reports compared the short-term outcomes of one stage laparoscopic resection with open resections and showed a similar or inferior amount of blood loss, a similar or lower complication rate, and a significant reduction of hospital stay for laparoscopic surgery respect to open surgery but much longer operating times for the laparoscopic technique. Few retrospective studies compared long term outcomes of laparoscopic one stage surgery with the outcomes of open one stage surgery and did not identify any differences about disease free survival and the overall survival. In conclusion, hepatic and colorectal SLR are a safe and effective approach characterized by less intraoperative blood loss, faster recovery of intestinal function, and shorter length of postoperative hospital stay. Moreover, laparoscopic approach is associated to lower rates of surgical complications without significant differences in the long-term outcomes compared to the open surgery.
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Affiliation(s)
- Giuseppe Sena
- Department of Vascular Surgery, “Pugliese-Ciaccio” Hospital, Catanzaro, Italy
| | | | - Fabio Marino
- Unit of Surgery, National Institute of Gastroenterology “Saverio de Bellis,” Research Hospital, Castellana Grotte, Italy
| | - Marta Goglia
- Department of General Surgery, “La Sapienza” University of Rome—Sant'Andrea University Hospital, Rome, Italy
| | - Aldo Rocca
- Department of Medicine and Health Sciences “V. Tiberio,” University of Molise, Campobasso, Italy
| | - Roberto L. Meniconi
- Department of General Surgery and Liver Transplantation, San Camillo Forlanini Hospital, Rome, Italy
| | - Gaetano Gallo
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro, Italy
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17
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Zhong Y, Ma T, Qiao T, Hu H, Li Z, Luo K, Wang Y, Tang Q, Wang G, Huang R, Wang X. Role of Phenotypes of Circulating Tumor Cells in the Diagnosis and Treatment of Colorectal Cancer. Cancer Manag Res 2021; 13:7077-7085. [PMID: 34531685 PMCID: PMC8439983 DOI: 10.2147/cmar.s316544] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To investigate the relationship between circulating tumor cells (CTCs) and their subpopulations and colorectal cancer (CRC). To explore the application of CTCs' numbers and positive rates in the diagnosis and treatment of CRC, and to assess the effect of surgery on CTCs numbers and positivity. METHODS We identified CTCs using the CanPatrol technique after enrollment. Peripheral blood samples were collected from 74 CRC patients before anti-tumor treatment. CTCs can be divided into the following three phenotypes: epithelial CTCs (E-CTCs) (EpCAM+, Vimentin-), mesenchymal CTCs (M-CTCs) (EpCAM-, Vimentin+), and mixed CTCs (E/M-CTCs) (EpCAM+, Vimentin+). CTCs and the proportion of subtypes were statistically compared with clinicopathological characteristics. RESULTS The positive rate of M-CTCs was significantly higher in patients with tumor size ≥5 cm (85.7% vs 49.1%, P = 0.004) and carcinoembryonic antigen (CEA) >5 ng/mL (83.3% vs 51.0% p = 0.024). Moreover, the T stage (T1 0, T2 33.3%, T3 59.4%, T4 100%, p < 0.0005) and TNM stage (stage I 11.8%, stage II 79.2%, stage III 64.3%, stage IV 100%, p < 0.0005) were correlated with the positive rate of M-CTCs. We also found that the proportion of M-CTCs was correlated with the T stage (p < 0.0005) and TNM stage (p=0.0200), but not with the N stage (p=0.6889). In survival analysis, M-CTCs >1 were found associated with worse disease-free survival (p=0.007). After treatment, the number and proportion of CTCs and M-CTCs were significantly reduced. CONCLUSION The positive rate of M-CTCs was associated with tumor size, T stage, TNM stage, vascular invasion, and CEA. As the disease progressed, the proportion of M-CTCs gradually increased, and the survival performance was worse in patients with a high positive rate of M-CTCs.
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Affiliation(s)
- Yuchen Zhong
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
- Department of Colorectal Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310002, People’s Republic of China
| | - Tianyi Ma
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Tianyu Qiao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Hanqing Hu
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Zhengliang Li
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Kangjia Luo
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Yuliuming Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Qingchao Tang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Guiyu Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
- Department of Colorectal Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310002, People’s Republic of China
| | - Rui Huang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Xishan Wang
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Cancer, Beijing, 100021, People’s Republic of China
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18
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Tajiri T, Hayashi H, Miyamoto Y, Imai K, Kitano Y, Kaida T, Sawayama H, Beppu T, Yamashita YI, Baba H. Clinical Impact of Operative Order in Laparoscopic Simultaneous Resection for Synchronous Colorectal Liver Metastases. CANCER DIAGNOSIS & PROGNOSIS 2021; 1:151-156. [PMID: 35399321 PMCID: PMC8962794 DOI: 10.21873/cdp.10020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/31/2021] [Indexed: 04/18/2023]
Abstract
BACKGROUND Curative resection for colorectal cancer and their synchronous liver metastases are increasingly performed. However, it is still unclear whether the operative order affects the surgical outcome in laparoscopic simultaneous resection of primary and liver metastatic lesions. PATIENTS AND METHODS A total of 27 patients underwent laparoscopic simultaneous resection of primary colorectal cancer and liver metastases at Kumamoto University Hospital. They were divided into two groups based on the order of resection: Colon-first (n=11) and liver-first (n=16) groups. The surgical outcomes between the two groups were retrospectively compared. RESULTS There was no significant difference in the perioperative surgical outcomes between the two groups except for operative blood loss, which was significantly less in the liver-first group [164 (range=5-820) versus 560 (range=95-2,016) ml, respectively] (p=0.0299). CONCLUSION In the simultaneous resection of primary and liver metastatic lesions, the operative order does not affect the short-term surgical outcomes except for operative blood loss.
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Affiliation(s)
- Takuya Tajiri
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - Yuki Kitano
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - Takayoshi Kaida
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | | | - Toru Beppu
- Department of Surgery, Yamaga City Hospital, Kumamoto, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
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19
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Kelm M, Schollbach J, Anger F, Wiegering A, Klein I, Germer CT, Schlegel N, Kunzmann V, Löb S. Prognostic impact of additive chemotherapy after curative resection of metachronous colorectal liver metastasis: a single-centre retrospective study. BMC Cancer 2021; 21:490. [PMID: 33941104 PMCID: PMC8091534 DOI: 10.1186/s12885-021-07941-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 02/21/2021] [Indexed: 01/05/2023] Open
Abstract
Background A prognostic benefit of additive chemotherapy in patients following resection of metachronous colorectal liver metastases (CRLM) remains controversial. Therefore, the goal of this retrospective study was to investigate the impact of perioperative chemotherapy on disease-free survival (DFS) and overall survival (OS) of patients after curative resection of metachronous CRLM. Methods In a retrospective single-centre study, patients after curative resection of metachronous CRLM were included and analysed for DFS and OS with regard to the administration of additive chemotherapy. The Kaplan-Meier method was applied to compare DFS and OS while Cox regression models were used to identify independent prognostic variables. Results Thirty-four of 75 patients were treated with additive 5-FU based chemotherapy. OS was significantly prolonged in this patient subgroup (62 vs 57 months; p = 0.032). Additive chemotherapy significantly improved 10-year survival rates (42% vs 0%, p = 0.023), but not 5-year survival (58% vs 42%, p = 0.24). Multivariate analysis identified additive chemotherapy (p = 0.016, HR 0.44, 95% CI 0.23–0.86), more than five CRLM (p = 0.026, HR 2.46, 95% CI 1.16–10.32) and disease recurrence (0.009, HR 2.70, 95% CI 1.29–5.65) as independent risk factors for OS. Conclusion Additive chemotherapy significantly prolonged OS and 10-year survival in patients after curative resection of metachronous CRLM. Randomized clinical trials are needed in the future to identify optimal chemotherapy regimens for those patients.
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Affiliation(s)
- Matthias Kelm
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.
| | - Julia Schollbach
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany
| | - Friedrich Anger
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany
| | - Armin Wiegering
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.,Theodor-Boveri-Institute, Biocenter, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.,Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany
| | - Ingo Klein
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.,Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany
| | - Christoph-Thomas Germer
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.,Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany
| | - Nicolas Schlegel
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany
| | - Volker Kunzmann
- Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany.,Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
| | - Stefan Löb
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.,Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany
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20
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Su P, Lai W, Liu L, Zeng Y, Xu H, Lan Q, Chu Z, Chu Z. Mesenchymal and Phosphatase of Regenerating Liver-3 Status in Circulating Tumor Cells May Serve as a Crucial Prognostic Marker for Assessing Relapse or Metastasis in Postoperative Patients With Colorectal Cancer. Clin Transl Gastroenterol 2020; 11:e00265. [PMID: 33512811 PMCID: PMC7743843 DOI: 10.14309/ctg.0000000000000265] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Circulating tumor cells (CTCs) and phosphatase of regenerating liver-3 (PRL-3) have been considered to be significant prognostic indicators in metastatic colorectal cancer (CRC). This study discusses the prognostic significance of mesenchymal CTCs with PRL-3 (M+ PRL-3+ CTCs) in postoperative patients with CRC. METHODS We detected CTC subtypes (including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs) and PRL-3 in CTCs from the peripheral blood samples of 156 patients. Receiver operating characteristic curve analysis, Kaplan-Meier analysis, and Cox proportional hazards regression analysis were performed to identify the prognostic value of mesenchymal CTCs with PRL-3+. Immunohistochemistry was used to detect the expression of PRL-3 in tumor tissues from some of the patients to explore the connection between CTCs and tissues. RESULTS All CTCs were positive in all samples, both mesenchymal CTCs and PRL-3-positive cells. The count of mesenchymal and PRL-3+ CTCs was significantly associated with recurrence, and the optimal cutoff value was 2 (area under the curve = 0.690, P < 0.001). In addition, these patients had a significantly shorter median disease-free survival than those who did not fulfill the criteria (8.5 vs 24 months, P < 0.001) according to multivariable and multinomial logistic regression. Immunohistochemistry was applied to explore the associations between PRL-3 expression and significant prognostic risk factors, including recurrence (R = 0.566; P < 0.001), and M+ PRL-3+ status in CTCs (R = 0.452; P = 0.001). DISCUSSION The status of M+ PRL-3+ in CTCs may serve as a crucial prognostic marker for assessing clinical outcomes in CRC.
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Affiliation(s)
- PengWei Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Lai
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lu Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yujie Zeng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Heyang Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiusheng Lan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ziqiang Chu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhonghua Chu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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21
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Yuan W, Cai W, Huang X, Peng S. Prognostic value of immune scores in the microenvironment of colorectal cancer. Oncol Lett 2020; 20:256. [PMID: 32994819 PMCID: PMC7509622 DOI: 10.3892/ol.2020.12119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 08/18/2020] [Indexed: 12/21/2022] Open
Abstract
Cancer immunotherapy has become an important means of cancer treatment; however, the complex composition and heterogeneity of the colorectal cancer (CRC) microenvironment pose a huge challenge to cancer immunotherapy. Using data downloaded from The Cancer Genome Atlas database, the differences in the microenvironment between cases with low and high immune scores were examined at the multiomics level using bioinformatics approaches. It was revealed that the samples with high immune scores had good cytolytic immune responses and relatively abundant stromal cells, as well as significant infiltration of 22 immune cell subsets and a high non-synonymous mutation burden and neoantigen burden. All of these characteristics contribute to a good prognosis. To better understand the impact of immune-related genes on prognosis, differentially expressed genes between the low and high immune score samples were identified and it was concluded that serpin family Emember 1 (SERPINE1) and ubiquitin C-terminal hydrolase L1 (UCHL1) may be potential therapeutic targets. The relationship between the immune score and the infiltration of 22 immune cells and the difference in SERPINE1 expression were verified by analyzing the GSE17536 and GSE21510 data sets downloaded from the Gene Expression Omnibus database. The present study analyzed the unique properties of immune cells in the CRC microenvironment, which are of great significance for understanding CRC immune mechanism and may also provide novel ideas for the targeted design of cancer immunotherapy.
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Affiliation(s)
- Wenliang Yuan
- Department of Data Science, College of Mathematics and Information Engineering, Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Wei Cai
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai 200093, P.R. China.,International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 200093, P.R. China
| | - Xiao Huang
- Department of Data Technology, College of Mathematics and Computer Science, Chizhou University, Chizhou, Anhui 247000, P.R. China
| | - Sihua Peng
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai 200093, P.R. China.,International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 200093, P.R. China
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22
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Zhang H, Li W, Fu C, Grimm R, Chen Z, Zhang W, Qiu L, Wang C, Zhang X, Yue L, Hu X, Guo W, Tong T. Comparison of intravoxel incoherent motion imaging, diffusion kurtosis imaging, and conventional DWI in predicting the chemotherapeutic response of colorectal liver metastases. Eur J Radiol 2020; 130:109149. [PMID: 32659615 DOI: 10.1016/j.ejrad.2020.109149] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 05/04/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To assess the usefulness and performance of intravoxel incoherent motion imaging (IVIM) with diffusion kurtosis imaging (DKI) and conventional DWI for predicting the chemotherapeutic response of colorectal liver metastases (CRLMs). METHOD A prospective study was conducted. Up to February 2018, forty consecutive patients treated with the standard first-line chemotherapy regimens were enrolled. MRI was performed within 1 week before chemotherapy, as well as 2-3 weeks and 6-8 weeks after chemotherapy. The apparent diffusion coefficient map, IVIM and DKI parameter maps were calculated using a prototype postprocessing software. The response was assessed by the Response Evaluation Criteria in Solid Tumors. The parameters were compared between the responding group (complete and partial response) and the nonresponding group (stable and progressive disease). RESULTS A total of 15 responding and 25 nonresponding patients were evaluated. Low baseline ADC, Dslow, and D values (P = 0.001, <0.001, and =0.003, respectively) and a high baseline K value (P = 0.002) were independently associated with a good response to chemotherapy. The combination of all the significant parameters yielded an AUC of 0.867. After treatment, the ADC, Dslow, and D values all showed an upward trend, while the K value showed a decreasing trend, but there were no significant differences (P > 0.05). CONCLUSION The study showed that the pretreatment IVIM (Dslow), DKI (D and K), and conventional DWI (ADC) parameters all demonstrated a good diagnostic performance in predicting the chemotherapeutic response of CRLMs.
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Affiliation(s)
- Huan Zhang
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenhua Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Caixia Fu
- MR Application Development, Siemens Shenzhen Magnetic Resonance Ltd., Shenzhen, China
| | - Robert Grimm
- MR Application Predevelopment, Siemens Healthcare, Erlangen, Germany
| | - Zhiyu Chen
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lixin Qiu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chenchen Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaowei Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Yue
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoxin Hu
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Tong Tong
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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23
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Araujo RLCD, Figueiredo MN, Sanctis MAD, Romagnolo LGC, Linhares MM, Melani AGF, Marescaux J. Decision making process in simultaneous laparoscopic resection of colorectal cancer and liver metastases. Review of literature. Acta Cir Bras 2020; 35:e202000308. [PMID: 32490901 PMCID: PMC7251979 DOI: 10.1590/s0102-865020200030000008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 01/20/2020] [Accepted: 02/22/2020] [Indexed: 12/24/2022] Open
Abstract
PURPOSE The benefits of laparoscopic approaches to treat colorectal cancer (CRC) and colorectal liver metastases (CRLM) separately are well established. However, there is no consensus about the optimal timing to approach the primary tumor and CRLM, whether simultaneously or staged. The objective of this review with practical reports is to discuss technical aspects required for patient selection to perform simultaneous laparoscopic approaches for CRC and CRLM. METHODS Literature review of oncological factors associated with patient selection for surgical treatment of CRLM and the use of laparoscopy in those cases, and report of technical aspects for simultaneous CRC and CRLM approaches. RESULTS Simultaneous laparoscopic resection has been successful in many series of selected patients, although it seems to be safer to perform minor and major liver resection with non-extended colorectal resections, and to avoid two high-risk procedures at the same time. CONCLUSIONS Simultaneous CRC and CRLM resections seem to be safe when patients are carefully selected, also considering the risk of recurrence concerning oncologic outcomes. The pre-planning of simultaneous resection is mandatory to plan trocar positioning, procedure sequencing, and patient position.
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Affiliation(s)
| | | | | | | | | | | | - Jacques Marescaux
- MD, Research Institute against Cancer of the Digestive System, Strasbourg, France. Manuscript writing, critical revision
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24
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Zhang Y, Wang Y, Yuan Y, Qiu J, Qiu Y, He W, Zheng Y, Wang Z, Gu Y, Lu Z, Chen G, Ding P, Wu X, Pan Z, Wan D, Li Y, Xu R, Yuan Y, Li B. Primary tumor location affects recurrence-free survival for patients with colorectal liver metastases after hepatectomy: a propensity score matching analysis. World J Surg Oncol 2020; 18:98. [PMID: 32423450 PMCID: PMC7236531 DOI: 10.1186/s12957-020-01875-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/07/2020] [Indexed: 01/05/2023] Open
Abstract
Background Whether primary tumor location of colorectal cancer (CRC) affects survival of patients after resection of liver metastases remains controversial. This study was conducted to investigate the differences in clinicopathological characteristics and prognosis between right-sided CRC and left-sided CRC patients with liver metastases after hepatectomy. Methods From 2002 to 2018, 611 patients with colorectal liver metastases (CRLM) who underwent hepatectomy at our center were reviewed. Primary tumors located from the cecum to transverse colon were defined as right-sided group (n = 141); tumors located from the splenic flexure to rectum were defined as left-sided group (n = 470). Patients were compared between two groups before and after a 1:1 propensity score matching (PSM) analysis. Results Before PSM, median survival time and 5-year overall survival (OS) rate in right-sided group were 77 months and 56.3%, and those in left-sided group were 64 months and 51.1%, respectively. After PSM, median survival time and 5-year OS rate in right-sided group were 77 months and 55.9%, and those in left-sided group were 58.8 months and 47.3%, respectively. The OS rates did not differ between two groups before and after PSM (P = 0.575, P = 0.453). However, significant different recurrence-free survival (RFS) rate was found before and after PSM between right-sided and left-sided group (P = 0.028, P = 0.003). Conclusions Compared to patients with left-sided primary tumors, patients with right-sided primary tumors had a worse RFS but similar OS. Careful preoperative evaluation, intensive preoperative chemotherapy, and frequent follow-up to detect early recurrence might be justified for CRLM patients with right-sided primary tumors.
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Affiliation(s)
- Yuanping Zhang
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yongjin Wang
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yichuan Yuan
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jiliang Qiu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yuxiong Qiu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wei He
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yun Zheng
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhiqiang Wang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yangkui Gu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Microinvasive Interventional Department, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhenhai Lu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Gong Chen
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Peirong Ding
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaojun Wu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhizhong Pan
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Desen Wan
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yuhong Li
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Microinvasive Interventional Department, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ruihua Xu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Microinvasive Interventional Department, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yunfei Yuan
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China. .,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China. .,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - Binkui Li
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China. .,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China. .,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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25
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Hou J, Guo C, Lyu G. Clinical significance of epithelial-mesenchymal transition typing of circulating tumour cells in colorectal cancer. Colorectal Dis 2020; 22:581-587. [PMID: 31868956 DOI: 10.1111/codi.14927] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 11/05/2019] [Indexed: 12/14/2022]
Abstract
AIM The aim was to determine the diagnostic value of epithelial-mesenchymal transition typing of circulating tumour cells (CTCs) in colorectal cancer (CRC). METHOD Peripheral blood samples were collected from 51 CRC patients before anti-tumour treatment from April 2016 to June 2018 at the Peking University Shenzhen Hospital. The blood samples were analysed using the CanPatrol CTC typing technique (SurExam, Guangzhou, China), which combines nanomembrane enrichment with mRNA in situ hybridization. Based on the marker expression, the CTCs were classified into epithelial, epithelial mesenchymal and mesenchymal (M-CTC) types. The correlation between the CTC counts and clinicopathological characteristics such as gender, age, TNM stage, lymph node metastasis and distant metastasis were analysed by univariate and multivariate Cox regression models. The overall survival and progression-free survival (PFS) of patients demarcated by CTC typing were analysed using the Kaplan-Meier method and log-rank tests. RESULT M-CTCs were detected more frequently in patients with lymph node metastasis (N2 81.8%; N1 72.7%; N0 38.9%) as well as distant metastasis (M0 50%; M1a 81.25%; M1b 85.7%) compared to those without metastasis. In addition, the presence of M-CTCs was significantly correlated with distant metastasis (P < 0.01). Univariate analysis showed that lymph node metastasis (P = 0.035), distant metastasis (P < 0.001) and total CTC count ≥ 4 (P = 0.007) and M-CTC count ≥ 1 (P < 0.001) were significantly associated with unfavourable PFS, and lymph node metastasis (P = 0.04), distant metastasis (P = 0.01) and M-CTC count ≥ 1 (P < 0.001) were significantly associated with unfavourable overall survival. Multivariate analysis showed that the presence of M-CTCs was the only independent prognostic factor for poor PFS, and patients with M-CTCs had significantly shorter PFS than those without (P = 0.011). CONCLUSION M-CTCs are significantly associated with CRC severity and metastasis, and M-CTC count is an independent predictor of prognosis.
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Affiliation(s)
- J Hou
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - C Guo
- Department of Biology, Southern University of Science and Technology, Shenzhen, China
| | - G Lyu
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, China
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26
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Vaz da Silva DG, Ribeiro HSC, Arra DASM, Torres SM, Diniz AL, Godoy AL, Farias IC, Costa WL, Coimbra FJF. Predictors of long-term survival in patients with hepatic resection of colorectal metastases: Analysis of a Brazilian Cancer Center Cohort. J Surg Oncol 2020; 121:893-900. [PMID: 32153041 DOI: 10.1002/jso.25893] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 02/22/2020] [Indexed: 11/09/2022]
Abstract
BACKGROUND Hepatic metastases are a major cause of death in patients with colorectal cancer. A comprehensive assessment of the prognostic factors associated with long-term survival could improve patient selection for surgical approaches and decrease morbidity and futile locoregional treatments. METHODS We performed a retrospective analysis of patients who underwent hepatectomy for colorectal liver metastases at a single center from 2000 to 2012. RESULTS To identify factors associated with 5- and 10-year overall (OS) and disease-free survival (DFS), we analyzed 280 patients and 150 patients in the 5- and 10-year cohorts, respectively. Only seven relapses occurred after 5 years of follow-up, and no relapses occurred after 10 years. Multivariable analysis indicated that bilobar disease and extra-hepatic disease before hepatectomy were independent 5- and 10-year predictors of OS, and major postoperative complications predicted OS in the 5-year survival cohort only. Our analysis indicated that prognostic factors associated with DFS included some confounders and was therefore inconclusive. CONCLUSIONS Taken together, our results suggest that the predictors of 5- and 10-year OS rates of colorectal cancer patients with hepatic metastases are similar, differing only by postoperative complications that influenced exclusively 5-year survival. Since no relapse occurred 10 years after hepatic resection, oncological remission is likely.
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Affiliation(s)
| | - Heber S C Ribeiro
- Department of Abdominal Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil
| | - Dante A S M Arra
- Department of Abdominal Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil
| | - Silvio M Torres
- Department of Abdominal Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil
| | - Alessandro L Diniz
- Department of Abdominal Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil
| | - André L Godoy
- Department of Abdominal Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil
| | - Igor C Farias
- Department of Abdominal Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil
| | - Wilson L Costa
- Department of Abdominal Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil.,Department of Medicine, Epidemiology, and Population Sciences, Dan L Duncan Comprehensive, Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Felipe J F Coimbra
- Department of Abdominal Surgery, A. C. Camargo Cancer Center, São Paulo, Brazil
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28
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Araujo RLC, Milani JM, Armentano DP, Moreira RB, Pinto GSF, de Castro LA, Lucchesi FR. Disappearing colorectal liver metastases: Strategies for the management of patients achieving a radiographic complete response after systemic chemotherapy. J Surg Oncol 2019; 121:848-856. [PMID: 31773747 DOI: 10.1002/jso.25784] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 11/14/2019] [Indexed: 12/12/2022]
Abstract
The mainstays of treatment for colorectal liver metastases (CRLMs) are surgery and chemotherapy. Chemotherapeutic benefits of tumor shrinkage and systemic control of micrometastases are in part counterbalanced by chemotoxicity that can modify the liver parenchyma, jeopardizing the detection of CRLM. This review addresses the clinical decision-making process in the context of radiographic and pathologic responses, the preoperative imaging workup, and the approaches to the liver for CRLM, which disappear after systemic chemotherapy.
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Affiliation(s)
- Raphael L C Araujo
- Department of Digestive Surgery, Escola Paulista de Medicina - UNIFESP, São Paulo, Brazil.,Department of Oncology, Americas Medical Service/Brazil, United Health Group, São Paulo, Brazil.,Hospital Israelita Albert Einstein, São Paulo, Brazil.,Post-Graduation Program, Barretos Cancer Hospital, Barretos, Brazil
| | - Jean Michel Milani
- Department of Digestive Surgery, Escola Paulista de Medicina - UNIFESP, São Paulo, Brazil
| | | | - Raphael Brandão Moreira
- Department of Oncology, Americas Medical Service/Brazil, United Health Group, São Paulo, Brazil
| | - Gustavo S F Pinto
- Department of Clinical Oncology, Barretos Cancer Hospital, Barretos, Brazil
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29
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Triantafyllidis I, Gayet B, Tsiakyroudi S, Tabchouri N, Beaussier M, Bennamoun M, Sarran A, Lefevre M, Louvet C, Fuks D. Perioperative and long-term outcomes of laparoscopic liver resections for non-colorectal liver metastases. Surg Endosc 2019; 34:3833-3844. [PMID: 31586246 DOI: 10.1007/s00464-019-07148-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 09/24/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND Liver is a common metastatic site not only of colorectal but of non-colorectal neoplasms, as well. However, resection of non-colorectal liver metastases (NCRLMs) remains controversial. The aim of this retrospective study was to analyze the short- and long-term outcomes of patients undergoing laparoscopic liver resection (LLR) for NCRLMs. METHODS From a prospectively maintained database between 2000 and 2018, patients undergoing LLR for colorectal liver metastases (CRLMs) and NCRLMs were selected. Clinicopathologic, operative, short- and long-term outcome data were collected, analyzed, and compared among patients with CRLMs and NCRLMs. RESULTS The primary tumor was colorectal in 354 (82.1%), neuroendocrine in 21 (4.9%), and non-colorectal, non-neuroendocrine in the remaining 56 (13%) patients. Major postoperative morbidities were 12.7%, 19%, and 3.6%, respectively (p = 0.001), whereas the mortality was 0.6% for patients with CRLMs and zero for patients with NCRLMs. The rate of R1 surgical margin was comparable (p = 0.432) among groups. According to the survival analysis, 3- and 5-year recurrence-free survival (RFS) rates were 76.1% and 64.3% in the CRLM group, 57.1% and 42.3% in the neuroendocrine liver metastase (NELM) group, 33% and 20.8% in the non-colorectal, non-neuroendocrine liver metastase (NCRNNELM) group (p = 0.001), respectively. Three- and 5-year overall survival (OS) rates were 88.3% and 82.7% in the CRLM group, 85.7% and 70.6% in the NELM group, 71.4% and 52.9% in the NCRNNELM group (p = 0.001), respectively. In total, 113 out of 354 (31.9%) patients with CRLMs, 2 out of 21(9.5%) with NELMs, and 8 out of 56 (14.3%) patients with NCRNNELMs underwent repeat LLR for recurrent metastatic tumors. CONCLUSION LLR is safe and feasible in the context of a multimodal management where an aggressive surgical approach, necessitating even complex procedures for bilobar multifocal metastases and repeat hepatectomy for recurrences, is the mainstay and may be of benefit in the long-term survival, in selected patients with NCRNNELMs.
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Affiliation(s)
- Ioannis Triantafyllidis
- Department of Digestive Oncologic and Metabolic Surgery, Institut Mutualiste Montsouris, Université Paris Descartes, 42 Boulevard Jourdan, 75014, Paris, France.,Department of General Surgery, General Hospital of Veria, 59132, Veria, Greece
| | - Brice Gayet
- Department of Digestive Oncologic and Metabolic Surgery, Institut Mutualiste Montsouris, Université Paris Descartes, 42 Boulevard Jourdan, 75014, Paris, France
| | - Sofia Tsiakyroudi
- Department of Digestive Oncologic and Metabolic Surgery, Institut Mutualiste Montsouris, Université Paris Descartes, 42 Boulevard Jourdan, 75014, Paris, France
| | - Nicolas Tabchouri
- Department of Digestive Oncologic and Metabolic Surgery, Institut Mutualiste Montsouris, Université Paris Descartes, 42 Boulevard Jourdan, 75014, Paris, France
| | - Marc Beaussier
- Department of Digestive Oncologic and Metabolic Surgery, Institut Mutualiste Montsouris, Université Paris Descartes, 42 Boulevard Jourdan, 75014, Paris, France
| | - Mostefa Bennamoun
- Department of Oncology, Institut Mutualiste Montsouris, 42 Boulevard Jourdan, 75014, Paris, France
| | - Anthony Sarran
- Department of Radiology, Institut Mutualiste Montsouris, 42 Boulevard Jourdan, 75014, Paris, France
| | - Marine Lefevre
- Department of Pathology, Institut Mutualiste Montsouris, 42 Boulevard Jourdan, 75014, Paris, France
| | - Christophe Louvet
- Department of Oncology, Institut Mutualiste Montsouris, 42 Boulevard Jourdan, 75014, Paris, France
| | - David Fuks
- Department of Digestive Oncologic and Metabolic Surgery, Institut Mutualiste Montsouris, Université Paris Descartes, 42 Boulevard Jourdan, 75014, Paris, France.
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Wang XY, Zhang R, Wang Z, Geng Y, Lin J, Ma K, Zuo JL, Lu L, Zhang JB, Zhu WW, Chen JH. Meta-analysis of the association between primary tumour location and prognosis after surgical resection of colorectal liver metastases. Br J Surg 2019; 106:1747-1760. [PMID: 31386192 DOI: 10.1002/bjs.11289] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 05/14/2019] [Accepted: 05/28/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Primary tumour location is emerging as an important prognostic factor in localized and metastatic colorectal cancers. However, its prognostic role in colorectal liver metastasis (CRLM) after hepatectomy remains controversial. A systematic review and meta-analysis was undertaken to evaluate its prognostic value. METHODS References were identified through searches of PubMed, Embase, Web of Science and the Cochrane Library comparing overall or disease-free survival after hepatic resection between patients with CRLM originating from right- or left-sided colorectal cancers. Data were pooled using hazard ratios (HRs) and 95 per cent confidence intervals according to a random-effects model. Meta-regression and subgroup analyses were conducted to assess the effect of underlying confounding factors on HR estimates and to adjust for this. RESULTS The final analysis included 21 953 patients from 45 study cohorts. Compared with left-sided primary tumour location, right-sided location was associated with worse overall survival (HR 1·39, 95 per cent c.i. 1·28 to 1·51; P < 0·001; prediction interval 1·00 to 1·93), and also tended to have a negative impact on disease-free survival (HR 1·18, 1·06 to 1·32; P = 0·004; prediction interval 0·79 to 1·75). Subgroup analysis showed that the negative effect of right-sided primary tumour location on overall survival was more prominent in the non-Asian population (HR 1·47, 1·33 to 1·62) than the Asian population (HR 1·18, 1·05 to 1·32) (P for interaction <0·01). CONCLUSION This study demonstrated a prognostic role for primary tumour location in patients with CRLM receiving hepatectomy, especially regarding overall survival. Adding primary tumour location may provide important optimization of prognosis prediction models for CRLM in current use.
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Affiliation(s)
- X-Y Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - R Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - Z Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - Y Geng
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - J Lin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - K Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - J-L Zuo
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - L Lu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - J-B Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - W-W Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
| | - J-H Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Cancer Metastasis, Fudan University, Shanghai, China
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Wang L, Zhou S, Zhang W, Wang J, Wang M, Hu X, Liu F, Zhang Y, Jiang B, Yuan H. Circulating tumor cells as an independent prognostic factor in advanced colorectal cancer: a retrospective study in 121 patients. Int J Colorectal Dis 2019; 34:589-597. [PMID: 30627849 DOI: 10.1007/s00384-018-03223-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE This study aimed to evaluate the prognostic value of circulating tumor cells (CTCs) in advanced colorectal cancer (CRC) patients during chemotherapy course. METHODS From January 2016 to September 2017, the clinicopathological variables, such as gender, age, tumor location, tumor de-differentiation, depth of invasion, lymphatic invasion, distant metastasis, TNM stage, CTCs enumeration during 2-6 cycles of chemotherapy, and serum carcinoembryonic antigen (CEA) level during the same period, of 121 newly acquired and histopathologically confirmed CRC patients were collected from the Shanghai Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine. All patients were followed up for survival until the end of November 2018. Statistical analysis focused on the associations between CTCs counts and clinicopathological variables. Overall survival (OS) and progression-free survival (PFS) among different prognostic factors were calculated using the Kaplan-Meier method, and the differences between the survival curves were compared by using the log-rank test. Factors of prognostic significance were investigated with the multivariate Cox regression analysis. RESULTS Here, 71 of 121 patients were CTC-positive, in which CTC-positive rate was positively correlated with the depth of invasion, lymphatic invasion, distant metastasis, TNM stage, and serum CEA level (P < 0.05 for all). However, no significant difference was found between CTC-positive and other clinicopathological variables (P > 0.05 for all), such as gender, age, tumor location, and tumor de-differentiation. CTCs counts gradually increased with the advancement of depth of invasion (P = 0.002), lymphatic invasion (P = 0.004), distant metastasis (P = 0.007), TNM stage (P = 0.001), serum CEA level (P = 0.001), and decreased tumor de-differentiation (P = 0.011). Furthermore, the Kaplan-Meier survival curves showed that patients with CTC-positive had a significantly unfavorable PFS (14 vs. 23 months, P = 0.001) and OS (18 vs. 25 months, P = 0.003). The multivariate Cox regression analyses revealed that the presence of CTCs during chemotherapy was an independent factor for unfavorable PFS (hazard ratio (HR) 2.682, P = 0.017, 95% confidence interval (CI) 1.193-6.029) and OS (HR 2.790, P = 0.048, 95% CI 1.010-7.705) in advanced CRC patients. CONCLUSIONS This study provided an evidence that the presence of CTCs may be valuable for predicting survival outcome, and CTCs was associated with unfavorable survival in advanced CRC patients during chemotherapy.
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Affiliation(s)
- Lili Wang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China
| | - Shichao Zhou
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China
| | - Wenying Zhang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China
| | - Jiongyi Wang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China
| | - Meiling Wang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China
| | - Xiaohua Hu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China
| | - Feng Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China
| | - Yanjie Zhang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China
| | - Bin Jiang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China.
| | - Haihua Yuan
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China.
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Xu F, Tang B, Jin TQ, Dai CL. Current status of surgical treatment of colorectal liver metastases. World J Clin Cases 2018; 6:716-734. [PMID: 30510936 PMCID: PMC6264988 DOI: 10.12998/wjcc.v6.i14.716] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 09/14/2018] [Accepted: 10/22/2018] [Indexed: 02/05/2023] Open
Abstract
Liver metastasis (LM) is one of the major causes of death in patients with colorectal cancer (CRC). Approximately 60% of CRC patients develop LM during the course of their illness. About 85% of these patients have unresectable disease at the time of presentation. Surgical resection is currently the only curative treatment for patients with colorectal LM (CRLM). In recent years, with the help of modern multimodality therapy including systemic chemotherapy, radiation therapy, and surgery, the outcomes of CRLM treatment have significantly improved. This article summarizes the current status of surgical treatment of CRLM including evaluation of resectability, treatment for resectable LM, conversion therapy and liver transplantation for unresectable cases, liver resection for recurrent CRLM and elderly patients, and surgery for concomitant hepatic and extra-hepatic metastatic disease (EHMD). We believe that with the help of modern multimodality therapy, an aggressive oncosurgical approach should be implemented as it has the possibility of achieving a cure, even when EHMD is present in patients with CRLM.
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Affiliation(s)
- Feng Xu
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning Province, China
| | - Bin Tang
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning Province, China
| | - Tian-Qiang Jin
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning Province, China
| | - Chao-Liu Dai
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning Province, China
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33
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QUIREZE JUNIOR C, BRASIL AMS, MORAIS LK, CAMPION ERL, TAVEIRA EJF, RASSI MC. METACHRONOUS COLORECTAL LIVER METASTASES HAS BETTER PROGNOSIS - IS IT TRUE? ARQUIVOS DE GASTROENTEROLOGIA 2018; 55:258-263. [DOI: 10.1590/s0004-2803.201800000-64] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 04/05/2018] [Indexed: 12/24/2022]
Abstract
ABSTRACT BACKGROUND: Liver metastases from colorectal cancer are an important public health problem due to the increasing incidence of colorectal cancer worldwide. Synchronous colorectal liver metastasis has been associated with worse survival, but this prognosis is controversial. OBJECTIVE: The objective of this study was to evaluate the recurrence-free survival and overall survival between groups of patients with metachronous and synchronous colorectal hepatic metastasis. METHODS: This was a retrospective analysis of medical records of patients with colorectal liver metastases seen from 2013 to 2016, divided into a metachronous and a synchronous group. The Cox regression model and the Kaplan-Meier method with log-rank test were used to compare survival between groups. RESULTS: The mean recurrence-free survival was 9.75 months and 50% at 1 year in the metachronous group and 19.73 months and 63.3% at 1 year in the synchronous group. The mean overall survival was 20.00 months and 6.2% at 3 years in the metachronous group and 30.39 months and 31.6% at 3 years in the synchronous group. Patients with metachronous hepatic metastasis presented worse overall survival in multivariate analysis. The use of biological drugs combined with chemotherapy was related to the best overall survival prognosis. CONCLUSION: Metachronous colorectal hepatic metastasis was associated with a worse prognosis for overall survival. There was no difference in recurrence-free survival between metachronous and synchronous metastases.
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34
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Mauri D, Zarkavelis G, Filis P, Tsali L, Zafeiri G, Papadaki A, Vassou A, Georgopoulos C, Pentheroudakis G. Postoperative chemotherapy with single-agent fluoropyrimidines after resection of colorectal cancer liver metastases: a meta-analysis of randomised trials. ESMO Open 2018; 3:e000343. [PMID: 30018809 PMCID: PMC6045754 DOI: 10.1136/esmoopen-2018-000343] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 03/21/2018] [Accepted: 03/22/2018] [Indexed: 12/21/2022] Open
Abstract
Surgical resection is the only option of cure for patients with metastatic colorectal cancer. Risk of recurrence after metastasectomy is around 75%. Use of adjuvant chemotherapy after metastasectomy is controversial.
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Affiliation(s)
- Davide Mauri
- Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.,Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN)
| | - George Zarkavelis
- Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.,Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN)
| | - Panagiotis Filis
- Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.,Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN)
| | - Lampriani Tsali
- Department of Internal Medicine, General Hospital of Arta, Arta, Greece
| | - Georgia Zafeiri
- Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.,Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN)
| | - Alexandra Papadaki
- Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece
| | - Amalia Vassou
- Department of Hematology, Ioannina University Hospital, Ioannina, Greece
| | - Christos Georgopoulos
- Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece
| | - George Pentheroudakis
- Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece
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35
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Zhou G, Noordam L, Sprengers D, Doukas M, Boor PPC, van Beek AA, Erkens R, Mancham S, Grünhagen D, Menon AG, Lange JF, Burger PJWA, Brandt A, Galjart B, Verhoef C, Kwekkeboom J, Bruno MJ. Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer. Oncoimmunology 2018; 7:e1448332. [PMID: 29900067 PMCID: PMC5993483 DOI: 10.1080/2162402x.2018.1448332] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 02/06/2023] Open
Abstract
Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.
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Affiliation(s)
- Guoying Zhou
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Lisanne Noordam
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Dave Sprengers
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Patrick P C Boor
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Adriaan A van Beek
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Remco Erkens
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Shanta Mancham
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Dirk Grünhagen
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Anand G Menon
- Department of Surgery, Havenziekenhuis and IJsselland Hospital, Rotterdam, the Netherlands
| | - Johan F Lange
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Pim J W A Burger
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Alexandra Brandt
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Boris Galjart
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Cornelis Verhoef
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Jaap Kwekkeboom
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Marco J Bruno
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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36
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Ang C, Herran LA, Lagunes DR, Klimstra DS, Kemeny NE. A Case Report of a Patient with Advanced Acinar Cell Carcinoma of the Pancreas: Long-Term Survival with Regional, Systemic and Targeted Therapy. TUMORI JOURNAL 2018; 99:e61-4. [DOI: 10.1177/030089161309900230] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Acinar cell carcinoma of the pancreas is an uncommon malignancy for which there are no prospective, randomized data to guide therapy. We describe the clinical course and management of a patient with advanced pancreatic acinar cell carcinoma who is alive seven years after diagnosis using systemic and regional chemotherapies as well as molecularly targeted agents.
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Affiliation(s)
- Celina Ang
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY
| | | | - Diane Reidy Lagunes
- Department of Medicine, Gastrointestinal Oncology Service, New York, NY, USA
| | - David S Klimstra
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Nancy E Kemeny
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY
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37
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Giuliani J, Bonetti A. The Pharmacological Costs of Complete Liver Resections in Unselected Advanced Colorectal Cancer Patients: Focus on Targeted Agents. A Review of Randomized Clinical Trials. J Gastrointest Cancer 2017; 47:341-350. [PMID: 27488729 DOI: 10.1007/s12029-016-9862-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the pharmacological costs of conversion chemotherapy with targeted biological agents in an unselected population of advanced colorectal cancer (CRC) patients in order to achieve an R0 liver resection. METHODS Full reports and updates of randomized clinical trials (RCTs) that compared at least two front-line therapy regimens with targeted biological agents for advanced CRC patients were selected. The present evaluation was restricted to randomized phase II and III trials. The costs of drugs are at the Pharmacy Hospital and are expressed in euros (€). RESULTS Our study began with the evaluation of 683 abstracts. Forty-eight trials were considered appropriate for further analysis. A more in-depth evaluation looking for the trials reporting the liver resection rates following conversion chemotherapy brought to the exclusion of other 37 trials, leaving 11 randomized trials (three phase II trials, including 522 patients and eight phase III trials, including 7191 patients). The pharmacological costs of conversion therapy increased with the substitution of prolonged infusion 5-Fluorouracil by capecitabine and, to a much higher extent, with the introduction of biologicals. CONCLUSIONS Two key issues are presented in this review. First, the pharmacological costs of commonly used front line regimens based on the targeted biological agents for the treatment of advanced CRC are highly variable. Second, the performance of the published schemes, in terms of resection rates, depends on patient's selection, tumor characteristics, and on the type of the scheme.
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Affiliation(s)
- Jacopo Giuliani
- Department of Medical Oncology, Mater Salutis Hospital, AULSS 21 della Regione Veneto, Legnago, VR, Italy. .,Department of Medical Oncology, ASL 21 della Regione Veneto, Via Gianella 1, 37045, Legnago, VR, Italy.
| | - Andrea Bonetti
- Department of Medical Oncology, Mater Salutis Hospital, AULSS 21 della Regione Veneto, Legnago, VR, Italy.,Department of Medical Oncology, ASL 21 della Regione Veneto, Via Gianella 1, 37045, Legnago, VR, Italy
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38
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Araujo RLC, Riechelmann RP, Fong Y. Patient selection for the surgical treatment of resectable colorectal liver metastases. J Surg Oncol 2016; 115:213-220. [PMID: 27778357 DOI: 10.1002/jso.24482] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Accepted: 09/30/2016] [Indexed: 12/14/2022]
Abstract
Advances in surgery and chemotherapy regimens have increased the long-term survival of patients with colorectal liver metastases (CRLM). Although liver resection remains an essential part of any curative strategy for resectable CRLM, chemotherapy regimens have also improved the long-term outcomes. However, the optimal timing for chemotherapy regimens remains unclear. Thus, this review addressed key points to aid the decision-making process regarding the timing of chemotherapy and surgery for patients with resectable CRLM. J. Surg. Oncol. 2017;115:213-220. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Raphael L C Araujo
- Department of Upper Gastrointestinal and Hepato-Pancreato-Biliary Surgery, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Rachel P Riechelmann
- Department of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, University of São Paulo Medical School, São Paulo, Brazil
| | - Yuman Fong
- Department of Surgery, City of Hope National Medical Center, Duarte, California
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39
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Morad SA, Bridges LC, Almeida Larrea AD, Mayen AL, MacDougall MR, Davis TS, Kester M, Cabot MC. Short-chain ceramides depress integrin cell surface expression and function in colorectal cancer cells. Cancer Lett 2016; 376:199-204. [DOI: 10.1016/j.canlet.2016.03.049] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 03/23/2016] [Accepted: 03/24/2016] [Indexed: 12/20/2022]
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Kanat O. Current treatment options for patients with initially unresectable isolated colorectal liver metastases. World J Clin Oncol 2016; 7:9-14. [PMID: 26862487 PMCID: PMC4734940 DOI: 10.5306/wjco.v7.i1.9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 10/02/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
The development of liver metastases is a common clinical entity in the clinical course of colorectal cancer. For patients with isolated liver involvement, surgical resection is the only treatment that can provide a chance of prolonged survival and cure. However, most of these patients are not initially eligible for the surgery. Selected patients with initially considered to have unresectable disease may become resectable after systemic (chemotherapy ± biological therapy) and loco-regional treatment modalities including hepatic arterial infusion. Patients who have colorectal liver metastases ideally should be referred to a multidisciplinary cancer care team in order to identify the most optimal management approach.
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Cho M, Gong J, Fakih M. The state of regional therapy in the management of metastatic colorectal cancer to the liver. Expert Rev Anticancer Ther 2016; 16:229-45. [PMID: 26652741 DOI: 10.1586/14737140.2016.1129277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the United States. Most colorectal cancer patients die from advanced disease, and two-thirds of CRC deaths are due to liver metastases. Liver resection provides the best curative option for patients with colorectal liver metastases (CRLM), yet only 20% of those patients are eligible for liver metastases resection for curative intent. Loco-regional treatment of CRLM may provide additional benefits in terms of down-staging for resection and prolonged hepatic disease control. This review focusses on hepatic arterial infusion, radioembolization and chemoembolization.
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Affiliation(s)
- May Cho
- a Department of Medical Oncology , City of Hope National Medical Center , Duarte , CA , USA
| | - Jun Gong
- a Department of Medical Oncology , City of Hope National Medical Center , Duarte , CA , USA
| | - Marwan Fakih
- a Department of Medical Oncology , City of Hope National Medical Center , Duarte , CA , USA
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Qadan M, D'Angelica MI. Complex Surgical Strategies to Improve Resectability in Borderline-Resectable Disease. CURRENT COLORECTAL CANCER REPORTS 2015; 11:369-377. [PMID: 28090195 DOI: 10.1007/s11888-015-0290-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is the third most common malignancy in the USA and continues to pose a significant epidemiologic problem, despite major advances in the treatment of patients with advanced disease. Up to 50 % of patients will develop metastatic disease at some point during the course of their disease, with the liver being the most common site of metastatic disease. In this review, we address the relatively poorly defined entity of borderline-resectable colorectal liver metastases. The workup and staging of borderline-resectable disease are discussed. We then discuss management strategies, including surgical techniques and medical therapies, which are currently utilized in order to improve resectability.
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Affiliation(s)
- Motaz Qadan
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, C898, New York, NY 10065, USA
| | - Michael I D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, C898, New York, NY 10065, USA
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Bouchaibi SE, Coenegrachts K, Bali MA, Absil J, Metens T, Matos C. Focal liver lesions detection: Comparison of respiratory-triggering, triggering and tracking navigator and tracking-only navigator in diffusion-weighted imaging. Eur J Radiol 2015; 84:1857-65. [PMID: 26119802 DOI: 10.1016/j.ejrad.2015.06.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 06/14/2015] [Accepted: 06/16/2015] [Indexed: 12/13/2022]
Abstract
PURPOSE To compare low b value (10s/mm(2)) spin-echo echo-planar (SE-EP) diffusion-weighted imaging (DWI) acquired with respiratory-triggering (RT), triggering and tracking navigator (TT), tracking only navigator (TRON) techniques for image quality and focal liver lesions (FLL) detection in non-cirrhotic patients. MATERIAL AND METHODS This bi-centric study was approved by the institutional review boards; informed consent was obtained. Eighty-three patients were prospectively included and SE-EP-DWI with RT, TT and TRON techniques were performed. DWI sequences were randomized and independently analyzed by two readers. The qualitative evaluation was based on a 3-point score for axial artifacts (motion, ghost, susceptibility artifacts and distortion) and stair-step artifacts. Sensitivity of FLL detection was calculated for all lesions together and after lesion size stratification (≤ 10 mm, >10-20mm and >20mm). The standard of reference consisted of a retrospective reading of the conventional MRI, the three DWI sequences and by follow-up (12 months): a total of 409 FLL were detected. Data between sequences was compared with non-parametric tests. Cohen's kappa coefficient was used for inter-observer agreement. RESULTS Image quality was comparable for RT and TT. TRON showed statistically significantly more axial artifacts for the two readers (p<0.05). Stair-step artifacts were not statistically significantly different between DWI sequences. Overall sensitivities for RT, TT, TRON were 85%, 86%, 82% and 86%, 89% 83%, respectively, for readers 1 and 2. The inter-observer agreement was very good. CONCLUSION Image quality was better for RT and TT compared to TRON. Overall sensitivities for FLL detection were comparable between techniques and readers.
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Affiliation(s)
- Said El Bouchaibi
- Department of Radiology, Clinics of MRI, Hôpital Erasme Université Libre de Bruxelles, 808 Route de Lennik B, 1070 Bruxelles, Belgium
| | - Kenneth Coenegrachts
- Department of Radiology AZ Sint-Jan Brugge - Oostende AV, Campus Brugge, Ruddershove 10, B-8000 Brugge, Belgium
| | - Maria Antonietta Bali
- Department of Radiology, Clinics of MRI, Hôpital Erasme Université Libre de Bruxelles, 808 Route de Lennik B, 1070 Bruxelles, Belgium
| | - Julie Absil
- Department of Radiology, Clinics of MRI, Hôpital Erasme Université Libre de Bruxelles, 808 Route de Lennik B, 1070 Bruxelles, Belgium
| | - Thierry Metens
- Department of Radiology, Clinics of MRI, Hôpital Erasme Université Libre de Bruxelles, 808 Route de Lennik B, 1070 Bruxelles, Belgium.
| | - Celso Matos
- Department of Radiology, Clinics of MRI, Hôpital Erasme Université Libre de Bruxelles, 808 Route de Lennik B, 1070 Bruxelles, Belgium
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44
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Pedroza-Gonzalez A, Zhou G, Vargas-Mendez E, Boor PP, Mancham S, Verhoef C, Polak WG, Grünhagen D, Pan Q, Janssen HLA, Garcia-Romo GS, Biermann K, Tjwa ET, IJzermans JN, Kwekkeboom J, Sprengers D. Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors. Oncoimmunology 2015; 4:e1008355. [PMID: 26155417 DOI: 10.1080/2162402x.2015.1008355] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 12/24/2014] [Accepted: 01/10/2015] [Indexed: 02/06/2023] Open
Abstract
CD4+ type 1 T regulatory (Tr1) cells have a crucial role in inducing tolerance. Immune regulation by these cells is mainly mediated through the secretion of high amounts of IL-10. Several studies have suggested that this regulatory population may be involved in tumor-mediated immune-suppression. However, direct evidence of a role for Tr1 cells in human solid tumors is lacking. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC; n = 39) or liver metastases from colorectal cancer (LM-CRC; n = 60) we identify a CD4+FoxP3-IL-13-IL-10+ T cell population in tumors of individuals with primary or secondary liver cancer that is characterized as Tr1 cells by the expression of CD49b and the lymphocyte activation gene 3 (LAG-3) and strong suppression activity of T cell responses in an IL-10 dependent manner. Importantly, the presence of tumor-infiltrating Tr1 cells is correlated with tumor infiltration of plasmacytoid dendritic cells (pDCs). pDCs exposed to tumor-derived factors enhance IL-10 production by Tr1 cells through up-regulation of the inducible co-stimulatory ligand (ICOS-L). These findings suggest a role for pDCs and ICOS-L in promoting intra-tumoral immunosuppression by Tr1 cells in human liver cancer, which may foster tumor progression and which might interfere with attempts of immunotherapeutic intervention.
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Affiliation(s)
- Alexander Pedroza-Gonzalez
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands ; Laboratory of Immunology Research and Medicine; Higher Studies Iztacala; National Autonomous University of Mexico; FES-Iztacala; UNAM , Mexico
| | - Guoying Zhou
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Ernesto Vargas-Mendez
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Patrick Pc Boor
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Shanta Mancham
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Cornelis Verhoef
- Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Wojciech G Polak
- Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Dirk Grünhagen
- Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Harry LA Janssen
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Gina S Garcia-Romo
- Department of Nephrology; Leiden University Medical Center ; Leiden, the Netherlands
| | - Katharina Biermann
- Department of Pathology; Erasmus MC-University Medical Center ; Rotterdam, the Netherlands
| | - Eric Ttl Tjwa
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Jan Nm IJzermans
- Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands ; Department of Gastroenterology and Hepatology; Academic Medical Center; University of Amsterdam ; the Netherlands
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Araujo RLC, Gönen M, Herman P. Chemotherapy for patients with colorectal liver metastases who underwent curative resection improves long-term outcomes: systematic review and meta-analysis. Ann Surg Oncol 2015; 22:3070-8. [PMID: 25586244 DOI: 10.1245/s10434-014-4354-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Indexed: 12/31/2022]
Abstract
BACKGROUND Hepatic resection is considered the standard of care for patients with resectable colorectal liver metastases (CRLM), but the benefits of using systemic chemotherapy for these patients have not been completely proven. Although systemic chemotherapy is likely to improve recurrence-free survival (RFS), no differences in overall survival (OS) have been demonstrated to date. This study aimed to compare surgery plus systemic chemotherapy, regardless timing of administration, with surgery alone, analyzing long-term outcomes for patients with CRLM who underwent liver resection with curative intent. METHODS Systematic review and meta-analysis of studies published from January 1991 to December 2013 were used to compare surgery alone and surgery plus chemotherapy for patients with CRLM who underwent liver resection with curative intent. All randomized clinical trials (RCTs) were included in the study. Selection of high-quality observational comparative studies (OCSs) was based on a validated tool, the Methodological Index for Nonrandomized Studies. Comparison of RFS and OS was performed using a fixed-effects model and the hazard ratio (HR). RESULTS Concerning OS, 5 studies (3 RCTs and 2 OCSs) comprising 2,475 patients were analyzed, and chemotherapy (1,024 patients) relatively improved OS rates for 23 % of the patients versus surgery alone (HR, 0.77; 95 % confidence interval [CI] 0.67-0.88; p < 0.001). Four studies, totaling 1,592 patients, reported RFS (3 using RCTs and 1 using OCSs), showing that chemotherapy (702 patients) relatively improved RFS for 29 % of the patients (HR, 0.71; 95 % CI 0.61-0.83; p < 0.001). CONCLUSION This meta-analysis demonstrated that the use of chemotherapy for patients with CRLM who underwent resection with curative intent is a worthwhile strategy for improving both RFS and OS.
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Affiliation(s)
- Raphael L C Araujo
- Liver Surgery Unit, Department of Gastroenterology, University of São Paulo Medical School, São Paulo, SP, Brazil,
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Simultaneous resection for rectal cancer with synchronous liver metastasis is a safe procedure. Am J Surg 2014; 209:935-42. [PMID: 25601556 DOI: 10.1016/j.amjsurg.2014.09.024] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/08/2014] [Accepted: 09/15/2014] [Indexed: 12/27/2022]
Abstract
BACKGROUND One quarter of colorectal cancer patients will present with liver metastasis at the time of diagnosis. Recent studies have shown that simultaneous resections are safe and feasible for stage IV colon cancer. Limited data are available for simultaneous surgery in stage IV rectal cancer patients. METHODS One hundred ninety-eight patients underwent surgical treatment for stage IV rectal cancer. In 145 (73%) patients, a simultaneous procedure was performed. Fifty-three (27%) patients underwent staged liver resection. A subpopulation of 69 (35%) patients underwent major liver resection (3 segments or more) and 30 (44%) patients with simultaneous surgery. RESULTS The demographics of the 2 groups were similar. Complication rates were comparable for simultaneous or staged resections, even in the group subjected to major liver resection. Total hospital stay was significantly shorter for the simultaneously resected patients (P < .01). CONCLUSIONS Simultaneous resection of rectal primaries and liver metastases is a safe procedure in carefully selected patients at high-volume institutions, even if major liver resections are required.
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Pedroza-Gonzalez A, Kwekkeboom J, Sprengers D. T-cell suppression mediated by regulatory T cells infiltrating hepatic tumors can be overcome by GITRL treatment. Oncoimmunology 2014; 2:e22450. [PMID: 23483229 PMCID: PMC3583921 DOI: 10.4161/onci.22450] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Recently, we reported the accumulation of CD4+FOXP3+ regulatory T cells (Tregs) within the tumor mass of patients bearing liver cancer. Tumor-infiltrating Tregs (TiTregs) are active and potent suppressors of antitumor immunity. Importantly, treatment with GITRL reduced the immunosuppression mediated by TiTregs.
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Affiliation(s)
- Alexander Pedroza-Gonzalez
- Department of Gastroenterology and Hepatology; Erasmus MC-University Medical Center; Rotterdam, The Netherlands
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48
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Abstract
To date, hepatic artery infusion (HAI) chemotherapy has primarily been investigated in the setting of colorectal cancer liver metastases (CRLM). Few studies have been conducted in North America regarding HAI chemotherapy for primary liver cancers (PLC) or noncolorectal liver metastases (non-CRLM). Despite decades of evaluation, controversy surrounding the use of HAI chemotherapy still exists. In this article the methods of HAI chemotherapy delivery, technical aspects of catheter and pump insertion, and specific complications of HAI chemotherapy are discussed. Outcomes of clinical trials and reviews of HAI chemotherapy in the setting of CRLM, PLC, and non-CRLM are evaluated.
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Affiliation(s)
- Julie N Leal
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - T Peter Kingham
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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49
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Rojas Llimpe FL, Di Fabio F, Ercolani G, Giampalma E, Cappelli A, Serra C, Castellucci P, D'Errico A, Golfieri R, Pinna AD, Pinto C. Imaging in resectable colorectal liver metastasis patients with or without preoperative chemotherapy: results of the PROMETEO-01 study. Br J Cancer 2014; 111:667-73. [PMID: 24983362 PMCID: PMC4134499 DOI: 10.1038/bjc.2014.351] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 04/23/2014] [Accepted: 06/02/2014] [Indexed: 12/19/2022] Open
Abstract
Background: The aim of the PROMETEO-01 Study was to define the diagnostic accuracy of imaging techniques in colorectal cancer liver metastasis (CRCLM) patients. Methods: Patients referred to Bologna S. Orsola-Malpighi Hospital performed a computed-tomography scan (CT), magnetic resonance (MR), 18F-FDG-PET/CTscan (PET/CT) and liver contrast-enhanced-ultrasound (CEUS); CEUS was also performed intraoperatively (i-CEUS). Every pathological lesion was compared with imaging data. Results: From December 2007 to August 2010, 84 patients were enrolled. A total of 51 (60.71%) resected patients were eligible for analysis. In the lesion-by-lesion analysis 175 resected lesions were evaluated: 67(38.3%) belonged to upfront resected patients (group-A) and 108 (61.7%) to chemotherapy-pretreated patients (group-B). In all patients the sensitivity of MR proved better than CT (91% vs 82% P=0.002), CEUS (91 vs 81% P=0.008) and PET/CT (91% vs 60% P=0.000), whereas PET/CT showed the lowest sensitivity. In group-A the sensitivity of i-CEUS, MR, CT, CEUS and PET/CT was 98%, 94%, 91%, 84% and 78%, respectively. In group-B the i-CEUS proved equivalent in sensitivity to MR (95% and 90%, respectively, P=0.227) and both were significantly more sensitive than other procedures. The CT sensitivity in group-B was lower than in group-A (77% vs 91%, P=0.024). Conclusions: A thoraco-abdominal CT provides an adequate baseline evaluation and guides judgment as to the resectability of CRCLM patients. In the subset of candidates for induction chemotherapy to increase the chance of liver resection, the most rational approach is to add MR for the staging and restaging of CRCLM.
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Affiliation(s)
- F L Rojas Llimpe
- Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - F Di Fabio
- Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - G Ercolani
- Liver Surgery Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - E Giampalma
- Radiology Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - A Cappelli
- Radiology Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - C Serra
- Internal Medicine Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - P Castellucci
- Nuclear Medicine Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - A D'Errico
- Pathology Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - R Golfieri
- Radiology Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - A D Pinna
- Liver Surgery Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - C Pinto
- Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna 40138, Italy
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50
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Liver metastases from primary rectal cancer: a multidisciplinary reverse approach. J Gastrointest Cancer 2014; 44:368-9. [PMID: 23054581 DOI: 10.1007/s12029-012-9444-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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