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1
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Razmi M, Tajik F, Hashemi F, Yazdanpanah A, Hashemi-Niasari F, Divsalar A. The Prognostic Importance of Ki-67 in Gastrointestinal Carcinomas: A Meta-analysis and Multi-omics Approach. J Gastrointest Cancer 2024; 55:599-624. [PMID: 38411875 DOI: 10.1007/s12029-024-01022-w] [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] [Accepted: 01/23/2024] [Indexed: 02/28/2024]
Abstract
PURPOSE This study aimed to determine if Ki-67, a commonly used marker to measure tumor proliferation, is a reliable prognostic factor in various types of gastrointestinal (GI) cancers based on current high-quality multivariable evidence. METHODS A comprehensive search was conducted in PubMed, Embase, Scopus, and ISI Web of Science databases to investigate the association between Ki-67 positivity and overall survival (OS) and disease/recurrence-free survival (DFS/RFS) in GI cancers. Heterogeneity was assessed using Chi-square-based Q and I2 analyses and publication bias using funnel plots and Egger's analysis. In addition, Ki-67 levels in different GI cancers were examined by different platforms. The prognostic capability of Ki-67, gene ontology (GO), and pathway enrichment analysis were obtained from GEPIA2 and STRING. RESULTS Totally, 61 studies, involving 13,034 patients, were deemed eligible for our evaluation. The combined hazard ratios (HRs) demonstrated the prediction ability of overexpressed Ki-67 for a worse OS (HR: 1.67, P < 0.001; HR: 1.37, P = 0.021) and DFS/RFS (HR: 2.06, P < 0.001) in hepatocellular and pancreatic malignancies, respectively, as confirmed by multi-omics databases. However, similar correlation was not found in esophageal, gastric, and colorectal cancers. Furthermore, most of the associations were identified to be robust based on different subcategories and publication bias assessment. Finally, enriched Ki-67-related genes were found to be involved in various important signaling pathways, such as cell cycle, P53 signaling network, and DNA damage responses. CONCLUSION This study supports that Ki-67 can serve as an independent prognostic biomarker for pancreatic and hepatocellular malignancies in clinical settings.
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Affiliation(s)
- Mahdieh Razmi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Fatemeh Tajik
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Surgery, University of California, Irvine, CA, USA
| | - Farideh Hashemi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ayna Yazdanpanah
- Department of Tissue Engineering and Regenerative Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Hashemi-Niasari
- Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Adeleh Divsalar
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
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2
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Liu Q, Ran D, Wang L, Feng J, Deng W, Mei D, Peng Y, Du C. Association between Ki67 expression and therapeutic outcome in colon cancer. Oncol Lett 2023; 25:272. [PMID: 37216165 PMCID: PMC10193363 DOI: 10.3892/ol.2023.13858] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 04/14/2023] [Indexed: 05/24/2023] Open
Abstract
Ki67 is a commonly used proliferation marker in pathological diagnosis of tumors; however, its prognostic value in colon cancer is controversial. A total of 312 consecutive patients with stage I-III colon cancer who underwent radical surgery with or without adjuvant chemotherapy were included in the present study. Ki67 expression was assessed using immunohistochemistry and was classified according to 25% intervals. The association between Ki67 expression and clinicopathological features was analyzed. Long-term postoperative survival, including disease-free survival (DFS) and overall survival, was calculated, and its association with Ki67 was analyzed. High Ki67 expression (>50%) was associated with improved DFS in patients treated with adjuvant chemotherapy postoperatively, but not in patients who received surgery alone (P=0.138). Ki67 expression was significantly associated with histological differentiation of the tumor (P=0.01), while it was not associated with other clinicopathological factors. Multivariate analysis demonstrated that pathological T and N stage were independent prognostic factors. In conclusion, high Ki67 expression was associated with a good therapeutic outcome in patients receiving adjuvant chemotherapy in colon cancer.
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Affiliation(s)
- Qi Liu
- Key University Laboratory of Metabolism and Health of Guangdong, Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
| | - Dongmei Ran
- Department of Pathology, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
- Digestive Tumor Center, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Liping Wang
- Digestive Tumor Center, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
- Department of Medical Oncology, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Jiajun Feng
- Department of General Surgery, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Wei Deng
- Department of Pathology, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Dongdong Mei
- Department of Pathology, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Yifan Peng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Changzheng Du
- Key University Laboratory of Metabolism and Health of Guangdong, Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
- Digestive Tumor Center, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
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Aldoori J, Cockbain AJ, Toogood GJ, Hull MA. Omega-3 polyunsaturated fatty acids: moving towards precision use for prevention and treatment of colorectal cancer. Gut 2022; 71:822-837. [PMID: 35115314 DOI: 10.1136/gutjnl-2021-326362] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022]
Abstract
Data from experimental studies have demonstrated that marine omega-3 polyunsaturated fatty acids (O3FAs) have anti-inflammatory and anticancer properties. In the last decade, large-scale randomised controlled trials of pharmacological delivery of O3FAs and prospective cohort studies of dietary O3FA intake have continued to investigate the relationship between O3FA intake and colorectal cancer (CRC) risk and mortality. Clinical data suggest that O3FAs have differential anti-CRC activity depending on several host factors (including pretreatment blood O3FA level, ethnicity and systemic inflammatory response) and tumour characteristics (including location in the colorectum, histological phenotype (eg, conventional adenoma or serrated polyp) and molecular features (eg, microsatellite instability, cyclooxygenase expression)). Recent data also highlight the need for further investigation of the effect of O3FAs on the gut microbiota as a possible anti-CRC mechanism, when used either alone or in combination with other anti-CRC therapies. Overall, these data point towards a precision approach to using O3FAs for optimal prevention and treatment of CRC based on mechanistic understanding of host, tumour and gut microbiota factors that predict anticancer activity of O3FAs.
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Affiliation(s)
- Joanna Aldoori
- Gastrointestinal & Surgical Sciences, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.,Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Andrew J Cockbain
- Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Giles J Toogood
- Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Mark A Hull
- Gastrointestinal & Surgical Sciences, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
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4
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Biopsy and Margins Optimize Outcomes after Thermal Ablation of Colorectal Liver Metastases. Cancers (Basel) 2022; 14:cancers14030693. [PMID: 35158963 PMCID: PMC8833800 DOI: 10.3390/cancers14030693] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/14/2022] [Accepted: 01/26/2022] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Thermal ablation (TA) is a non-surgical treatment of cancer that has been used with success in the treatment of colorectal liver metastases (CLM). TA consists of burning the cancer and a rim of surrounding tissue (margin) with a special needle placed in the tumor under image guidance. Despite the technological evolution of TA, tumor progression/recurrence rates remain higher than expected. We present a method that combines tissue and imaging tests performed immediately after ablation to determine whether there is complete tumor destruction or remaining live cancer cells that can cause tumor progression/recurrence. This information can provide guidance for additional treatments for patients with evidence of residual cancer, i.e.,: additional TA at the same or subsequent sitting, or additional chemotherapy and short-interval imaging follow-up to detect recurrence. The presented method proposes a clinical practice paradigm change that can improve clinical outcomes in a large population of patients with CLM treated by TA. Abstract Background: Thermal ablation is a definitive local treatment for selected colorectal liver metastases (CLM) that can be ablated with adequate margins. A critical limitation has been local tumor progression (LTP). Methods: This prospective, single-group, phase 2 study enrolled patients with CLM < 5 cm in maximum diameter, at a tertiary cancer center between November 2009 and February 2019. Biopsy of the ablation zone center and margin was performed immediately after ablation. Viable tumor in tissue biopsy and ablation margins < 5 mm were assessed as predictors of 12-month LTP. Results: We enrolled 107 patients with 182 CLMs. Mean tumor size was 2.0 (range, 0.6–4.6) cm. Microwave ablation was used in 51% and radiofrequency ablation in 49% of tumors. The 12- and 24-month cumulative incidence of LTP was 22% (95% confidence interval [CI]: 17, 29) and 29% (95% CI: 23, 36), respectively. LTP at 12 months was 7% (95% CI: 3, 14) for the biopsy tumor-negative ablation zone with margins ≥ 5 mm vs. 63% (95% CI: 35, 85) for the biopsy-positive ablation zone with margins < 5 mm (p < 0.001). Conclusions: Biopsy-proven complete tumor ablation with margins of at least 5 mm achieves optimal local tumor control for CLM, regardless of the ablation modality used.
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Martin SZ, Wagner DC, Hörner N, Horst D, Lang H, Tagscherer KE, Roth W. Ex vivo tissue slice culture system to measure drug-response rates of hepatic metastatic colorectal cancer. BMC Cancer 2019; 19:1030. [PMID: 31675944 PMCID: PMC6824140 DOI: 10.1186/s12885-019-6270-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 10/16/2019] [Indexed: 02/08/2023] Open
Abstract
Background The lack of predictive biomarkers or test systems contributes to high failure rates of systemic therapy in metastasized colorectal carcinoma, accounting for a still unfavorable prognosis. Here, we present an ex vivo functional assay to measure drug-response based on a tissue slice culture approach. Methods Tumor tissue slices of hepatic metastases of nine patients suffering from colorectal carcinoma were cultivated for 72 h and treated with different concentrations of the clinically relevant drugs Oxaliplatin, Cetuximab and Pembrolizumab. Easy to use, objective and automated analysis routines based on the Halo platform were developed to measure changes in proliferative activity and the morphometric make-up of the tumor. Apoptotic indices were assessed semiquantitatively. Results Untreated tumor tissue slices showed high morphological comparability with the original “in vivo”-tumor, preserving proliferation and stromal-tumor interactions. All but one patients showed a dosage dependent susceptibility to treatment with Oxaliplatin, whereas only two patients showed responses to Cetuximab and Pembrolizumab, respectively. Furthermore, we identified possible non-responders to Cetuximab therapy in absence of RAS-mutations. Conclusions This is the first time to demonstrate feasibility of the tissue slice culture approach for metastatic tissue of colorectal carcinoma. An automated readout of proliferation and tumor-morphometry allows for quantification of drug susceptibility. This strongly indicates a potential value of this technique as a patient-specific test-system of targeted therapy in metastatic colorectal cancer. Co-clinical trials are needed to customize for clinical application and to define adequate read-out cut-off values.
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Affiliation(s)
- Steve Z Martin
- Institute of Pathology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany. .,Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte, 10117, Berlin, Germany.
| | - Daniel C Wagner
- Institute of Pathology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Nina Hörner
- Institute of Pathology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - David Horst
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte, 10117, Berlin, Germany
| | - Hauke Lang
- Department of General Visceral and Transplantation Surgery, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Katrin E Tagscherer
- Institute of Pathology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
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6
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Luo ZW, Zhu MG, Zhang ZQ, Ye FJ, Huang WH, Luo XZ. Increased expression of Ki-67 is a poor prognostic marker for colorectal cancer patients: a meta analysis. BMC Cancer 2019; 19:123. [PMID: 30727976 PMCID: PMC6364416 DOI: 10.1186/s12885-019-5324-y] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 01/28/2019] [Indexed: 12/14/2022] Open
Abstract
Background The prognostic value of Ki-67 expression in colorectal cancer patients was controversial. Therefore, this meta analysis was conducted to ascertain the prognostic value of Ki-67 expression in colorectal cancer patients. Methods The electronic databases, including EMBASE, PubMed, Cochrane Library and Web of Knowledge database, were searched from January 1970 to July 2017. The pooled hazard ratios and 95% confidence intervals were calculated to evaluate the prognostic value of Ki-67 expression for colorectal cancer patients. Results Totally 34 eligible studies and 6180 colorectal cancer patients were included in the present meta analysis. The pooled hazard ratios were 1.54(95% CI 1.17–2.02, P = 0.005) for overall survival and 1.43(1.12–1.83, P = 0.008) for disease free survival in univariate analysis. After adjustment of other prognostic factors, the pooled HR was 1.50(95% CI 1.02–2.22, P = 0.03) for overall survival in multivariate analysis. Conclusion The present meta analysis demonstrated that high Ki-67 expression is significantly correlated with poor overall survival and disease free survival, indicating that high Ki-67 expression may serve as a valuable predictive method for poor prognosis of colorectal cancer patients.
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Affiliation(s)
- Zhao-Wen Luo
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
| | - Ming-Gu Zhu
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
| | - Zhi-Qiao Zhang
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China.
| | - Feng-Jun Ye
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
| | - Wen-Heng Huang
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
| | - Xue-Zhang Luo
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
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7
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Torén W, Ansari D, Andersson R. Immunohistochemical investigation of prognostic biomarkers in resected colorectal liver metastases: a systematic review and meta-analysis. Cancer Cell Int 2018; 18:217. [PMID: 30602942 PMCID: PMC6307223 DOI: 10.1186/s12935-018-0715-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 12/18/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Many studies have investigated the prognostic role of biomarkers in colorectal liver metastases (CRLM). However, no biomarker has been established in routine clinical practice. The aim of this study was to scrutinize the current literature for biomarkers evaluated by immunohistochemistry as prognostic markers in patients with resected CRLM. METHODS A systematic review was performed according to the PRISMA guidelines. Articles were identified in the PubMed database with selected search terms and by cross-references search. The REMARK quality criteria were applied. Markers were included if they reported the prognostic impact of immunohistochemical markers in a multivariable setting in relation to overall survival (OS). A meta-analysis was conducted when more than one original article provided survival data of a marker. RESULTS In total, 26 biomarkers were identified as independent significant markers for OS in resected CRLM. These biomarkers were found to be involved in multiple oncogenic signalling pathways that control cell growth, apoptosis, angiogenesis and evasion of immune detection. Among these biomarker candidates were Ki-67, EGFR, p53, hTERT, CD34, TSP-1, KISS1, Aurora kinase A and CDX2. CD34 and TSP-1 were reported as significantly associated with survival by more than one study and where therefore pooled in a meta-analysis. CONCLUSION A number of independent prognostic biomarkers for resected CRLM were identified. However, most markers were evaluated in a retrospective setting with small patient cohorts, without external validation. Large, prospective, multicentre studies with standardised methods are needed before biomarkers can translated into the clinic.
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Affiliation(s)
- William Torén
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, SE-221 85 Lund, Sweden
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8
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Fernández Moro C, Bozóky B, Gerling M. Growth patterns of colorectal cancer liver metastases and their impact on prognosis: a systematic review. BMJ Open Gastroenterol 2018; 5:e000217. [PMID: 30073092 PMCID: PMC6067357 DOI: 10.1136/bmjgast-2018-000217] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 06/07/2018] [Accepted: 06/17/2018] [Indexed: 01/15/2023] Open
Abstract
Background Colorectal cancer liver metastases (CRLM) grow in distinct histological patterns that have been associated with outcome after surgical resection. We conducted a systematic review to evaluate the frequency of different CRLM growth patterns and their impact on prognosis. Methods We searched Embase and MEDLINE databases from inception to 1 December 2017 to identify studies that reported CRLM growth pattern histopathology, their frequencies, and/or data related to outcome. Results We included a total of 23 studies (2432 patients with CRLM) published between 1991 and 2017. There were variations in the terminology used to describe the growth patterns as well as in their histopathological definitions. A 'desmoplastic' pattern was most frequently considered, followed by 'pushing' and 'replacement' patterns. Data supported the presence of both intralesional and interlesional heterogeneity. There were no differences in growth pattern distribution stratified by chemotherapy. While heterogeneity of histopathology assessment precluded formal meta-analysis, the majority of articles found favourable outcomes for desmoplastic and unfavourable outcomes for replacement CRLM, independently of when the study was conducted. Conclusions The results suggest that CRLM growth patterns may have prognostic potential and that they may be considered for standardised routine histopathological reporting. Further understanding of the different growth patterns may provide important insights into the biological mechanisms that underlie metastatic growth in the liver.
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Affiliation(s)
- Carlos Fernández Moro
- Division of Pathology, Department of Laboratory Medicine (LabMed), Karolinska Institute, Stockholm, Sweden.,Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden
| | - Béla Bozóky
- Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden
| | - Marco Gerling
- Department of Biosciences and Nutrition, NEO, Karolinska Institutet, Huddinge, Sweden.,Tema Cancer, Karolinska University Hospital, Solna, Sweden
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Donadon M, Lleo A, Di Tommaso L, Soldani C, Franceschini B, Roncalli M, Torzilli G. The Shifting Paradigm of Prognostic Factors of Colorectal Liver Metastases: From Tumor-Centered to Host Immune-Centered Factors. Front Oncol 2018; 8:181. [PMID: 29892573 PMCID: PMC5985314 DOI: 10.3389/fonc.2018.00181] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 05/09/2018] [Indexed: 12/20/2022] Open
Abstract
The determinants of prognosis in patients with colorectal liver metastases (CLM) have been traditionally searched among the tumoral factors, either of the primary colorectal tumor or of the CLM. While many different scoring systems have been developed based on those clinic-pathological factors with disparate results, there has been the introduction of genetic biological markers that added a theranostic perspective. More recently, other important elements, such as those factors related to the host immune system, have been proposed as determinants of prognosis of CLM patients. In the present work, we review the current prognostic factors of CLM patients as well as the burgeoning shifting paradigm of prognostication that relies on the host immune system.
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Affiliation(s)
- Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Italy
- Department of Biomedical Science, Humanitas University, Rozzano, Italy
| | - Ana Lleo
- Department of Biomedical Science, Humanitas University, Rozzano, Italy
- Department of Internal Medicine, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Luca Di Tommaso
- Department of Biomedical Science, Humanitas University, Rozzano, Italy
- Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Cristiana Soldani
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Barbara Franceschini
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Massimo Roncalli
- Department of Biomedical Science, Humanitas University, Rozzano, Italy
- Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Italy
- Department of Biomedical Science, Humanitas University, Rozzano, Italy
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10
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Teraoku H, Morine Y, Ikemoto T, Saito Y, Yamada S, Yoshikawa M, Takasu C, Higashijima J, Imura S, Shimada M. Role of thrombospondin-1 expression in colorectal liver metastasis and its molecular mechanism. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2016; 23:565-73. [PMID: 27404020 DOI: 10.1002/jhbp.376] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 07/08/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND Thrombospondin-1 (THBS-1), a glycoprotein, is an endogenous inhibitor of angiogenesis and tumor growth. In this study, we investigated the clinical role and mechanism of THBS-1 expression in colorectal liver metastases, focusing on the relationships between its expression and tumor growth, epithelial-mesenchymal transition (EMT), and expression of other relevant molecules. METHODS Ninety-four patients who initially underwent curative hepatic resection were enrolled in this study and correlations between expression of THBS-1 (THBS-1 high [n = 35] and THBS-1 low [n = 59]) and tumor growth, Ki-67 labeling index (Ki-67 LI), expression of other relevant molecules, and microvessel density (MVD) investigated. RESULTS THBS-1 low expression correlated with more advanced grade of liver and lymph node metastases and significantly worse overall survival than strong THBS-1 expression (3-year survival: 96.7% vs. 65.4%, P < 0.01). Multivariate analysis identified THBS-1 low expression as an independent prognostic factor (HR 2.82, 95% CI 1.21-7.71, P = 0.01). THBS-1 low expression correlated positively with high Ki-67 LI (P < 0.05) and inversely with E-cadherin (P < 0.05) and hypoxia inducible factor-1α (HIF-1α) expression (P < 0.05); THBS-1 expression and MVD were not significantly correlated. CONCLUSIONS Low THBS-1 expression may be an independent poor prognostic factor that affects tumor growth and EMT acquisition. Additionally, THBS-1 may be regulated by the HIF-1 pathway.
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Affiliation(s)
- Hiroki Teraoku
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yuji Morine
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yu Saito
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shinichiro Yamada
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Masato Yoshikawa
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Chie Takasu
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Jun Higashijima
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Satoru Imura
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Mitsuo Shimada
- Department of Surgery, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
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11
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Lau LF, Murone C, Williams DS, Standish R, Lee ST, Christophi C, Scott AM, Muralidharan V. Metabolic response evaluation for colorectal liver metastases and correlation to pathologic response and tumour markers. ANZ J Surg 2016; 88:E108-E113. [PMID: 27452367 DOI: 10.1111/ans.13680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 05/30/2016] [Accepted: 05/31/2016] [Indexed: 11/28/2022]
Abstract
BACKGROUND Tumour metabolic response to chemotherapy is increasingly recognized as a prognostic indicator for colorectal cancer liver metastases (CRCLM). However, its clinical role and the underlying biological mechanism of its prognostic ability are unclear. This study compares metabolic to pathologic response for CRCLM, and correlates metabolic response to tumour expression of six key biomarkers. METHODS Thirty-seven patients who had positron emission tomography imaging before and after pre-operative chemotherapy prior to liver resection for CRCLM were included. Metabolic response was assessed according to the positron emission tomography response criteria in solid tumours (PERCIST) and correlated to recurrence-free and overall survival. PERCIST was compared to tumour regression grading, computed tomography (CT) response, tumour necrosis and mucin and immunohistochemical expression of Ki-67, hypoxia inducible factor 1α, vascular endothelial growth factor, p53, p16 and vimentin. Area under the receiver operating characteristic curve (AUC), Kaplan-Meier survival, Spearman's correlation (rs ) and multivariate Cox regression analyses were used. RESULTS PERCIST correlated significantly to 2-year mortality (AUC = 0.162, P < 0.01) and 2-year recurrence (AUC = 0.284, P = 0.03). Metabolically responsive tumours conferred a better overall survival (P = 0.01) and recurrence-free survival (P = 0.03). Tumour regression grading did not stratify for outcome. Metabolic response was significantly correlated to Ki-67 and p16 expression (rs = 0.559 and rs = -0.549, respectively). Multivariate analysis revealed only PERCIST to be correlated to death and recurrence. CONCLUSION Pre-operative PERCIST assessment of CRCLM was more prognostic than pathologic and CT response assessment. Metabolic non-response correlated with tumour proliferation and loss of tumour suppression.
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Affiliation(s)
- Lawrence F Lau
- Department of Surgery, Austin Hospital, The University of Melbourne, Heidelberg, Victoria, Australia
| | - Carmel Murone
- Department of Pathology, Austin Hospital, The University of Melbourne, Heidelberg, Victoria, Australia.,Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
| | - David S Williams
- Department of Pathology, Austin Hospital, The University of Melbourne, Heidelberg, Victoria, Australia.,Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
| | - Richard Standish
- Department of Pathology, Austin Hospital, The University of Melbourne, Heidelberg, Victoria, Australia
| | - Sze Ting Lee
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,Department of Molecular Imaging and Therapy, Austin Hospital, Heidelberg, Victoria, Australia
| | - Christopher Christophi
- Department of Surgery, Austin Hospital, The University of Melbourne, Heidelberg, Victoria, Australia
| | - Andrew M Scott
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,Department of Molecular Imaging and Therapy, Austin Hospital, Heidelberg, Victoria, Australia
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12
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Besenhard MO, Jarzabek M, O'Farrell AC, Callanan JJ, Prehn JH, Byrne AT, Huber HJ. Modelling tumour cell proliferation from vascular structure using tissue decomposition into avascular elements. J Theor Biol 2016; 402:129-43. [PMID: 27155046 DOI: 10.1016/j.jtbi.2016.04.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 04/06/2016] [Accepted: 04/23/2016] [Indexed: 01/09/2023]
Abstract
Computer models allow the mechanistically detailed study of tumour proliferation and its dependency on nutrients. However, the computational study of large vascular tumours requires detailed information on the 3-dimensional vessel network and rather high computation times due to complex geometries. This study puts forward the idea of partitioning vascularised tissue into connected avascular elements that can exchange cells and nutrients between each other. Our method is able to rapidly calculate the evolution of proliferating as well as dead and quiescent cells, and hence a proliferative index, from a given amount and distribution of vascularisation of arbitrary complexity. Applying our model, we found that a heterogeneous vessel distribution provoked a higher proliferative index, suggesting increased malignancy, and increased the amount of dead cells compared to a more static tumour environment when a homogenous vessel distribution was assumed. We subsequently demonstrated that under certain amounts of vascularisation, cell proliferation may even increase when vessel density decreases, followed by a subsequent decrease of proliferation. This effect was due to a trade-off between an increase in compensatory proliferation for replacing dead cells and a decrease of cell population due to lack of oxygen supply in lowly vascularised tumours. Findings were illustrated by an ectopic colorectal cancer mouse xenograft model. Our presented approach can be in the future applied to study the effect of cytostatic, cytotoxic and anti-angiogenic chemotherapy and is ideally suited for translational systems biology, where rapid interaction between theory and experiment is essential.
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Affiliation(s)
- Maximilian O Besenhard
- Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; Research Centre Pharmaceutical Engineering (RCPE) GmbH, Inffeldgasse 13, 8010 Graz, Austria
| | - Monika Jarzabek
- Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Alice C O'Farrell
- Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - John J Callanan
- Department of Biomedical Sciences, Ross University School of Veterinary Medicine, St Kitts, West Indies
| | - Jochen Hm Prehn
- Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Annette T Byrne
- Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; UCD School of Biomolecular & Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
| | - Heinrich J Huber
- Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, Box 911, 3000 Leuven, Belgium.
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13
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Sotirchos VS, Petrovic LM, Gönen M, Klimstra DS, Do RKG, Petre EN, Garcia AR, Barlas A, Erinjeri JP, Brown KT, Covey AM, Alago W, Brody LA, DeMatteo RP, Kemeny NE, Solomon SB, Manova-Todorova KO, Sofocleous CT. Colorectal Cancer Liver Metastases: Biopsy of the Ablation Zone and Margins Can Be Used to Predict Oncologic Outcome. Radiology 2016; 280:949-59. [PMID: 27010254 DOI: 10.1148/radiol.2016151005] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose To establish the prognostic value of biopsy of the central and marginal ablation zones for time to local tumor progression (LTP) after radiofrequency (RF) ablation of colorectal cancer liver metastasis (CLM). Materials and Methods A total of 47 patients with 67 CLMs were enrolled in this prospective institutional review board-approved and HIPAA-compliant study between November 2009 and August 2012. Mean tumor size was 2.1 cm (range, 0.6-4.3 cm). Biopsy of the center and margin of the ablation zone was performed immediately after RF ablation (mean number of biopsy samples per ablation zone, 1.9) and was evaluated for the presence of viable tumor cells. Samples containing tumor cells at morphologic evaluation were further interrogated with immunohistochemistry and were classified as either positive, viable tumor (V) or negative, necrotic (N). Minimal ablation margin size was evaluated in the first postablation CT study performed 4-8 weeks after ablation. Variables were evaluated as predictors of time to LTP with the competing-risks model (uni- and multivariate analyses). Results Technical effectiveness was evident in 66 of 67 (98%) ablated lesions on the first contrast material-enhanced CT images at 4-8-week follow-up. The cumulative incidence of LTP at 12-month follow-up was 22% (95% confidence interval [CI]: 12, 32). Samples from 16 (24%) of 67 ablation zones were classified as viable tumor. At univariate analysis, tumor size, minimal margin size, and biopsy results were significant in predicting LTP. When these variables were subsequently entered in a multivariate model, margin size of less than 5 mm (P < .001; hazard ratio [HR], 6.7) and positive biopsy results (P = .008; HR, 3.4) were significant. LTP within 12 months after RF ablation was noted in 3% (95% CI: 0, 9) of necrotic CLMs with margins of at least 5 mm. Conclusion Biopsy proof of complete tumor ablation and minimal ablation margins of at least 5 mm are independent predictors of LTP and yield the best oncologic outcomes. (©) RSNA, 2016.
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Affiliation(s)
- Vlasios S Sotirchos
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Lydia M Petrovic
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Mithat Gönen
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - David S Klimstra
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Richard K G Do
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Elena N Petre
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Alessandra R Garcia
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Afsar Barlas
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Joseph P Erinjeri
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Karen T Brown
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Anne M Covey
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - William Alago
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Lynn A Brody
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Ronald P DeMatteo
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Nancy E Kemeny
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Stephen B Solomon
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Katia O Manova-Todorova
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
| | - Constantinos T Sofocleous
- From the Section of Interventional Radiology, Department of Radiology (V.S.S., E.N.P., J.P.E., K.T.B., A.M.C., W.A., L.A.B., S.B.S., C.T.S.), Departments of Epidemiology and Biostatistics (M.G.), Pathology (D.S.K.), Radiology (R.K.G.D., A.R.G.), Molecular Cytology (A.B., K.O.M.), Surgery (R.P.D.), and Medicine (N.E.K.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; and Department of Pathology, University of Southern California University Hospital, Los Angeles, Calif (L.M.P.)
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14
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Eefsen RL, Engelholm L, Willemoe GL, Van den Eynden GG, Laerum OD, Christensen IJ, Rolff HC, Høyer-Hansen G, Osterlind K, Vainer B, Illemann M. Microvessel density and endothelial cell proliferation levels in colorectal liver metastases from patients given neo-adjuvant cytotoxic chemotherapy and bevacizumab. Int J Cancer 2015; 138:1777-84. [PMID: 26510166 DOI: 10.1002/ijc.29904] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 08/28/2015] [Accepted: 10/09/2015] [Indexed: 01/28/2023]
Abstract
The treatment of patients with colorectal liver metastasis has improved significantly and first line therapy is often combined chemotherapy and bevacizumab, although it is unknown who responds to this regimen. Colorectal liver metastases grow in different histological growth patterns showing differences in angiogenesis. To identify possible response markers, histological markers of angiogenesis were assessed. Patients who underwent resection of colorectal liver metastasis at Rigshospitalet, Copenhagen, Denmark from 2007 to 2011 were included (n = 254) including untreated and patients treated with chemotherapy or chemotherapy plus bevacizumab. The resected liver metastases were characterised with respect to growth pattern, endothelial and tumour cell proliferation as well as microvessel density and tumour regression. Tumour regression grade of liver metastases differed significantly between untreated/chemotherapy treated patients in comparison to chemotherapy plus bevacizumab treated patients (both p < 0.0001). Microvessel density was decreased in liver metastases from patients treated with bevacizumab in comparison to those from untreated/chemotherapy-treated patients (p = 0.006/p = 0.002). Tumour cell proliferation assessed by Ki67 expression correlated to a shorter recurrence free survival in the total patient cohort. In conclusion, liver metastases from patients treated with neo-adjuvant chemotherapy and bevacizumab had significantly lower microvessel densities and tumour regression grades when compared to liver metastases from untreated or chemotherapy treated patients. This may indicate that bevacizumab treatment results in altered vascular biology and tumour viability, with possible tumour reducing effect.
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Affiliation(s)
- Rikke Løvendahl Eefsen
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.,Department of Oncology, Rigshospitalet, Copenhagen, Denmark
| | - Lars Engelholm
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Gro L Willemoe
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Ole Didrik Laerum
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Medicine, the Gade Laboratory of Pathology, University of Bergen, Norway
| | - Ib Jarle Christensen
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Hans Christian Rolff
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.,Department of Surgery, Rigshospitalet, Copenhagen, Denmark
| | - Gunilla Høyer-Hansen
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Kell Osterlind
- Department of Oncology, Rigshospitalet, Copenhagen, Denmark
| | - Ben Vainer
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Martin Illemann
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
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15
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Nielsen K, Rolff HC, Eefsen RL, Vainer B. The morphological growth patterns of colorectal liver metastases are prognostic for overall survival. Mod Pathol 2014; 27:1641-1648. [PMID: 24851832 DOI: 10.1038/modpathol.2014.4] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Accepted: 12/20/2013] [Indexed: 02/08/2023]
Abstract
Colorectal metastases in the liver grow according to three histological patterns: a pushing pattern, a replacement pattern, and a desmoplastic pattern. The objective of the current study was to explore the prognostic significance of these three growth patterns for survival. The study included 217 consecutive patients, liver resected between 2007 and 2011 due to hepatic metastases from colorectal adenocarcinoma. The growth patterns were assessed on archival hematoxylin and eosin-stained tissue sections. In 150 metastases, the density of the immune cell infiltrate at the tumor periphery was judged by a semi-quantitative method. The prevalence of the pushing-type, the desmoplastic-type, and the replacement-type was 33%, 32%, and 11%, respectively; 24% of the metastases displayed a mixed pattern. Kaplan-Meier analysis and Cox regression demonstrated a prognostic significance of the growth patterns (P=0.0006, log-rank test), as the replacement pattern appeared as an independent predictor of poor overall survival. For patients with replacement growth, the hazard of death was 2-2.5 times higher than for patients with pushing growth (P=0.004, cox regression) or mixed growth (P=0.01), and nearly four times higher than for patients with desmoplastic growth (P<0.0001). The negative prognostic effect of the replacement growth pattern was even more pronounced after adjusting for tumor size. Desmoplastic growth corresponded with small tumor size, dense lymphocytic infiltration and a more favorable prognosis. Eventually, the growth patterns may contribute to a histology-based prognostic biomarker for patients with colorectal liver metastases.
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Affiliation(s)
- Kåre Nielsen
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Hans C Rolff
- 1] Department of Surgical Gastroenterology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark [2] The Finsen Laboratory, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Rikke L Eefsen
- 1] The Finsen Laboratory, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark [2] Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ben Vainer
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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16
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Cockbain AJ, Volpato M, Race AD, Munarini A, Fazio C, Belluzzi A, Loadman PM, Toogood GJ, Hull MA. Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid. Gut 2014; 63:1760-8. [PMID: 24470281 DOI: 10.1136/gutjnl-2013-306445] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM). DESIGN We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA-FFA 2 g daily in patients undergoing liver resection surgery for CRCLM. The patients took EPA-FFA (n=43) or placebo (n=45) prior to surgery. The primary end-point was the CRCLM Ki67 proliferation index (PI). Secondary end-points included safety and tolerability of EPA-FFA, tumour fatty acid content and CD31-positive vascularity. We also analysed overall survival (OS) and disease-free survival (DFS). RESULTS The median (range) duration of EPA-FFA treatment was 30 (12-65) days. Treatment groups were well matched with no significant difference in disease burden at surgery or preoperative chemotherapy. EPA-FFA treatment was well tolerated with no excess of postoperative complications. Tumour tissue from EPA-FFA-treated patients demonstrated a 40% increase in EPA content (p=0.0008), no difference in Ki67 PI, but reduced vascularity in 'EPA-naïve' individuals (p=0.075). EPA-FFA also demonstrated antiangiogenic activity in vitro. In the first 18 months after CRCLM resection, EPA-FFA-treated individuals obtained OS benefit compared with placebo, although early CRC recurrence rates were similar. CONCLUSIONS EPA-FFA therapy is safe and well tolerated in patients with advanced CRC undergoing liver surgery. EPA-FFA may have antiangiogenic properties. Remarkably, limited preoperative treatment may provide postoperative OS benefit. Phase III clinical evaluation of prolonged EPA-FFA treatment in CRCLM patients is warranted. TRIAL IDENTIFIER ClinicalTrials.gov NCT01070355.
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Affiliation(s)
- Andrew J Cockbain
- Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, UK Department of Hepatobiliary Surgery, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UK
| | - Milene Volpato
- Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, UK
| | - Amanda D Race
- Yorkshire Experimental Cancer Medicine Centre, Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
| | - Alessandra Munarini
- Department of Gastroenterology, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Chiara Fazio
- Department of Gastroenterology, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Andrea Belluzzi
- Department of Gastroenterology, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Paul M Loadman
- Yorkshire Experimental Cancer Medicine Centre, Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
| | - Giles J Toogood
- Department of Hepatobiliary Surgery, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UK
| | - Mark A Hull
- Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, UK
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17
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Comparison between simultaneous resection and staged resection of synchronous colorectal cancer with resectable liver metastases: a meta-analysis. Eur Surg 2014. [DOI: 10.1007/s10353-014-0286-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Invasion pattern and histologic features of tumor aggressiveness correlate with MMR protein expression, but are independent of activating KRAS and BRAF mutations in CRC. Virchows Arch 2014; 465:155-63. [PMID: 24915895 DOI: 10.1007/s00428-014-1604-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 05/21/2014] [Accepted: 05/26/2014] [Indexed: 12/21/2022]
Abstract
KRAS/BRAF mutation testing and mismatch repair (MMR) protein immunohistochemistry have an established role in routine diagnostic evaluation of colorectal carcinoma (CRC). However, since the exact impact of these molecular characteristics on tumor morphology and behavior is still subject to research, the aim of our study was to examine associations between molecular and morphologic features that had not been analyzed in this combination before. KRAS (codons 12, 13, and 61) and BRAF (codon 600) mutation status and MMR protein expression were analyzed in a consecutive series of 117 CRC samples using DNA pyrosequencing and immunohistochemistry. Tumor cell budding, infiltration pattern, and peritumoral lymphocytic (PTL) reaction was assessed applying established criteria. Molecular and morphological findings were correlated applying chi-square and Fisher's exact test. We found KRAS or BRAF mutations in 40 and 8 % of samples, while loss of MMR protein expression was observed in 11 %. Tumor budding was significantly associated with infiltrative growth, absence of PTLs, and blood and lymph vessel infiltration. Neither KRAS nor BRAF mutations were associated with a certain growth pattern or budding intensity of CRC, but loss of MMR protein expression was found in context with BRAF mutation, expanding growth, and presence of PTLs. Our results confirm an association between loss of MMR protein expression, presence of activating BRAF mutation, expanding growth, and PTL reaction as well as between tumor budding, infiltrative growth pattern, and tumor aggressiveness; however, there was no such association between the presence of an activating KRAS or BRAF mutation and a distinct invasion pattern or tumor aggressiveness in CRC.
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Yuan SX, Tao QF, Wang J, Yang F, Liu L, Wang LL, Zhang J, Yang Y, Liu H, Wang F, Sun SH, Zhou WP. Antisense long non-coding RNA PCNA-AS1 promotes tumor growth by regulating proliferating cell nuclear antigen in hepatocellular carcinoma. Cancer Lett 2014; 349:87-94. [PMID: 24704293 DOI: 10.1016/j.canlet.2014.03.029] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 03/21/2014] [Accepted: 03/25/2014] [Indexed: 12/15/2022]
Abstract
About 61-72% of transcribed regions possess long noncoding RNAs in antisense orientation (Antisense long noncoding RNAs, aslncRNAs). However, the function of aslncRNAs in HCC remains unclear. We found numerous aslncRNAs were deregulated and might be involved in regulatory gene-net of HCC. The PCNA-AS1, antisense to PCNA, is significantly up-regulated in HCC and could promote tumor growth in vitro and in vivo. The effects of PCNA-AS1 rely on regulation of PCNA via forming RNA hybridization to increase PCNA mRNA stability. We concluded that aslncRNAs might act as upstream regulators in HCC and PCNA-AS1 could serve as a novel therapeutic target.
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Affiliation(s)
- Sheng-Xian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
| | - Qi-Fei Tao
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
| | - Jie Wang
- Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - Fu Yang
- Department of Medical Genetics, Second Military Medical University, Shanghai, China.
| | - Lei Liu
- Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - Li-Li Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
| | - Jin Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
| | - Fang Wang
- Department of Medical Genetics, Second Military Medical University, Shanghai, China.
| | - Shu-Han Sun
- Department of Medical Genetics, Second Military Medical University, Shanghai, China.
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
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Ivanecz A, Kavalar R, Palfy M, Pivec V, Sremec M, Horvat M, Potrč S. Can we improve the clinical risk score? The prognostic value of p53, Ki-67 and thymidylate synthase in patients undergoing radical resection of colorectal liver metastases. HPB (Oxford) 2014; 16:235-42. [PMID: 23509992 PMCID: PMC3945849 DOI: 10.1111/hpb.12089] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 02/04/2013] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The aim of this study was to assess whether biological markers can provide prognostic information additional to that supplied by the clinical risk score (CRS) in patients with colorectal liver metastases. METHODS A retrospective review of a prospectively maintained database was conducted. Patients selected for this study were treated between 1996 and 2011 with potentially curative liver surgery. Expressions of p53, Ki-67 and thymidylate synthase were assayed using immunohistochemical techniques on tissue microarrays. RESULTS A total of 98 (24%) of 406 patients met the inclusion criteria. The median follow-up was 103 months. Analysis revealed a correlation between p53 protein overexpression and high CRS (P = 0.058). Following multivariate analysis, only high CRS remained as an independent negative prognostic predictor of survival (P = 0.018), as well as an indicator of early recurrence of disease (P = 0.010). Of the biological markers investigated, only Ki-67 overexpression was identified as a positive predictor of survival on multivariate analysis (P = 0.038). CONCLUSIONS Ki-67 overexpression was a positive predictor of survival. Only high CRS remained an independent negative prognostic predictor.
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Affiliation(s)
- Arpad Ivanecz
- Department of Abdominal and General Surgery, University Medical Centre MariborMaribor, Slovenia,Correspondence Arpad Ivanecz, Department of Abdominal and General Surgery, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia. Tel: + 386 41 962402. Fax: + 386 2 321 1257. E-mail:
| | - Rajko Kavalar
- Department of Pathology, University Medical Centre MariborMaribor, Slovenia
| | - Miroslav Palfy
- Department of Medical Research, University Medical Centre MariborMaribor, Slovenia
| | - Vid Pivec
- Department of Abdominal and General Surgery, University Medical Centre MariborMaribor, Slovenia
| | - Marko Sremec
- Department of Abdominal and General Surgery, University Medical Centre MariborMaribor, Slovenia
| | - Matjaž Horvat
- Department of Abdominal and General Surgery, University Medical Centre MariborMaribor, Slovenia
| | - Stojan Potrč
- Department of Abdominal and General Surgery, University Medical Centre MariborMaribor, Slovenia
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Spolverato G, Ejaz A, Azad N, Pawlik TM. Surgery for colorectal liver metastases: The evolution of determining prognosis. World J Gastrointest Oncol 2013; 5:207-221. [PMID: 24363829 PMCID: PMC3868716 DOI: 10.4251/wjgo.v5.i12.207] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 11/05/2013] [Accepted: 11/16/2013] [Indexed: 02/05/2023] Open
Abstract
Despite improvements in the multi-modality treatment of colorectal liver metastasis (CRLM), survival after resection remains varied. Determining prognosis after surgical resection has historically been predicated on preoperative clinicopathological factors such as primary tumor stage, carcinoembryonic antigen levels, number of liver metastases, presence of extrahepatic disease, as well as other factors. While scoring systems have been developed by combining certain preoperative factors, these have been inconsistent in accurately determining prognosis. There has been increasing interest in the use of biologic and molecular markers to predict prognosis following CRLM. The role of markers such as KRAS, BRAF, p53, human telomerase reverse transcriptase, thymidylate synthase, Ki-67, and hypoxia inducible factor-1α and their correlation with accurately predicting survival after surgical resection have been supported by several studies. Furthermore, other elements such as pathological response to chemotherapy and the presence of circulating tumor cells have shown promise in accurately determining prognosis after resection for colorectal liver metastasis. We herein review past, present, and possible future markers of prognosis among colorectal cancer patients with liver metastasis undergoing resection with curative intent.
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Ueda Y, Yasuda K, Inomata M, Shiraishi N, Yokoyama S, Kitano S. Biological predictors of survival in stage II colorectal cancer. Mol Clin Oncol 2013; 1:643-648. [PMID: 24649222 PMCID: PMC3915554 DOI: 10.3892/mco.2013.126] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Accepted: 04/23/2013] [Indexed: 01/28/2023] Open
Abstract
The routine use of postoperative adjuvant chemotherapy in patients with stage II colorectal cancer is not recommended. However, the incidence of tumor recurrence or distant metastasis in these patients is reported to be 25–35%. The identification of high-risk patients with stage II colorectal cancer remains difficult. Therefore, the aim of this study was to determine the risk factors that may help identify stage II colorectal cancer patients with unfavorable prognosis. Paraffin-embedded tissue samples from 109 patients with stage II colorectal cancer following curative operation were analyzed. Thirteen clinicopathological variables and 5 biological markers were assessed using immunohistochemistry, including p53 (tumor suppressor gene), CD10 (tumor invasion marker), CD34 (angiogenic marker), Ki-67 (cell proliferation index) and CAM 5.2 (marker of lymph node micrometastasis) and investigated for associations with disease-specific survival. Univariate analysis revealed bowel obstruction, lymph node micrometastasis and lymphatic invasion (P<0.01) to be highly significant factors for determining the 5-year disease-specific survival. By contrast, the multivariate analysis revealed lymph node micrometastasis and lymphatic invasion to be independent prognostic factors. Stage II colorectal cancer patients with lymph node micrometastasis and lymphatic invasion may therefore be suitable candidates for adjuvant chemotherapy to improve prognosis.
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Affiliation(s)
- Yoshitake Ueda
- Departments of Gastroenterological Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Kazuhiro Yasuda
- Departments of Gastroenterological Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Masafumi Inomata
- Departments of Gastroenterological Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Norio Shiraishi
- Departments of Gastroenterological Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Shigeo Yokoyama
- Pathology, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan
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Li ZQ, Liu K, Duan JC, Li Z, Su CQ, Yang JH. Meta-analysis of simultaneous versus staged resection for synchronous colorectal liver metastases. Hepatol Res 2013; 43:72-83. [PMID: 22971038 DOI: 10.1111/j.1872-034x.2012.01050.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
AIM There is no clear consensus on the optimal timing of surgical resection for synchronous colorectal liver metastases (SCLM). This study is a meta-analysis of the available evidence. METHODS Systematic review and meta-analysis of trials comparing outcomes following simultaneous resection with staged resection for SCLM published from 1990 to 2010 in PubMed, Embase, Ovid and Medline. Pooled odds ratios (OR) or weighted mean differences (WMD) with 95% confidence intervals (95% CI) were calculated using either the fixed effects or random effects model. RESULTS Nineteen non-randomized controlled trials (NRCT) studies were included in this analysis. These studies included a total of 2724 patients: 1116 underwent simultaneous resection and 1608 underwent staged resection. Meta-analysis showed that shorter hospital stay (P < 0.001) and lower total complication rate (P < 0.001) were observed in patients undergoing simultaneous resection group. The overall survival rate in the simultaneous resection group did not statistically differ with that in the staged resection group at 1 year (P = 0.13), 3 years (P = 0.26), 5 years (P = 0.38), as well as the 1, 3 and 5 years disease-free survival rates (respectively, P = 0.55; P = 0.16; P = 0.12). No significant difference was noted between the two groups in terms of mortality (P = 0.16), intraoperative blood loss (P = 0.06) and recurrence (P = 0.47). CONCLUSION Simultaneous resection is safe and efficient in the treatment of patients with SCLM while avoiding a second laparotomy. In selected patients, simultaneous resection might be considered as the preferred approach. However, the findings have to be carefully interpreted due to the lower level of evidence and the existence of heterogeneity.
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Affiliation(s)
- Zhi-Qing Li
- Medical College of Soochow University, Suzhou City, Jiangsu ProvinceDepartments of Hepatic Surgery Molecular Oncology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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Sofocleous CT, Garg S, Petrovic LM, Gonen M, Petre EN, Klimstra DS, Solomon SB, Brown KT, Brody LA, Covey AM, Dematteo RP, Schwartz L, Kemeny NE. Ki-67 is a prognostic biomarker of survival after radiofrequency ablation of liver malignancies. Ann Surg Oncol 2012; 19:4262-9. [PMID: 22752375 DOI: 10.1245/s10434-012-2461-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Indexed: 01/26/2023]
Abstract
PURPOSE To assess the predictive value of examinations of tissue adherent to multitined electrodes on local tumor progression-free survival (LPFS) and overall survival (OS) after liver tumor radiofrequency ablation (RFA). METHODS An institutional review board-approved, Health Insurance Portability and Accountability Act-compliant review identified 68 liver tumors treated with RFA in 63 patients with at least 3 years' follow-up. Tissue adherent to the electrode after liver tumor RFA was evaluated with proliferation (Ki-67) and apoptotic (caspase-3) markers. LPFS and OS were evaluated by Kaplan-Meier methodology and the log-rank test. Multivariate analysis assessed the effect of tumor size, pathology, and post-RFA tissue characteristics on LPFS and OS. RESULTS Post-RFA tissue examination classified 55 of the 68 tumors as completely ablated with coagulation necrosis, with cells positive for caspase-3 and negative for Ki-67 (CN). Thirteen had viable Ki-67-positive tumor cells. Mean liver tumor size was larger in the viable (V) group versus the CN group (3.4 vs. 2.5 cm, respectively; P = .017). For the V and CN groups, respectively, local tumor progression occurred in 12 (92 %) of 13 and 23 (42 %) of 55 specimens. One, 3-, and 5-year LPFS was 8 %, 8 %, and 8 %, and 79 %, 47 %, and 47 % (P < .001) for the V and CN groups, respectively. During a 63-month median follow-up, 92 % of patients in the V group and 58 % in the CN group died, resulting in 1-, 3-, and 5-year OS of 92 %, 25 %, and 8 % vs. 92 %, 59 %, and 33 % (P = .032), respectively. CONCLUSIONS Ki-67-positive tumor cells on the electrode after liver tumor RFA is an independent predictor of LPFS and OS. Size, initially thought to be an independent risk factor for local tumor progression in tumors 3-5 cm, does not hold its significance at long follow-up.
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Affiliation(s)
- Constantinos T Sofocleous
- Section of Interventional Radiology, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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25
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Liver Resection for Multiple Colorectal Liver Metastases with Surgery Up-front Approach: Bi-institutional Analysis of 736 Consecutive Cases. World J Surg 2012; 36:2171-8. [DOI: 10.1007/s00268-012-1616-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Tan EK, Ooi LLPJ. Colorectal Cancer Liver Metastases – Understanding the Differences in the Management of Synchronous and Metachronous Disease. ANNALS OF THE ACADEMY OF MEDICINE, SINGAPORE 2010. [DOI: 10.47102/annals-acadmedsg.v39n9p719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Introduction: Metastatic disease to the liver in colorectal cancer is a common entity that may present synchronously or metachronously. While increasing surgical experience has improved survival outcomes, some evidence suggest that synchronous lesions should be managed differently. This review aims to update current literature on differences between the outcomes and management of synchronous and metachronous disease. Materials and Methods: Systematic review of MEDLINE database up till November 2008. Results: Discrete differences in tumour biology have been identified in separate studies. Twenty-one articles comparing outcomes were reviewed. Definitions of metachronicity varied from anytime after primary tumour evaluation to 1 year after surgery for primary tumour. Most studies reported that synchronous lesions were associated with poorer survival rates (8% to 16% reduction over 5 years). Sixteen articles comparing combined vs staged resections for synchronous tumour showed comparable morbidity and mortality. Benefits over staged resections included shorter hospital stays and earlier initiation of chemotherapy. Suitability for combined resection depended on patient age and constitution, primary tumour characteristics, size and the number of liver metastases, and the extent of liver involvement. Conclusions: Surgery remains the only treatment option that offers a chance of long-term survival for patients amenable to curative resection. Synchronicity suggests more aggressive disease although a unifying theory for biological differences explaining the disparity in tumour behaviour has not been found. Combined resection of primary tumour and synchronous metastases is a viable option pending careful patient selection and institutional experience. Given the current evidence, management of synchronous and metachronous colorectal liver metastases needs to be individualised to the needs of each patient.
Key words: Colorectal neoplasms, Liver neoplasms, Neoplasm metastasis, Synchronous Cancer, Metachronous cancer
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Smith MD, McCall JL. Systematic review of tumour number and outcome after radical treatment of colorectal liver metastases. Br J Surg 2009; 96:1101-13. [PMID: 19787755 DOI: 10.1002/bjs.6735] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Abstract
Background
Resection of colorectal liver metastases (CLMs) is potentially curative but the effect of tumour number on prognosis is uncertain. This study compared the prognosis after resection and/or ablation of between one and three, or four or more CLMs.
Methods
A systematic literature review from January 2000 to June 2008 was performed. Study selection and data extraction were standardized, and analysis included assessment of methodological quality, heterogeneity and bias. Main outcomes were 3- and 5-year survival. A meta-analysis comparing radical treatment in the two groups was performed using the hazard ratio for overall survival.
Results
Of 1307 studies screened, 46 (9934 patients) were included in the analysis. Methodological quality was variable, and there was significant heterogeneity and reporting bias. The overall 5-year survival rate after radical treatment ranged from 7 to 58 per cent. Pooled hazard ratio for overall survival was 1·67 (95 per cent confidence interval 1·43 to 1·95; P < 0·001). Median reported 5-year survival for patients with four or more CLMs was 17·1 per cent.
Conclusion
Radical treatment of more than three CLMs results in poorer overall survival. Nevertheless, 5-year survival is achievable and the number of lesions should not, of itself, be used to exclude patients from surgery.
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Affiliation(s)
- M D Smith
- Department of Surgery, Auckland City Hospital, Auckland, New Zealand
| | - J L McCall
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
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Shimada H, Tanaka K, Endou I, Ichikawa Y. Treatment for colorectal liver metastases: a review. Langenbecks Arch Surg 2009; 394:973-83. [PMID: 19582473 DOI: 10.1007/s00423-009-0530-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Accepted: 06/18/2009] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Over the past decade, the emergence of surgical adjuncts such as portal vein embolization, two-stage hepatectomy, and ablative therapies not only decreases mortality and morbidity after an extended hepatectomy but also broadens the indication for surgical treatment of liver metastasis from colorectal cancer. Combination chemotherapeutic regimens, namely 5-fluorouracil/folinic acid with irinotecan or oxaliplatin, and targeted monochromal antibodies can downsize the tumor burden to the extent that formerly unresectable metastases can sometimes be excised. DISCUSSION The 5-year survival rate following liver resection ranges between 25% and 58%. During the 5-fluorouracil/folinic acid with oxaliplatin and 5-fluorouracil/folinic acid with irinotecan treatment period, the patients who were deemed to be resectable should be considered as surgical candidates regardless of the associated adverse predictive factors. The emergence of epidermal growth factor receptor antibody agents, which act effectively in patients with Kras wild-type tumor, fosters treatment individualization. CONCLUSION The efficacy of the perioperative chemotherapy on survival benefit for resectable liver metastases has not been justified. However, the timing and indication of surgical treatment paradigm in colorectal liver metastasis, including for synchronous disease and extrahepatic disease, are dramatically changing with the development of chemotherapeutic agents.
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Affiliation(s)
- Hiroshi Shimada
- The Medical Division of the Head Office, Japan Labor Health and Welfare Organization, Kawasaki, Japan.
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Pamecha V, Levene A, Grillo F, Woodward N, Dhillon A, Davidson BR. Effect of portal vein embolisation on the growth rate of colorectal liver metastases. Br J Cancer 2009; 100:617-22. [PMID: 19209170 PMCID: PMC2653734 DOI: 10.1038/sj.bjc.6604872] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2008] [Revised: 12/08/2008] [Accepted: 12/09/2008] [Indexed: 12/13/2022] Open
Abstract
Portal vein embolisation (PVE) is used to increase the remnant liver volume before major liver resection for colorectal metastases. The resection rate after PVE is 60-70%, mainly limited by disease progression. The effect of PVE on tumour growth rate has not been investigated. The objective of this study was to compare the growth characteristics of resected colorectal liver metastases in patients undergoing pre-operative PVE with those of matched controls who had not undergone PVE. There were 22 patients who had undergone preoperative PVE and 20 matched controls. Tumour growth rate was calculated by the change in tumour volume (CT/MRI volumetric assessment) from diagnosis to resection. Resected histological specimens were examined by two histopathologists independently for cell differentiation, percentage tumour cell necrosis and mitotic rate. Immunochemical staining with Ki67 was carried out using the MIB-1 monoclonal antibody and quantified using a Glasgow cell-counting graticule. The groups were comparable in demographics, stage of primary disease, volume of liver metastases at presentation and chemotherapy received. The tumour growth rate calculated from imaging was more rapid in the PVE group compared with that in controls (control: 0.05+/-0.25 ml day(-1), PVE: 0.36+/-0.68 ml day(-1), P=0.06). Histology showed no difference in the degree of differentiation, extent of necrosis or apoptosis between the two groups. However, mitotic rate was higher post PVE, as was the proliferation index Ki67 (P=0.04). This study has confirmed that tumour growth rate increased following PVE and that this is related to increased tumour cell division.
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Affiliation(s)
- V Pamecha
- Department of Hepato Pancreatico Biliary and Liver Transplant Surgery, Royal Free Hospital, University College London, London, UK
| | - A Levene
- Department of Pathology, Royal Free Hospital, University College London, London, UK
| | - F Grillo
- Department of Pathology, Royal Free Hospital, University College London, London, UK
| | - N Woodward
- Department of Radiology, Royal Free Hospital, University College London, London, UK
| | - A Dhillon
- Department of Pathology, Royal Free Hospital, University College London, London, UK
| | - B R Davidson
- Department of Hepato Pancreatico Biliary and Liver Transplant Surgery, Royal Free Hospital, University College London, London, UK
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Sofocleous CT, Nascimento RG, Petrovic LM, Klimstra DS, Gonen M, Brown KT, Brody LA, Covey AM, Thornton RH, Fong Y, Solomon SB, Schwartz LH, DeMatteo RP, Getrajdman GI. Histopathologic and immunohistochemical features of tissue adherent to multitined electrodes after RF ablation of liver malignancies can help predict local tumor progression: initial results. Radiology 2008; 249:364-74. [PMID: 18796687 DOI: 10.1148/radiol.2491071752] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
PURPOSE To determine whether histopathologic and immunohistochemical features of tissue adherent to electrodes after radiofrequency (RF) ablation of liver malignancies can help predict local tumor progression (LTP). MATERIALS AND METHODS Institutional review board waiver and informed consent were obtained. Histologic and immunohistochemical examinations of tissue adherent to electrodes after RF ablation of liver malignancies were performed, with application of proliferation (Ki-67) and apoptosis (caspase-3) markers. Clinical and technical information were prospectively collected for an HIPAA-registered database. Medical records and imaging were reviewed to determine LTP for treated tumors smaller than 5 cm in diameter. LTP-free and survival rates were assessed with Kaplan-Meier method; differences between groups assessed with permutation log-rank test. Multivariate analysis assessed with Cox regression for factors related to LTP. RESULTS Sixty-eight malignant tumors treated with RF ablation were identified. Fifty-five tissue specimens were classified as coagulation necrosis (CN), thermal artifact only, or tumor cells positive for caspase-3/negative for Ki-67; and 13 as viable tumor cells (Ki-67 positive). Mean tumor size was larger in viable (3.4 cm) than in CN (2.5 cm) group before treatment (P = .01). For viable and CN groups, LTP occurred in 12 (92%) of 13 and 16 (29%) of 55 specimens, respectively; 1-year LTP-free rates were 0% and 74%, respectively (P < .001). Multivariate analysis confirmed that viable cells comprise independent risk factor for LTP (P < .001). The odds of LTP is six times greater in viable group compared with CN group for tumors 3-5 cm (hazard ratio: 5.9, 95% confidence interval: 2.4, 14.5) and 10 times greater for tumors smaller than 3 cm (hazard ratio: 10.1, 95% confidence interval: 1.7, 57.5). Median survival was 32.7 months. CONCLUSION Evidence of Ki-67-positive tumor cells on the electrode after hepatic RF ablation is an independent predictor of LTP.
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Affiliation(s)
- Constantinos T Sofocleous
- Section of Interventional Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room H-118, New York, NY 10065, USA.
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Nakano H, Ishida Y, Hatakeyama T, Sakuraba K, Hayashi M, Sakurai O, Hataya K. Contrast-enhanced intraoperative ultrasonography equipped with late Kupffer-phase image obtained by sonazoid in patients with colorectal liver metastases. World J Gastroenterol 2008; 14:3207-3211. [PMID: 18506927 PMCID: PMC2712854 DOI: 10.3748/wjg.14.3207] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2008] [Revised: 04/16/2008] [Accepted: 04/23/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To find occult metastases during hepatectomy in patients with colorectal cancer liver metastases (CRCLM), contrast-enhanced intraoperative ultrasonography (CE-IOUS) was performed using a new microbubble agent, sonazoid, which provides a parenchyma-specific contrast image based on its accumulation in the Kupffer cells. METHODS Eight patients with CRCLM underwent CE-IOUS using sonazoid before hepatectomy. The liver was investigated during a late Kupffer-phase imaging, which is a valuable characteristic of sonazoid. RESULTS CE-IOUS using sonazoid provided the early vascular- and sinusoidal-phase images for 10 min followed by the late Kupffer-phase image up to 30 min after the injection of sonazoid. IOUS did not provide new findings of metastatic lesion in the 8 patients. However, during the late Kupffer-phase image of sonazoid, a metastatic lesion was newly found in two of the 8 patients. These newly detected lesions were removed by an additional hepatectomy and histopathologically diagnosed as a metastasis. CONCLUSION CE-IOUS using sonazoid can allow surgeons to investigate the whole liver with enough time and to find new metastases intraoperatively.
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Abstract
Colorectal cancer is the fourth most common type of cancer in the West and the second leading cause of cancer-related deaths in the United States. Approximately 35 to 55% of patients with colorectal cancer develop hepatic metastases during the course of their disease. Surgical resection of colorectal liver metastases represents the only chance at potential cure, and long-term survival can be achieved in 35 to 58% of patients after resection. The goal of hepatic resection should be to resect all metastases with negative histologic margins while preserving sufficient functional hepatic parenchyma. In patients with extensive metastatic disease who would otherwise be unresectable, ablative approaches can be used instead of or combined with hepatic resection. The use of portal vein embolization and preoperative chemotherapy may also expand the population of patients who are candidates for surgical treatment. Despite these advances, many patients still experience a recurrence after hepatic resection. More active systemic chemotherapy agents are now available and are being increasingly employed as adjuvant therapy either before or after surgery. Modern treatment of colorectal liver metastasis requires a multidisciplinary approach in an effort to increase the number of patients who may benefit from surgical treatment of colorectal cancer liver metastasis.
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Affiliation(s)
- Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 22187-6681, USA
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Mandalà M, Mosconi S, Quadri A, Milesi L, Labianca R. Neoadjuvant chemotherapy for patients with liver metastases from colorectal cancer. Expert Rev Anticancer Ther 2007; 7:887-97. [PMID: 17555399 DOI: 10.1586/14737140.7.6.887] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Colorectal cancer is the second most common type of cancer in industrialized countries. Despite improved resection procedures and optimized adjuvant chemotherapy, local or distant recurrences occur in 22-25% of patients with stage II/III colon cancer. Approximately 30% of patients have advanced disease at presentation. The liver is the most common site of colorectal metastases and, interestingly, 20-30% of patients with colorectal cancer have liver-only metastases. The combined modality of chemotherapy and surgery increases overall survival and the chance of cure for metastatic patients, even if there is no agreement in terms of the best schedule and how long the treatment must last. In this paper, we review the role and the rationale of neoadjuvant chemotherapy within a multimodal approach, and discuss remaining questions and future directions.
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Affiliation(s)
- Mario Mandalà
- Unit of Medical Oncology, Ospedali Riuniti, Bergamo, Italy
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Abstract
At some point in the natural course of colorectal cancer up to 50% of patients will develop metastasis to the liver. Historically only 20% of these patients would have to be deemed resectable, with an intent to cure, at the time of presentation. But with recent improvements in cross-sectional imaging, chemotherapeutic agents and advances in the techniques of surgical resection the emphasis of resection has now changed to 'who is not resectable' as opposed to 'who is resectable'. There are few contraindications to liver resection on the proviso that the patient is fit enough. As a result of this paradigm shift, 5 year survival rates are approaching 60%. Historically liver resection was perceived as a formidable operation but now liver resection for CRLM is safe and specialist centres are reporting mortality rates of less than 1%. This review briefly covers the standard techniques currently employed and some of the recent innovations being developed to improve resectability.
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Affiliation(s)
- R Lochan
- Department of Hepatobiliary Surgery, The Freeman Hospital, High Heaton, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, UK
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35
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Pawlik TM, Choti MA. Shifting from clinical to biologic indicators of prognosis after resection of hepatic colorectal metastases. Curr Oncol Rep 2007; 9:193-201. [PMID: 17430690 DOI: 10.1007/s11912-007-0021-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Following resection of hepatic colorectal metastases, there are few criteria for predicting which patients have more aggressive disease and are, therefore, more likely to experience recurrence and reduced survival. Traditionally, primary tumor stage, preoperative carcinoembryonic antigen level, time from primary tumor treatment to diagnosis of hepatic metastases (disease-free interval), hepatic tumor size, number of hepatic metastases, and presence of extrahepatic disease have been reported to be predictors of survival after resection. However, the data regarding the prognostic importance of these clinicopathologic factors are inconsistent and conflicting. Therefore, conventional clinicopathologic factors may be inadequate for the purposes of prognostication. More recently, there has been increased interest in identifying biologic indicators that may help better define patients at risk for recurrence after hepatic resection for colorectal metastases. Recent studies have shown that proliferation markers such as p53 expression, tritiated thymidine uptake, thymidylate synthase, Ki-67, and human telomerase reverse transcriptase may be better predictors of outcome after resection of hepatic colorectal metastases. Moreover, tumor response to preoperative chemotherapy may also prove to be a useful predictor of outcome following liver resection for colorectal metastases.
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Affiliation(s)
- Timothy M Pawlik
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD 22187-6681, USA
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Neal CP, Garcea G, Doucas H, Manson MM, Sutton CD, Dennison AR, Berry DP. Molecular prognostic markers in resectable colorectal liver metastases: A systematic review. Eur J Cancer 2006; 42:1728-43. [PMID: 16815701 DOI: 10.1016/j.ejca.2006.01.056] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2005] [Accepted: 01/03/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND Determination of prognosis in patients with resectable colorectal liver metastases (CLM) is desirable in order to improve case selection for surgery and tailor adjuvant treatment according to individual recurrence risk. Conventional clinicopathological factors lack the sensitivity to accurately achieve this goal. Consideration of tumour biology and the identification of molecular prognostic markers may allow more accurate risk stratification. METHOD This systematic review examines evidence from published manuscripts looking at molecular markers in resectable colorectal liver metastases and their correlation with disease recurrence and survival following hepatectomy. RESULTS Studies have yielded promising results in the search for prognostic molecular markers of CLM. Molecular biomarkers from varied aspects of tumour biology have been examined and a number of these, including proliferation indices, telomerase, thymidylate synthase, microvessel density and thrombospondin-1 appear to have prognostic utility in this context. Validation of other markers, notably p53, has been limited by a failure of methodologies to account for their biological complexity. CONCLUSIONS A biomarker-based approach may yield significant benefits through informed treatment of resectable metastatic colorectal malignancy. Standardised retrospective analyses are necessary to confirm preliminary findings and identify existing and novel markers for inclusion into prospective studies. Assessment and verification of multiple molecular markers in this manner may allow molecular profiling of metastases and tailoring of therapy according to the biological aggressiveness of individual tumours. The advent of genomic- and proteomic-based technologies will allow the simultaneous analysis of multiple molecular markers and the derivation of disease profiles associated with disease recurrence and poor survival.
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Affiliation(s)
- C P Neal
- Department of Biochemistry, Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom.
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Pawlik TM, Choti MA. Shifting from clinical to biologic indicators of prognosis after resection of hepatic colorectal metastases. CURRENT COLORECTAL CANCER REPORTS 2006. [DOI: 10.1007/s11888-006-0007-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Watson AJM. An overview of apoptosis and the prevention of colorectal cancer. Crit Rev Oncol Hematol 2005; 57:107-21. [PMID: 16326109 DOI: 10.1016/j.critrevonc.2005.06.005] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2005] [Revised: 06/29/2005] [Accepted: 06/29/2005] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer arises as a result of the accumulation of genetic errors many of which affect the control of apoptosis. Effective chemoprevention strategies for colorectal cancer must rectify these genetic defects. Mutation of apc is often the initiating genetic lesion in colorectal cancers that develop along the chromosomal instability pathway. Depending on the cellular context, loss of apc activates the Wnt signalling pathway causing immediate widespread apoptosis of colorectal epithelial cells and defects in differentiation and cell migration. Only cells that are inherently resistant to apoptosis survive this initial wave of apoptosis. These surviving cells constitute the epithelial population that develop into adenomas. Two gene targets of the Wnt signalling pathway are of particular relevance to apoptosis. Although controversial, survivin may function to inhibit apoptosis. MYC has two outputs in normal cells, the induction of apoptosis and proliferation. These opposing functions work so that MYC can only induce cell proliferation in cells if apoptosis is disabled. p53 couples apoptosis to mitogenic signals and survival pathways. Under some circumstances, NF-kappaB can act as an inhibitor of apoptosis possibly through increased expression of bcl-x(L). Tumours that evolve by the microsatellite instability pathway often have mutations in the proapoptotic gene bax. Colonic adenomas express cyclo-oxygenase-2 (COX-2) and may be targets of chemoprevention before the development of malignancy. However, the recent discovery that coxibs increase the risk of serious cardiovascular events limits their use as chemopreventive agents. Nevertheless, aspirin remains a drug of great interest as it is already known to reduce the risk of colorectal cancer by up to 50%. The balance of evidence shows that high vegetable fibre diets can prevent colorectal cancer, probably via the fermentation of butyrate enhancing the apoptotic response to DNA damage.
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Affiliation(s)
- Alastair J M Watson
- Division of Gastroenterology, School of Clinical Science, University of Liverpool, Liverpool, UK.
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Dômont J, Pawlik TM, Boige V, Rose M, Weber JC, Hoff PM, Brown TD, Zorzi D, Morat L, Pignon JP, Rashid A, Jaeck D, Sabatier L, Elias D, Tursz T, Soria JC, Vauthey JN. Catalytic Subunit of Human Telomerase Reverse Transcriptase Is an Independent Predictor of Survival in Patients Undergoing Curative Resection of Hepatic Colorectal Metastases: A Multicenter Analysis. J Clin Oncol 2005; 23:3086-93. [PMID: 15860868 DOI: 10.1200/jco.2005.06.944] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Purpose To determine the role of the catalytic subunit of human telomerase reverse transcriptase (hTERT) in predicting survival after resection of hepatic colorectal metastases (CRM). Patients and Methods Two hundred one patients who underwent curative resection of hepatic CRM between 1990 and 2000 were identified from a multicenter database. The CRM were analyzed for hTERT nucleolar expression by standard immunohistochemical techniques. hTERT expression and known clinicopathologic factors of survival were examined. Results With a median follow-up of 80 months, 152 patients (75.6%) had died; the 5-year overall survival was 30.7%. On univariate analysis, number of metastases greater than two (P = .0005), extrahepatic disease (P = .0054), disease-free interval less than 12 months (P = .006), carcinoembryonic antigen level greater than 200 ng/mL (P = .0071), and positive hTERT nucleolar staining (P < .0001) were associated with decreased survival. On multivariate analysis, three factors independently predicted survival: number of metastases (relative risk [RR] = 1.74; P = .0011); disease-free interval (RR = 1.70; P = .0035); and positive hTERT nucleolar staining (RR = 2.03; P < .0001). Patients with none or one of these factors had a 5-year survival rate of 48%, whereas those with two or three of these factors had a 5-year survival of 15% (P < .0001). Conclusion hTERT nucleolar expression is associated with worse survival after resection of hepatic CRM. hTERT expression in conjunction with number of hepatic metastases and disease-free interval may permit more accurate prediction of survival after resection of hepatic CRM.
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Affiliation(s)
- Julien Dômont
- Institut Gustave Roussy, Division of Cancer Médecine, 39 Rue Camille Desmoulins, 94805 Villejuif, France
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Nan KJ, Ruan ZP, Jing Z, Qin HX, Wang HY, Guo H, Xu R. Expression of fragile histidine triad in primary hepatocellular carcinoma and its relation with cell proliferation and apoptosis. World J Gastroenterol 2005; 11:228-31. [PMID: 15633221 PMCID: PMC4205407 DOI: 10.3748/wjg.v11.i2.228] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the expression of fragile histidine triad (FHIT) gene protein, product of a candidate tumor suppressor, and to investigate the relationship between FHIT, cell apoptosis and proliferation, and pathological features of primary hepatocellular carcinoma (HCC).
METHODS: Forty-seven HCC and ten normal liver specimens were collected during surgical operation between 2001 and 2003. FHIT and proliferating cell nuclear antigen (PCNA) expression were detected by immunohistochemistry, and apoptotic level was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay on the tissue sections.
RESULTS: All normal liver tissues showed a strong expression of FHIT, whereas 28 of 47 (59.6%) carcinomas showed a significant loss or absence of FHIT expression (P = 0.001). The proportion of reduced FHIT expression in those carcinomas at stages III-IV (70.6%) and in those with extrahepatic metastasis (86.7%) showed an increasing trend compared with those at stages I-II (30.8%, P = 0.013) and those without metastasis (46.9%, P = 0.010) respectively. Apoptotic incidence in advanced TNM stage carcinoma and those with positive FHIT expression was higher than that in early stage carcinoma (P = 0.030) and in those with negative FHIT expression (P = 0.044) respectively. The proliferating potential of hepatocellular carcinoma was associated with FHIT expression (P = 0.016) and the aggressive feature (P = 0.019). Kaplan-Meier analysis demonstrated that the survival time of these 47 patients correlated with TNM stage, FHIT expression and metastasis.
CONCLUSION: There is marked loss or absence of FHIT expression, as well as abnormal apoptosis-proliferation balance in HCC. FHIT may play an important role in carcinogenesis and development of HCC.
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Affiliation(s)
- Ke-Jun Nan
- Department of Oncology, First Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
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Miyagawa S, Soeda J, Takagi S, Miwa S, Ichikawa E, Noike T. Prognostic significance of mature dendritic cells and factors associated with their accumulation in metastatic liver tumors from colorectal cancer. Hum Pathol 2004; 35:1392-6. [PMID: 15668897 DOI: 10.1016/j.humpath.2004.07.018] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Although dendritic cells (DCs) play an important role in tumor immunity, their prognostic significance and factors related to mature DCs have not been addressed in metastatic liver tumors. In surgically resected, paraffin-embedded tissue sections from 70 patients with colorectal liver metastasis, CD83 (a marker of mature DCs) positive cells and cancer cells positive for the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay were counted. Expression of gp96, which is considered to participate in the maturation of DCs, was also evaluated. CD83-positive cells were observed predominantly in the cancer invasive margin. Patients with CD83-positive cell counts of <2 per field had a significantly poorer prognosis (5-year survival rate 47.5% vs 23.1%; P=0.0184). Patients with >0.83% apoptotic cancer cells had significantly higher numbers of CD83-positive cells (7.3 +/- 7.3 vs 4.0 +/- 5.1; P=0.039). Patients with immunohistochemically positive gp96 expression in tumors had significantly higher numbers of CD83-positive cells than those with negative gp96 expression (6.0 +/- 6.5 vs 1.4 +/- 2.3; P=0.0108). Patients with metachronous occurrence of liver metastasis had significantly higher numbers of CD83 positive cells than those with synchronous detection (6.3 +/- 6.5 vs 3.9 +/- 5.9; P=0.0313). Although the number of apoptotic cancer cells, degree of tumor gp96 expression, and synchronous or metachronous occurrence of liver metastasis did not directly influence patient outcome, they did influence the number of CD83-positive cells in the cancer invasive margin, which was a significant prognostic factor in patients with colorectal liver metastasis.
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Affiliation(s)
- Shinichi Miyagawa
- Department of Surgery, Shinshu University School of Medicine, Nagano, Japan
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Haddad R, Ogilvie RT, Croitoru M, Muniz V, Gryfe R, Pollet A, Shanmugathasan P, Fitzgerald T, Law CHL, Hanna SS, Jothy S, Redston M, Gallinger S, Smith AJ. Microsatellite Instability as a Prognostic Factor in Resected Colorectal Cancer Liver Metastases. Ann Surg Oncol 2004; 11:977-82. [PMID: 15525826 DOI: 10.1245/aso.2004.03.585] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are currently recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Untreated CRC hepatic metastases are incurable and are associated with a median survival of 4 to 12 months. Conversely, surgical resection in selected patients results in a 20% to 50% cure rate. The aim of this study was to investigate the prognostic importance of MSI-H in patients undergoing resection of hepatic CRC metastases. METHODS DNA was extracted from paraffin-embedded, resected metastatic CRC liver lesions and corresponding normal liver parenchyma from 190 patients. MSI-H status was determined by polymerase chain reaction-based evaluation of the noncoding mononucleotide repeats BAT-25 and BAT-26. RESULTS MSI was detected in tumors from 5 (2.7%) of the 190 CRC patients. All MSI-H tumors were in patients with node-positive CRC primary tumors. The median survival after hepatic resection of MSI-H and non-MSI-H tumors was 67 and 61 months, respectively (P = .9). CONCLUSIONS These data suggest that MSI-H is not a common feature in resected CRC liver metastases and do not suggest a role for MSI in stratifying good versus poor prognosis in these patients.
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Affiliation(s)
- Riad Haddad
- Sunnybrook and Women's Health Sciences Centre, T-Wing, Room T2-057, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5
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Smith DL, Soria JC, Morat L, Yang Q, Sabatier L, Liu DD, Nemr RA, Rashid A, Vauthey JN. Human telomerase reverse transcriptase (hTERT) and Ki-67 are better predictors of survival than established clinical indicators in patients undergoing curative hepatic resection for colorectal metastases. Ann Surg Oncol 2004; 11:45-51. [PMID: 14699033 DOI: 10.1007/bf02524345] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND We evaluated hTERT and Ki-67 expression in patients who underwent curative resection of hepatic colorectal metastases to determine if these markers of cell proliferation correlated better with survival than an established scoring system that is based on clinical predictors. METHODS Patients operated on between 1993 and 1997 whose survival time was known were analyzed. For each patient, the clinical prognostic score was derived on the basis of primary node status, disease-free interval, number of hepatic tumors, largest tumor, and carcinoembryonic antigen level, and tumor specimens were analyzed for Ki-67 and hTERT with use of standard immunohistochemical techniques. The immunohistochemical analysis was blinded to all patient characteristics. RESULTS The study included 66 patients. Twenty-six survived less than 2 years after surgery, 19 survived 2-5 years, and 21 survived more than 5 years. Ki-67 positivity and hTERT positivity (labeling indexes greater than or equal to 50%) were observed in 24 patients and 23 patients, respectively. The clinical score did not predict survival, although there was a weak trend toward a lower score in patients with better survival. Both Ki-67 (P =.04) and hTERT (P =.0001) correlated better with survival than did the clinical score. CONCLUSIONS In patients undergoing curative resection of hepatic colorectal metastases, hTERT and Ki-67 are better predictors of survival than is a score based on clinical features.
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Affiliation(s)
- David L Smith
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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Jaeck D. The significance of hepatic pedicle lymph nodes metastases in surgical management of colorectal liver metastases and of other liver malignancies. Ann Surg Oncol 2004; 10:1007-11. [PMID: 14597437 DOI: 10.1245/aso.2003.09.903] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Surgical resection of colorectal liver metastases (CLM) is the only hope for cure, with a 5-year survival rate ranging from 20% to 54%. However, the resectability rate of CLM is reported to be <20%. This limitation is mainly due to insufficient remnant liver and to extrahepatic disease. Among extrahepatic locations, lymph node metastases are often considered indications of a very poor prognosis and a contra-indication to resection. METHODS and RESULTS Our studies showed that the prevalence of hepatic pedicle lymph node metastases ranges from 10% to 20%. When located near the hilum and along the hepatic pedicle (area 1) they should not be considered an absolute contra-indication to resection of CLM, and an extended lymphadenectomy should be performed. However, when they reach the celiac trunk (area 2), there is no survival benefit after resection of CLM. For other cases of liver malignancies, lymph node dissection seems justified only in cases of fibrolamellar hepatocellular carcinoma and in case of hilar cholangiocarcinoma. However, few data are available, and they are controversial. CONCLUSIONS There is a need for more evaluation of lymph node involvement, at least in patients with high risk of such an extension, i.e., patients with more than three metastases, located in segment 4 or 5. There is also a need for prospective trials in order to evaluate the survival benefit of liver resection in such circumstances and the impact of extensive lymphadenectomy.
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Affiliation(s)
- Daniel Jaeck
- Centre de Chirurgie Viscérale et de Transplantation, Hôpital de Hautepierre, Strasbourg, France.
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Tanaka K, Shimada H, Miura M, Fujii Y, Yamaguchi S, Endo I, Sekido H, Togo S, Ike H. Metastatic tumor doubling time: most important prehepatectomy predictor of survival and nonrecurrence of hepatic colorectal cancer metastasis. World J Surg 2004; 28:263-70. [PMID: 14961200 DOI: 10.1007/s00268-003-7088-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We determined the relative value of the metastatic colorectal cancer doubling time as a predictor of recurrence and survival after hepatectomy in comparison with other established predictors. Consecutive patients who underwent hepatic resection ( n = 144) for colorectal cancer liver metastases were studied retrospectively to identify factors that influence overall survival and recurrence in the remnant liver. Overall 5-year survival and nonrecurrence rates were 49.8% and 50.8%, respectively. By multivariate analysis, large liver tumors ( p = 0.038), p53 expression by the liver tumor (p = 0.011), and a short liver metastasis doubling time (< or = 45 days, p = 0.013) negatively affected survival; doubling times > 45 days (adjusted relative risk 0.06; p < 0.001) positively influenced disease-free survival. In patients with remnant liver recurrence, a short doubling time was associated with short disease-free intervals (7.3 +/- 6.2 months), multiple metastases (63.6%), and fewer attempts at repeat hepatectomy (22.7%). The doubling time determines tumor size and reflects the patient's immune and nutritional status. A short doubling time is the most reliable risk factor for multiple metastases, early recurrence, and poor prognosis. Further studies with a larger number of patients are needed to confirm this conclusion.
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Affiliation(s)
- Kuniya Tanaka
- Department of Surgery II, Yokohama City University School of Medicine, 4-57 Urafune-cho, Minami-ku, 232-0024 Yokohama, Japan
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Ding SJ, Li Y, Tan YX, Jiang MR, Tian B, Liu YK, Shao XX, Ye SL, Wu JR, Zeng R, Wang HY, Tang ZY, Xia QC. From proteomic analysis to clinical significance: overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics 2003; 3:73-81. [PMID: 14593079 DOI: 10.1074/mcp.m300094-mcp200] [Citation(s) in RCA: 169] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To better understand the mechanism underlying the hepatocellular carcinoma (HCC) metastasis and to search potential markers for HCC prognosis, differential proteomic analysis on two well-established HCC cell strains with high and low metastatic potentials, MHCC97-H and MHCC97-L, was conducted using two-dimensional gel electrophoresis followed by matrix-assisted laser desorption/time-of-flight mass spectrometry. Cytokeratin 19 (CK19) was identified and found to be overexpressed in MHCC97-H as compared with MHCC97-L. This result was further confirmed by two-dimensional Western blot analysis and immunofluorescence assay. Furthermore, one-dimensional Western blot analysis showed consistently increased CK19 expression in progressively more metastatic cells. Immunohistochemical study on 102 human HCC specimens revealed that more patients in the CK19-positive group had overt intrahepatic metastases (satellite nodules, p < 0.05; vascular tumor emboli, p < 0.001; tumor node metastatis staging, p < 0.001). CK19 fragment CYFRA 21-1 levels measured in sera from nude mice model of human HCC metastasis with radioimmunoassay increased in parallel with tumor progression and rose remarkably when pulmonary metastases occurred. The results demonstrated that overexpression of CK19 in HCC cells is related to metastatic behavior. Serum CK19 level might reflect the pathological progression in some HCC and may be a useful marker for predicting tumor metastasis and a therapeutic target for the treatment of HCC patients with metastases.
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MESH Headings
- Animals
- Biomarkers, Tumor
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Electrophoresis, Gel, Two-Dimensional
- Humans
- Keratins/genetics
- Keratins/metabolism
- Liver Neoplasms/diagnosis
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Lung Neoplasms/pathology
- Lung Neoplasms/secondary
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Metastasis
- Peptide Fragments/genetics
- Peptide Fragments/metabolism
- Proteome/analysis
- Random Allocation
- Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Affiliation(s)
- Shi-Jian Ding
- Research Center for Proteome Analysis, Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, Shanghai 200031, People's Republic of China
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Abstract
AIM: To analyse the prognostic factors in 165 colorectal patients aged ≥ 70.
METHODS: One hundred and sixty-five elderly patients with colorectal cancer diagnosed by histology were entered into the retrospective study between 1994 and 2001. Patients were given optimal operation alone, chemotherapy after operation, or chemotherapy alone according to tumor stage, histology, physical strength, and co-morbid problems. Survival rate was calculated by Kaplan-Meier method, and compared with meaningful variances by Log-rank method. Prognostic factors were analyzed by Cox regression.
RESULTS: The 1, 2, 3, 4, 5 year survival rate (all-cause mortality) was 87.76%, 65.96%, 52.05%, 42.77%, 40.51%, respectively. The mean survival time was 41.89 ± 2.33 months (95%CI: 37.33-46.45 months), and the median survival time was 37 months. Univariate analysis showed that factors such as age, nodal metastasis, treatment method, Duke’s stage, gross findings, kind of histology, and degree of differentiation had influences on the survival rate. Multivariate analysis showed that factors such as treatment method, Duke’s stage, kind of histology and degree of differentiation were independent prognostic factors.
CONCLUSION: This study suggests that the prognosis of elderly colorectal cancer patients is influenced by several factors. Most of elderly patients can endure surgery and/or chemotherapy, and have a long-time survival and good quality of life.
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Affiliation(s)
- Ke-Jun Nan
- Department of Oncology, First Hospital of Xi'an Jiaotong University, 1 Jiankang Xilu, Xi'an 710061, Shaanxi Province, China
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Fenwick SW, Toogood GJ, Lodge JPA, Hull MA. The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases. Gastroenterology 2003; 125:716-29. [PMID: 12949718 DOI: 10.1016/s0016-5085(03)01061-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS Cyclooxygenase-2 (COX-2) is a potential target for chemotherapy of colorectal cancer (CRC). We tested the antineoplastic activity of the selective COX-2 inhibitor rofecoxib on human CRC liver metastases by measuring surrogate markers of tumor growth and angiogenesis in a randomized, double-blind, placebo-controlled trial. METHODS Patients undergoing liver resection surgery for metastatic disease were randomized to receive rofecoxib 25 mg daily or placebo before surgery (duration, >14 days). The apoptosis index (AI; neocytokeratin 18), proliferation index (PI; Ki-67), and microvessel density (MVD; CD31) were measured in metastases by immunohistochemistry. The effect of rofecoxib on COX-2-positive HCA-7 human CRC cell PGE(2) synthesis, proliferation, and apoptosis in vitro was also investigated. RESULTS Patients who received rofecoxib (n = 23) and placebo (n = 21) were well matched regarding clinical and metastasis characteristics. The mean (range) duration of rofecoxib therapy was 26 (14-46) days. Rofecoxib-treated metastases had a 29% decrease in MVD (mean, 25.1 [SEM, 2.7] per hpf) compared with placebo-treated tissue (32.5 [SEM, 4.5] per hpf; P = 0.15). There was little difference in AI (rofecoxib mean, 2.03% [SEM, 0.43%] vs. placebo 1.39% [SEM, 0.39%]) or PI (rofecoxib 54.7% [SEM, 5.1%] vs. placebo 52.6% [SEM, 5.6%]). Rofecoxib-induced growth arrest and apoptosis of HCA-7 cells occurred only at concentrations (>10 micromol/L), which were significantly higher than the IC(50) for COX-2 inhibition. CONCLUSIONS Rofecoxib may negatively regulate angiogenesis in human CRC liver metastases. The absence of a significant, direct effect of rofecoxib on epithelial cells in liver metastases in vivo mirrors the lack of activity on human CRC cells at pharmacologically relevant concentrations in vitro.
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Weber JC, Bachellier P, Oussoultzoglou E, Jaeck D. Simultaneous resection of colorectal primary tumour and synchronous liver metastases. Br J Surg 2003; 90:956-62. [PMID: 12905548 DOI: 10.1002/bjs.4132] [Citation(s) in RCA: 173] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND The surgical strategy for treatment of synchronous colorectal liver metastases remains controversial. The outcome and overall survival of patients presenting with such metastases, treated either by simultaneous resection or by delayed resection, were evaluated. METHODS From 1987 to 2000, 97 patients presented with synchronous colorectal liver metastases, of whom 35 (36 per cent) underwent a simultaneous resection and 62 patients (64 per cent) a delayed resection. Simultaneous resection was considered prospectively for patients with fewer than four unilobar metastases. RESULTS Age, blood transfusion requirements, operating time, duration of inflow occlusion, hospital stay and mortality rate were similar in the two groups. The morbidity rate did not differ significantly (23 per cent after simultaneous resection and 32 per cent after delayed resection). The location of the primary tumour and extent of liver resection did not influence the morbidity rate significantly in the simultaneous resection group. The overall survival rate was 94, 45 and 21 per cent at 1, 3 and 5 years respectively after simultaneous resection, and 92, 45 and 22 per cent after delayed resection. CONCLUSION In selected patients, simultaneous resection of the colorectal primary tumour and liver metastases does not increase mortality or morbidity rates compared with delayed resection, even if a left colectomy and/or a major hepatectomy are required.
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Affiliation(s)
- J C Weber
- Service de Chirurgie Générale, Hépatique et Endocrinienne, Hôpital de Hautepierre, Strasbourg, France
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Qin LX, Tang ZY. The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol 2002; 8:385-92. [PMID: 12046056 PMCID: PMC4656407 DOI: 10.3748/wjg.v8.i3.385] [Citation(s) in RCA: 236] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2002] [Revised: 04/23/2002] [Accepted: 05/08/2002] [Indexed: 02/06/2023] Open
Abstract
The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
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Affiliation(s)
- Lun-Xiu Qin
- Liver Cancer Institute and Zhongshan Hospital, Fudan university, 136 Yi Xue Yuan Road, Shanghai 200032, China
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