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Das T, Mondal S, Das S, Das S, Das Saha K. Enhanced anticancer activity of (-)-epigallocatechin-3-gallate (EGCG) encapsulated NPs toward colon cancer cell lines. Free Radic Res 2024; 58:565-582. [PMID: 38810269 DOI: 10.1080/10715762.2024.2360013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/08/2024] [Accepted: 05/15/2024] [Indexed: 05/31/2024]
Abstract
(-)-Epigallocatechin-3-gallate (EGCG), a bioactive polyphenol of green tea, has chemo-preventive effects against various cancer cells. Nanoparticles (NPs) carrying different ligands are able to specifically interact with their receptors on different cancer cells that can provide effective release of cytotoxic drugs. In the present study, we have prepared EGCG entrapped NPs using PLGA (poly(d,l-lactide-co-glycolide)). Polyethylene glycol (PEG) and folic acid (FA) via double emulsion solvent evaporation (DESE) method obtained PLGA-EGCG (P-E), PLGA-PEG-EGCG (PP-E), and PLGA-PEG-FA-EGCG (PPF-E). Nanoformulations had been characterized with 1H NMR and FT-IR techniques, AFM, and DLS. PPF-E NPs showed an average size of 220 nm. Analysis of zeta potential confirmed the stability of NPs. HCT-116, HT-29, HCT-15, and HEK 293 cells were treated with both the prepared NPs and free EGCG (0-140 μM). Result showed PPF-E NPs had improved delivery, uptake and cell cytotoxicity toward human folic acid receptor-positive (FR+) colorectal cancer (CRC) cells as mainly on HCT-116 compared to HT-29, but not on the folic acid-negative cells (FR-) as HCT-15. PPF-E NPs enhanced intracellular reactive oxygen species (ROS) level in absence of N-acetyl-l-cysteine (NAC), elevated DNA fragmentation level, and increased apoptotic cell death at higher doses compared to other two NPs and free EGCG. In conclusion, PPF-E NPs exerted greater efficacy than PP-E, P-E, and free EGCG in HCT-116 cells.
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Affiliation(s)
- Tanushree Das
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sanchaita Mondal
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sujata Das
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sanjib Das
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Krishna Das Saha
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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Yang C, Jiang Y, Zhang K, Zhu X, Li J, Yu H, Chen J, Gu X, Gan Z, Yu Q. Photodynamic Therapy Derived Personalized Whole Cell Tumor Vaccine Prevents Postsurgery Tumor Recurrence and Metastasis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2308456. [PMID: 38342675 DOI: 10.1002/smll.202308456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 01/03/2024] [Indexed: 02/13/2024]
Abstract
In order to avoid the time-consuming and laborious identification of tumor-specific antigens (TSAs) during the traditional vaccine fabrication process, a versatile photodynamic therapy (PDT)-based method is developed to construct a whole-tumor antigen tumor vaccine (TV) from surgically resected tumor tissues for personalized immunotherapy. Mucoadhesive nanoparticles containing small-molecular photosensitizer are fabricated and directly co-incubated with suspended tumor cells obtained after cytoreduction surgery. After irradiation with a 405 nm laser, potent immunogenic cell death of cancer cells could be induced. Along with the release of TSAs, the as-prepared TV could activate safe and robust tumor-specific immune responses, leading to efficient suppression of postsurgery tumor recurrence and metastasis. The as-prepared TV cannot only be applied alone through various administration routes but also synergize with immunoadjuvant, chemotherapeutics, and immune checkpoint blockers to exert more potent immune responses. This work provides an alternative way to promote the clinical translation of PDT, which is generally restricted by the limited penetration of light. Moreover, the versatile strategy of vaccine fabrication also facilitates the clinical application of personalized whole-cell tumor vaccines.
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Affiliation(s)
- Chunyu Yang
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Chemical Resource Engineering, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Yitong Jiang
- The State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Kaixin Zhang
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Chemical Resource Engineering, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Xianqi Zhu
- The State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Jianlin Li
- The State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Haiwang Yu
- The State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Jiawei Chen
- The State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Xinggui Gu
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Chemical Resource Engineering, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
- Beijing National Laboratory for Molecular Sciences, Beijing, 100190, China
| | - Zhihua Gan
- The State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Qingsong Yu
- The State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
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Malik AK, Mahendran B, Lochan R, White SA. Liver Transplantation for Nonresectable Colorectal Liver Metastases (CRLM). Indian J Surg Oncol 2024; 15:255-260. [PMID: 38818008 PMCID: PMC11133248 DOI: 10.1007/s13193-023-01827-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/28/2023] [Indexed: 06/01/2024] Open
Abstract
Transplantation represents the most radical locoregional therapy through removal of the liver, associated vasculature and locoregional lymph nodes, and replacing it with an allograft. Recent evidence has demonstrated that transplantation for unresectable CRLM is feasible with acceptable post-transplant outcomes in a highly selected cohort of patients. Controversy exists regarding whether transplantation is an appropriate treatment for such patients, due to concerns regarding disease recurrence in the transplanted graft in an immunosuppressed recipient along with utilising a donor liver which are in short supply. Expanding the indications for liver transplantation may also limit access for other patients with end-stage liver disease having ethical implications due to the effect of increasing the waiting list. In this review, we summarise the current evidence for liver transplantation in patients with nonresectable CRLM and highlight unresolved controversies and future directions for this type of treatment.
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Affiliation(s)
- Abdullah K. Malik
- Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- NIHR Blood and Transplant Research Unit, Newcastle University, Newcastle Upon Tyne, UK
| | - Balaji Mahendran
- Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- NIHR Blood and Transplant Research Unit, Newcastle University, Newcastle Upon Tyne, UK
| | - Rajiv Lochan
- Department of Hepatobiliary and Liver Transplantation Surgery, Manipal Hospitals, Bangalore, India
| | - Steven A. White
- Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
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Chen Y, Zhu D, Chen M, Xu Y, Ye Q, Wang X, Xu P, Feng Q, Ji M, Wei Y, Fan J, Xu J. Impact of Surgical Management for Relapse After Conversion Hepatectomy for Initially Unresectable Colorectal Liver Metastasis: A Retrospective Cohort Study. Clin Colorectal Cancer 2023; 22:464-473.e5. [PMID: 37730473 DOI: 10.1016/j.clcc.2023.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/26/2023] [Accepted: 08/29/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND For patients with initially unresectable colorectal liver metastasis (IU-CRLM) receiving conversion therapy, disease relapse after conversion hepatectomy is common. However, few studies have focused on the assessment and management of relapse following conversion hepatectomy for IU-CRLM. METHODS In the retrospective cohort study, 255 patients with IU-CRLM received conversion therapy and underwent subsequent R0 resection. The treatment effects of repeated liver-directed treatment (RLDT) versus non-RLDT for liver relapse were examined. Survival analysis was evaluated with the use of Cox proportional hazards methods. The importance of RLDT was further confirmed in the propensity score matching (PSM) and subgroup analyses. RESULTS The 5-year overall survival (OS) rate after conversion hepatectomy was 34.9%. Liver relapse was observed in 208 patients. Of these patients, 106 underwent RLDT (65 underwent repeated hepatectomy and the remainder underwent ablation treatment), while 102 received only palliative chemotherapy. The relapse patients who underwent RLDT had a significantly longer OS than those who did not (hazard ratio (HR): 0.382, 95% CI: 0.259-0.563; P<0.001). In a multivariable analysis, RLDT was independently associated to prolonged survival (HR: 0.309, 95%CI: 0.181-0.529; P<0.001). In the PSM and subgroup analyses, RLDT consistently showed evidence of prolonging OS significantly. CONCLUSION For IU-CRLM patients with liver relapse following conversion hepatectomy, the RLDT is essential for cure and prolonged survival. To avoid missing the opportunity for RLDT, intensive disease surveillance should be proposed.
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Affiliation(s)
- Yijiao Chen
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dexiang Zhu
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Miao Chen
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuqiu Xu
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qinghai Ye
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoying Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Pingping Xu
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive
| | - Qingyang Feng
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Meiling Ji
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive
| | - Ye Wei
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jianmin Xu
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
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Rangarajan K, Lazzereschi L, Votano D, Hamady Z. Breast cancer liver metastases: systematic review and time to event meta-analysis with comparison between available treatments. Ann R Coll Surg Engl 2023; 105:293-305. [PMID: 35175853 PMCID: PMC10066639 DOI: 10.1308/rcsann.2021.0308] [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] [Accepted: 10/23/2021] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION The current gold standard treatment for breast cancer liver metastases (BCLM) is systemic chemotherapy and/or hormonal therapy. Nonetheless, greater consideration has been given to local therapeutic strategies in recent years. We sought to compare survival outcomes for available systemic and local treatments for BCLM, specifically surgical resection and radiofrequency ablation. METHODS A review of the PubMed (MEDLINE), Embase and Cochrane Library databases was conducted. Data from included studies were extracted and subjected to time-to-event data synthesis, algorithmically reconstructing individual patient-level data from published Kaplan-Meier survival curves. FINDINGS A total of 54 studies were included, comprising data for 5,430 patients (surgery, n=2,063; ablation, n=305; chemotherapy, n=3,062). Analysis of the reconstructed data demonstrated survival rates at 1, 3 and 5 years of 90%, 65.9% and 53%, respectively, for the surgical group, 83%, 49% and 35% for the ablation group and 53%, 24% and 14% for the chemotherapy group (p<0.0001). CONCLUSION Local therapeutic interventions such as liver resection and radiofrequency ablation are effective treatments for BCLM, particularly in patients with metastatic disease localised to the liver. Although the data from this review support surgical resection for BCLM, further prospective studies for managing oligometastatic breast cancer disease are required.
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Affiliation(s)
| | - L Lazzereschi
- University Hospital Southampton NHS Foundation Trust, UK
| | - D Votano
- Ashford & St. Peter’s Hospitals NHS Foundation Trust, UK
| | - Z Hamady
- Ashford & St. Peter’s Hospitals NHS Foundation Trust, UK
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Tasoudis PT, Ziogas IA, Alexopoulos SP, Fung JJ, Tsoulfas G. Role of liver transplantation in the management of colorectal liver metastases: Challenges and opportunities. World J Clin Oncol 2021; 12:1193-1201. [PMID: 35070738 PMCID: PMC8716993 DOI: 10.5306/wjco.v12.i12.1193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/29/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver is the most common site of colorectal cancer metastasis. Complete resection of the metastatic tumor is currently the only treatment modality available with a potential for cure. However, only 20% of colorectal liver metastases (CRLM) are considered resectable at the time of presentation. Liver transplantation (LT) has been proposed as an alternative oncologic treatment for patients with unresectable CRLM. This review summarizes the published experiences of LT in the setting of unresectable CRLM from the previous decades and discusses the challenges and future horizons in the field. Contemporary experiences that come mostly from countries with broader access to liver grafts are also explored and their promising findings in terms of overall survival (OS) and disease-free survival (DFS) are outlined along with their study design and methods. The rationale of establishing specific patient selection criteria and the dilemmas around immunosuppressive regimens in patients undergoing LT for CRLM are also highlighted. Additionally, this review describes the findings of studies comparing LT vs chemotherapy alone and LT vs portal vein embolization plus resection for CRLM in terms of OS and DFS. Last but not least, we present current perspectives and ongoing prospective trials that try to elucidate the role of LT for CRLM.
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Affiliation(s)
| | - Ioannis A Ziogas
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Sophoclis P Alexopoulos
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - John J Fung
- Department of Surgery, University of Chicago Medicine Transplant Institute, Chicago, IL 60637, United States
| | - Georgios Tsoulfas
- Department of Transplant Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
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Chan BKY, Elmasry M, Forootan SS, Russomanno G, Bunday TM, Zhang F, Brillant N, Starkey Lewis PJ, Aird R, Ricci E, Andrews TD, Sison-Young RL, Schofield AL, Fang Y, Lister A, Sharkey JW, Poptani H, Kitteringham NR, Forbes SJ, Malik HZ, Fenwick SW, Park BK, Goldring CE, Copple IM. Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration. Hepatology 2021; 74:973-986. [PMID: 33872408 DOI: 10.1002/hep.31859] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 03/25/2021] [Accepted: 04/08/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration. APPROACH AND RESULTS Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO-Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild-type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO-Me, highlighting the potential relevance of our findings to patients. CONCLUSIONS Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.
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Affiliation(s)
- Benjamin K Y Chan
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
- Department of Hepatobiliary SurgeryAintree University HospitalLiverpool University Hospitals NHS Foundation TrustLiverpoolUnited Kingdom
| | - Mohamed Elmasry
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Shiva S Forootan
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Giusy Russomanno
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Tobias M Bunday
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Fang Zhang
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Nathalie Brillant
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Philip J Starkey Lewis
- Medical Research Council Centre for Regenerative MedicineEdinburgh BioQuarterLittle France DriveUniversity of EdinburghEdinburghUnited Kingdom
| | - Rhona Aird
- Medical Research Council Centre for Regenerative MedicineEdinburgh BioQuarterLittle France DriveUniversity of EdinburghEdinburghUnited Kingdom
| | - Emanuele Ricci
- Department of Veterinary AnatomyPhysiology & PathologyInstitute of InfectionVeterinary & Ecological SciencesUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Timothy D Andrews
- Department of PathologyRoyal Liverpool University HospitalLiverpool University Hospitals NHS Foundation TrustLiverpoolUnited Kingdom
| | - Rowena L Sison-Young
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Amy L Schofield
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Yongxiang Fang
- Centre for Genomic ResearchInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Adam Lister
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Jack W Sharkey
- Centre for Preclinical ImagingInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Harish Poptani
- Centre for Preclinical ImagingInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Neil R Kitteringham
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Stuart J Forbes
- Medical Research Council Centre for Regenerative MedicineEdinburgh BioQuarterLittle France DriveUniversity of EdinburghEdinburghUnited Kingdom
| | - Hassan Z Malik
- Department of Hepatobiliary SurgeryAintree University HospitalLiverpool University Hospitals NHS Foundation TrustLiverpoolUnited Kingdom
| | - Stephen W Fenwick
- Department of Hepatobiliary SurgeryAintree University HospitalLiverpool University Hospitals NHS Foundation TrustLiverpoolUnited Kingdom
| | - B Kevin Park
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Christopher E Goldring
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
| | - Ian M Copple
- Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom
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Chen Q, Mao R, Zhao J, Bi X, Li Z, Huang Z, Zhang Y, Zhou J, Zhao H, Cai J. From the completion of neoadjuvant chemotherapy to surgery for colorectal cancer liver metastasis: What is the optimal timing? Cancer Med 2020; 9:7849-7862. [PMID: 32886456 PMCID: PMC7643690 DOI: 10.1002/cam4.3283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 05/21/2020] [Accepted: 06/11/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Neoadjuvant chemotherapy (NAC) has been widely performed in the treatment of colorectal cancer liver metastasis (CRLM) patients, but the optimal timing of surgery after NAC is unclear. The aim of this study was to investigate the optimal timing of surgery. METHODS From December 2010 to May 2018, 101 consecutive patients who received NAC followed by liver resection for CRLM were included in this study. The main outcome parameters were pathological response, progression-free survival (PFS), and overall survival (OS). The effect of time to surgery (TTS) on patient outcomes, defined as a high TTS and a low TTS according to an X-tile analysis, was investigated. To adjust for potential selection bias, propensity score matching at 1:2 was performed with two high TTS patients matched to one low TTS patient. Kaplan-Meier curves, logistic regression analyses, and Cox regression models were used for the data analysis. RESULTS The optimal cut-off value for the TTS was 5 weeks by X-tile analysis. The patients in this study were divided into low (≤5 weeks, n = 27) and high (>5 weeks, n = 74) TTS groups. Patients with a high TTS were more likely to have an unfavorable pathological response (75.7% vs 48.1%, P = .008). In multivariate analysis, a low TTS significantly predicted a better pathological response (OR = 3.397, 95% CI: 1.116-10.344, P = .031). Compared to patients with a high TTS, patients with a low TTS had significantly better PFS (P < .001, mPFS: 16 months vs 7 months) and better OS (P = .037, mOS: not reached vs 36 months). Multivariate analysis revealed that a TTS > 5 weeks was an independent predictor of decreased PFS (HR = 2.041, 95% CI: 1.152-3.616, P = .014) but not OS. After propensity matching, the patients with a low TTS had significantly better PFS (P < .001, mPFS: 18.2 months vs 10 months) and an equivalent OS (P = .115, mOS: not reached vs 41 months). Multivariate analysis revealed that a TTS > 5 weeks was an independent predictor of decreased PFS (HR = 3.031, 95% CI: 1.494-6.149, P = .002) but not OS. CONCLUSION The longer TTS after the completion of NAC may be disadvantageous for a favorable pathological response and long-term PFS. These results should be validated prospectively in a randomized trial.
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Affiliation(s)
- Qichen Chen
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Rui Mao
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jianjun Zhao
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xinyu Bi
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhiyu Li
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhen Huang
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yefan Zhang
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jianguo Zhou
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Hong Zhao
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jianqiang Cai
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Mahlmann JC, Wirth TC, Hartleben B, Schrem H, Mahlmann JF, Kaltenborn A, Klempnauer J, Kulik U. Chemotherapy and Hepatic Steatosis: Impact on Postoperative Morbidity and Survival after Liver Resection for Colorectal Liver Metastases. Visc Med 2020; 37:198-205. [PMID: 34250077 DOI: 10.1159/000510661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 08/03/2020] [Indexed: 01/22/2023] Open
Abstract
Background Hepatic steatosis and chemotherapy in the treatment of colorectal liver metastases (CLM) are often linked to increased mortality and morbidity after liver resection. This study evaluates the influence of macrovesicular hepatic steatosis and chemotherapeutic regimes on graded morbidity and mortality after liver resection for CLM. Methods A total of 323 cases of liver resection for CLM were retrospectively analysed using univariable and multivariable linear, ordinal and Cox regression analyses. The resected liver tissue was re-evaluated by a single observer to determine the grade and type of hepatic steatosis. Results Macrovesicular steatosis did not influence postoperative morbidity and survival, as evidenced by risk-adjusted multivariable Cox regression analysis (p = 0.521). Conversion chemotherapy containing oxaliplatin was an independent and significant risk factor for mortality in risk-adjusted multivariable Cox regression analysis (p = 0.005). Identified independently, significant risk factors for postoperative morbidity were neoadjuvant treatment of metastases of the primary tumour with irinotecan (p = 0.003), the duration of surgery in minutes (p = 0.001) and the number of intraoperatively transfused packed red blood cells (p ≤ 0.001). Surprisingly, macrovesicular hepatic steatosis was not a risk factor for postoperative morbidity and was even associated with lower rates of complications (p = 0.006). Conclusion The results emphasize the multifactorial influence of preoperative liver damage and chemotherapy on the severity of postoperative morbidity, as well as the significant impact of conversion chemotherapy containing oxaliplatin on survival.
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Affiliation(s)
- Jan C Mahlmann
- General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Thomas C Wirth
- Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Harald Schrem
- Division of Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Jens F Mahlmann
- Departament d'Astronomia i Astrofísica, Universitat de València, Valencia, Spain
| | - Alexander Kaltenborn
- General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Jürgen Klempnauer
- General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Ulf Kulik
- General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
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10
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Giannis D, Sideris G, Kakos CD, Katsaros I, Ziogas IA. The role of liver transplantation for colorectal liver metastases: A systematic review and pooled analysis. Transplant Rev (Orlando) 2020; 34:100570. [DOI: 10.1016/j.trre.2020.100570] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/20/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023]
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11
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Tirotta F, Hodson J, Parente A, Pasquali S, Sutcliffe R, Desai A, Muiesan P, Ford SJ, Fiore M, Gronchi A, Almond LM. Liver resection for sarcoma metastases: A systematic review and experience from two European centres. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2020; 46:1807-1813. [PMID: 32798014 DOI: 10.1016/j.ejso.2020.05.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/22/2020] [Accepted: 05/28/2020] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Studies reporting outcomes of liver resection for sarcoma metastases (LRSM) typically include gastrointestinal stromal tumours (GIST), or pooled analyses of "non-colorectal liver metastases", which do not reflect the subgroup of patients with sarcomatous liver metastases. This study aimed to perform a systematic review to evaluate oncological and surgical outcomes in patients undergoing LRSM, and to report new data from two tertiary institutions. METHODS MEDLINE and the Cochrane Library were searched for studies reporting oncological and surgical outcomes after LRSM, following PRISMA guidelines. Studies reporting liver resection for GIST were excluded. The resulting studies were pooled, with data from two European centres. RESULTS Six studies of LSRM were included, comprising 212 patients from previously reported series and 24 patients from ours, with median follow-up times of 18-53 months. Postoperative mortality rates ranged from 0 to 9%, and the pooled overall survival (OS) was 89% (95% CI: 83-96%), and 31% (95% CI: 14-47%) at one and five years, respectively (median: 36 months). The presence of synchronous extra-hepatic metastases was found to be a significant risk factor for shorter OS in two cohorts, with hazard ratios of 3.7 (p < 0.001) and 9.1 (p = 0.016), respectively. The largest reported series also found larger metastases (≥100 mm), lack of response to chemotherapy and a shorter disease-free interval to be associated with significantly shorter OS after LSRM. CONCLUSIONS Patients undergoing LRSM with negative prognostic factors such as the presence of extra-hepatic metastases are unlikely to benefit from surgery. Acceptable medium- and long-term survival may be achievable in highly selected patients.
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Affiliation(s)
- Fabio Tirotta
- Department of Sarcoma and General Surgery, Midlands Abdominal and Retroperitoneal Sarcoma Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom; Department of HPB Surgery, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - James Hodson
- Department of Medical Statistics, Institute of Translational Medicine, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Alessandro Parente
- Department of HPB Surgery, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Sandro Pasquali
- Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Robert Sutcliffe
- Department of HPB Surgery, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Anant Desai
- Department of Sarcoma and General Surgery, Midlands Abdominal and Retroperitoneal Sarcoma Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Paolo Muiesan
- Department of HPB Surgery, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Samuel J Ford
- Department of Sarcoma and General Surgery, Midlands Abdominal and Retroperitoneal Sarcoma Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Marco Fiore
- Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Gronchi
- Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - L Max Almond
- Department of Sarcoma and General Surgery, Midlands Abdominal and Retroperitoneal Sarcoma Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
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Liver transplantation for non-resectable colorectal liver metastasis: where we are and where we are going. Langenbecks Arch Surg 2020; 405:255-264. [PMID: 32333096 DOI: 10.1007/s00423-020-01883-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 04/15/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Almost 50% of patients diagnosed with colorectal cancer (CRC) will develop liver metastasis (LM). Although their only long-term curative treatment is surgery, less than half of these patients can be eventually resected. Therefore, palliative chemotherapy is offered as a definitive option, though with poor results. Recently, the University of Oslo group has published encouraging results in the treatment of these patients with liver transplantation (LT), whereby worldwide interest in this option has been renewed. METHODS A literature review of LT for patients with unresectable colorectal metastasis was performed. This included information regarding patient selection, complications, overall survival (OS) and disease-free survival (DFS), immunosuppression, chemotherapy, and description of the ongoing trials. RESULTS Improvements in OS and DFS have been observed in consecutive published prospective trials, as patient selection has been refined. Papers reporting OS of patients who randomly presented similar selection criteria also exhibited good results. CONCLUSION LT within the available therapeutic options in patients with CRC-LM seems to be a compelling alternative in carefully selected patients. The ongoing trials will provide valuable information regarding selection criteria, immunosuppressive therapy and different modalities of adjuvant chemotherapy, which are, to our knowledge, the vital platform of LT in CRC-LM. Although some of the developing techniques involve living donors, graft availability for these patients remains a matter of major concern.
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Chen Q, Wu C, Zhao H, Wu J, Zhao J, Bi X, Li Z, Huang Z, Zhang Y, Zhou J, Cai J. Neo-adjuvant Chemotherapy-Induced Neutropenia Is Associated with Histological Responses and Outcomes after the Resection of Colorectal Liver Metastases. J Gastrointest Surg 2020; 24:659-670. [PMID: 30937711 DOI: 10.1007/s11605-019-04202-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 03/07/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND Neutropenia, the major adverse event in chemotherapy, is associated with favourable clinical outcome in several solid tumours. We aimed to investigate the predictive value of neo-adjuvant chemotherapy (NAC)-induced neutropenia for the pathological response and prognosis in colorectal liver metastases (CRLM) patients. METHODS A retrospective review was performed in 141 CRLM patients receiving NAC followed by liver resection. A logistic regression was applied to analyse potential predictors. A Cox proportional hazards analysis was used to analyse survival. RESULTS Neutropenia due to NAC was observed in 42.6% (60/141) of all patients, and grade 3/4 neutropenia was noted in 31.7% (19/60). A pathological response (tumour regression grade (TRG) 1-3) was reported in 46.1% (65/141) of patients. Multivariate analysis showed that neutropenia significantly predicted the favourable pathological response (OR = 3.718, 95% CI 1.716-8.329, P = 0.001), as well as targeted therapy, good differentiation and preoperative CEA < 10 ng/ml as independent predictors of favourable histological response. Of the patients, 54.6% (77/141) had postoperative complications, including 28 major complications (28/77, 36.4%). Severe neutropenia significantly predicted postoperative major complications in multivariate analysis (OR = 4.077, 95% CI 1.184-14.038, P = 0.026). Compared to patients without neutropenia, patients with neutropenia had significantly better progression-free survival (PFS) (P = 0.007; mPFS, 10.2 months vs. 6.7 months). Patients with histological response had significantly better PFS than patients with no histological response (P = 0.001; mPFS, 10.0 months vs. 5.5 months). According to multivariate analyses, neutropenia was a significant predictor for better PFS (HR = 0.613, 95% CI 0.406-0.925, P = 0.020) but not OS. CONCLUSIONS For CRLM patients receiving NAC followed by liver resection, NAC-induced neutropenia was a significant predictor of favourable pathological response, postoperative major complications and better prognosis, which makes it useful for CRLM patients in guiding treatment approaches and prognosis assessments.
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Affiliation(s)
- Qichen Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chaorui Wu
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jianxiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhiyu Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yefan Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
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15
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KRAS mutational status impacts pathologic response to pre-hepatectomy chemotherapy: a study from the International Genetic Consortium for Liver Metastases. HPB (Oxford) 2019; 21:1527-1534. [PMID: 30979646 DOI: 10.1016/j.hpb.2019.03.368] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 01/08/2019] [Accepted: 03/14/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined. METHODS Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (>50% vs <50%, respectively). Multivariable logistic regression was used to identify factors associated with major response. RESULTS 319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P = 0.01) and wtKRAS status remained independently associated with a major response (P = 0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P = 0.023). CONCLUSIONS Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.
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16
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Jian M, Chang W, Ren L, Liu T, Chen Y, Wei Y, Lin Q, Xu J, Qin X. Predictive And Prognostic Value Of Hepatic Steatosis In Conversion Therapy For Colorectal Liver-limited Metastases: A Propensity Score Matching Analysis. Cancer Manag Res 2019; 11:8315-8326. [PMID: 31571989 PMCID: PMC6750205 DOI: 10.2147/cmar.s210185] [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: 03/28/2019] [Accepted: 09/01/2019] [Indexed: 01/07/2023] Open
Abstract
Purpose To evaluate the role of hepatic steatosis (HS) in patients with synchronous colorectal liver-limited metastases (CLLMs) undergoing conversion therapy. Patients and methods From March 2013 to March 2017, a total of 406 patients with initially unresectable CLLMs accepted conversion therapy in multidisciplinary team (MDT). Before the implementation of conversion therapy, all patients underwent CT scan to assess the presence of hepatic steatosis and divided into the HS group (n = 124) and the non-HS group (n = 282). After using propensity score matching (PSM) to eliminate the potential confounding bias of the two groups, the conversion hepatectomy rate and long-term oncological survival in two groups were compared. Results After 1:1 PSM, no significant difference was observed at baseline between patients in the HS group (n = 119) and the non-HS group (n = 119). Patients in the HS group had higher conversion hepatectomy rate from MDT evaluation (31.1% vs 18.5%, P = 0.029) and actual hepatectomy rate (30.2% vs 18.5%, P = 0.030), when compared with patients in the non-HS group, respectively. In addition, the HS group achieved better progression-free survival (PFS, P = 0.047) and overall survival (OS, P = 0.035) than that of the non-HS group. Multivariate logistic analysis confirmed that pretreatment HS was an independent predictor for conversion hepatectomy rate (OR, 2.393; 95% CI, 1.463–4.315, P = 0.001), and multivariate Cox analysis revealed that HS was an independent prognostic factor for PFS (HR, 0.493, 95% CI 0.281–0.866, P = 0.014) and OS (HR, 0.559, 95% CI 0.398–0.785, P = 0.001). Conclusion For CLLM patients who underwent conversion therapy, hepatic steatosis could be an effective predictor for conversion hepatectomy rate and an independent prognostic factor for PFS and OS.
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Affiliation(s)
- Mi Jian
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
| | - Wenju Chang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
| | - Li Ren
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
| | - Tianyu Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
| | - Yijiao Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
| | - Ye Wei
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
| | - Qi Lin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
| | - Jianmin Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
| | - Xinyu Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Zhongshan Hospital, Fudan University, Shanghai 200030, People's Republic of China
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17
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Barresi V, Fioravanzo A, Pecori S, Tomezzoli A, Reggiani Bonetti L. The histopathologic report of surgically resected colorectal liver metastases: What is clinically relevant? Pathol Res Pract 2019; 215:152547. [PMID: 31371210 DOI: 10.1016/j.prp.2019.152547] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 07/12/2019] [Accepted: 07/17/2019] [Indexed: 02/08/2023]
Abstract
Colorectal carcinoma (CRC) is one of the most common malignancies and a major cause of cancer-related death worldwide. The liver is the most frequent site of metastatic spread, so that about half of the patients with CRC have or develop liver metastases (LM) during the clinical course of the disease. Colorectal LM can potentially be cured by surgery, but most patients still experience disease progression and recurrence after the surgical treatment. Prediction of a patient's post-surgical clinical course is mainly based on clinical parameters or the histopathological features of the primary tumor, while little attention is given to the pathological characteristics of the LM. In this paper, we review the prognostic relevance of the gross and microscopic pathological features observed in surgically resected LM and propose which information should be included in the histopathological report to guide surgeons and oncologists for the subsequent therapeutic management.
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Affiliation(s)
- Valeria Barresi
- Department of Diagnostics and Public Health, Polyclinic G.B. Rossi, P.le L.A. Scuro, 1, 37134, Verona, Italy.
| | - Adele Fioravanzo
- Department of Diagnostics and Public Health, Polyclinic G.B. Rossi, P.le L.A. Scuro, 1, 37134, Verona, Italy
| | - Sara Pecori
- Department of Diagnostics and Public Health, Polyclinic G.B. Rossi, P.le L.A. Scuro, 1, 37134, Verona, Italy
| | - Anna Tomezzoli
- Department of Diagnostics and Public Health, Polyclinic G.B. Rossi, P.le L.A. Scuro, 1, 37134, Verona, Italy
| | - Luca Reggiani Bonetti
- Department of Laboratory Integrated Activities, Anatomic Pathology and Legal Medicine, University of Modena and Reggio Emilia, Modena, Italy
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18
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Dasari BVM, Pathanki A, Hodson J, Roberts KJ, Marudanayagam R, Mirza DF, Isaac J, Sutcliffe RP, Muiesan P. Propensity-matched analysis of the influence of perioperative statin therapy on outcomes after liver resection. BJS Open 2019; 3:509-515. [PMID: 31388643 PMCID: PMC6677106 DOI: 10.1002/bjs5.50155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/18/2019] [Indexed: 11/11/2022] Open
Abstract
Background Perioperative use of statins is reported to improve postoperative outcomes after cardiac and non‐cardiovascular surgery. The aim of this study was to investigate the influence of statins on postoperative outcomes including complications of grade IIIa and above, posthepatectomy liver failure (PHLF), and 90‐day mortality rates after liver resection. Methods Patients who underwent hepatectomy between 2013 and 2017 were reviewed to identify statin users and non‐users (controls). Propensity matching was conducted for age, BMI, type of surgery and preoperative co‐morbidities to compare subgroups. Univariable and multivariable analyses were performed for the following outcomes: 90‐day mortality, significant postoperative complications and PHLF. Results Of 890 patients who had liver resection during the study period, 162 (18·2 per cent) were taking perioperative statins. Propensity analysis selected two matched groups, each comprising 154 patients. Overall, 81 patients (9·1 per cent) developed complications of grade IIIa or above, and the 90‐day mortality rate was 3·4 per cent (30 patients), with no statistically significant difference when the groups were compared before and after matching. The rate of PHLF was significantly lower in patients on perioperative statins than in those not taking statins (10·5 versus 17·3 per cent respectively; P = 0·033); similar results were found after propensity matching (10·4 versus 20·8 per cent respectively; P = 0·026). Conclusion The rate of PHLF was significantly lower in patients taking perioperative statins, but there was no statistically significant difference in severe complications and mortality rates.
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Affiliation(s)
- B V M Dasari
- Department of Hepatobiliary and Pancreatic Surgery, Queen Elizabeth Hospital, Birmingham, UK
| | - A Pathanki
- Department of Hepatobiliary and Pancreatic Surgery, Queen Elizabeth Hospital, Birmingham, UK
| | - J Hodson
- Institute of Translational Medicine, Queen Elizabeth Hospital, Birmingham, UK
| | - K J Roberts
- Department of Hepatobiliary and Pancreatic Surgery, Queen Elizabeth Hospital, Birmingham, UK
| | - R Marudanayagam
- Department of Hepatobiliary and Pancreatic Surgery, Queen Elizabeth Hospital, Birmingham, UK
| | - D F Mirza
- Department of Hepatobiliary and Pancreatic Surgery, Queen Elizabeth Hospital, Birmingham, UK
| | - J Isaac
- Department of Hepatobiliary and Pancreatic Surgery, Queen Elizabeth Hospital, Birmingham, UK
| | - R P Sutcliffe
- Department of Hepatobiliary and Pancreatic Surgery, Queen Elizabeth Hospital, Birmingham, UK
| | - P Muiesan
- Department of Hepatobiliary and Pancreatic Surgery, Queen Elizabeth Hospital, Birmingham, UK
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19
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Liver transplantation for unresectable malignancies: Beyond hepatocellular carcinoma. Eur J Surg Oncol 2019; 45:2268-2278. [PMID: 31387755 DOI: 10.1016/j.ejso.2019.07.024] [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: 03/03/2019] [Revised: 07/02/2019] [Accepted: 07/18/2019] [Indexed: 12/12/2022] Open
Abstract
Indications for liver transplantation have expanded over the past few decades owing to improved outcomes and better understanding of underlying pathologies. In particular, there has been a growing interest in the field of transplant oncology in recent years that has led to considerable developments which have pushed the boundaries of malignant indications for liver transplantation beyond hepatocellular carcinoma (HCC). In this article, we review and summarise the published evidence for liver transplantation in non-HCC primary and metastatic liver malignancies and highlight ongoing clinical trials that address unresolved questions therein. We also examine the current technical, immunological and oncological challenges that face liver transplantation in this growing field and explore potential approaches to overcome these barriers.
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20
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Butler CT, Kennedy SA, Buckley A, Doyle R, Conroy E, Gallagher WM, O'Sullivan J, Kennedy BN. 1,4-dihydroxy quininib attenuates growth of colorectal cancer cells and xenografts and regulates the TIE-2 signaling pathway in patient tumours. Oncotarget 2019; 10:3725-3744. [PMID: 31217905 PMCID: PMC6557215 DOI: 10.18632/oncotarget.26966] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 04/21/2019] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer associated deaths in developed countries. Cancer progression and metastatic spread is reliant on new blood vasculature, or angiogenesis. Tumour-related angiogenesis is regulated by pro- and anti-angiogenic factors secreted from malignant tissue in a stepwise process. Previously we structurally modified the small anti-angiogenic molecule quininib and discovered a more potent anti-angiogenic compound 1, 4 dihydroxy quininib (Q8), an antagonist of cysteinyl leukotriene receptor-1 with VEGF-independent bioactivity. Here, Q8, quininib (Q1) and five structural analogues were assayed for anti-tumorigenic effects in pre-clinical cancer models. Q8 reduced clone formation of the human colorectal cancer cell line HT29-Luc2. Gene silencing of CysLT1 in HT29-Luc2 cells significantly reduced expression of calpain-2. In human ex vivo colorectal cancer tumour explants, Q8 significantly decreased the secretion of both TIE-2 and VCAM-1 expression. In vivo Q8 was well tolerated up to 50 mg/kg by Balb/C mice and significantly more effective at reducing tumour volume in colorectal tumour xenografts compared to the parent drug quininib. In tumour xenografts, Q8 significantly reduced expression of the angiogenic marker calpain-2. In summary, we propose Q8 may act on the TIE-2-Angiopoietin signalling pathway to significantly inhibit the process of tumour angiogenesis in colorectal cancer.
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Affiliation(s)
- Clare T Butler
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, Dublin, Ireland
| | - Susan A Kennedy
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin, Ireland
| | - Amy Buckley
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin, Ireland
| | - Ronan Doyle
- Department of Histopathology, Trinity College Dublin Central Pathology Laboratory, St James's Hospital, Dublin, Ireland
| | - Emer Conroy
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, Dublin, Ireland
| | - William M Gallagher
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, Dublin, Ireland
| | - Jacintha O'Sullivan
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.,These authors contributed equally to this work
| | - Breandán N Kennedy
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, Dublin, Ireland.,These authors contributed equally to this work
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Chen Q, Zhao H, Wu J, Cai J, Li C, Zhao J, Bi X, Li Z, Huang Z, Zhang Y, Cui W, Zhou J. Preoperative D-dimer and Gamma-Glutamyltranspeptidase Predict Major Complications and Survival in Colorectal Liver Metastases Patients After Resection. Transl Oncol 2019; 12:996-1004. [PMID: 31125760 PMCID: PMC6531870 DOI: 10.1016/j.tranon.2019.04.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 04/11/2019] [Accepted: 04/16/2019] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES: To investigate the predictive value of the pre-operative D-dimer and gamma-glutamyltranspeptidase (GGT) for the prognosis in colorectal liver metastases (CRLM) patients after hepatic resection. METHODS: Two hundred and ninety-two patients between December 2008 and December 2016 and 101 patients at our center from January 2017 to December 2018 were selected as a training set and validation set, respectively. The combination of the pre-operative D-dimer and GGT status (CPDG score) was scored as follows: elevated D-dimer levels with elevated GGT levels was allocated a score of 2, decreased D-dimer levels with decreased GGT levels was allocated a score of 0, and all other combinations were allocated a score of 1. In the training set, a logistic regression was applied to explore potential predictors of major postoperative complications. A Cox proportional hazards analysis was used to analyze survival. We further verified our findings in the validation set. RESULTS: Major complications occurred in 43 (14.7%) and 25 (24.8%) patients in the training set and validation set, respectively. In the training set, multivariate analysis showed that elevated GGT levels and elevated D-dimer levels independently predicted major complications respectively. In the multivariate analyses, elevated pre-operative D-dimer levels remained independently associated with decreased overall survival (OS) (hazard ratio [HR] = 1.751, 95% confidence interval [CI]: 1.139-2.691, P = .01). The CPDG score was an independent prognostic factor for major complications and OS in the multivariate analyses. The predictive ability of the CPDG score was higher than either factor alone. A Kaplan-Meier survival analysis showed that compared with patients with CPDG score = 1 or CPDG score = 0, patients with a CPDG score = 2 had worsened OS. Furthermore, for OS comparisons, the differences between any two groups were significant. In the validation set, elevated GGT and D-dimer were also suggested to predict worse progression-free survival (PFS) and to be independently associated with major complications. CONCLUSIONS: The pre-operative D-dimer levels, GGT levels and CPDG score are reliable biomarkers to predict post-operative major complications or survival in CRLM patients after hepatic resection, which make it useful for CRLM patients in guiding surveillance approaches and prognosis assessments.
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Affiliation(s)
- Qichen Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianxiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Cong Li
- Department of colorectal surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiyu Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yefan Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Cui
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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22
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Goumard C, Nancy You Y, Okuno M, Kutlu O, Chen HC, Simoneau E, Vega EA, Chun YS, David Tzeng C, Eng C, Vauthey JN, Conrad C. Minimally invasive management of the entire treatment sequence in patients with stage IV colorectal cancer: a propensity-score weighting analysis. HPB (Oxford) 2018; 20:1150-1156. [PMID: 30005993 DOI: 10.1016/j.hpb.2018.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 05/11/2018] [Accepted: 05/19/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND In patients with stage IV colorectal cancer (CRC), minimally invasive surgery (MIS) may offer optimal oncologic outcome with low morbidity. However, the relative benefit of MIS compared to open surgery in patients requiring multistage resections has not been evaluated. METHODS Patients who underwent totally minimally invasive (TMI) or totally open (TO) resections of CRC primary and liver metastases (CLM) in 2009-2016 were analyzed. Inverse probability of weighted adjustment by propensity score was performed before analyzing risk factors for complications and survival. RESULTS The study included 43 TMI and 121 TO patients. Before and after adjustment, TMI patients had significantly less cumulated postoperative complications (41% vs. 59%, p = 0.001), blood loss (median 100 vs. 200 ml, p = 0.001) and shorter length of hospital stay (median 4.5 vs. 6.0 days, p < 0.001). Multivariate analysis identified TO approach vs. MIS (OR = 2.4, p < 0.001), major liver resection (OR = 4.4, p < 0.001), and multiple CLM (OR = 2.3, p = 0.001) as independent risk factors for complications. 5-year overall survival was comparable (81% vs 68%, p = 0.59). CONCLUSION In patients with CRC undergoing multistage surgical treatment, MIS resection contributes to optimal perioperative outcomes without compromise in oncologic outcomes.
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Affiliation(s)
- Claire Goumard
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Y Nancy You
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Masayuki Okuno
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Onur Kutlu
- Department of Surgery, University of Miami, Miami, FL, USA
| | - Hsiang-Chun Chen
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Eve Simoneau
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Eduardo A Vega
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun-Shin Chun
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - C David Tzeng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cathy Eng
- Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Claudius Conrad
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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23
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Ratti F, Fiorentini G, Cipriani F, Catena M, Paganelli M, Aldrighetti L. Laparoscopic vs Open Surgery for Colorectal Liver Metastases. JAMA Surg 2018; 153:1028-1035. [PMID: 30027220 PMCID: PMC6583700 DOI: 10.1001/jamasurg.2018.2107] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 04/22/2018] [Indexed: 12/18/2022]
Abstract
Importance Surgery represents the mainstay treatment of colorectal liver metastases. Indications for the laparoscopic approach in this setting have been widened and there is a need to confirm the benefits of minimally invasive liver surgery (MILS) in patients with complex disease states. Objective To compare outcomes of laparoscopic surgery with those of open surgery for liver metastases from colorectal cancer, focusing on the characteristics of modern MILS and therefore overcoming possible selection bias related to different policies for patients' eligibility for MILS over time. Design, Setting, and Participants A cohort study of 885 resections performed for liver metastases from colorectal cancer between January 1, 2004, and June 30, 2017, at the Hepatobiliary Surgery Unit of San Raffaele Hospital, Milano, Italy, comprising 187 laparoscopic and 698 open resections. Procedures performed using the MILS approach with a ratio of MILS to total resections per year of more than 30% were considered and were matched by propensity scores (ratio of 1:4) to procedures performed using the open approach with a ratio of MILS to total resections per year of less than 30%. Main Outcomes and Measures The primary end point was short-term outcomes, including morbidity, mortality, functional recovery, and interval between surgery and adjuvant treatments; the secondary end point was long-term outcomes. Results Among this cohort (104 patients in the MILS group; 46 women and 58 men; median age, 62 years [range, 35-81 years]; and 412 patients in the open group; 181 women and 231 men; median age, 60 years [range, 37-80 years]), primary end-point data showed a significantly higher incidence of postoperative morbidity in patients who underwent open resections compared with those who underwent MILS (94 [22.8%] vs 21 [20.2%]; P = .04). Patients in the MILS group had fewer major complications (Dindo-Clavien grades III-V) compared with patients in the open group (Dindo-Clavien grades III-V; 7 [6.7%] vs 35 [8.5%]; P = .03) as well as shorter lengths of stay (median [range] duration, 3 [2-35] vs 5 [4-37] days; P = .02). Oncologic results were not compromised by the laparoscopic approach. Conclusions and Relevance In this study, the results of the propensity score matching analysis between modern laparoscopic surgery and previous open surgery appear to confer more comparable cohorts for complexity, further supporting the advantages of laparoscopy in the surgical treatment of liver metastases from colorectal cancer. The increase in use that laparoscopy has experienced appears to be based on increased feasibility, widening of eligibility criteria for patients, enhanced clinical effectiveness, and oncologic outcomes. All these elements together suggest that up to 70% of patients appear to be candidates for this minimally invasive surgical approach in high-volume centers.
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Affiliation(s)
- Francesca Ratti
- Hepatobiliary Surgery Division, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milano, Italy
| | - Guido Fiorentini
- Hepatobiliary Surgery Division, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milano, Italy
| | - Federica Cipriani
- Hepatobiliary Surgery Division, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milano, Italy
| | - Marco Catena
- Hepatobiliary Surgery Division, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milano, Italy
| | - Michele Paganelli
- Hepatobiliary Surgery Division, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milano, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milano, Italy
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24
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Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence. Surg Oncol 2018; 27:280-288. [PMID: 29937183 DOI: 10.1016/j.suronc.2018.05.012] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 04/27/2018] [Accepted: 05/03/2018] [Indexed: 12/16/2022]
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25
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Goumard C, Marcal LP, Wang WL, Somaiah N, Okuno M, Roland CL, Tzeng CWD, Chun YS, Feig BW, Vauthey JN, Conrad C. Long-Term Survival According to Histology and Radiologic Response to Preoperative Chemotherapy in 126 Patients Undergoing Resection of Non-GIST Sarcoma Liver Metastases. Ann Surg Oncol 2018; 25:107-116. [PMID: 29116489 DOI: 10.1245/s10434-017-6144-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND Non-gastrointestinal stromal tumor sarcomas (NGSs) have heterogeneous histology, and this heterogeneity may lead to uncertainty regarding the prognosis of patients with liver metastases from NGS (NGSLM) and decision regarding their surgical management. Furthermore, the role of preoperative chemotherapy in treatment of NGSLM remains poorly defined. We investigated long-term survival and its correlation to response to preoperative chemotherapy in patients with NGSLM. PATIENTS AND METHOD Patients who underwent liver resection for NGSLM during 1998-2015 were identified. Clinical, histopathologic, and survival data were analyzed. Multivariate analysis was performed using a Cox proportional hazards model. RESULTS 126 patients [62 (49%) with leiomyosarcoma] were included. Five-year overall survival (OS) and recurrence-free survival (RFS) rates were 49.3 and 14.9%, respectively. Survival did not differ by histologic subtype, primary tumor location, or use of preoperative or postoperative chemotherapy. NGSLM ≥ 10 cm and extrahepatic metastases at NGSLM diagnosis were the only independent risk factors for OS. In the 83 (66%) patients with metachronous NSGLM, disease-free interval > 6 months was associated with improved OS and RFS. Among the 65 patients (52%) who received preoperative chemotherapy, radiologic response according to Choi criteria specifically was associated with improved OS (p = 0.04), but radiologic response according to RECIST 1.1 criteria was not. CONCLUSIONS Resection of NGSLM led to a 5-year OS rate of 49%, independent of histologic subtype and primary tumor location. Choi criteria (which take into account tumor density) are superior to RECIST 1.1 in assessing radiologic response and should be used to assess response to preoperative chemotherapy.
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Affiliation(s)
- Claire Goumard
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Leonardo P Marcal
- Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wei-Lien Wang
- Division of Pathology/Laboratory Medicine, Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Neeta Somaiah
- Division of Cancer Medicine, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Masayuki Okuno
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christina L Roland
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ching-Wei D Tzeng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun Shin Chun
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Barry W Feig
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Claudius Conrad
- Department of Surgical Oncology, Hepato-Pancreato-Biliary Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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26
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Chakedis J, Squires MH, Beal EW, Hughes T, Lewis H, Paredes A, Al-Mansour M, Sun S, Cloyd JM, Pawlik TM. Update on current problems in colorectal liver metastasis. Curr Probl Surg 2017; 54:554-602. [PMID: 29198365 DOI: 10.1067/j.cpsurg.2017.10.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Jeffrey Chakedis
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Malcolm H Squires
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Eliza W Beal
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Tasha Hughes
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Heather Lewis
- University of Colorado Health System, Fort Collins, CO
| | - Anghela Paredes
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Mazen Al-Mansour
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Steven Sun
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Jordan M Cloyd
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Timothy M Pawlik
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH.
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27
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Fonseca GM, Herman P, Faraj SF, Kruger JAP, Coelho FF, Jeismann VB, Cecconello I, Alves VAF, Pawlik TM, de Mello ES. Pathological factors and prognosis of resected liver metastases of colorectal carcinoma: implications and proposal for a pathological reporting protocol. Histopathology 2017; 72:377-390. [PMID: 28858385 DOI: 10.1111/his.13378] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Colorectal cancer is a leading cause of death worldwide. The liver is the most common site of distant metastases, and surgery is the only potentially curative treatment, although the recurrence rate following surgery is high. In order to define prognosis after surgery, many histopathological features have been identified in the primary tumour. In turn, pathologists routinely report specific findings to guide oncologists on the decision to recommend adjuvant therapy. In general, the pathological report of resected colorectal liver metastases is limited to confirmation of the malignancy and details regarding the margin status. Most pathological reports of a liver resection for colorectal liver metastasis lack information on other important features that have been reported to be independent prognostic factors. We herein review the evidence to support a more detailed pathological report of the resected liver specimen, with attention to: the number and size of liver metastases; margin size; the presence of lymphatic, vascular, perineural and biliary invasion; mucinous pattern; tumour growth pattern; the presence of a tumour pseudocapsule; and the pathological response to neoadjuvant chemotherapy. In addition, we propose a new protocol for the evaluation of colorectal liver metastasis resection specimens.
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Affiliation(s)
- Gilton M Fonseca
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo Medical School, São Paulo, Brazil
| | - Paulo Herman
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo Medical School, São Paulo, Brazil
| | - Sheila F Faraj
- Department of Pathology, São Paulo State Cancer Institute, University of São Paulo Medical School, São Paulo, Brazil
| | - Jaime A P Kruger
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo Medical School, São Paulo, Brazil
| | - Fabricio F Coelho
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo Medical School, São Paulo, Brazil
| | - Vagner B Jeismann
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo Medical School, São Paulo, Brazil
| | - Ivan Cecconello
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo Medical School, São Paulo, Brazil
| | - Venancio A F Alves
- Department of Pathology, São Paulo State Cancer Institute, University of São Paulo Medical School, São Paulo, Brazil
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Evandro S de Mello
- Department of Pathology, São Paulo State Cancer Institute, University of São Paulo Medical School, São Paulo, Brazil
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28
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Jablonowski LJ, Teraphongphom NT, Wheatley MA. Drug Delivery from a Multi-faceted Ultrasound Contrast Agent: Influence of Shell Composition. Mol Pharm 2017; 14:3448-3456. [DOI: 10.1021/acs.molpharmaceut.7b00451] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Lauren J. Jablonowski
- School
of Biomedical Engineering, Science, and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, Pennsylvania 19104, United States
| | - Nutte T. Teraphongphom
- School
of Biomedical Engineering, Science, and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, Pennsylvania 19104, United States
| | - Margaret A. Wheatley
- School
of Biomedical Engineering, Science, and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, Pennsylvania 19104, United States
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29
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Moris D, Tsilimigras DI, Chakedis J, Beal EW, Felekouras E, Vernadakis S, Schizas D, Fung JJ, Pawlik TM. Liver transplantation for unresectable colorectal liver metastases: A systematic review. J Surg Oncol 2017; 116:288-297. [PMID: 28513862 DOI: 10.1002/jso.24671] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023]
Abstract
The use of liver transplantation (LT) for liver metastases attempted in the early 1990's was associated with poor perioperative outcomes and unacceptably low overall survival. Recently, there has been renewed interest in LT as a treatment option for colorectal liver metastases (CLM) in countries where organ supply is high. To date, no meticulous analysis about the efficacy, safety and outcomes of LT in CLM patients has been published. We present the first systematic review on the subject.
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Affiliation(s)
- Dimitrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
| | - Diamantis I Tsilimigras
- First Department of Surgery, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Jeffery Chakedis
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
| | - Eliza W Beal
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
| | - Evangelos Felekouras
- First Department of Surgery, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Spiridon Vernadakis
- Transplantation Unit, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - John J Fung
- Department of Surgery, University of Chicago Medicine Transplant Institute, University of Chicago, Chicago, Illinois
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio
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