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Chen X, Heisser T, Cardoso R, Hoffmeister M, Brenner H. Personalized Initial Screening Age for Colorectal Cancer in Individuals at Average Risk. JAMA Netw Open 2023; 6:e2339670. [PMID: 37878311 PMCID: PMC10600582 DOI: 10.1001/jamanetworkopen.2023.39670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 09/12/2023] [Indexed: 10/26/2023] Open
Abstract
Importance Colorectal cancer (CRC) risk varies widely in the population at average risk without a family history, but there are no established routines for translating this variation into personalized starting ages of screening. Objective To illustrate derivation of risk-adapted starting ages of CRC screening based on the concept of risk advancement period (RAP) using sex and a polygenic risk score (PRS) as an example. Design, Setting, and Participants This cohort study included participants in the UK Biobank study recruited in England, Wales, and Scotland between March 13, 2006, and October 1, 2010. Participants were aged 40 to 69 years, with no previous bowel cancer screening and no family history of CRC. Follow-up of cancer data was completed February 29, 2020, for England and Wales and January 31, 2021, for Scotland. The censoring date for death data was September 30, 2021, for England and Wales and October 31, 2021, for Scotland. Exposures Data on age, sex, and family history were collected at the baseline interview. A PRS was calculated based on 139 CRC-related risk loci. Main Outcomes and Measures Hazard ratios (HRs) of sex and PRS with CRC risk and mortality were estimated using Cox proportional hazards regression models and were translated to RAPs to quantify how many years of age earlier or later men and individuals in higher or lower PRS deciles would reach risks comparable with those of the reference group (ie, women or those in the 5th and 6th PRS deciles). Results Among 242 779 participants (median age, 55 [IQR, 48-61] years; 55.7% women), 2714 incident CRC cases were identified during a median follow-up of 11.2 (IQR, 10.5-11.8) years and 758 deaths during a median follow-up of 12.8 (IQR, 12.0-13.4) years. The HRs of CRC risk were 1.57 (95% CI, 1.46-1.70) for men vs women and ranged from 0.51 (95% CI, 0.41-0.62) to 2.29 (95% CI, 2.01-2.62) across PRS deciles compared with the reference. The RAPs were 5.6 (95% CI, 4.6-6.6) years for men vs women and ranged from -8.4 (95% CI, -11.0 to -5.9) to 10.3 (95% CI, 8.5-12.1) years across PRS deciles compared with the reference deciles. Risk-adapted starting ages of screening would vary by 24 years between men in the highest PRS decile and women in the lowest PRS decile. Similar results were obtained regarding CRC mortality. Conclusions and Relevance In this large cohort study including women and men at average risk of CRC, risk-adapted starting ages of screening strongly varied by sex and a PRS. The RAP concept could easily accommodate additional factors for defining personalized starting ages of screening.
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Affiliation(s)
- Xuechen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Thomas Heisser
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Rafael Cardoso
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany
- German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany
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Prognostic impact of the number of resected lymph node on survival in Colorectal Cancer. JOURNAL OF COLOPROCTOLOGY 2021. [DOI: 10.1016/j.jcol.2016.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Abstract
Introduction Colorectal Cancer (CRC) is the third most common cancer and the second leading cause of death in Western countries. In Portugal, in the North, emerges as the second most common cancer. The presence of lymph node metastasis is an important predictor of overall and disease-free survival and several studies recommend the evaluation of at least 12–14 regional lymph nodes, as it contributes to improve cancer staging and patient outcomes.
Aims Epidemiological characterization of the studied population and identify a possible relationship between the number of lymph nodes evaluated in the surgical specimen and survival.
Methods We preceded to the study of 1065 CCR patients, submitted to surgical resection between 1 January 2000 and 31 August 2012, in Braga Hospital.
Discussion/Conclusion The results of the epidemiological characterization of this population are coincident with those described in the literature. It was observed a significant correlation between age, tumor size, serosal invasion, differentiation, tumor penetration, venous and lymphatic invasion, metastasis, TNM stage and the number of lymph nodes evaluated. However, we did not observe a statistically significant correlation between patient survival and number of lymph nodes evaluated (p > 0.05). A possible explanation is the practice of oncologists, addressing patients with less than 12 nodes identified in the surgical specimen as “N-positive” and undergoing adjuvant therapy. A better harvest and careful analysis of lymph nodes would lead to more accurate staging, avoiding overtreatment and side effects associated, and allow better economic management of hospital resources, in real N0 patients.
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Tian Y, Kharazmi E, Brenner H, Xu X, Sundquist K, Sundquist J, Fallah M. Calculating the Starting Age for Screening in Relatives of Patients With Colorectal Cancer Based on Data From Large Nationwide Data Sets. Gastroenterology 2020; 159:159-168.e3. [PMID: 32251666 DOI: 10.1053/j.gastro.2020.03.063] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 02/17/2020] [Accepted: 03/24/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Although colorectal cancer (CRC) screening guidelines acknowledge the need for earlier screening for high-risk individuals, such as those with family history of CRC, there is limited information on how many years earlier these high-risk individuals should be screened; current practice is based on weak evidence. We aimed to provide risk-adapted recommendations on the starting age of CRC screening for individuals with different family histories. METHODS We collected data from nationwide family-cancer data sets in Sweden and calculated risk-adapted starting ages of screening for individuals with different family histories of CRC. Family history was defined as a dynamic (time-dependent) variable, allowing for changes during the follow-up period of 1958 through 2015. RESULTS During a follow-up of 12,829,251 individuals with genealogy information, 173,796 developed CRC. The 10-year cumulative risk for the average-risk population at age 50 years (the guideline-recommended age for screening) was 0.44%. Individuals with different family histories of CRC attained this equivalent 0.44% risk 3-29 years earlier than their peers in the general population without such a family history. For example, individuals with 1 affected first-degree relative diagnosed before age 45 years reached the corresponding risk level 16 years earlier. CONCLUSIONS We determined risk-adapted starting ages of CRC screening for close or distant relatives of patients with CRC, using high quality nationwide data sets. These findings might be used in counselling individuals about the appropriate age to start CRC screening, to optimize screening practice, and to supplement guidelines for CRC screening.
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Affiliation(s)
- Yu Tian
- Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany; Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Elham Kharazmi
- Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany; Center for Primary Health Care Research, Lund University, Malmö, Sweden.
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany
| | - Xing Xu
- Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany; Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden; Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Community-Based Healthcare Research and Education, Department of Functional Pathology, School of Medicine, Shimane University, Japan
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden; Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Community-Based Healthcare Research and Education, Department of Functional Pathology, School of Medicine, Shimane University, Japan
| | - Mahdi Fallah
- Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany; Center for Primary Health Care Research, Lund University, Malmö, Sweden.
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Martins SF, Mariano V, Rodrigues M, Longatto-Filho A. Human papillomavirus (HPV) 16 infection is not detected in rectal carcinoma. Infect Agent Cancer 2020; 15:17. [PMID: 32165915 PMCID: PMC7059378 DOI: 10.1186/s13027-020-00281-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/19/2020] [Indexed: 12/18/2022] Open
Abstract
Introduction Persistence of human papillomavirus (HPV) infections is associated with squamous cell carcinomas of different human anatomic sites. Several studies have suggested a potential role for HPV infection, particularly HPV16 genotype, in rectal cancer carcinogenesis.. The aim of this study was to assess the frequency of oncogenic HPV 16 viral DNA sequences in rectal carcinomas cases retrieved from the pathology archive of Braga Hospital, North Portuga. Methods TaqMan-based type-specific real-time PCR for HPV 16 was performed using primers and probe targeting HPV16 E7 region. Results Most of the rectal cancer patients (88.5%, n = 206 patients), were symptomatic at diagnosis. The majority of the lesions (55.3%, n = 129) presented malignancies of polypoid/vegetant phenotype. 26.8% (n = 63) had synchronic metastasis at diagnosis. 26.2% (n = 61) patients had clinical indication for neoadjuvant therapy. Most patients with rectal cancer were stage IV (19.7% patients), followed by stage IIA (19.3%) and stage I (18.5%). All cases of the present series tested negative for HPV16. Conclusion The total of negative tests for HPV 16 infection is a robust argument to support the assumption that HPV 16 infection, despite of previous evidences, is not involved in rectal cancer carcinogenesis and progression.
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Affiliation(s)
- Sandra F Martins
- 1Life and Health Science Research Institute (ICVS), School of Health Sciences, School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Braga, Portugal.,Coloproctology Unit, Braga Hospital, Braga, Portugal
| | - Vânia Mariano
- Molecular Oncology Research Center, Barretos, São Paulo, Brazil
| | | | - Adhemar Longatto-Filho
- 1Life and Health Science Research Institute (ICVS), School of Health Sciences, School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Braga, Portugal.,Molecular Oncology Research Center, Barretos, São Paulo, Brazil.,5Laboratory of Medical Investigation (LIM) 14, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil
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Paciej-Gołębiowska P, Pikala M, Maniecka-Bryła I. Years of life lost due to malignant neoplasms of the digestive system in Poland in the years 2000-2014. United European Gastroenterol J 2018; 6:943-951. [PMID: 30023073 DOI: 10.1177/2050640618764714] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 02/17/2018] [Indexed: 12/29/2022] Open
Abstract
Background Every fourth death that occurs in Poland is caused by a malignant neoplasm. A particularly negative epidemiological situation relates to colorectal cancers; in 2015 they constituted the fifth most important cause of years of life lost (YLL) in Poland. Objective We aimed to analyse YLL due to malignant neoplasms of the digestive system in Poland in between 2000 and 2014. Methods The study material included a database containing information gathered from 5,601,568 death certificates of Poles who died in 2000-2014. YLLs were calculated with the use of the standard expected years of life lost index (SEYLL). Results In the 15-year study period, malignant neoplasms of the digestive system contributed to 213,041 deaths in males and 177,644 deaths in females, which corresponded to a loss of 158.6 years per 10,000 men and 105.3 years per 10,000 women. Neoplasms of the large intestine (23.6%), stomach (22.0%) and pancreas (17.4%) contributed the most. A time trend analysis revealed (p < 0.05) a growing tendency of YLLs due to neoplasms of the large intestine and pancreas, and a decreasing trend due to neoplasms of the stomach. Conclusion Malignant neoplasms of the digestive system, especially of the large intestine, are becoming a more common cause of premature mortality in Poland.
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Affiliation(s)
| | - Małgorzata Pikala
- Department of Epidemiology and Biostatistics, Medical University of Lodz, Łódź, Poland
| | - Irena Maniecka-Bryła
- Department of Epidemiology and Biostatistics, Medical University of Lodz, Łódź, Poland
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Altobelli E, D’Aloisio F, Angeletti PM. Colorectal cancer screening in countries of European Council outside of the EU-28. World J Gastroenterol 2016; 22:4946-57. [PMID: 27239121 PMCID: PMC4873887 DOI: 10.3748/wjg.v22.i20.4946] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 04/13/2016] [Accepted: 05/04/2016] [Indexed: 02/07/2023] Open
Abstract
AIM To provide an update on colorectal cancer (CRC) screening programmes in non-European Union (EU)-28 Council of Europe member states as of December 2015. METHODS The mission of the Council of Europe is to protect and promote human rights in its 47 member countries. Its 19 non-EU member states are Albania, Andorra, Armenia, Azerbaijan, Bosnia and Herzegovina, Republika Srpska, Georgia, Iceland, Liechtenstein, Republic of Moldova, Monaco, Montenegro, Norway, Russian Federation, San Marino, Serbia, Switzerland, FYR of Macedonia, Turkey, and Ukraine (EU-19). The main data source were GLOBOCAN, IARC, WHO, EUCAN, NORDCAN, ENCR, volume X of the CI5, the ministerial and Public Health Agency websites of the individual countries, PubMed, EMBASE, registries of some websites and the www.cochranelibrary.com, Scopus, www.clinicaltrials.gov, www.clinicaltrialsregister.eu, Research gate, Google and data extracted from screening programme results. RESULTS Our results show that epidemiological data quality varies broadly between EU-28 and EU-19 countries. In terms of incidence, only 30% of EU-19 countries rank high in data quality as opposed to 86% of EU-28 states. The same applies to mortality data, since 52% of EU-19 countries as against all EU-28 countries are found in the high ranks. Assessment of the method of collection of incidence data showed that only 32% of EU-19 countries are found in the top three quality classes as against 89% of EU-28 countries. For the mortality data, 63% of EU-19 countries are found in the highest ranks as opposed to all EU-28 member states. Interestingly, comparison of neighbouring countries offering regional screening shows, for instance, that incidence and mortality rates are respectively 38.9 and 13.0 in Norway and 29.2 and 10.9 in Sweden, whereas in Finland, where a national organised programme is available, they are respectively 23.5 and 9.3. CONCLUSION Cancer screening should be viewed as a key health care tool, also because investing in screening protects the weakest in the population, decreases the social burden of cancer, and reduces all types of health care costs, including those for radical surgery, long-term hospitalisation, and chemotherapy.
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Ki-67 Expression in CRC Lymph Node Metastasis Does Not Predict Survival. BIOMED RESEARCH INTERNATIONAL 2015; 2015:131685. [PMID: 26448927 PMCID: PMC4584044 DOI: 10.1155/2015/131685] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 02/02/2015] [Indexed: 01/15/2023]
Abstract
Colorectal cancer is one of the most common malignancies and a leading cause of cancer death worldwide. Molecular markers may improve clinicopathologic staging and provide a basis to guide novel therapeutic strategies which target specific tumour-associated molecules according to individual tumour biology; however, so far, no ideal molecular marker has been found to predict disease progression. We tested Ki-67 proliferation marker in primary and lymph node metastasis of CRC. We observed a statistical significant difference between the positive rates of neoplastic cells positively stained by Ki-67 in both sites, with remarkable increased number of Ki-67 positive cells in primary tumor cells compared to cancer cells that invaded lymph nodes. We can speculate that the metastatic CRC in lymph node can be more resistant to the drugs that target cellular division.
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Prostate-specific membrane antigen (PSMA) immunoexpression in the neovasculature of colorectal carcinoma in Egyptian patients. Pathol Res Pract 2014; 210:759-63. [PMID: 24951241 DOI: 10.1016/j.prp.2014.05.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 04/07/2014] [Accepted: 05/16/2014] [Indexed: 12/25/2022]
Abstract
In Egypt colorectal carcinoma (CRC) is the most common type of malignancy of the digestive system. Selectively inhibiting neoangiogenesis by targeting tumor-associated blood vessels is an important therapeutic strategy. Prostate specific membrane antigen (PSMA) is expressed in the tumor-associated neovasculature of most solid cancers making it an interesting therapeutic target. We thought to study the expression of PSMA in a series of CRCs in order to test for its possible use as a target for antiangiogenic cancer therapy in Egyptian patients. One hundred CRC cases were retrieved. Representative sections from each tumor were subjected to immunohistochemistry using PSMA antibodies and CD31 antibodies as reference marker. Accordingly vascular endothelial cell immunoreactivity was semiquantitatively scored. PSMA immunostaining was positive in the neovasculature of 75% of tumors. A statistically significant relation was found between PSMA immunostaining and distant metastasis as well as vascular invasion. The present findings strengthen the evidence on the potential usefulness of PSMA as a therapeutic vascular target. This study is the first to demonstrate a positive relation between PSMA expression in CRC and distant metastasis as well vascular invasion, suggesting that PSMA may play a significant role in vascular invasion and subsequent metastasis.
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Altobelli E, Lattanzi A, Paduano R, Varassi G, di Orio F. Colorectal cancer prevention in Europe: burden of disease and status of screening programs. Prev Med 2014; 62:132-41. [PMID: 24530610 DOI: 10.1016/j.ypmed.2014.02.010] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 12/26/2013] [Accepted: 02/02/2014] [Indexed: 12/12/2022]
Abstract
Colorectal cancer is a major public health challenge worldwide. In Europe it is the first malignancy in terms of incidence and the second in terms of mortality in both genders. Despite evidence indicating that removal of premalignant and early-stage cancer lesion scan greatly reduce mortality, remarkable differences are still found among countries both in terms of organized screening programs and of the tests used. In 2003 the European Council recommended that priority be given to activation of organized cancer screening programs, and various states have been making significant efforts to adopt effective prevention programs with international quality standards and centralizing screening organization and result evaluation. After a 2008 European Union report on the state of screening program, activation highlighted that little more than 50% (12/22) of Member States had colorectal cancer screening programs, Screening programs have been adopted or earlier pilot projects have been extended nationwide. This paper examines the state of activation and the screening strategies of colorectal cancer screening programs in EU States as of July 2013.
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Affiliation(s)
- E Altobelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy; Epidemiologic and Social Marketing Unit, AUSL 4 Teramo, Italy.
| | - A Lattanzi
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
| | - R Paduano
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
| | | | - F di Orio
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
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Weng YR, Kong X, Yu YN, Wang YC, Hong J, Zhao SL, Fang JY. The role of ERK2 in colorectal carcinogenesis is partly regulated by TRAPPC4. Mol Carcinog 2013; 53 Suppl 1:E72-84. [DOI: 10.1002/mc.22031] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 03/03/2013] [Accepted: 03/12/2013] [Indexed: 11/08/2022]
Affiliation(s)
- Yu-Rong Weng
- Division of Gastroenterology and Hepatology; Renji Hospital,Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes; Shanghai China
| | - Xuan Kong
- Division of Gastroenterology and Hepatology; Renji Hospital,Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes; Shanghai China
| | - Ya-Nan Yu
- Division of Gastroenterology and Hepatology; Renji Hospital,Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes; Shanghai China
| | - Ying-Chao Wang
- Division of Gastroenterology and Hepatology; Renji Hospital,Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes; Shanghai China
| | - Jie Hong
- Division of Gastroenterology and Hepatology; Renji Hospital,Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes; Shanghai China
| | - Shu-Liang Zhao
- Division of Gastroenterology and Hepatology; Renji Hospital,Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes; Shanghai China
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology; Renji Hospital,Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes; Shanghai China
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Sousa WATD, Rodrigues LV, Silva RGD, Vieira FL. Immunohistochemical evaluation of p53 and Ki-67 proteins in colorectal adenomas. ARQUIVOS DE GASTROENTEROLOGIA 2012; 49:35-40. [PMID: 22481684 DOI: 10.1590/s0004-28032012000100007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 08/23/2011] [Indexed: 11/22/2022]
Abstract
CONTEXT The appearance of adenomas and their progression to adenocarcinomas is the result of an accumulation of genetic changes in cells of the intestinal mucosa inherited or acquired during life. Several proteins have been studied in relation to the development and progression of colorectal cancer, including tumor protein p53 (p53) and antigen identified by monoclonal antibody Ki-67 (Ki-67). OBJECTIVE To evaluate the expression of p53 and Ki-67 in colorectal adenomas and correlate the observed levels with clinical and pathologic findings. METHOD The sample consisted of 50 adenomatous polyps from patients undergoing colonoscopy. After performing polypectomy, polyps were preserved in a formalin solution with 10% (vol./vol.) phosphate buffer, submitted for routine preparation of sections and slides and stained with hematoxylin and eosin. For each adenoma we then performed immunohistochemistry to detect specific p53 and Ki-67 proteins using a streptavidin-biotin-peroxidase enzyme immunoassay. RESULTS p53 was detected in 18% of the adenomas. The average Ki-67 protein index (i.Ki-67) was 0.49. A statistically significant difference was observed in p53 (P = 0.0003) and Ki-67 (P = 0.02) expression between adenomas with low- and high-grade dysplasia, particularly for p53. The expression of Ki-67 was greater in rectal adenomas than in colic adenomas (P = 0.02). No relationship was found between the expression of the two proteins in the sample. CONCLUSION The p53 protein is expressed in a proportion of adenomas, while the Ki-67 protein was expressed in all adenomas. The expression of p53 was higher in adenomas with high-grade dysplasia. The expression of Ki-67 was higher in rectal adenomas and in adenomas with high-grade dysplasia.
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Martins SF, Reis RM, Rodrigues AM, Baltazar F, Filho AL. Role of endoglin and VEGF family expression in colorectal cancer prognosis and anti-angiogenic therapies. World J Clin Oncol 2011; 2:272-80. [PMID: 21773077 PMCID: PMC3139037 DOI: 10.5306/wjco.v2.i6.272] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 03/02/2011] [Accepted: 04/05/2011] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the cancer models and most of the carcinogenic steps are presently well understood. Therefore, successful preventive measures are currently used in medical practice. However, CRC is still an important public health problem as it is the third most common cancer and the fourth most frequent cause of cancer death worldwide. Nowadays, pathologic stage is a unique and well-recognized prognostic indicator, however, more accurate indicators of the biologic behavior of CRC are expected to improve the specificity of medical treatment. Angiogenesis plays an important role in the growth and progression of cancer but its role as a prognostic factor is still controversial. Probably the most important clinical implication of tumor angiogenesis is the development of anti-angiogenic therapy. The goal of this review is to critically evaluate the role of angiogenic markers, assessed by either endoglin-related microvessel density or expression of vascular endothelial growth factor family members in the CRC setting and discuss the role of these angiogenic markers in anti-angiogenic therapies.
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Affiliation(s)
- Sandra F Martins
- Sandra F Martins, Rui M Reis, Fátima Baltazar, Adhemar Longatto Filho, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Portugal - Campos of Gualtar - 4710-057 Braga, Portugal
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AROME. Guidelines, minimal requirements and standard of cancer care around the Mediterranean Area: Report from the Collaborative AROME (Association of Radiotherapy and Oncology of the Mediterranean Area) working parties. Crit Rev Oncol Hematol 2011; 78:1-16. [DOI: 10.1016/j.critrevonc.2010.03.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Revised: 03/11/2010] [Accepted: 03/24/2010] [Indexed: 11/30/2022] Open
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Cammarota R, Bertolini V, Pennesi G, Bucci EO, Gottardi O, Garlanda C, Laghi L, Barberis MC, Sessa F, Noonan DM, Albini A. The tumor microenvironment of colorectal cancer: stromal TLR-4 expression as a potential prognostic marker. J Transl Med 2010; 8:112. [PMID: 21059221 PMCID: PMC2997091 DOI: 10.1186/1479-5876-8-112] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 11/08/2010] [Indexed: 12/16/2022] Open
Abstract
Background Colorectal cancer can be efficiently treated when found at early stages, thus the search for novel markers is of paramount importance. Since inflammation is associated with cancer progression and angiogenesis, we investigated expression of cytokines like IL-6 and other mediators that play a key role in the innate immune system, in particular toll like receptor 4 (TLR4), in the microenvironment of lesions from different stages of colon disease progression, from ulcerative colitis to adenoma and adenocarcinoma to find useful markers. Methods The presence of inflammatory cells and expression of key cytokines involved in the inflammation process were quantified by immunohistochemistry in specific tissue compartments (epithelial, stromal, endothelial) by immunohistochemistry. A murine azoxymethane/dextran sulfate model in which Tir8, a negative regulator of the inflammatory response, was ablated was used to confirm the clinical observations. 116 Archival tissue samples from patients with different stages of colorectal disease: 13 cases of ulcerative colitis (UC), 34 tubular or tubulo-villous adenomas (AD), and 53 infiltrating adenocarcinomas. 16 specimens of healthy mucosa surgically removed with the cancerous tissue were used as a control. Results The differences between healthy tissues and the diverse lesions was characterized by a marked inflammatory-angiogenic reaction, with significantly (P < 0.05) higher numbers of CD68, CD15, and CD31 expressing cells in all diseased tissues that correlated with increasing grade of malignancy. We noted down-regulation of a potential modulator molecule, Hepatocyte Growth Factor, in all diseased tissues (P < 0.05). TLR-4 and IL6 expression in the tumor microenvironment were associated with adenocarcinoma in human samples and in the murine model. We found that adenocarcinoma patients (pT1-4) with higher TLR-4 expression in stromal compartment had a significantly increased risk in disease progression. In those patients with a diagnosis of pT3 (33 cases) colon cancer, those with very high levels of TLR-4 in the tumor stroma relapsed significantly earlier than those with lower expression levels. Conclusions These data suggest that high TLR-4 expression in the tumor microenvironment represents a possible marker of disease progression in colon cancer.
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Affiliation(s)
- Rosaria Cammarota
- Oncology Research Laboratory, Science and Technology Park, IRCCS MultiMedica, (via Fantoli 16/15), Milan, (20138), Italy
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Meza R, Jeon J, Renehan AG, Luebeck EG. Colorectal cancer incidence trends in the United States and United kingdom: evidence of right- to left-sided biological gradients with implications for screening. Cancer Res 2010; 70:5419-29. [PMID: 20530677 DOI: 10.1158/0008-5472.can-09-4417] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Several lines of evidence support the premise that screening colonoscopy reduces colorectal cancer (CRC) incidence, but there may be differential benefits for right- and left-sided tumors. To better understand the biological basis of this differential effect, we derived biomathematical models of CRC incidence trends in U.S. and U.K. populations, representing relatively high- and low-prevalence screening, respectively. Using the Surveillance Epidemiology and End Results (SEER) and the Office for National Statistics (ONS) registries (both 1973-2006), we derived stochastic multistage clonal expansion (MSCE) models for right-sided (proximal colon) and left-sided (distal colon and rectal) tumors. The MSCE concept is based on the initiation-promotion-progression paradigm of carcinogenesis and provides a quantitative description of natural tumor development from the initiation of an adenoma (via biallelic tumor suppressor gene inactivation) to the clinical detection of CRC. From 1,228,036 (SEER: 340,582; ONS: 887,454) cases, parameter estimates for models adjusted for calendar-year and birth-cohort effects showed that adenoma initiation rates were higher for right-sided tumors, whereas, paradoxically, adenoma growth rates were higher for left-sided tumors. The net effect was a higher cancer risk in the right colon only after age 70 years. Consistent with this finding, simulations of adenoma development predicted that the relative prevalence for right- versus left-sided tumors increases with increasing age, a differential effect most striking in women. Using a realistic biomathematical description of CRC development for two nationally representative registries, we show age- and sex-dependent biological gradients for right- and left-sided colorectal tumors. These findings argue for an age-, sex-, and site-directed approach to CRC screening.
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Affiliation(s)
- Rafael Meza
- Centre for Disease Control, University of British Columbia, Vancouver, Canada.
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Colon cancer and the elderly: from screening to treatment in management of GI disease in the elderly. Best Pract Res Clin Gastroenterol 2009; 23:889-907. [PMID: 19942166 PMCID: PMC3742312 DOI: 10.1016/j.bpg.2009.10.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2009] [Revised: 10/08/2009] [Accepted: 10/14/2009] [Indexed: 01/31/2023]
Abstract
Colorectal cancer is one of the commonest tumours in the Westernized world affecting mainly the elderly. This neoplasm in older individuals occurs more often in the right colon and grows more rapidly than in the young, often shows a mucinous histology and mismatch repair gene changes. Effective screening permits discovery of colorectal cancer at an early highly treatable stage and allows for detection and removal of premalignant colorectal adenomas. Screening methods that focus on cancer detection use fecal assays for the presence of blood or altered DNA, those for detection of adenomas (and early cancer) use endoscopic or computerised radiologic techniques. Broad use of screening methods has lowered colorectal cancer development by about 50%. In addition, prevention of the earliest stage of colon carcinogenesis has been shown to be effective in small prospective studies and epidemiologic surveys but have not been employed in the general population. Since 1996 the chemotherapeutic armamentarium for metastatic colorectal cancer has grown beyond 5-fluorouracil to include an oral 5-fluorouracil prodrug, capecitabine as well as irinotecan and oxaliplatin. Three targeted monoclonal antibodies (Moabs), bevacizumab (an anti-vascular endothelial growth factor Moab) and cetuximab/panitumumab, both anti-epidermal growth factor receptor inhibitors, have also earned regulatory approval. Most stage IV patients are treated with all of these drugs over 2 or 3 sequential lines of palliative chemotherapy and attain median survivals approaching 24 months. Lastly, adjuvant oxaliplatin plus 5-fluorouracil for high risk resected stage II and stage III colon cancer patient has led to substantial improvement in cure rates. With appropriate care of age associated comorbidities these treatment modalities are feasible and effective in the geriatric population.
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