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Mihailov R, Dima C, Constantin BG, Dimofte F, Craescu M, Moroianu L, Candussi LI, Lutenco V, Mihailov OM, Lutenco V. Prognostic Factors of Postoperative Mortality in Patients with Complicated Right Colon Cancer. Life (Basel) 2025; 15:350. [PMID: 40141695 PMCID: PMC11943528 DOI: 10.3390/life15030350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/14/2025] [Accepted: 02/21/2025] [Indexed: 03/28/2025] Open
Abstract
The incidence of right colon cancer presenting in a stage with complications is significant. There are major differences in therapeutic approach between elective colon cancer surgery and emergency surgery. Complications such as hemorrhage, obstruction, and perforation require careful evaluation of prognostic factors, with morbidity and mortality rates being much higher compared to elective colon surgery. We retrospectively analyzed a group of 95 patients admitted in an emergency to the County Emergency Hospital St. Apostol Apostol Andrei Galati with complicated tumors of the right colon-occlusive, perforated, or hemorrhagic. A series of clinical and biological parameters were followed in order to identify the prognostic factors in the occurrence of death. We analyzed the specialized literature, comparing our study with other similar research from the most important databases. The postoperative death rate in patients with complicated right colon cancer was high. Most complications were occlusive, followed by hemorrhagic and perforative.
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Affiliation(s)
- Raul Mihailov
- “Dunarea de Jos” Faculty of Medicine and Pharmacy, University of Galati, 800008 Galați, Romania; (R.M.); (B.G.C.); (F.D.); (M.C.); (L.M.); (L.I.C.); (O.M.M.); (V.L.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 800008 Galați, Romania
| | - Corina Dima
- “Dunarea de Jos”Faculty of Sciences and Environment, University of Galati, 800008 Galați, Romania
| | - Bianca Georgiana Constantin
- “Dunarea de Jos” Faculty of Medicine and Pharmacy, University of Galati, 800008 Galați, Romania; (R.M.); (B.G.C.); (F.D.); (M.C.); (L.M.); (L.I.C.); (O.M.M.); (V.L.)
| | - Florentin Dimofte
- “Dunarea de Jos” Faculty of Medicine and Pharmacy, University of Galati, 800008 Galați, Romania; (R.M.); (B.G.C.); (F.D.); (M.C.); (L.M.); (L.I.C.); (O.M.M.); (V.L.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 800008 Galați, Romania
| | - Mihaela Craescu
- “Dunarea de Jos” Faculty of Medicine and Pharmacy, University of Galati, 800008 Galați, Romania; (R.M.); (B.G.C.); (F.D.); (M.C.); (L.M.); (L.I.C.); (O.M.M.); (V.L.)
| | - Lavinia Moroianu
- “Dunarea de Jos” Faculty of Medicine and Pharmacy, University of Galati, 800008 Galați, Romania; (R.M.); (B.G.C.); (F.D.); (M.C.); (L.M.); (L.I.C.); (O.M.M.); (V.L.)
| | - Laura Iuliana Candussi
- “Dunarea de Jos” Faculty of Medicine and Pharmacy, University of Galati, 800008 Galați, Romania; (R.M.); (B.G.C.); (F.D.); (M.C.); (L.M.); (L.I.C.); (O.M.M.); (V.L.)
| | - Virginia Lutenco
- “Sf. Ioan” Emergency Clinical Hospital for Children, 800008 Galați, Romania;
| | - Oana Mariana Mihailov
- “Dunarea de Jos” Faculty of Medicine and Pharmacy, University of Galati, 800008 Galați, Romania; (R.M.); (B.G.C.); (F.D.); (M.C.); (L.M.); (L.I.C.); (O.M.M.); (V.L.)
| | - Valerii Lutenco
- “Dunarea de Jos” Faculty of Medicine and Pharmacy, University of Galati, 800008 Galați, Romania; (R.M.); (B.G.C.); (F.D.); (M.C.); (L.M.); (L.I.C.); (O.M.M.); (V.L.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 800008 Galați, Romania
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Liang L, Kong C, Li J, Liu G, Wei J, Wang G, Wang Q, Yang Y, Shi D, Li X, Ma Y. Distinct microbes, metabolites, and the host genome define the multi-omics profiles in right-sided and left-sided colon cancer. MICROBIOME 2024; 12:274. [PMID: 39731152 DOI: 10.1186/s40168-024-01987-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 11/22/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND Studies have reported clinical heterogeneity between right-sided colon cancer (RCC) and left-sided colon cancer (LCC). However, none of these studies used multi-omics analysis combining genetic regulation, microbiota, and metabolites to explain the site-specific difference. METHODS Here, 494 participants from a 16S rRNA gene sequencing cohort (50 RCC, 114 LCC, and 100 healthy controls) and a multi-omics cohort (63 RCC, 79 LCC, and 88 healthy controls) were analyzed. 16S rRNA gene, metagenomic sequencing, and metabolomics analyses of fecal samples were evaluated to identify tumor location-related bacteria and metabolites. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) were conducted to obtain the mutation burden and genomic expression pattern. RESULTS We found unique profiles of the intestinal microbiome, metabolome, and host genome between RCC and LCC. The bacteria Flavonifractor plautii (Fp) and Fusobacterium nucleatum, the metabolites L-phenylalanine, and the host genes PHLDA1 and WBP1 were the key omics features of RCC; whereas the bacteria Bacteroides sp. A1C1 (B.A1C1) and Parvimonas micra, the metabolites L-citrulline and D-ornithine, and the host genes TCF25 and HLA-DRB5 were considered the dominant omics features in LCC. Multi-omics correlation analysis indicated that RCC-enriched Fp was related to the accumulation of the metabolite L-phenylalanine and the suppressed WBP1 signal in RCC patients. In addition, LCC-enriched B.A1C1 was associated with the accumulation of the metabolites D-ornithine and L-citrulline as well as activation of the genes TCF25, HLA-DRB5, and AC079354.1. CONCLUSION Our findings identify previously unknown links between intestinal microbiota alterations, metabolites, and host genomics in RCC vs. LCC, suggesting that it may be possible to treat colorectal cancer (CRC) by targeting the gut microbiota-host interaction. Video Abstract.
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Affiliation(s)
- Lei Liang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Kong
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jinming Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guang Liu
- Guangdong Hongyuan Pukang Medical Technology Co., Ltd., Guangdong, China
| | - Jinwang Wei
- GenomiCare Biotechnology Co. Ltd., Shanghai, China
| | - Guan Wang
- GenomiCare Biotechnology Co. Ltd., Shanghai, China
| | - Qinying Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yongzhi Yang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Debing Shi
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yanlei Ma
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Zhang C, Ma M, Zhao Z, Feng Z, Chu T, Wang Y, Liu J, Wan X. Gut mucosal microbiota profiles linked to development of positional-specific human colorectal cancer. AIMS Microbiol 2024; 10:812-832. [PMID: 39628718 PMCID: PMC11609426 DOI: 10.3934/microbiol.2024035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/03/2024] [Accepted: 09/09/2024] [Indexed: 12/06/2024] Open
Abstract
Colorectal cancer (CRC) continuously ranks as the third most common cause of cancer-related deaths worldwide. Based on anatomical classifications and clinical diagnoses, CRC is classified into right-sided, left-sided, and rectal CRC. Importantly, the three types of positional-specific CRC affect the prognosis outcomes, thus indicating that positional-specific treatments for CRC are required. Emerging evidence suggests that besides host genetic and epigenetic alterations, gut mucosal microbiota is linked to gut inflammation, CRC occurrence, and prognoses. However, gut mucosal microbiota associated with positional-specific CRC are poorly investigated. Here, we report the gut mucosal microbiota profiles associated with these three types of CRC. Our analysis showed that the unique composition and biodiversity of bacterial taxa are linked to positional-specific CRC. We found that a combination of bacterial taxa can serve as potential biomarkers to distinguish the three types of CRC. Further investigations of the physiological roles of bacteria associated with positional-specific CRC may help understand the mechanism of CRC progression in different anatomical locations under the impact of gut mucosal microbiota.
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Affiliation(s)
- Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Nankai University, Tianjin, China
- Tianjin Institute of Coloproctology, Tianjin, China
| | - Mingqian Ma
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhenying Zhao
- Department of Colorectal Surgery, Tianjin Union Medical Center, Nankai University, Tianjin, China
| | - Zhiqiang Feng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tianhao Chu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yijia Wang
- Tianjin institute of spinal surgery, Tianjin Union Medical Center, Nankai University, Tianjin, China
| | - Jun Liu
- Department of Radiology, The Fourth Central Hospital Affiliated to Nankai University, Tianjin, China
| | - Xuehua Wan
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
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Guo W, Zhang C, Wang X, Dou D, Chen D, Li J. Resolving the difference between left-sided and right-sided colorectal cancer by single-cell sequencing. JCI Insight 2021; 7:152616. [PMID: 34793335 PMCID: PMC8765049 DOI: 10.1172/jci.insight.152616] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 11/17/2021] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways, and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells from 3 left-sided and 3 right-sided CRC patients were profiled by single-cell RNA-Seq (scRNA-Seq). Right-sided CRC harbors a significant proportion of exhausted CD8+ T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of preexhausted/exhausted T cells were favorable prognostic markers. Notably, we identified a potentially novel RBP4+NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.
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Affiliation(s)
- Wei Guo
- Department of Colorectal Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cuiyu Zhang
- Department of Physiology, Shandong University, Jinan, China
| | - Xia Wang
- Department of Physiology, Shandong University, Jinan, China
| | - Dandan Dou
- Department of Physiology, Shandong University, Jinan, China
| | - Dawei Chen
- Interdisciplinary Cluster for Applied Genoproteomics (GIGA) Stem Cells, Université de Liège, Liège, Belgium
| | - Jingxin Li
- Department of Physiology, Shandong University, Jinan, China
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5
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Zakharenko MV, Bozhenko VK, Kiseleva YY, Dzhikiya EL, Stanoevich US, Kulinich TM, Melnikova NV, Senchukova AL, Urakova AB, Grunin IB, Goncharov SV, Bliznyukov OP, Solodkiy VA. [The study of mRNA expression profiles of main cell function regulator genes in unchanged colonic mucosa from healthy donors]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2021; 67:366-373. [PMID: 34414896 DOI: 10.18097/pbmc20216704366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
A comparative analysis of molecular genetic phenotypes of mucous membrane cells in five anatomical regions of the colon in a group of healthy donors was conducted by comparing mRNA expression profiles of 62 genes involved in the regulation of vital cellular function. We used 181 biopsy samples of morphologically unchanged colonic mucosa, obtained from the colon (ascending, transverse-colon, descending, sigmoid) and rectum sections during prophylactic colonoscopy of 58 donors with no colon pathology. The mRNA levels for 62 genes involved in the regulation of apoptosis, proliferation, transcription, differentiation, cell-cell adhesion, and immune response were assessed by RT-PCR. Statistically significant differences were found for the molecular phenotypes of five sections of the colon. The results of the study can serve as a basis for creating a reference database (values of expression profiles), developing methods of differential diagnostics and screening of various pathologies of the colon.
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Affiliation(s)
- M V Zakharenko
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - V K Bozhenko
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - Ya Yu Kiseleva
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - E L Dzhikiya
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - U S Stanoevich
- Kursk Regional Clinical Oncology Center, Kislino, Russia
| | - T M Kulinich
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - N V Melnikova
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - A L Senchukova
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - A B Urakova
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - I B Grunin
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - S V Goncharov
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - O P Bliznyukov
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
| | - V A Solodkiy
- Russian Scientific Center of Roentgenoradiology, Moscow, Russia
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Aomatsu N, Maeda K, Uchima Y, Matsutani S, Tsujio G, Miyamoto H, Okada T, Kurihara S, Nishii T, Tachimori A, Ikeda K, Takeuchi K. Multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine: A case report. Neuropeptides 2021; 88:102160. [PMID: 34004454 DOI: 10.1016/j.npep.2021.102160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/05/2021] [Accepted: 05/09/2021] [Indexed: 10/21/2022]
Abstract
FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is the preferred first-line treatment for right-sided metastatic colorectal cancer with RAS mutation. However, severe adverse events are common in Japanese patients. We report the successful management of multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine. A 68-year-old man presented with epigastralgia and appetite loss and was diagnosed with multiple stage IV colorectal cancers. Colonoscopy identified type II tumors in the ascending colon, sigmoid colon, and upper rectum. Histopathological examination of a biopsy specimen revealed well- to moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed multiple pulmonary nodules and para-aortic lymph node swelling. Laparoscopic loop-ileostomy was performed to avoid bowel obstruction due to severe stenosis of ascending colon cancer. Intraoperative observation revealed two white nodules suggestive of metastasis in the lateral area of the liver. Therefore, we diagnosed multiple stage IV colorectal cancers with multiple metastases (lung, liver, and distant lymph nodes). His postoperative course was uneventful, and chemotherapy was started. Since the cancer cells harbored a RAS mutation, he received FOLFOXIRI plus bevacizumab. Japanese Kampo medicine consisting of Hangeshashinto and Juzen-taiho-to, to prevent diarrhea and fatigue, was administered daily. After 12 courses of chemotherapy, though circumferential stenosis still existed in the ascending colon, the tumors in the sigmoid colon and upper rectum were unclear. Enhanced computed tomography showed shrinkage of the pulmonary nodules and para-aortic lymph node; therefore, laparoscopic-assisted ileocecal resection was performed. The postoperative histopathological examination revealed moderately differentiated adenocarcinoma. The patient recovered uneventfully, and Kampo medicine consisting of Ninjin'yoeito was administered for postoperative weakness. Administration of adjuvant chemotherapy in this patient led to a near complete response that has been maintained without recurrence for 2 years and 8 months without reduced quality of life.
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Affiliation(s)
- Naoki Aomatsu
- Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan.
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan
| | | | | | - Gen Tsujio
- Department of Surgery Center, Fuchu Hospital, Osaka, Japan
| | | | - Takuma Okada
- Department of Surgery Center, Fuchu Hospital, Osaka, Japan
| | | | - Takafumi Nishii
- Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan
| | - Akiko Tachimori
- Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan
| | - Katsumi Ikeda
- Department of Breast Surgical Oncology, Osaka City General Hospital, Osaka, Japan
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An Y, Zhou J, Lin G, Wu H, Cong L, Li Y, Qiu X, Shi W. Clinicopathological and Molecular Characteristics of Colorectal Signet Ring Cell Carcinoma: A Review. Pathol Oncol Res 2021; 27:1609859. [PMID: 34381313 PMCID: PMC8351516 DOI: 10.3389/pore.2021.1609859] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/14/2021] [Indexed: 12/24/2022]
Abstract
Colorectal signet ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer (CRC) with unique characteristics. Due to the limited researches on it, a comprehensive and in-depth understanding of this subtype is still lacking. In this article, we summarize the clinicopathological features and molecular characteristics of colorectal SRCC based on a literature review. Clinically, SRCC has been associated with young age, proximal site preference, advanced tumor stage, high histological grade, high rate of lymph node involvement, frequent peritoneal metastasis, and a significantly poor prognosis. Regarding molecular characteristics, in SRCC, the mutation burden of the classic signaling pathways that include WNT/β-catenin, RAS/RAF/MAPK, and PI3K/AKT/mTOR signaling pathways are generally reduced. In contrast, some genes related to the “epithelial-mesenchymal transition (EMT) process” and the “stem cell properties”, including RNF43, CDH1, and SMAD4, as well as the related TGF-β signaling pathway have been observed more frequently altered in SRCC than in conventional adenocarcinoma (AC). In many studies but not in others, SRCC showed a higher frequency of BRAF mutation, microsatellite instability-high (MSI-H) and CpG island methylator phenotype (CIMP) positive status compared to AC. It has been proposed that colorectal SRCC consists of two subtypes, in which the MSI+/CIMP+/BRAF+/CD3+/PD-L1+ hypermethylated genotype is more common in the proximal colon, and may represent the potential candidate for immunotherapy. Understanding the special molecular mechanisms related to the aggressive biology of SRCC is of great importance, which may provide a theoretical basis for the development of more targeted and effective treatments for this refractory disease.
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Affiliation(s)
- Yang An
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaolin Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guole Lin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Cong
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunhao Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyuan Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weikun Shi
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Datorre JG, de Carvalho AC, Guimarães DP, Reis RM. The Role of Fusobacterium nucleatum in Colorectal Carcinogenesis. Pathobiology 2020; 88:127-140. [PMID: 33291114 DOI: 10.1159/000512175] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 10/06/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent and deadly neoplasms worldwide. Genetic factors, lifestyle habits, and inflammation are important risk factors associated with CRC development. In recent years, growing evidence has supporting the significant role of the intestinal microbiome in CRC carcinogenesis. Disturbances in the healthy microbial balance, known as dysbiosis, are frequently observed in these patients. Pathogenic microorganisms that induce intestinal dysbiosis have become an important target to determine the role of bacterial infection in tumorigenesis. Interestingly, the presence of different bacterial strains, such as Fusobacterium nucleatum, has been detected in tissue and stool from patients with CRC and associated with substantial clinical and molecular features, as well as with patient therapy response. Therefore, understanding how the presence and levels of F. nucleatumstrains in the gut affect the risk of CRC onset and progression may inform suitable candidates for interventions focused on modulation of this bacteria. Here we review new insights into the role of gut microbiota in CRC carcinogenesis and the clinical utility of using the detection of F. nucleatum in different settings such as screening, prognosis, and microbiota modulation as a means to prevent cancer, augment therapies, and reduce adverse effects of treatment.
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Affiliation(s)
| | | | - Denise Peixoto Guimarães
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.,Department of Prevention, Barretos Cancer Hospital, Barretos, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil, .,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal, .,ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal,
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9
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Tyler CJ, Guzman M, Lundborg LR, Yeasmin S, Perez-Jeldres T, Yarur A, Behm B, Dulai PS, Patel D, Bamias G, Rivera-Nieves J. Inherent Immune Cell Variation Within Colonic Segments Presents Challenges for Clinical Trial Design. J Crohns Colitis 2020; 14:1364-1377. [PMID: 32239151 PMCID: PMC7533898 DOI: 10.1093/ecco-jcc/jjaa067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Intestinal biopsy sampling during IBD trials represents a valuable adjunct strategy for understanding drug responses at the tissue level. Given the length and distinctive embryonic origins of the proximal and distal colon, we investigated whether inherent regional differences of immune cell composition could introduce confounders when sampling different disease stages, or pre/post drug administration. Here, we capitalise on novel mass cytometry technology to perform deep immunophenotyping of distinct healthy colonic segments, using the limited numbers of biopsies that can be harvested from patients. METHODS Biopsies [2.8 mm] were collected from the caecum, transverse colon, descending colon, and rectum of normal volunteers. Intestinal leukocytes were isolated, stained with a panel of 37 antibodies, and mass cytometry data acquired. RESULTS Site-specific patterns of leukocyte localisation were observed. The proximal colon featured increased CD8+ T cells [particularly resident memory], monocytes, and CD19+ B cells. Conversely, the distal colon and rectum tissues exhibited enrichment for CD4+ T cells and antibody-secreting cells. The transverse colon displayed increased abundance of both γδ T cells and NK cells. Subsets of leukocyte lineages also displayed gradients of expression along the colon length. CONCLUSIONS Our results show an inherent regional immune cell variation within colonic segments, indicating that regional mucosal signatures must be considered when assessing disease stages or the prospective effects of trial drugs on leukocyte subsets. Precise protocols for intestinal sampling must be implemented to allow for the proper interpretation of potential differences observed within leukocyte lineages present in the colonic lamina propria.
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Affiliation(s)
- Christopher J Tyler
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- San Diego VA Medical Center, San Diego, CA, USA
| | - Mauricio Guzman
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- San Diego VA Medical Center, San Diego, CA, USA
| | - Luke R Lundborg
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- San Diego VA Medical Center, San Diego, CA, USA
| | - Shaila Yeasmin
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- San Diego VA Medical Center, San Diego, CA, USA
| | - Tamara Perez-Jeldres
- Universidad Católica de Chile, Santiago, Chile
- Hospital San Borja Arriarán, Santiago, Chile
| | - Andres Yarur
- Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Brian Behm
- Division of Gastroenterology, University of Virginia, Charlottesville, VI, USA
| | | | - Derek Patel
- San Diego VA Medical Center, San Diego, CA, USA
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Jesús Rivera-Nieves
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- San Diego VA Medical Center, San Diego, CA, USA
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The treatment paradigm of right-sided metastatic colon cancer: harboring BRAF mutation makes the difference. Int J Colorectal Dis 2020; 35:1513-1527. [PMID: 32382835 DOI: 10.1007/s00384-020-03589-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy. METHODS A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted. RESULTS We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively). CONCLUSIONS Our study demonstrated that BRAF status makes the difference in treatment's outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.
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11
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de Boer NL, Rovers K, Burger JWA, Madsen EVE, Brandt-Kerkhof ARM, Kok NFM, de Wilt JHW, de Reuver PH, Bos A, de Hingh IHJT, Verhoef C. A population-based study on the prognostic impact of primary tumor sidedness in patients with peritoneal metastases from colon cancer. Cancer Med 2020; 9:5851-5859. [PMID: 32614506 PMCID: PMC7433839 DOI: 10.1002/cam4.3243] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/15/2020] [Accepted: 05/29/2020] [Indexed: 01/05/2023] Open
Abstract
Primary tumor location is an established prognostic factor in patients with (metastatic) colon cancer. Colon tumors can be divided into left‐sided and right‐sided tumors. The aim of this study was to determine the impact of primary tumor location on treatment and overall survival (OS) in patients with peritoneal metastases (PM) from colon cancer. This study is a retrospective, population‐based cohort study. Records of patients diagnosed with colon cancer and synchronous PM, from 1995 through 2016, were retrieved from the Netherlands Cancer Registry (NCR). Data on diagnosis, staging, and treatment were extracted from the medical records by specifically trained NCR personnel. Information on survival status was updated annually using a computerized link with the national civil registry. In total, 7930 patients were included in this study; 4555 (57.4%) had a right‐sided and 3375 (42.6%) had a left‐sided primary tumor. In multivariable analysis right‐sided primary tumor was associated with worse OS (HR: 1.11, 95% CI 1.03‐1.19, P = .007). Of all patients diagnosed with PM, 564 (7.1%) underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS‐HIPEC). Patients with left‐sided primary tumors were more often candidates for CRS‐HIPEC (6.5% vs. 8.0%, P = .008). OS of patients with right‐ and left‐sided tumors who underwent CRS‐HIPEC did not significantly differ. In conclusion, primary right‐sided colon cancer was an independent prognostic factor for decreased OS in patients diagnosed with synchronous PM. In patients treated with CRS‐HIPEC location of the primary tumor did not influence survival.
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Affiliation(s)
- Nadine L de Boer
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Koen Rovers
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - Jacobus W A Burger
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - Eva V E Madsen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | | | - Niels F M Kok
- Department of Surgery, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | | | - Amanda Bos
- Department of Research & Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands
| | | | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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12
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Oliveira RC, Abrantes AM, Tralhão JG, Botelho MF. The role of mouse models in colorectal cancer research-The need and the importance of the orthotopic models. Animal Model Exp Med 2020; 3:1-8. [PMID: 32318654 PMCID: PMC7167241 DOI: 10.1002/ame2.12102] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/06/2020] [Accepted: 02/21/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer is a worldwide health burden, with high incidence and mortality, especially in the advanced stages of the disease. Preclinical models are very important and valuable to discover and validate early and specific biomarkers as well as new therapeutic targets. In order to accomplish that, the animal models must replicate the clinical evolution of the disease in all of its phases. In this article, we review the existent mouse models, with their strengths and weaknesses in the replication of human cancer disease progression, with major focus on orthotopic models.
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Affiliation(s)
- Rui C. Oliveira
- Biophysics UnitFaculty of MedicineUniversity of CoimbraCoimbraPortugal
- Pathology DepartmentUniversity Hospital (CHUC)CoimbraPortugal
| | - Ana Margarida Abrantes
- Biophysics UnitFaculty of MedicineUniversity of CoimbraCoimbraPortugal
- Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO)CoimbraPortugal
| | - José Guilherme Tralhão
- Biophysics UnitFaculty of MedicineUniversity of CoimbraCoimbraPortugal
- Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO)CoimbraPortugal
- Surgery A DepartmentFaculty of MedicineUniversity Hospital (CHUC)CoimbraPortugal
| | - Maria Filomena Botelho
- Biophysics UnitFaculty of MedicineUniversity of CoimbraCoimbraPortugal
- Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO)CoimbraPortugal
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13
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Mendis S, Beck S, Lee B, Lee M, Wong R, Kosmider S, Shapiro J, Yip D, Steel S, Nott L, Jennens R, Lipton L, Burge M, Field K, Ananda S, Wong HL, Gibbs P. Right versus left sided metastatic colorectal cancer: Teasing out clinicopathologic drivers of disparity in survival. Asia Pac J Clin Oncol 2019; 15:136-143. [PMID: 30761750 DOI: 10.1111/ajco.13135] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 01/16/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) patients with a right-sided primary (RC) have an inferior survival to mCRC arising from a left-sided primary (LC). Previous analyses have suggested multiple factors contribute. METHODS The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry prospectively captured data on consecutive mCRC patients. RC were defined as tumors proximal to the splenic flexure; LC were those at and distal to the splenic flexure and included rectal cancers. Patient, tumor, treatment, and survival data were analyzed stratified by side. RESULTS Of 2306 patients enrolled from July 2009-March 2018, 747 (32%) had an RC. Patients with RC were older, more likely to be female and have a Charlson score ≥3. RC were more frequently BRAF mutated, deficient in mismatch repair, associated with peritoneal metastases, and less likely to receive chemotherapy. Progression-free survival on first-line systemic therapy was inferior for RC patients (8.1 vs. 10.8 months, hazard ratio [HR] for progression in RC 1.38, P < 0.001). Median overall survival for all RC patients was inferior (19.6 vs. 27.5 months, HR for death in RC 1.44, P < 0.001), and inferior within the treated (21 vs. 29.5 months, HR 1.52, P < 0.001) and untreated subgroups (5.9 vs. 10.3 months, HR 1.38, P = 0.009). Primary side remained a significant factor for overall survival in multivariate analysis. CONCLUSION Our data from a real-world population confirms the poorer prognosis associated with RC. Primary tumor location remains significantly associated with overall survival even when adjusting for multiple factors, indicating the existence of further side-based differences that are as yet undefined.
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Affiliation(s)
- Shehara Mendis
- Footscray Hospital, Western Health, Footscray, Victoria, Australia
| | - Sophie Beck
- Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Belinda Lee
- Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Royal Melbourne Hospital, Parkville, Victoria, Australia
- Faculty of Medicine & Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
| | - Margaret Lee
- Footscray Hospital, Western Health, Footscray, Victoria, Australia
- Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Royal Melbourne Hospital, Parkville, Victoria, Australia
- Faculty of Medicine & Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
- Box Hill Hospital, Eastern Health, Box Hill, Victoria, Australia
| | - Rachel Wong
- Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Box Hill Hospital, Eastern Health, Box Hill, Victoria, Australia
- Faculty of Nursing & Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Suzanne Kosmider
- Footscray Hospital, Western Health, Footscray, Victoria, Australia
| | | | - Desmond Yip
- Canberra and Calvary Hospitals, Garran, Australian Capital Territory, Australia
- ANU Medical School, The Canberra Hospital, Garran, Australian Capital Territory, Australia
| | - Simone Steel
- Peninsula Private Hospital, Frankston, Victoria, Australia
| | - Louise Nott
- Royal Hobart Hospital, Hobart, Tasmania, Australia
| | | | - Lara Lipton
- Footscray Hospital, Western Health, Footscray, Victoria, Australia
- Cabrini Health, Malvern, Victoria, Australia
| | - Matthew Burge
- Royal Brisbane Hospital, Herston, Queensland, Australia
| | - Kathryn Field
- Royal Melbourne Hospital, Parkville, Victoria, Australia
- Faculty of Medicine & Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
| | - Sumitra Ananda
- Footscray Hospital, Western Health, Footscray, Victoria, Australia
| | - Hui-Li Wong
- Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Peter Gibbs
- Footscray Hospital, Western Health, Footscray, Victoria, Australia
- Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Royal Melbourne Hospital, Parkville, Victoria, Australia
- Faculty of Medicine & Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
- BioGrid Australia, Melbourne, Australia
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14
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Tapia Rico G, Price T, Tebbutt N, Hardingham J, Lee C, Buizen L, Wilson K, Gebski V, Townsend A. Right or Left Primary Site of Colorectal Cancer: Outcomes From the Molecular Analysis of the AGITG MAX Trial. Clin Colorectal Cancer 2019; 18:141-148. [PMID: 30713134 DOI: 10.1016/j.clcc.2018.12.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/02/2018] [Accepted: 12/11/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND For metastatic colorectal cancer, previous reports have described differences in biology and outcome, including response to biologic agents, based on whether the primary tumor is right- or left-sided. We explored the molecular markers from the AGITG MAX trial. PATIENTS AND METHODS The AGITG MAX trial was a randomized study comparing capecitabine versus capecitabine + bevacizumab versus capecitabine + bevacizumab + mitomycin C as first-line therapy in advanced colorectal cancer. Patients were classified as having right-sided (caecum to transverse colon) or left-sided (descending colon to rectum) disease according to anatomic location. Baseline characteristics and previously described molecular profiles were compared by side of primary tumor. Survival outcomes were analyzed by the Kaplan-Meier approach and proportional hazards regression modeling. RESULTS Among the 471 patients, the location of primary tumor was known in 440 patients (93%). Molecular profile was known in 298 patients (63%). Twenty-eight percent had right-sided primary tumors. Major differences between right and left are as follows: female 49% versus 33% (P < .01), BRAF mutant 16% versus 3.5% (P ≤ .001), and phosphatase and tensin homolog (PTEN) loss 27.6% versus 53% (P = .01). There were no differences in RAS mutation, PIK3CA mutation, or high versus low expression of assessed angiogenic markers. Right-sided primary lesion predicted a poor outcome for median overall survival: right-sided disease 13.2 months versus left-sided disease 20 months (P = .001; hazard ratio [HR] = 0.67; 95% confidence interval [CI], 0.53-0.85), but not for progression-free survival (HR 0.96; 95% CI, 0.78-1.20). The relative treatment effect did not differ significantly according to location of primary tumor: right primary tumor HR (bevacizumab containing arm vs. capecitabine monotherapy arm) was 0.82 (95% CI, 0.54-1.22), and left primary HR (bevacizumab containing arm vs. capecitabine monotherapy arm) was 0.51 (95% CI, 0.4-0.63) (interaction P = .10). CONCLUSION There are more negative prognostic factors in patients with right-sided primary tumors, in particular high BRAF mutations, and these patients have inferior overall survival compared to those with a left-sided primary tumor. There was no suggestion that side of primary site had any impact on bevacizumab effect on progression-free survival.
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Affiliation(s)
- Gonzalo Tapia Rico
- Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia.
| | - Timothy Price
- Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia; Basil Hetzel Institute, Woodville, Australia; University of Sydney, Sydney, Australia
| | - Niall Tebbutt
- University of Sydney, Sydney, Australia; Department of Medical Oncology, Austin Health, Melbourne, Australia
| | - Jennifer Hardingham
- Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia; Basil Hetzel Institute, Woodville, Australia
| | - Chee Lee
- NHMRC Clinical Trials Centre, Sydney, Australia
| | - Luke Buizen
- NHMRC Clinical Trials Centre, Sydney, Australia
| | - Kate Wilson
- NHMRC Clinical Trials Centre, Sydney, Australia
| | - Val Gebski
- NHMRC Clinical Trials Centre, Sydney, Australia
| | - Amanda Townsend
- Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia; Basil Hetzel Institute, Woodville, Australia
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15
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Cremolini C, Antoniotti C, Lonardi S, Bergamo F, Cortesi E, Tomasello G, Moretto R, Ronzoni M, Racca P, Loupakis F, Zaniboni A, Tonini G, Buonadonna A, Marmorino F, Allegrini G, Granetto C, Masi G, Zagonel V, Sensi E, Fontanini G, Boni L, Falcone A. Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO. Ann Oncol 2018; 29:1528-1534. [DOI: 10.1093/annonc/mdy140] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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16
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Kamran SC, Clark JW, Zheng H, Borger DR, Blaszkowsky LS, Allen JN, Kwak EL, Wo JY, Parikh AR, Nipp RD, Murphy JE, Goyal L, Zhu AX, Iafrate AJ, Corcoran RB, Ryan DP, Hong TS. Primary tumor sidedness is an independent prognostic marker for survival in metastatic colorectal cancer: Results from a large retrospective cohort with mutational analysis. Cancer Med 2018; 7:2934-2942. [PMID: 29771009 PMCID: PMC6051212 DOI: 10.1002/cam4.1558] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 03/28/2018] [Accepted: 04/24/2018] [Indexed: 12/14/2022] Open
Abstract
Recent reports demonstrate inferior outcomes associated with primary right‐sided vs left‐sided colorectal tumors in patients with metastatic colorectal cancer (mCRC). We sought to describe our experience with mCRC patients on whom we have molecular data to determine whether primary tumor sidedness was an independent prognostic marker for overall survival (OS). mCRC patients with documented primary tumor sidedness who received mutational profiling between 2009 and 2014 were identified (n = 367, median follow‐up 30.4 months). Mutational profiling for >150 mutations across commonly mutated cancer genes including RAS, PIK3CA, BRAF, and PTEN as well as treatment data, including receipt of a biologic agent, were collected. Univariable/multivariable models were used to analyze relationships between collected data and OS. Among 367 patients, sidedness breakdown was as follows: 234 left (64%), 133 right (36%). 56% were male, with a median age at diagnosis of 57 (range 24‐89). A total of 143 patients had RAS mutations. Five‐year OS was 41%, median OS was 54 months (range 1‐149). Five‐year OS for left‐ vs right‐sided tumors was 46% vs 24% (P < .0001). On univariable analysis, among both RAS wildtype and mutant tumors, left‐sided tumors continued to have improved OS vs right‐sided tumors (HR: 0.49, 95% CI: 0.34‐0.69 RAS wildtype; HR: 0.61, 95% CI: 0.40‐0.95 RAS mutant). Left‐sidedness was an important prognostic factor for OS among RAS wildtype patients despite treatment with or without a biologic agent (P < .05). Left‐sidedness remained significant for improved OS on multivariable analysis (P < .0001). Left‐sided primary tumor remained most important prognostic factor for OS, even when adjusting for mutational status and receipt of biologic agent.
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Affiliation(s)
- Sophia C Kamran
- Harvard Radiation Oncology Program, Boston, MA, USA.,Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Jeffrey W Clark
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Hui Zheng
- Biostatistics, Massachusetts General Hospital, Boston, MA, USA
| | - Darrell R Borger
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | | | - Jill N Allen
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Eunice L Kwak
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Aparna R Parikh
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Ryan D Nipp
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Janet E Murphy
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Lipika Goyal
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Andrew X Zhu
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - A John Iafrate
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Ryan B Corcoran
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - David P Ryan
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
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17
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Caetano-Oliveira R, Gomes MA, Abrantes AM, Tavares-Silva E, Oliveira MC, Laranjo M, Queirós DB, Casalta-Lopes J, Pires S, Carvalho L, Gouveia R, Santos PR, Priolli DG, Tralhão JG, Botelho MF. Revisiting colorectal cancer animal model - An improved metastatic model for distal rectosigmoid colon carcinoma. ACTA ACUST UNITED AC 2018; 25:89-99. [PMID: 29628185 DOI: 10.1016/j.pathophys.2018.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 12/26/2017] [Accepted: 02/04/2018] [Indexed: 01/24/2023]
Abstract
Colorectal cancer (CRC) is the second most frequent and fatal cancer in Western countries. Understanding its biology with different incidence along the colon and rectum, genetic profile and how these factors contribute to local/distant progression, has been hampered by the lack of a suitable CRC model. We report a reproducible model, using human CRC cell lines (CL) (WiDr, LS1034, C2BBe1) injected (1 × 107 cells/animal) in RNU rats (n = 55) which underwent cecostomy and descending colostomy with mucosal-cutaneous fistula of the sigmoid colon. CL were characterized by immunohistochemistry: CK20, CDX2, P53, vimentin, Ki67, CD44, CD133, E-cadherin, β-catenin and CEA; cancer stem cells-immune system interaction was studied and tumor progression was assessed with nuclear medicine imaging (99mTc-MIBI). Animals developed locally invasive tumors and with WiDr neural invasion was registered. Cancer stem cells were detected in WiDr (CD44 positive). All the cell lines stimulated the immune system, being WiDr the most aggressive. Imaging studies demonstrated tumor uptake. With this CRC model we can study the microenvironment role and tumor-stroma interactions. All CL developed primary disease, but only the WiDR established neural invasion which may represent a metastatic pathway. This model can help unveiling the underlying metastatic mechanisms, and ultimately test better therapeutic approaches for CRC.
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Affiliation(s)
- Rui Caetano-Oliveira
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Pathology Department, University Hospital (CHUC), Coimbra, Portugal
| | | | - Ana Margarida Abrantes
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Coimbra, Portugal
| | - Edgar Tavares-Silva
- Surgery A Department, University Hospital (CHUC), Faculty of Medicine, Coimbra, Portugal
| | - Marco Carvalho Oliveira
- Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Immunology Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Mafalda Laranjo
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Coimbra, Portugal
| | - Débora Basílio Queirós
- Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Immunology Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - João Casalta-Lopes
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Radiotherapy Department, University Hospital (CHUC), Faculty of Medicine, Coimbra, Portugal
| | - Salomé Pires
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Coimbra, Portugal
| | - Lina Carvalho
- Institute of Anatomic Pathology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Rosa Gouveia
- Thanatology Service of the National Institute of Legal Medicine (Center Delegation), Coimbra, Portugal
| | - Paulo Rodrigues Santos
- Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Coimbra, Portugal; Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Immunology Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Denise Gonçalves Priolli
- Postgraduate Program Strictu Senso in Health Science, Sao Francisco University Medical School, Brazil
| | - José Guilherme Tralhão
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Coimbra, Portugal; Surgery A Department, University Hospital (CHUC), Faculty of Medicine, Coimbra, Portugal
| | - Maria Filomena Botelho
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Coimbra, Portugal.
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18
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Yang L, He W, Kong P, Jiang C, Yang Q, Xie Q, Xia LP. Clinical baseline and prognostic difference of platelet lymphocyte ratio (PLR) in right-sided and let-sided colon cancers. BMC Cancer 2017; 17:873. [PMID: 29262803 PMCID: PMC5738180 DOI: 10.1186/s12885-017-3862-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/23/2017] [Indexed: 01/05/2023] Open
Abstract
Background Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ with respect to their biology and genomic patterns, but inflammatory index variation did not fully investigate. This study aimed to examine the difference of inflammatory indexes and its value between RCC and LCC. Methods The differences of common clinicopathologic factors, inflammatory indexes including PLR (Platelet lymphocyte ratio) between LCC and RCC were analyzed in the training cohort with logistic regression model, subsequently, confirmed in validation cohort. Kaplan-Meier analysis was applied for the analysis of the survival difference distinguished by the PLR and the Nonparametric Test was adopted to demonstrate the difference of PLR variation with the standard TNM classification between RCC and LCC. Results A total of 1846 CRC patients entered the study, 744 (40.3%) patients were RCC, 1102 (59.7%) were LCC. The patients’ number in both cohorts was 923. It was found that LCC patients in the training cohort significantly to be with higher CEA, adenocarcinoma, early UICC/AJCC stage, p-MMR (mismatch-repair proficient), and lower PLR, and the later four features were confirm in validation cohort. Higher PLR, the unique inflammatory index, was significantly associated with poorer OS in LCC cohort (P = 0.002) and was elevated with the TNM stage in the LCC patients (P < 0.001), however, the two relationships did not sustain in RCC patients. Conclusion Expect the classical characteristics, PLR, an inexpensive and easily assessable inflammatory index was found first time to be significant differ between LCC and RCC. Further, elevated PLR associated with poor OS (overall survival) in the LCC and more common in advanced TNM stage. Electronic supplementary material The online version of this article (10.1186/s12885-017-3862-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lin Yang
- Sun Yat-sen University cancer center, 651 Dongfeng Road east, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wenzhuo He
- Sun Yat-sen University cancer center, 651 Dongfeng Road east, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Pengfei Kong
- Sun Yat-sen University cancer center, 651 Dongfeng Road east, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chang Jiang
- Sun Yat-sen University cancer center, 651 Dongfeng Road east, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qiong Yang
- The Sun-yat sen memorial hospital, Guangzhou, China
| | - Qiankun Xie
- Sun Yat-sen University cancer center, 651 Dongfeng Road east, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Liang Ping Xia
- Sun Yat-sen University cancer center, 651 Dongfeng Road east, Guangzhou, 510060, China. .,State Key Laboratory of Oncology in Southern China, Guangzhou, China. .,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Yang L, He W, Yang Q, Kong P, Xie Q, Jiang C, Zhang B, Xia LP. Combination of primary tumor location and mismatch repair status guides adjuvant chemotherapy in stage II colon cancer. Oncotarget 2017; 8:99136-99149. [PMID: 29228759 PMCID: PMC5716799 DOI: 10.18632/oncotarget.21839] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 09/22/2017] [Indexed: 01/05/2023] Open
Abstract
Background Current opinions on the benefits of adjuvant chemotherapy for stage II colon cancer are divided and reformative election of these patients is required. We examined whether the primary tumor location based on mismatch repair status and other risk factors could better inform the current guideline. Materials and Methods A total of 673 consecutive patients with stage II colon cancer were included in the analysis. Differences in the common clinicopathological factors between left-sided colon cancer and right-sided colon cancer were analyzed using Fisher's exact analysis. Kaplan-Meier analysis was used to distinguish the survival difference by primary tumor location and/or MMR status. Results RCC had a shorter overall survival (P = 0.001) and Disease-free survival (P = 0.050) than LCC but was associated with survival benefit from adjuvant chemotherapy (P = 0.001 and P = 0.011 for OS and DFS, respectively). Mismatch repair-proficient had a shorter OS (P = 0.036) and disease free survival (P = 0.034) than mismatch-repair deficient but chemotherapy improved the OS (P = 0.007). When the primary tumor location and MMR status were combined, the PMMR/RCC was the only subgroup that could benefit from adjuvant chemotherapy (P < 0.001 and P = 0.002 for OS and DFS, respectively). Other tumors such as DMMR/RCC, DMMR/LCC, and PMMR/LCC did not benefit. Conclusions The observed survival benefits in PMMR/RCC patients treated with adjuvant chemotherapy will allow better selection of patients for chemotherapy who are in stage II.
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Affiliation(s)
- Lin Yang
- Sun Yat-Sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wenzhuo He
- Sun Yat-Sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qiong Yang
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Pengfei Kong
- Sun Yat-Sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qiankun Xie
- Sun Yat-Sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chang Jiang
- Sun Yat-Sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Bei Zhang
- Sun Yat-Sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Liang Ping Xia
- Sun Yat-Sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in Southern China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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20
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Chiu JW, Krzyzanowska MK, Serra S, Knox JJ, Dhani NC, Mackay H, Hedley D, Moore M, Liu G, Burkes RL, Brezden-Masley C, Roehrl MH, Craddock KJ, Tsao MS, Zhang T, Yu C, Kamel-Reid S, Siu LL, Bedard PL, Chen EX. Molecular Profiling of Patients With Advanced Colorectal Cancer: Princess Margaret Cancer Centre Experience. Clin Colorectal Cancer 2017; 17:73-79. [PMID: 29128266 DOI: 10.1016/j.clcc.2017.10.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 09/22/2017] [Accepted: 10/14/2017] [Indexed: 01/05/2023]
Abstract
BACKGROUND Molecular aberrations in KRAS, NRAS, BRAF, and PIK3CA have been well-described in advanced colorectal cancer. The incidences of other mutations are less known. We report results of molecular profiling of advanced colorectal cancer in an academic cancer center. PATIENTS AND METHODS Patients with advanced colorectal were enrolled in an institution-wide molecular profiling program. Profiling was performed on formalin-fixed paraffin embedded archival tissues using a customized MassArray panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Cancer Panel (48 genes, 212 amplicons, ≥ 500× coverage) in a Clinical Laboratory Improvement Amendments-certified laboratory. PTEN was determined by immunohistochemistry. RESULTS From March 2012 to April 2014, 245 patients were enrolled. At least one mutation was found in 54% (97/178) and 91% (61/67) of patients using MassArray or MiSeq platforms, respectively (P < .01). Of all patients, KRAS G12/13 mutation was identified in 39%, and non-G12/13 KRAS, BRAF, or NRAS mutations were present in 9%, 6%, and 4%, respectively. Other common mutations included TP53 (68.7%), APC (41.8%), and PIK3CA (13.5%). Co-mutation with KRAS, NRAS, or BRAF was found in 75% of patients with PIK3CA mutation. Of 106 patients with known PTEN immunohistochemistry status, 16% were negative. A higher average number of mutations were observed in right versus left colorectal cancer (P < .01), with 13 of 14 BRAF mutations located in right colon cancer. CONCLUSION Mutations are common in advanced colorectal cancer. Right colon cancers harbor more genetic aberrations than left colon or rectal cancers. These aberrations may contribute to differential outcomes to anti-epidermal growth factor receptor therapy among patients with right colon, left colon, or rectal cancers.
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Affiliation(s)
- Joanne W Chiu
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Monika K Krzyzanowska
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Stefano Serra
- Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada
| | - Jennifer J Knox
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Neesha C Dhani
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Helen Mackay
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - David Hedley
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Malcolm Moore
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Geoffrey Liu
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Ronald L Burkes
- Department of Medicine, Division of Medical Oncology and Hematology, Mount Sinai Hospital, Toronto, ON, Canada
| | | | - Michael H Roehrl
- Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada
| | - Kenneth J Craddock
- Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada
| | - Ming-Sound Tsao
- Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada
| | - Tong Zhang
- Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada
| | - Celeste Yu
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Suzanne Kamel-Reid
- Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada
| | - Lillian L Siu
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Philippe L Bedard
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Eric X Chen
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada.
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Abstract
OPINION STATEMENT Colorectal cancer (CRC) is the third most common cancer worldwide. CRC has been thought to be less common in Asia compared to Western countries. However, the incidence rates of CRC in Asia are high and there is an increasing trend in the Asian population. Furthermore, colorectal cancer accounts for the greatest number of all incidences of CRC in Asia. The increasing adoption of a Western lifestyle, particularly in dietary habits, is likely the most important factor contributing to the rapid increase in colon cancer incidence; it is noteworthy that trends for rectal cancer were flat. The etiology of colon and rectal cancer is a bit different. The risks of distal colon and rectal cancers are more likely to be related to environmental factors, such as polluted surface water sources, alcohol consumption, and habitual smoking. The lack of great change in the incidence of rectal cancer might be due to weaker associations with such lifestyle factors. Therefore, it has been hypothesized that proximal and distal sections of the colon and rectum are two different organs in terms of function and genetic background. It may mean differences in differential sensitivities and exposures to carcinogens. However, despite the decrease in whole incidence, the CRC incidence in young adults in Western countries are reversely increasing, especially in rectal cancer, due to reasons largely unknown. Although the treatment algorithm is different between Asia and western countries, globally, the survival rate for patients with rectal cancer has risen during the past 10 years. Screening contributes a great deal to reducing the incidence and improving survival. Most countries in Asia, such as China, need nationwide registration and screening systems to provide better data.
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Affiliation(s)
- Yanhong Deng
- Department of Medical Oncology, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Supported by National Key Clinical Discipline, The Sixth Affiliated Hospital, Sun Yat-sen University , 26 Yuancun Er Heng Road, Guangzhou, 510655, China.
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22
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Estradiol Has Differential Effects on Acute Colonic Inflammation in the Presence and Absence of Estrogen Receptor β Expression. Dig Dis Sci 2017; 62:1977-1984. [PMID: 28573506 PMCID: PMC5751962 DOI: 10.1007/s10620-017-4631-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 05/24/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) increases the risk of developing colon cancer. This risk is higher in men compared to women, implicating a role for female hormones in the protection against this disease. Studies from our laboratory demonstrated that estradiol (E2) protects against inflammation-associated colon tumor formation when administered following chemical carcinogen and induction of chronic colitis. AIM This study seeks to better understand the effect of E2 on acute colitis in the presence and absence of estrogen receptor β (ERβ). METHODS Inflammation was induced by 2,4,6-trinitrobenzenesulfonic acid in wild-type (WT) and ERβ knockout (ERβKO) mice implanted with a control or E2-containing pellet and killed 5 days later. Inflammation and injury were scored by a pathologist. Apoptosis and proliferation were assessed by immunohistochemistry. Cytokines were measured by multiplex analysis. RESULTS E2 treatment reduced inflammation in the middle colon in WT mice and the distal colon in ERβKO mice compared to control mice. WT mice had reduced IL-6, IL-12, IL-17, GM-CSF, IFN-γ, MCP-1, MIP-1α, and TNF-α, and ERβKO had reduced IL-6 and IFN-γ expression in response to E2. Injury scores were lower in E2-treated ERβKO mice compared to control ERβKO mice. ERβKO mice had increased proliferation in the basal third of crypts in the distal colon and decreased apoptosis in the proximal colon. CONCLUSIONS These data suggest that E2 has differential protective effects against acute colitis in the presence or absence of ERβ and provide insight into how E2 may protect against IBD.
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23
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Yang M, Yeatman TJ. Molecular stratification of colorectal cancer populations and its use in directing precision medicine. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2017. [DOI: 10.1080/23808993.2017.1362316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Mingli Yang
- Gibbs Research Institute, Gibbs Cancer Center & Research Institute, Spartanburg, SC 29303, USA
| | - Timothy J Yeatman
- Gibbs Research Institute, Gibbs Cancer Center & Research Institute, Spartanburg, SC 29303, USA
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24
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Doi H, Uemoto K, Suzuki O, Yamada K, Masai N, Tatsumi D, Shiomi H, Oh RJ. Effect of primary tumor location and tumor size on the response to radiotherapy for liver metastases from colorectal cancer. Oncol Lett 2017; 14:453-460. [PMID: 28693191 PMCID: PMC5494798 DOI: 10.3892/ol.2017.6167] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Accepted: 03/31/2017] [Indexed: 02/07/2023] Open
Abstract
Metastatic liver tumors (MLTs) from colorectal cancer (CRC) are often treated with stereotactic body radiation therapy (SBRT). The present study aimed to examine the predictive factors for response of MLTs to SBRT. A total of 39 MLTs from 24 patients with CRC were retrospectively analyzed. Radiotherapy for MLT was typically performed with a prescribed dose equivalent to a biologically effective dose (BED)10 of 100 Gy. The median follow-up period was 16 months (range, 5-64 months). The median prescribed dose and total BED10 were 56 Gy (range, 45-72 Gy) and 97.5 Gy (range, 71.7-115.5 Gy), respectively, in a median of 8 fractions (range, 4-33 fractions). The 1- and 2-year local control rates were 67.2 and 35.9%, respectively. For patients with MLT treated with ablative SBRT (BED10 ≥100 Gy in ≤5 fractions), the 1- and 2-year local control rates were 83.3 and 62.5%, respectively. Univariate analysis showed that primary tumor location (left-sided colon), maximum tumor diameter (≤30 mm) and ablative SBRT (BED10 ≥100 Gy in ≤5 fractions) were significantly associated with improved local control (P=0.0058, P=0.0059 and P=0.0268, respectively). Multivariate analysis showed that tumor diameter was significantly associated with improved local control (P=0.0314). In addition, patients who received ablative SBRT had significantly prolonged overall survival times compared with those treated with non-ablative SBRT (P=0.0261). To conclude, tumors ≤30 mm that can be treated with ablative SBRT are associated with good local control rates. The primary tumor location may affect the radiosensitivity of MLTs.
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Affiliation(s)
- Hiroshi Doi
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Kenji Uemoto
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
- Division of Health Sciences, Osaka University Graduate School of Medicine and Health Science, Suita, Osaka 565-0871, Japan
| | - Osamu Suzuki
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
- Department of Carbon Ion Radiotherapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Koichi Yamada
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
| | - Norihisa Masai
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
| | | | - Hiroya Shiomi
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
| | - Ryoong-Jin Oh
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
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25
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Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan. Eur J Cancer Prev 2017; 26:269-276. [DOI: 10.1097/cej.0000000000000255] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab. Br J Cancer 2017. [PMID: 28632725 PMCID: PMC5537494 DOI: 10.1038/bjc.2017.178] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting. METHODS We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months. RESULTS Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN⩾2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN⩾2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001). CONCLUSIONS In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies.
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27
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Brungs D, Aghmesheh M, de Souza P, Ng W, Chua W, Carolan M, Clingan P, Healey E, Rose J, Tubaro T, Ranson M. Sidedness is prognostic in locoregional colon cancer: an analysis of 9509 Australian patients. BMC Cancer 2017; 17:251. [PMID: 28390415 PMCID: PMC5385038 DOI: 10.1186/s12885-017-3255-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 04/01/2017] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND/AIM Right sided colon cancer (RsCC) is proposed to be a distinct disease entity to left sided colon cancer (LsCC). We seek to confirm primary tumour location as an independent prognostic factor in locoregional colorectal cancer. METHODS All patients with stage I - III primary adenocarcinoma of colon were identified from the New South Wales (NSW) clinical cancer registry (2006-2013). Primary tumour location (RsCC vs LsCC) survival analyses were conducted using the Kaplan-Meier method, and adjusted hazard ratios for 5-year all-cause mortality (OS) and 5-year cancer specific mortality (CSS) were obtained using Cox proportional hazards regression. RESULTS We identified 9509 patients including 5051 patients with RsCC and 4458 with LsCC. Patients with RsCC were more likely to be older, female, have a higher Charlson comorbidity index, and have worse tumour prognostic factors. In univariate analysis of all stages combined, those patients with RsCC had a worse overall survival (OS, HR 1.20 95% CI 1.11-1.29, p < 0.0001), although this was not significant in the multivariate analysis (HR 0.96 95% CI 0.89-1.04, p = 0.35). Stage I patients with RsCC had a trend to improved OS (multivariate HR 0.84 95% CI 0.69-1.01, p = 0.07) and a significantly improved CSS (multivariate HR 0.51 95% CI 0.35-0.75, p = 0.0006). In stage II patients with RsCC there was a significantly improved OS (multivariate HR 0.85 95% CI 0.75-0.98, p = 0.02) and CSS (multivariate HR 0.59 95% CI 0.45-0.78, p = 0.0002) compared to LsCC. In stage III patients, those with RsCC had a worse OS (multivariate HR 1.13 95% CI 1.01-1.26, p = 0.032) and a trend to worse CSS (multivariate HR 1.12 95% CI 0.94-1.33, p = 0.22). CONCLUSIONS Primary tumour location is an important prognostic factor in locoregional colon cancer with an effect that varies by stage. RsCC is associated with lower all-cause mortality in stage II, and higher all-cause mortality in stage III.
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Affiliation(s)
- Daniel Brungs
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia. .,School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. .,Illawarra Cancer Centre, Wollongong Hospital, Wollongong, NSW, Australia. .,CONCERT-Translational Cancer Research Centre, Sydney, NSW, Australia.
| | - Morteza Aghmesheh
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.,Illawarra Cancer Centre, Wollongong Hospital, Wollongong, NSW, Australia.,CONCERT-Translational Cancer Research Centre, Sydney, NSW, Australia
| | - Paul de Souza
- CONCERT-Translational Cancer Research Centre, Sydney, NSW, Australia.,Medical Oncology Department, Liverpool Hospital, Sydney, NSW, Australia.,Ingham Institute for Applied Medical Research, Liverpool Hospital, Sydney, NSW, Australia.,School of Medicine, Western Sydney University, Sydney, NSW, Australia.,South Western Medical School, University of New South Wales, Sydney, NSW, Australia
| | - Weng Ng
- CONCERT-Translational Cancer Research Centre, Sydney, NSW, Australia.,Medical Oncology Department, Liverpool Hospital, Sydney, NSW, Australia.,Ingham Institute for Applied Medical Research, Liverpool Hospital, Sydney, NSW, Australia
| | - Wei Chua
- CONCERT-Translational Cancer Research Centre, Sydney, NSW, Australia.,Medical Oncology Department, Liverpool Hospital, Sydney, NSW, Australia.,Ingham Institute for Applied Medical Research, Liverpool Hospital, Sydney, NSW, Australia
| | - Martin Carolan
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.,Illawarra Cancer Centre, Wollongong Hospital, Wollongong, NSW, Australia.,CONCERT-Translational Cancer Research Centre, Sydney, NSW, Australia
| | - Philip Clingan
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.,Illawarra Cancer Centre, Wollongong Hospital, Wollongong, NSW, Australia
| | - Emma Healey
- Illawarra Cancer Centre, Wollongong Hospital, Wollongong, NSW, Australia
| | - June Rose
- Illawarra Cancer Centre, Wollongong Hospital, Wollongong, NSW, Australia
| | - Tameika Tubaro
- Illawarra Cancer Centre, Wollongong Hospital, Wollongong, NSW, Australia
| | - Marie Ranson
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.,School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.,CONCERT-Translational Cancer Research Centre, Sydney, NSW, Australia
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28
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Moretto R, Cremolini C, Rossini D, Pietrantonio F, Battaglin F, Mennitto A, Bergamo F, Loupakis F, Marmorino F, Berenato R, Marsico VA, Caporale M, Antoniotti C, Masi G, Salvatore L, Borelli B, Fontanini G, Lonardi S, De Braud F, Falcone A. Location of Primary Tumor and Benefit From Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer. Oncologist 2016; 21:988-94. [PMID: 27382031 PMCID: PMC4978565 DOI: 10.1634/theoncologist.2016-0084] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 04/14/2016] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. PATIENTS AND METHODS Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. RESULTS Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p = .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p < .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97; 95% confidence interval: 2.09-7.53; p < .0001). CONCLUSION Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti-EGFRs. IMPLICATIONS FOR PRACTICE Right- and left-sided colorectal tumors have peculiar epidemiological and clinicopathological characteristics, distinct gene expression profiles and genetic alterations, and different prognoses. This study assessed the potential predictive impact of primary tumor site with regard to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment in patients with RAS and BRAF wild-type metastatic colorectal cancer. The results demonstrated the lack of activity of anti-EGFRs in RAS and BRAF wild-type, right-sided tumors, thus suggesting a potential role for primary tumor location in driving treatment choices.
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Affiliation(s)
- Roberto Moretto
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Chiara Cremolini
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Daniele Rossini
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Battaglin
- Unit of Medical Oncology 1, Istituto Oncologico Veneto, Istituti di Ricovero e Cura a Carattere Scientifico, Padua, Italy
| | - Alessia Mennitto
- Medical Oncology Department, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Bergamo
- Unit of Medical Oncology 1, Istituto Oncologico Veneto, Istituti di Ricovero e Cura a Carattere Scientifico, Padua, Italy
| | - Fotios Loupakis
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Federica Marmorino
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Rosa Berenato
- Medical Oncology Department, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
| | - Valentina Angela Marsico
- Unit of Medical Oncology 1, Istituto Oncologico Veneto, Istituti di Ricovero e Cura a Carattere Scientifico, Padua, Italy
| | - Marta Caporale
- Medical Oncology Department, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
| | - Carlotta Antoniotti
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Gianluca Masi
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Lisa Salvatore
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Beatrice Borelli
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
| | - Gabriella Fontanini
- Division of Pathology, Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, Pisa, Italy
| | - Sara Lonardi
- Unit of Medical Oncology 1, Istituto Oncologico Veneto, Istituti di Ricovero e Cura a Carattere Scientifico, Padua, Italy
| | - Filippo De Braud
- Medical Oncology Department, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
| | - Alfredo Falcone
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy
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Zhou Z, Zhang H, Lai J, Diao D, Li W, Dang C, Song Y. Relationships between p14ARF Gene Methylation and Clinicopathological Features of Colorectal Cancer: A Meta-Analysis. PLoS One 2016; 11:e0152050. [PMID: 26999279 PMCID: PMC4801177 DOI: 10.1371/journal.pone.0152050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 03/08/2016] [Indexed: 12/31/2022] Open
Abstract
We conducted a meta-analysis to explore the relationships between p14ARF gene methylation and clinicopathological features of colorectal cancer (CRC). Databases, including Pubmed, Embase and Cochrane Library, were searched and, finally, a total of 18 eligible researches encompassing 1988 CRC patients were selected. Combined odds ratios (ORs) with 95% confidence intervals (95% CIs) were evaluated under a fixed effects model for absence of heterogeneity. Significant associations were observed between p14ARF gene methylation and tumor location (OR = 2.35, 95% CI: 1.55–3.55, P = 0.001), microsatellite instability (MSI) status (OR = 3.28, 95% CI: 2.12–5.07, P<0.0001). However, there were no significant associations between p14ARF gene methylation and tumor stage, tumor differentiation. We concluded that p14ARF gene methylation may be significantly associated with tumor location, and MSI status of CRC.
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Affiliation(s)
- Zhangjian Zhou
- Division of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, 277 W, Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Hao Zhang
- Division of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, 277 W, Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Jianguo Lai
- Division of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, 277 W, Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Dongmei Diao
- Division of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, 277 W, Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Wenhan Li
- Division of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, 277 W, Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Chengxue Dang
- Division of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, 277 W, Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Yongchun Song
- Division of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, 277 W, Yanta Road, Xi'an, 710061, Shaanxi, China
- * E-mail:
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30
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Han C, Shin A, Lee J, Lee J, Park JW, Oh JH, Kim J. Dietary calcium intake and the risk of colorectal cancer: a case control study. BMC Cancer 2015; 15:966. [PMID: 26675033 PMCID: PMC4682267 DOI: 10.1186/s12885-015-1963-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 11/20/2015] [Indexed: 01/31/2023] Open
Abstract
Background High intake of dietary calcium has been thought to be a protective factor against colorectal cancer. To explore the dose-response relationship in the associations between dietary calcium intake and colorectal cancer risk by cancer location, we conducted a case-control study among Korean population, whose dietary calcium intake levels are relatively low. Methods The colorectal cancer cases and controls were recruited from the National Cancer Center in Korea between August 2010 and August 2013. Information on dietary calcium intake was assessed using a semi-quantitative food frequency questionnaire and locations of the colorectal cancers were classified as proximal colon cancer, distal colon cancer, and rectal cancer. Binary and polytomous logistic regression models were used to evaluate the association between dietary calcium intake and risk of colorectal cancer. Results A total of 922 colorectal cancer cases and 2766 controls were included in the final analysis. Compared with the lowest calcium intake quartile, the highest quartile group showed a significantly reduced risk of colorectal cancer in both men and women. (Odds ratio (OR): 0.16, 95 % confidence interval (CI): 0.11–0.24 for men; OR: 0.16, 95 % CI: 0.09–0.29 for women). Among the highest calcium intake groups, decrease in cancer risk was observed across all sub-sites of colorectum in both men and women. Conclusion In conclusion, calcium consumption was inversely related to colorectal cancer risk in Korean population where national average calcium intake level is relatively lower than Western countries. A decreased risk of colorectal cancer by calcium intake was observed in all sub-sites in men and women. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1963-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Changwoo Han
- Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehakro, Jongno-gu, 110-779, Seoul, South Korea
| | - Aesun Shin
- Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehakro, Jongno-gu, 110-779, Seoul, South Korea.
| | - Jeonghee Lee
- Molecular Epidemiology Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, 410-769, Gyeonggi-do, South Korea
| | - Jeeyoo Lee
- Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehakro, Jongno-gu, 110-779, Seoul, South Korea.,Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Republic of Korea
| | - Ji Won Park
- Center for Colorectal Cancer, National Cancer Center, Goyang-si, Republic of Korea.,Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae Hwan Oh
- Center for Colorectal Cancer, National Cancer Center, Goyang-si, Republic of Korea
| | - Jeongseon Kim
- Molecular Epidemiology Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, 410-769, Gyeonggi-do, South Korea.
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Xu KY, Li YC, Wu JP, Gu J. Clinical significance of differential expression of interleukin 8 mRNA in left-sided and right-sided colon cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:4822-4830. [DOI: 10.11569/wcjd.v23.i30.4822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the differential expression of interleukin 8 (IL-8) between left-sided and right-sided colon cancer and to analyze its clinical significance.
METHODS: Eighty patients who received radical resection for stage II or III colon cancer were involved, including 40 patients with left-sided colon cancer (LSCC) and 40 with right-sided colon cancer (RSCC). Paired cancer and normal colon mucosal specimens were collected from each patient. The gene expression of IL-8 was detected by real-time quantitative PCR. Subsequently, the relationship between IL-8 expression and clinicopathological variables as well as prognosis was analyzed.
RESULTS: The mRNA expression of IL-8 in colon cancer was significantly higher than that in normal colon mucosa (P < 0.01). IL-8 expression was significantly higher in RSCC than in LSCC (P = 0.004). High IL-8 expression was closely related with RSCC (65% vs 35%, P = 0.007), bigger tumor size (5.2 cm vs 4.1 cm, P = 0.014) and tumor infiltrating lymphocytes (27.5% vs 10%,P = 0.045). In patients with LSCC, the survival of patients with high IL-8 expression was significantly shorter than that in patients with low IL-8 expression (37.0 mo vs 59.2 mo, P = 0.006). However, among patients with RSCC, patients with high IL-8 expression tended to have a better prognosis than patients with low expression (63.8 mo vs 54.5 mo, P = 0.151). Multivariate analysis demonstrated that T4 infiltration (RR = 6.514, 95%CI: 1.209-35.102, P = 0.029) and lymphatic/vascular invasion (RR = 6.272, 95%CI: 1.352-29.092, P = 0.019) were independent prognostic factors of RSCC, and high IL-8 expression (RR = 3.279, 95%CI: 0.973-11.051, P = 0.045), T4 infiltration (RR = 4.546, 95%CI: 1.335-15.481, P = 0.015), lymph node metastasis (RR = 5.918, 95%CI: 1.439-24.334, P = 0.014) and lymphatic/vascular invasion (RR = 3.663, 95%CI: 1.089-12.320, P = 0.036) were independent prognostic factors of LSCC.
CONCLUSION: The gene expression of IL-8 is significantly different between RSCC and LSCC. High IL-8 expression has a different prognostic impact on RSCC and LSCC. RSCC and LSCC are two potentially heterogeneous groups with differences in molecular and carcinogenic mechanisms.
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Huang CW, Tsai HL, Huang MY, Huang CM, Yeh YS, Ma CJ, Wang JY. Different clinicopathologic features and favorable outcomes of patients with stage III left-sided colon cancer. World J Surg Oncol 2015; 13:257. [PMID: 26311139 PMCID: PMC4551706 DOI: 10.1186/s12957-015-0640-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 07/01/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND We evaluated the clinicopathologic features and outcomes of Taiwanese patients with right-sided versus left-sided colon cancer according to various cancer stages. METHODS A total of 1095 patients with primary colorectal cancer (CRC) undergoing surgery at a single-institution were enrolled. We analyzed patient differences in terms of clinicopathologic features, overall survival (OS) and cancer-specific survival (CSS) of right- versus left-sided colon cancer. RESULTS Right-sided colon cancers were noted in 249 (22.7%) patients, and left-sided colon cancers were noted in 846 (77.3%) patients. Right-sided colon cancers were found to be significantly larger (P = 0.003) and poorly differentiated (P < 0.001), while also exhibiting advanced depth of tumor invasion (P = 0.002) and advanced UICC/AJCC stage (P = 0.016). Patients with right-sided colon cancers had both poorer OS and CSS than those with left-sided colon cancers (P = 0.021 and 0.023, respectively). However, analysis by various stages revealed significant OS and CSS differences (P = 0.002 and 0.002, respectively) between right-sided and left-sided colon cancers only in stage III patients. CONCLUSIONS This study demonstrated poorer OS and CSS in patients with right-sided versus those with left-sided colon cancers, but significant differences were noted only in stage III patients.
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Affiliation(s)
- Ching-Wen Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Hsiang-Lin Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of General Surgery Medicine, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Program of Bachelor of Health Beauty, School of Medical and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
| | - Ming-Yii Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Chun-Ming Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Yung-Sung Yeh
- Division of Trauma, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Cheng-Jen Ma
- Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Jaw-Yuan Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Loupakis F, Yang D, Yau L, Feng S, Cremolini C, Zhang W, Maus MKH, Antoniotti C, Langer C, Scherer SJ, Müller T, Hurwitz HI, Saltz L, Falcone A, Lenz HJ. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst 2015; 107:dju427. [PMID: 25713148 DOI: 10.1093/jnci/dju427] [Citation(s) in RCA: 350] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). METHODS We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. RESULTS Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. CONCLUSIONS These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.
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Affiliation(s)
- Fotios Loupakis
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Dongyun Yang
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Linda Yau
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Shibao Feng
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Chiara Cremolini
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Wu Zhang
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Martin K H Maus
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Carlotta Antoniotti
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Christiane Langer
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Stefan J Scherer
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Thomas Müller
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Herbert I Hurwitz
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Leonard Saltz
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Alfredo Falcone
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM)
| | - Heinz-Josef Lenz
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
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Rawłuszko-Wieczorek AA, Siera A, Horbacka K, Horst N, Krokowicz P, Jagodziński PP. Clinical significance of DNA methylation mRNA levels of TET family members in colorectal cancer. J Cancer Res Clin Oncol 2015; 141:1379-92. [PMID: 25557833 PMCID: PMC4469774 DOI: 10.1007/s00432-014-1901-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/18/2014] [Indexed: 12/13/2022]
Abstract
Purpose
Ten eleven translocation (TET) enzyme activity is essential for active DNA demethylation in biological processes, and their altered expression has been observed in various malignancies. Therefore, we investigated DNA methylation and mRNA levels of all TETs in colorectal cancer (CRC) patients. Methods TET mRNA levels were evaluated using quantitative RT-PCR in primary cancerous and histopathologically unchanged colorectal tissues from patients who underwent radical surgical colon resection (n = 113). DNA methylation levels of the TET CpG island were assessed using bisulfite DNA sequencing and high-resolution melting analysis. Results We found reduced transcript levels of TET1, TET2 and TET3 in cancerous tissue compared with their histopathologically unchanged counterparts (p = 0.000011; p = 0.000001; p = 0.00031, respectively). Importantly, multivariate Cox regression analysis revealed favorable overall survival (OS) and disease-free survival (DFS) outcomes for patients with high TET2 mRNA levels in histopathologically unchanged tissue (HROS = 0.091, 95 % CI 0.011–0.77, p = 0.028; HRDFS = 0.21, 95 % CI 0.04–1.06, p = 0.059). Moreover, we found no DNA methylation in the TET2 and TET3 promoter regions in cancerous and histopathologically unchanged tissue. In contrast, we reported TET1 DNA hypermethylation in a small fraction of patients (n = 12/113). Conclusion To best of our knowledge, our study is the first to investigate TET mRNA levels in a cohort of CRC patients and correlate them with patients’ prognosis. Present study provides the evidence that TET2 mRNA expression may be an independent prognostic factor for disease recurrence and outcome. Additionally, our findings initially indicate the importance of DNA methylation in regulating TET1 expression. Electronic supplementary material The online version of this article (doi:10.1007/s00432-014-1901-2) contains supplementary material, which is available to authorized users.
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Mokarram P, Estiar MA, Ashktorab H. Methylation in Colorectal Cancer. EPIGENETICS TERRITORY AND CANCER 2015:373-455. [DOI: 10.1007/978-94-017-9639-2_13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Maus MKH, Hanna DL, Stephens CL, Astrow SH, Yang D, Grimminger PP, Loupakis F, Hsiang JH, Zeger G, Wakatsuki T, Barzi A, Lenz HJ. Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy. THE PHARMACOGENOMICS JOURNAL 2014; 15:354-62. [PMID: 25532759 PMCID: PMC4478287 DOI: 10.1038/tpj.2014.73] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 09/02/2014] [Accepted: 09/19/2014] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with genetic profiles and clinical outcomes dependent on the anatomic location of the primary tumor. How location impacts the molecular makeup of a tumor and how prognostic and predictive biomarkers differ between proximal versus distal colon cancers is not well established. We investigated the associations between tumor location, KRAS and BRAF mutation status, and the mRNA expression of proteins involved in major signaling pathways, including tumor growth (EGFR), angiogenesis (VEGFR2), DNA repair (ERCC1) and fluoropyrimidine metabolism (TS). FFPE tumor specimens from 431 advanced CRC patients were analyzed. The presence of 7 different KRAS base substitutions and the BRAF V600E mutation was determined. ERCC1, TS, EGFR and VEGFR2 mRNA expression levels were detected by RT-PCR. BRAF mutations were significantly more common in the proximal colon (p<0.001), whereas KRAS mutations occurred at similar frequencies throughout the colorectum. Rectal cancers had significantly higher ERCC1 and VEGFR2 mRNA levels compared to distal and proximal colon tumors (p=0.001), and increased TS levels compared to distal colon cancers (p=0.02). Mutant KRAS status was associated with lower ERCC1, TS, EGFR, and VEGFR2 gene expression in multivariate analysis. In a subgroup analysis, this association remained significant for all genes in the proximal colon and for VEGFR2 expression in rectal cancers. The mRNA expression patterns of predictive and prognostic biomarkers as well as associations with KRAS and BRAF mutation status depend on primary tumor location. Prospective studies are warranted to confirm these findings and determine the underlying mechanisms.
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Affiliation(s)
- M K H Maus
- 1] Department of General, Visceral and Tumor Surgery, University of Cologne, Cologne, Germany [2] Response Genetics, Inc., Los Angeles, CA, USA
| | - D L Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | | | - S H Astrow
- Response Genetics, Inc., Los Angeles, CA, USA
| | - D Yang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - P P Grimminger
- Department of General, Visceral and Tumor Surgery, University of Cologne, Cologne, Germany
| | - F Loupakis
- 1] Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA [2] Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Instituto Toscano, Tumori, Italy
| | - J H Hsiang
- Response Genetics, Inc., Los Angeles, CA, USA
| | - G Zeger
- 1] Response Genetics, Inc., Los Angeles, CA, USA [2] Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - T Wakatsuki
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - A Barzi
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - H-J Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
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Price TJ, Beeke C, Ullah S, Padbury R, Maddern G, Roder D, Townsend AR, Moore J, Roy A, Tomita Y, Karapetis C. Does the primary site of colorectal cancer impact outcomes for patients with metastatic disease? Cancer 2014; 121:830-5. [PMID: 25377235 DOI: 10.1002/cncr.29129] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 09/07/2014] [Accepted: 09/23/2014] [Indexed: 01/11/2023]
Abstract
BACKGROUND Previous reports have described differences in biology and outcome for colorectal cancer based on whether the primary is right or left sided. Further division by right, left, and rectum or even exact primary site has also been explored. Possible differences in response to biological agents have also been reported based on side of primary lesion. METHODS We explored the South Australian registry for metastatic colorectal cancer to assess if there were any differences in patient characteristics, prognostic markers, and treatment received and outcomes based on whether the primary was right or left sided. We also explored if differences exist based on left colon and rectum and by exact primary site. RESULTS Two thousand nine hundred seventy-two patients were analyzed. Thirty-five percent had a right-sided primary. The median overall survival for the entire group right versus left was 9.6 versus 20.3 months (P < .001). Multivariate analysis confirmed side of primary as an independent prognostic factor. For the group that had active therapy, defined as chemotherapy (± metastasis resection), median overall survival was right, 18.2 months; and left, 29.4 months (P < .001). Importantly, we found no suggestion of major differences if left side was divided by left colon and rectum, and trends by individual site still supported a left and right division. CONCLUSIONS Patients with a right-sided primary have more negative prognostic factors and indeed have inferior outcomes compared with those with a left-sided primary. Our data with further breakdown by exact site still favor a simple left-versus-right division moving forward for metastatic colorectal cancer.
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Affiliation(s)
- Timothy J Price
- Department Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Adelaide, South Australia, Australia
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MicroRNAs 146a and 147b biomarkers for colorectal tumor's localization. BIOMED RESEARCH INTERNATIONAL 2014; 2014:584852. [PMID: 24800242 PMCID: PMC3985145 DOI: 10.1155/2014/584852] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 02/11/2014] [Accepted: 02/27/2014] [Indexed: 12/18/2022]
Abstract
The recently identified class of microRNAs (miRs) provided a new insight into cancer research, since abnormalities of members of microRNAs family have been found in various types of cancer. However, the relationship between five miRNAs (miR146a, miR155, miR21, miR135a, and miR147b) and colorectal cancer remains unclear. In the present study, we examined expression of these miRNAs in 25 pair-matched colon cancer tissues and normal colon mucosa. The expression levels of miR146a, miR155, miR21, miR135a, and miR147b were quantified by real-time PCR. We found that miR21, miR146a, and miR135a were all expressed at higher levels in colon tumors. On the other hand, miR146a and miR147b expressions are significantly higher in left colon compared to right colon. These two miRs, especially miR146a, seemed to be markers for the left colon tumors. Moreover, significant proportional and inverse correlations were found between miR expressions in tumor and healthy tissue, and the correlations profiles were different depending on cancer localization. Taken together, these results lead us to suggest the presence of different mechanisms regulating miRs expression and consequently their target genes in left and right colon. So the pathway of colorectal carcinogenesis would be different according to the site of the tumor.
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Lu YJ, Lin PC, Lin CC, Wang HS, Yang SH, Jiang JK, Lan YT, Lin TC, Liang WY, Chen WS, Lin JK, Chang SC. The impact of the lymph node ratio is greater than traditional lymph node status in stage III colorectal cancer patients. World J Surg 2014. [PMID: 23609344 DOI: 10.1007/s00268-0132051-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The prognostic value of nodal status in colorectal cancer (CRC) patients may be influenced by the total number of lymph nodes (LNs) harvested. This study evaluates the impact of LN ratio (LNR) on CRC patients' outcome. METHODS A total of 612 stage III CRC patients who underwent curative-intent surgery between 2004 and 2008 were enrolled. The measured end point was postoperative disease-free survival (DFS) and overall survival (OS). RESULTS The metastatic LN numbers were significantly higher in patients with more than 12 LN harvested (4.6 ± 5.81 vs. 2.7 ± 1.97, P < 0.001). The mean LNR was 22.9 ± 20 % (range = 2-100 %, median = 16.7 %). As the cutoff value of LNR was set above 17 %, the impact of the LNR on 5-year DFS became statistically significant. In univariate analysis, the 5-year DFS and OS for patients with high-LNR tumors was 54.4 and 57.3 %, respectively, significantly lower than those for patients with low-LNR tumors (72.8 and 76.4 %; P < 0.001). In multivariate analysis, the independent factors affecting the 5-year DFS and OS were tumor depth, carcinoembryonic antigen level, and LNR. CONCLUSION The LNR, set at the median value or 17 %, could be an independent prognostic factor for stage III CRC patients.
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Affiliation(s)
- Yen-Jung Lu
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan
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Lu YJ, Lin PC, Lin CC, Wang HS, Yang SH, Jiang JK, Lan YT, Lin TC, Liang WY, Chen WS, Lin JK, Chang SC. The impact of the lymph node ratio is greater than traditional lymph node status in stage III colorectal cancer patients. World J Surg 2014; 37:1927-33. [PMID: 23609344 DOI: 10.1007/s00268-013-2051-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The prognostic value of nodal status in colorectal cancer (CRC) patients may be influenced by the total number of lymph nodes (LNs) harvested. This study evaluates the impact of LN ratio (LNR) on CRC patients' outcome. METHODS A total of 612 stage III CRC patients who underwent curative-intent surgery between 2004 and 2008 were enrolled. The measured end point was postoperative disease-free survival (DFS) and overall survival (OS). RESULTS The metastatic LN numbers were significantly higher in patients with more than 12 LN harvested (4.6 ± 5.81 vs. 2.7 ± 1.97, P < 0.001). The mean LNR was 22.9 ± 20 % (range = 2-100 %, median = 16.7 %). As the cutoff value of LNR was set above 17 %, the impact of the LNR on 5-year DFS became statistically significant. In univariate analysis, the 5-year DFS and OS for patients with high-LNR tumors was 54.4 and 57.3 %, respectively, significantly lower than those for patients with low-LNR tumors (72.8 and 76.4 %; P < 0.001). In multivariate analysis, the independent factors affecting the 5-year DFS and OS were tumor depth, carcinoembryonic antigen level, and LNR. CONCLUSION The LNR, set at the median value or 17 %, could be an independent prognostic factor for stage III CRC patients.
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Affiliation(s)
- Yen-Jung Lu
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan
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Priolli DG, Abrantes AM, Neves S, Gonçalves AC, Lopes CO, Martinez NP, Cardinalli IA, Ribeiro ABS, Botelho MF. Microenvironment influence on human colon adenocarcinoma phenotypes and matrix metalloproteinase-2, p53 and β-catenin tumor expressions from identical monoclonal cell tumor in the orthotopic model in athymic nude rats. Scand J Gastroenterol 2014; 49:309-16. [PMID: 24325610 DOI: 10.3109/00365521.2013.869350] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The present study aims to identify differences between left and right colon adenocarcinoma arising from identical clonal cell and to find out if microenvironment has any influence on matrix metalloproteinase-2 (MMP2), p53 and β-catenin tumor expressions. MATERIAL AND METHODS. Rats (RNU) were submitted to cecostomy to obtain the orthotopic model of right colon tumor (n = 10), while for the left colon model (n = 10), a colon diversion and distal mucous fistula in the descending colon was used. Cultivated human colon adenocarcinoma cells (WiDr) were inoculated in stomas submucosa. Histopathological analysis, real-time reverse transcription-PCR for β-catenin, p53 and MMP2, as well as immunohistochemical analysis for p53 and β-catenin expression were conducted. Central tendency, variance analysis and the Livak delta-delta-CT method were used for statistical analysis, adopting a 5% significance level. RESULTS. All tumors from the left colon exhibited infiltrative ulceration, while in the right colon tumor growth was predominantly exophytic (67%). In the left colon, tumor growth was undifferentiated (100%), while it was moderately differentiated in the right colon (83%). In right colon tumors, MMP2, p53, and β-catenin gene expressions were higher than compared to left colon (p = 4.59354E-05, p = 0.0035179, p = 0.00093798, respectively, for MMP2, p53 and β-catenin). β-catenin and p53 results obtained by real-time polymerase chain reaction were confirmed by immunohistochemistry assay (p = 0.01 and p = 0.001, respectively, for β-catenin and p53). CONCLUSION. Left and right human colon adenocarcinomas developed in animal models have distinct phenotypes even when they have the same clonal origin. Microenvironment has influenced p53, β-catenin, and MMP2 expression in animal models of colon cancer.
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Voorham QJM, Janssen J, Tijssen M, Snellenberg S, Mongera S, van Grieken NCT, Grabsch H, Kliment M, Rembacken BJ, Mulder CJJ, van Engeland M, Meijer GA, Steenbergen RDM, Carvalho B. Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas. BMC Cancer 2013; 13:603. [PMID: 24350795 PMCID: PMC3878219 DOI: 10.1186/1471-2407-13-603] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 12/09/2013] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas. METHODS Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples. RESULTS Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05). CONCLUSIONS Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Beatriz Carvalho
- Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
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Winner M, Mooney SJ, Hershman DL, Feingold DL, Allendorf JD, Wright JD, Neugut AI. Incidence and predictors of bowel obstruction in elderly patients with stage IV colon cancer: a population-based cohort study. JAMA Surg 2013; 148:715-22. [PMID: 23740130 DOI: 10.1001/jamasurg.2013.1] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
IMPORTANCE Research has been limited on the incidence, mechanisms, etiology, and treatment of symptoms that require palliation in patients with terminal cancer. Bowel obstruction (BO) is a common complication of advanced abdominal cancer, including colon cancer, for which small, single-institution studies have suggested an incidence rate of 15% to 29%. Large population-based studies examining the incidence or risk factors associated with BO in cancer are lacking. OBJECTIVE To investigate the incidence and risk factors associated with BO in patients with stage IV colon cancer. DESIGN AND SETTING Retrospective cohort, population-based study of patients in the Surveillance, Epidemiology, and End Results and Medicare claims linked databases who were diagnosed as having stage IV colon cancer from January 1, 1991, through December 31, 2005. PATIENTS Patients 65 years or older with stage IV colon cancer (n = 12 553). MAIN OUTCOMES AND MEASURES Time to BO, defined by inpatient hospitalization for BO. We used Cox proportional hazards regression models to determine associations between BO and patient, prior treatment, and tumor features. RESULTS We identified 1004 patients with stage IV colon cancer subsequently hospitalized with BO (8.0%). In multivariable analysis, proximal tumor site (hazard ratio, 1.22 [95% CI, 1.07-1.40]), high tumor grade (1.34 [1.16-1.55]), mucinous histological type (1.27 [1.08-1.50]), and nodal stage N2 (1.52 [1.26-1.84]) were associated with increased risk of BO, as was the presence of obstruction at cancer diagnosis (1.75 [1.47-2.04]). A more recent diagnosis was associated with decreased risk of subsequent obstruction (hazard ratio, 0.84 [95% CI, 0.72-0.98]). CONCLUSIONS AND RELEVANCE In this large population of patients with stage IV colon cancer, BO after diagnosis was less common (8.0%) than previously reported. Risk was associated with site and histological type of the primary tumor. Future studies will explore management and outcomes in this serious, common complication.
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Affiliation(s)
- Megan Winner
- Department of Surgery, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York4Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
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Massat NJ, Moss SM, Halloran SP, Duffy SW. Screening and Primary prevention of Colorectal Cancer: a Review of sex-specific and site-specific differences. J Med Screen 2013; 20:125-48. [DOI: 10.1177/0969141313501292] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Colorectal cancer (CRC) is the second commonest cancer in England. Incidence rates for colorectal adenomas and advanced colorectal neoplasia are higher in men than in women of all age groups. The male-to-female ratio for CRC incidence rates differs for different parts of the large bowel. Objective To summarize the current evidence on colorectal screening and prevention, focussing on potential differences in benefits between sexes and colorectal sites. Methods (i), We reviewed the evidence from randomized controlled trials (RCTs) of the impact of different screening approaches on CRC incidence and mortality, overall, for each sex separately, and for subsites of the large bowel. (ii) We reviewed studies comparing detection parameters for faecal immunochemical tests for haemoglobin (FIT) with guaiac FOBt (gFOBt). (iii) The role of aspirin in CRC prevention in the general population was reviewed using evidence from RCTs, with specific emphasis on the differences observed between sexes and lesion site. Results (i) Our intention-to-treat random-effects meta-analysis showed that once-only flexible sigmoidoscopy (FS) screening performed on average-risk individuals aged 55 + decreased CRC incidence by 18% and mortality by 28%, but sex-specific results were lacking. (ii) Modern quantitative FIT were superior to qualitative gFOBt in average-risk population screening in their ability to discriminate between individuals with and without colorectal neoplasia. Some recent FIT studies suggest varying operating characteristics in men and women. (iii) Evidence of an effect of aspirin on the incidence of CRC (in particular, proximal disease) in both sexes aged 40 and over at average-risk of CRC is emerging. Conclusions We encourage researchers of CRC screening and prevention to publish their results by sex where possible. Pilot studies should be undertaken before implementation of quantitative FIT in a national screening programme to establish the appropriate threshold. Finally, individual risk assessment for CRC and non-CRC events, will be necessary to make an informed decision on whether a patient should receive aspirin chemoprevention.
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Affiliation(s)
- Nathalie J Massat
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
| | - Sue M Moss
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
| | - Stephen P Halloran
- Royal Surrey County Hospital NHS Foundation Trust and the University of Surrey, Guildford, UK
| | - Stephen W Duffy
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
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Shao YC, Chang YY, Lin JK, Lin CC, Wang HS, Yang SH, Jiang JK, Lan YT, Lin TC, Li AFY, Chen WS, Chang SC. Neoadjuvant chemotherapy can improve outcome of colorectal cancer patients with unresectable metastasis. Int J Colorectal Dis 2013; 28:1359-65. [PMID: 23695387 DOI: 10.1007/s00384-013-1713-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/08/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND The prognosis for colorectal cancer (CRC) patients with unresectable metastases is dismal. This study compared outcomes of different metastatic treatments. PATIENTS AND METHODS We collected 653 CRC cases with unresectable metastases including 490 cases receiving primary tumor resection then chemotherapy (surgery group) and 163 patients receiving neoadjuvant chemotherapy then did or did not receive operations (chemotherapy (C/T) group) from 2004 to 2010. The statistical endpoint was overall survival from the date of diagnosis. RESULTS In the C/T group, 124 (76%) patients received an operation after 9.0 ± 6.2 months of chemotherapy, including 57 (34.9%) patients with curative surgery. The C/T group had a higher proportion of T4 lesions (37.4%) than the surgery group (26.9%). Survival of the C/T group was longer than that of the surgery group (28.8 ± 8.8 vs. 24.3 ± 7.5 months; p = 0.043). Survival of 57 patients receiving curative surgery was 36.0 ± 6.3 months, which was significantly better than that of the 67 patients receiving palliative resection (25.2 ± 5.6, p < 0.001). In the surgery group, 42 (8.6%) patients received curative metastasectomy after 8.5 ± 7.1 months of postoperative chemotherapy; survival was 30.8 ± 7.8 months, which was significantly better than that of patients who did not receive metastasectomy (22.4 ± 6.3 months). In multivariate analysis, poor differentiation, lymphovascular invasion, isolated cancer nodules, clinical risk score, and curative surgery were independent prognostic factors of overall patient survival. CONCLUSIONS Neoadjuvant chemotherapy can improve outcome of CRC patients with unresectable metastases.
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Affiliation(s)
- Yen-Chen Shao
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan
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Fang YJ, Wu XJ, Zhao Q, Li LR, Lu ZH, Ding PR, Zhang RX, Kong LH, Wang FL, Lin JZ, Chen G, Pan ZZ, Wan DS. Hospital-based colorectal cancer survival trend of different tumor locations from 1960s to 2000s. PLoS One 2013; 8:e73528. [PMID: 24069202 PMCID: PMC3772028 DOI: 10.1371/journal.pone.0073528] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 07/22/2013] [Indexed: 01/01/2023] Open
Abstract
Background Our aim is to explore the trend of association between the survival rates of colorectal cancer (CRC) and the different clinical characteristics in patients registered from 1960s to 2000s. We hypothesized that the survival rate of CRC increases over time and varies according to anatomic subsites. Methods Information from a total of 4558 stage T(1-4)N(1-2)M0 CRC patients registered from 1960s to 2008 were analyzed. The association of CRC overall survival with age, gender, tumor locations, time, histopathology types, pathology grades, no. of examined lymph nodes, the T stage, and the N stage was analyzed. The assessment of the influence of prognostic factors on patient survival was performed using Cox’s proportional hazard regression models. Results From 1960 to 2008, the studied CRC patients included 2625 (57.6%) and 1933 (42.4%) males and females, respectively. These included 1896 (41.6%) colon cancers, and 2662 (58.4%) rectum cancers. The 5-year survival rate was 49%, 58%, 58%, 70%, and 77% for the time duration of 1960s, 1970s, 1980s, 1990s and 2000s, respectively. An increased 5-year survival rate was observed in the colon cancer and rectum cancer patients. Patients older than 60 years of age were more likely to develop colonic cancer (sigmoid) than rectum cancer (49.2% vs. 39.9%). The Cox regression model showed that only rectum cancer survival was related to time duration. Conclusion The overall survival and 5-year survival rates showed an increase from the 1960s to 2000s. There is a trend of rightward shift of tumor location in CRC patients.
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Affiliation(s)
- Yu-Jing Fang
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China ; Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
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Li L, Fu X, Zhang W, Xiao L, Qiu Y, Peng Y, Shi L, Chen X, Zhou X, Deng M. Wnt signaling pathway is activated in right colon serrated polyps correlating to specific molecular form of β-catenin. Hum Pathol 2013; 44:1079-88. [DOI: 10.1016/j.humpath.2012.09.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2012] [Revised: 09/12/2012] [Accepted: 09/14/2012] [Indexed: 12/31/2022]
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Yuan Y, Li MD, Hu HG, Dong CX, Chen JQ, Li XF, Li JJ, Shen H. Prognostic and survival analysis of 837 Chinese colorectal cancer patients. World J Gastroenterol 2013; 19:2650-2659. [PMID: 23674872 PMCID: PMC3645383 DOI: 10.3748/wjg.v19.i17.2650] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 11/27/2012] [Accepted: 03/07/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a prognostic model to predict survival of patients with colorectal cancer (CRC).
METHODS: Survival data of 837 CRC patients undergoing surgery between 1996 and 2006 were collected and analyzed by univariate analysis and Cox proportional hazard regression model to reveal the prognostic factors for CRC. All data were recorded using a standard data form and analyzed using SPSS version 18.0 (SPSS, Chicago, IL, United States). Survival curves were calculated by the Kaplan-Meier method. The log rank test was used to assess differences in survival. Univariate hazard ratios and significant and independent predictors of disease-specific survival and were identified by Cox proportional hazard analysis. The stepwise procedure was set to a threshold of 0.05. Statistical significance was defined as P < 0.05.
RESULTS: The survival rate was 74% at 3 years and 68% at 5 years. The results of univariate analysis suggested age, preoperative obstruction, serum carcinoembryonic antigen level at diagnosis, status of resection, tumor size, histological grade, pathological type, lymphovascular invasion, invasion of adjacent organs, and tumor node metastasis (TNM) staging were positive prognostic factors (P < 0.05). Lymph node ratio (LNR) was also a strong prognostic factor in stage III CRC (P < 0.0001). We divided 341 stage III patients into three groups according to LNR values (LNR1, LNR ≤ 0.33, n = 211; LNR2, LNR 0.34-0.66, n = 76; and LNR3, LNR ≥ 0.67, n = 54). Univariate analysis showed a significant statistical difference in 3-year survival among these groups: LNR1, 73%; LNR2, 55%; and LNR3, 42% (P < 0.0001). The multivariate analysis results showed that histological grade, depth of bowel wall invasion, and number of metastatic lymph nodes were the most important prognostic factors for CRC if we did not consider the interaction of the TNM staging system (P < 0.05). When the TNM staging was taken into account, histological grade lost its statistical significance, while the specific TNM staging system showed a statistically significant difference (P < 0.0001).
CONCLUSION: The overall survival of CRC patients has improved between 1996 and 2006. LNR is a powerful factor for estimating the survival of stage III CRC patients.
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Clapin HF, Fritschi L, Iacopetta B, Heyworth JS. Dietary and supplemental folate and the risk of left- and right-sided colorectal cancer. Nutr Cancer 2012; 64:937-45. [PMID: 23035886 DOI: 10.1080/01635581.2012.715718] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Epidemiological evidence suggests that folate may lower the risk of colorectal cancer (CRC) although studies have been inconsistent and some have indicated differences in the effects of naturally occurring dietary folate and the synthetic form of this vitamin, folic acid. Most studies to date have considered CRC as a single disease; however, cancers that develop on the left and right sides of the colorectum display important phenotypic differences, suggesting they may also have different risk factors. A population-based case-control study was conducted in Western Australia to examine the relationship between intake of both natural dietary folate and supplements containing folic acid and the risk of left- and right-sided CRC. Data were available for 850 cases (575 left-sided and 275 right-sided) and 958 controls. Odds ratios were calculated using multinomial logistic regression models. There was no association between natural dietary folate intake and risk of either left-or right-sided CRC. Supplement use similarly had no significant effect on right-sided CRC. However, long-term supplement users (4+ yr) were at lower risk of left-sided CRC than those who had not taken supplements (OR = 0.65, 95% CI, 0.50-0.86) and there was a significant trend in risk reduction as duration of use increased (P < 0.01).
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Affiliation(s)
- Helen F Clapin
- School of Population Health, The University of Western Australia, Crawley, Australia
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Lin PC, Lin JK, Lin CC, Wang HS, Yang SH, Jiang JK, Lan YT, Lin TC, Li AFY, Chen WS, Chang SC. Carbohydrate antigen 19-9 is a valuable prognostic factor in colorectal cancer patients with normal levels of carcinoembryonic antigen and may help predict lung metastasis. Int J Colorectal Dis 2012; 27:1333-8. [PMID: 22426691 DOI: 10.1007/s00384-012-1447-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/29/2012] [Indexed: 02/04/2023]
Abstract
PURPOSE We retrospectively analyzed preoperative levels of carbohydrate antigen (CA) 19-9 in colorectal cancer (CRC) patients to determine the prognostic value of CA19-9 in CRC patients with normal carcinoembryonic antigen (CEA) levels. METHODS A total of 639 patients who underwent curative surgery at Taipei Veterans General Hospital between 2002 and 2006 were enrolled. We excluded 254 patients (39.7 %) with high preoperative CEA levels and analyzed 385 patients with normal CEA levels. The measured endpoint was the postoperative disease-free survival (DFS). The prognostic value of CA19-9 was determined using log-rank test and Cox regression analysis. RESULTS High CA19-9 levels were significantly associated with advanced disease and were detected in 5.8 % of patients with stage I disease, 11.7 % of those with stage II disease, and 22.5 % of those with stage III disease (P < 0.001). The 5-year DFS in patients with normal CA19-9 levels was 82.0 %, which was significantly higher than that in patients with high CA19-9 levels (68 %; P < 0.001). In a multivariate analysis, the most important independent factor affecting the 5-year DFS was tumor-node-metastasis stage (95 % CI, 1.26-2.36; HR = 1.72). After stratification by other factors, high CA19-9 level remained an independent prognostic factor for patients with normal CEA levels. Patients with high CA19-9 levels also showed a higher incidence of lung metastasis (23.1 %) than those with normal CA19-9 levels (7.2 %). CONCLUSIONS CA19-9 may be a prognostic factor for CRC patients with normal CEA levels. An aggressive follow-up protocol for lung metastasis should be used for these patients.
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Affiliation(s)
- Pei-Ching Lin
- Department of Clinical Pathology, Yang-Ming Campus, Taipei City Hospital, Taipei, Taiwan
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