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Greco L, Rubbino F, Ferrari C, Cameletti M, Grizzi F, Bonelli F, Malesci A, Mazzone M, Ricciardiello L, Laghi L. Association of Fusobacterium nucleatum with colorectal cancer molecular subtypes and its outcome: a systematic review. GUT MICROBIOME (CAMBRIDGE, ENGLAND) 2025; 6:e5. [PMID: 40297307 PMCID: PMC12035788 DOI: 10.1017/gmb.2025.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/30/2025]
Abstract
Colorectal cancer (CRC) represents a relevant public health problem, with high incidence and mortality in Western countries. CRC can occur as sporadic (65%-75%), common familial (25%), or as a consequence of an inherited predisposition (up to 10%). While unravelling its genetic basis has been a long trip leading to relevant clinical implementation over more than 30 years, other contributing factors remain to be clarified. Among these, micro-organisms have emerged as critical players in the development and progression of the disease, as well as for CRC treatment response. Fusobacterium nucleatum (Fn) has been associated with CRC development in both pre-clinical models and clinical settings. Fusobacteria are core members of the human oral microbiome, while being less prevalent in the healthy gut, prompting questions about their localization in CRC and its precursor lesions. This review aims to critically discuss the evidence connecting Fn with CRC pathogenesis, its molecular subtypes and clinical outcomes.
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Affiliation(s)
- Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Clarissa Ferrari
- Research and Clinical Trials Office, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | | | - Fabio Grizzi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Milan, Italy
| | | | | | - Massimiliano Mazzone
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Macrophage Dynamics Lab, IRCCS Humanitas Research Hospital, Milan, Italy
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Luigi Ricciardiello
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas at MD Anderson Cancer Center, Houston, TX, USA
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
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Rustgi SD, Soddano J, Ingram M, Hampel H, Hur C, Kastrinos F. Cost-Effectiveness of Lynch Syndrome Identification Strategies in Individuals with Colorectal Cancer and the Impact on At-Risk Relatives. Clin Gastroenterol Hepatol 2025:S1542-3565(25)00144-2. [PMID: 40010417 DOI: 10.1016/j.cgh.2025.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 12/23/2024] [Accepted: 01/07/2025] [Indexed: 02/28/2025]
Abstract
BACKGROUND & AIMS Universal screening for Lynch syndrome (LS) is recommended for all patients diagnosed with colorectal cancer (CRC). A benefit of LS screening in CRC is cascade testing (CT), whereby at-risk relatives are tested for the familial pathogenic LS variant and undergo intensive surveillance for CRC prevention/early detection if identified with LS. There is not yet universal uptake of CT; we quantify the impact on CRC-related outcomes in first-degree relatives (FDRs). METHODS We developed a microsimulation model to quantify the impact of CT on CRC incidence and mortality in FDRs (parents, siblings, children) of individuals with CRC screened for LS. For FDRs, the primary outcome was the number of CRC cases and CRC-related deaths, by age of relative; secondary outcomes included life-years gained, quality-adjusted life-years, number of colonoscopies, and costs associated with CT, surveillance, and cancer care. RESULTS With CT for all eligible FDRs, we estimate 61.0% decrease in CRC cases and 78.5% decrease in CRC mortality. Although CT led to an average 11 more lifetime colonoscopies, there was modest increase in life-years gained and quality-adjusted life-years and decreased costs because of savings from cancer treatment. CONCLUSIONS This model quantifies the benefits of CT for at-risk FDRs of newly identified individuals with CRC and LS. The decrease in CRC incidence across generations can be used to facilitate discussions with relatives to improve uptake of CT. Further studies to optimize the uptake of CT are paramount to decrease risk of CRC in LS.
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Affiliation(s)
- Sheila D Rustgi
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Josephine Soddano
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Myles Ingram
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Heather Hampel
- Division of Clinical Cancer Genomics, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California
| | - Chin Hur
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Fay Kastrinos
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.
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Cotan HT, Emilescu RA, Iaciu CI, Orlov-Slavu CM, Olaru MC, Popa AM, Jinga M, Nitipir C, Schreiner OD, Ciobanu RC. Prognostic and Predictive Determinants of Colorectal Cancer: A Comprehensive Review. Cancers (Basel) 2024; 16:3928. [PMID: 39682117 DOI: 10.3390/cancers16233928] [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: 11/06/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health burden, necessitating a thorough understanding of prognostic and predictive factors to enhance patient outcomes. This systematic review aims to comprehensively evaluate prognostic and predictive determinants in CRC, encompassing both traditional and emerging biomarkers. A systematic search of major electronic databases was conducted to identify relevant studies published from 1995 up to 2024. Eligible articles were critically appraised, and data extraction was performed according to predefined criteria. The prognostic determinants examined included clinicopathological features such as tumor stage, grade, and lymph node involvement, as well as molecular biomarkers including RAS, BRAF, and MSI status. Predictive determinants encompassed biomarkers influencing response to targeted therapies and immunotherapy, such as HER2 and Immunoscore. The review also explores novel prognostic and predictive markers, including tumor microenvironment characteristics and liquid biopsy-based biomarkers. Synthesizing evidence from diverse studies, this review provides insights into the prognostic and predictive landscape of CRC, highlighting the potential clinical implications of identified determinants. Understanding the multifaceted nature of prognostic and predictive factors in CRC is imperative for the advancement of personalized treatment strategies and improvement of patient outcomes.
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Affiliation(s)
- Horia T Cotan
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Radu A Emilescu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cristian I Iaciu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cristina M Orlov-Slavu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Mihaela C Olaru
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Ana M Popa
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Mariana Jinga
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cornelia Nitipir
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Oliver Daniel Schreiner
- Regional Institute of Oncology Iasi, 2-4 General Henri Mathias Berthelot Street, 700483 Iasi, Romania
- Department 3-Medical Sciences, Grigore T. Popa University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
- Department of Electrical Measurements and Materials, Gheorghe Asachi Technical University, 700050 Iasi, Romania
| | - Romeo Cristian Ciobanu
- Department of Electrical Measurements and Materials, Gheorghe Asachi Technical University, 700050 Iasi, Romania
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Ekmekciu I, Zucha DM, Christmann J, Wisser S, Heuer V, Sargin B, Hollerbach S, Lamberti C, Müller L, Lugnier C, Verdoodt B, Denz R, Terzer T, Feder I, Reinacher-Schick A, Tannapfel A, Tischoff I. Exploring the molecular profile of localized colon cancer: insights from the AIO Colopredict Plus registry. Front Oncol 2024; 14:1434791. [PMID: 39628993 PMCID: PMC11612501 DOI: 10.3389/fonc.2024.1434791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 09/11/2024] [Indexed: 12/06/2024] Open
Abstract
Introduction Understanding the mutational landscape of colon cancer (CC) is crucial for targeted therapy development. Microsatellite instability (MSI-H), rat sarcoma (RAS), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations (MT) are pivotal markers. Further investigation into clinicopathological features of RAS and BRAF MT in microsatellite stable (MSS) and MSI-H tumors is warranted. Methods A retrospective analysis of 4883 localized CC patients (pts.) was conducted. Molecular profiling assessed MSI, KRAS, NRAS, and BRAF MT. Correlation with clinicopathological data employed ANOVA and Chi-square tests. Disease-free survival (DFS) and overall survival (OS) were analyzed adjusting for age, gender, sidedness, UICC stage, Charlson Comorbidity Index (CCI). A Cox model incorporated all variables as covariates. Results This analysis included 4883 pts. (2302 female/2572 male, 3865 (79.2%) MSS, 1018 (20.8%) MSI-H). MSS pts. had more All-Wild Type (WT), KRAS MT, and NRAS MT tumors vs. MSI-H pts. (42.1% vs. 21.1%; 39.8% vs. 15.4%; 3.6% vs. 0.7%; p<0.001 for each). BRAF MT tumors (95.5% BRAF V600E MT) were more prevalent in MSI-H individuals (62.8% vs. 8.1%, p<0.001). KRAS and BRAF MT tumors were more frequently right-sided, while BRAF MT tumors were associated with female gender, advanced disease stage, lymph node positivity, and poorer differentiation in the MSS subset (p<0.001). Common KRAS mutations included p.G12D (30.44%) and p.G12V (21.3%) in MSS and p.G13D (28.9%) and p.G12D (22.37%) in MSI-H. NRAS MT tumors were dominated by codon 61 mutations (51.7%). Survival analysis revealed worst prognosis in BRAF MT MSS tumors (DFS: HR 1.74 (95% CI 1.15-2.62, p=0.009; OS: HR 1.61 (95% CI 0.99-2.6), p=0.055). The 3-years DFS and 5-years OS rates were lowest in this subset (61.6% and 57.7% respectively). Discussion These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies.
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Affiliation(s)
- Ira Ekmekciu
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | | | - Sarah Wisser
- Institute of Pathology, Ruhr University, Bochum, Germany
| | - Vera Heuer
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - Buelent Sargin
- Hematology and Medical Oncology, St-Marien-Hospital Lunen, Lunen, Germany
| | - Stephan Hollerbach
- Department of Gastroenterology, Allgemeines Krankenhaus (AKH) Celle, Celle, Germany
| | | | | | - Celine Lugnier
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | - Robin Denz
- Department of Medical Informatics, Biometrics and Epidemiology, Ruhr University, Bochum, Germany
| | - Tobias Terzer
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - Inke Feder
- Institute of Pathology, Ruhr University, Bochum, Germany
| | - Anke Reinacher-Schick
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | - Iris Tischoff
- Institute of Pathology, Ruhr University, Bochum, Germany
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Wu X, Liu W, Wang Y, Wang K, Xing B. Association of various RAS codon mutations and prognostic outcomes of patients with colorectal liver metastases after hepatectomy. Cancer Med 2024; 13:e70168. [PMID: 39377605 PMCID: PMC11459679 DOI: 10.1002/cam4.70168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 11/14/2023] [Accepted: 08/19/2024] [Indexed: 10/09/2024] Open
Abstract
PURPOSE The prognostic and predictive value of RAS mutations in patients with colorectal liver metastases (CRLM) who have undergone hepatectomy holds substantial importance. The present study aimed to investigate the impact of different RAS codon mutations on long-term survival in CRLM patients. METHODS A retrospective analysis was conducted on clinicopathological data from 399 CRLM patients with RAS mutations who underwent hepatectomy between January 2000 and December 2020. The RAS mutation gene status was assessed in KRAS codons (G12, G13, Q61, and A146) and NRAS codons (G12, G13, and Q61). Survival curves were generated using the Kaplan-Meier plotter and compared using the log-rank test. Univariate and multivariate analyses were performed to analyze the clinicopathological data. RESULTS In the entire cohort, patients with KRAS G12 mutations exhibited the most favorable prognosis (p = 0.018). Comparatively, patients harboring KRAS Q61 mutations experienced poorer overall survival (OS) with a median of 15 months versus 33 months (p = 0.011) when compared to those with KRAS G12 mutations. Moreover, patients with NRAS Q61 mutations also showed decreased OS with a median of 26 months versus 33 months (p = 0.020) in comparison to KRAS G12 mutation patients. The results of multivariate analysis showed that both KRAS Q61 mutation (HR 2.130; 95% CI 1.088-4.168; p = 0.027) and NRAS Q61 mutation (HR 2.877; 95% CI 1.398-5.922; p = 0.004) were independent influencing factors of OS. Based on all identified risk factors, patients with RAS mutation were divided into high-risk and low-risk groups. Notably, in the high-risk group, the incorporation of postoperative chemotherapy was associated with longer OS, while it did not improve the survival of patients in the low-risk group. CONCLUSIONS KRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high-risk.
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Affiliation(s)
- Xiao‐Gang Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Hepatopancreatobiliary Surgery Department IPeking University Cancer Hospital & InstituteBeijingChina
| | - Wei Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Hepatopancreatobiliary Surgery Department IPeking University Cancer Hospital & InstituteBeijingChina
| | - Yan‐Yan Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Hepatopancreatobiliary Surgery Department IPeking University Cancer Hospital & InstituteBeijingChina
| | - Kun Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Hepatopancreatobiliary Surgery Department IPeking University Cancer Hospital & InstituteBeijingChina
| | - Bao‐Cai Xing
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Hepatopancreatobiliary Surgery Department IPeking University Cancer Hospital & InstituteBeijingChina
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Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
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Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
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Tan C, Wang Q, Yao S. Effects of Adjuvant Chemotherapy on Early-onset Stage II Colon Cancer at Different Tumor Sites. Am J Clin Oncol 2024; 47:253-258. [PMID: 38251762 DOI: 10.1097/coc.0000000000001084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
OBJECTIVES Left-sided colon cancer (LSCC) and right-sided colon cancer (RSCC) have shown distinct clinical and prognostic features. We investigated the effect of adjuvant chemotherapy (ACT) on cause-specific survival (CSS) in patients with stage II LSCC and RSCC. METHODS Using the Surveillance, Epidemiology and End Results (SEER) database, a cohort of patients with stage II colon cancer, aged between 20 and 49 years was identified. Both Cox proportional hazards regression and Kaplan-Meier survival analysis as well as propensity score matching were used. RESULTS Overall, 5633 patients were eligible. Patients with RSCC were more likely to be male, black, and younger, with a poor grade and histologic type, and were more likely to have more regional nodes examined and larger tumor size. After propensity score matching, CSS was significantly superior in patients with RSCC compared to those with LSCC (Hazard Ratio (HR): 0.80, 95% CI: 0.68-0.95, P =0.01). However, no survival benefit was observed for patients with LSCC after ACT (HR: 1.10, 95% CI: 0.90-1.35, P =0.35), and surprisingly, ACT was found to do more harm than good in patients with RSCC (HR: 1.31, 95% CI: 1.05-1.63, P =0.02). Even among patients with high-risk features such as T4 stage and regional nodes examined<12 in both groups, ACT still did not improve CSS except for T4 stage LSCC (HR: 0.65, 95% CI: 0.44-0.97, P =0.02). CONCLUSIONS The results of this analysis indicate that the prognosis of RSCC is better than that of LSCC in stage II colon cancer, and ACT did not improve CSS in patients with either LSCC or RSCC. Even in patients with parts of high-risk features, ACT still did not improve CSS, except for T4 stage LSCC.
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Affiliation(s)
- Chang Tan
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine
| | - Qianqian Wang
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine
| | - Shukun Yao
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
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Ulanja MB, Asafo‐Agyei KO, Neelam V, Beutler BD, Antwi‐Amoabeng D, Governor SB, Rahman GA, Djankpa FT, Ulanja RN, Nteim GB, Mabrouk T, Amankwah M, Alese OB. Survival trends for left and right sided colon cancer using population-based SEER database: A forty-five-year analysis from 1975 to 2019. Cancer Med 2024; 13:e7145. [PMID: 38651190 PMCID: PMC11036079 DOI: 10.1002/cam4.7145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 03/13/2024] [Accepted: 03/17/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Survival differences between left-sided colon cancer (LSCC) and right-sided colon cancer (RSCC) has been previously reported with mixed results, with various study periods not accounting for other causes of mortality. PURPOSE We sought to assess the trends in colon cancer cause- specific survival (CSS) and overall survival (OS) based on sidedness. METHOD Fine-Gray competing risk and Cox models were used to analyze Surveillance, Epidemiology, and End Results (SEER) population-based cohort from 1975 to 2019. Various interval periods were identified based on the timeline of clinical adoption of modern chemotherapy (1975-1989, interval period A; 1990-2004, B; and 2005-2019, C). RESULTS Of the 227,637 patients, 50.1% were female and 46.2% were RSCC. RSCC was more common for African Americans (51.5%), older patients (age ≥65; 51.4%), females (50.4%), while LSCC was more common among Whites (53.1%; p < 0.001), younger patients (age 18-49, 64.6%; 50-64, 62.3%; p < 0.001), males (58.1%; p < 0.001). The Median CSS for LSCC and RCC were 19.3 and 16.7 years respectively for interval period A (1975-1989). Median CSS for interval periods B and C were not reached (more than half of the cohort was still living at the end of the follow-up period). Adjusted CSS was superior for LSCC versus RSCC for the most recent interval period C (HR 0.89; 0.86-0.92; p < 0.001). LSCC consistently showed superior OS for all study periods. Stage stratification showed worse CSS for localized and regional LSCC in the earlier study periods, but the risk attenuated over time. However, left sided distant disease had superior CSS per stage for all interval periods. OS was better for LSCC irrespective of stage, with gradual improvement over time. CONCLUSION LSCC was associated with superior survival compared to right sided tumors. With the adoption of modern chemotherapy regimens, prognosis between LSCC and RSCC became more divergent in favor of LSCC. Colon cancer clinical trials should strongly consider tumor sidedness as an enrollment factor.
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Affiliation(s)
- Mark B. Ulanja
- CHRISTUS Ochsner St. Patrick HospitalLake CharlesLouisianaUSA
| | | | - Vijay Neelam
- CHRISTUS Ochsner St. Patrick HospitalLake CharlesLouisianaUSA
| | - Bryce D. Beutler
- Department of Radiology, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | | | - Samuel B. Governor
- Saint Louis University College for Public Health and Social JusticeSaint LouisMissouriUSA
| | - Ganiyu A. Rahman
- Department of Surgery, School of Medical SciencesUniversity of Cape CoastCape CoastGhana
| | - Francis T. Djankpa
- Department of Physiology, School of Medical SciencesUniversity of Cape CoastCape CoastGhana
| | - Reginald N. Ulanja
- Department of Physiology, School of Medical SciencesUniversity of Cape CoastCape CoastGhana
| | - Grace B. Nteim
- Department of Physiology, School of Medical SciencesUniversity of Cape CoastCape CoastGhana
| | - Tarig Mabrouk
- CHRISTUS Ochsner St. Patrick HospitalLake CharlesLouisianaUSA
| | - Millicent Amankwah
- Department of Hematology Oncology, Feist‐Weiller Cancer CenterLouisiana State University Health ShreveportLouisianaUSA
| | - Olatunji B. Alese
- Department of Hematology and OncologyWinship Cancer Institute, Emory UniversityAtlantaGeorgiaUSA
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Vogel A, Murugesan K, Kendre G, Quintanilha JCF, Ross JS, Brummer T, Saborowski A. Association of RNF43 Genetic Alterations With BRAF V600E and MSI high in Colorectal Cancer. JCO Precis Oncol 2024; 8:e2300411. [PMID: 38394466 DOI: 10.1200/po.23.00411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/14/2023] [Accepted: 12/05/2023] [Indexed: 02/25/2024] Open
Abstract
PURPOSE Recent studies have provided evidence for a predictive value of RNF43 genetic alterations (GAs) as biomarkers for targeted therapies in microsatellite-stable (MSS) colorectal cancer (CRC). These data have the potential to prioritize treatment strategies in patients with BRAFV600E-mutant CRC and help to identify a subgroup that is more likely to derive benefit versus those patients for whom alternative treatment approaches are needed. We were therefore interested in defining the precise frequency of BRAFV600E and RNF43 GAs and their respective overlap in a large cohort of patients with CRC. METHODS To address this question, we performed a retrospective analysis that included 52,969 patients diagnosed with CRC from the FoundationCORE database. RESULTS We observed a striking association of RNF43 GAs with MSI and tumor mutational burden status and BRAFV600E mutations. Overall, 23% of MSS patients with confirmed BRAFV600E mutation harbor an RNF43 GA-which accounts for 1.1% of all patients with CRC and for 15.7% of all CRC BRAFV600E cases. CONCLUSION Ongoing phase III clinical trials, such as BREAKWATER, should aim to incorporate broader genetic profiling to further validate the superior sensitivity of patients with RNF43-mutant, MSS BRAFV600E CRC to anti-EGFR-/BRAFi-based therapies.
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Affiliation(s)
- Arndt Vogel
- Toronto General Hospital, Princess Margaret Cancer Centre, Toronto, ON, Canada
- Hannover Medical School, Hannover, Germany
| | | | - Gajanan Kendre
- Department of Life Science, National Institute of Technology Rourkela (NITR), Rourkela, India
| | | | | | - Tilman Brummer
- Institute of Molecular Medicine and Cell Research, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center, University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany
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Leibold J, Tsanov KM, Amor C, Ho YJ, Sánchez-Rivera FJ, Feucht J, Baslan T, Chen HA, Tian S, Simon J, Wuest A, Wilkinson JE, Lowe SW. Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease. NATURE CANCER 2024; 5:315-329. [PMID: 38177458 PMCID: PMC10899107 DOI: 10.1038/s43018-023-00686-w] [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: 03/22/2022] [Accepted: 11/10/2023] [Indexed: 01/06/2024]
Abstract
Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.
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Affiliation(s)
- Josef Leibold
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany.
- iFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany.
| | - Kaloyan M Tsanov
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Corina Amor
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
| | - Yu-Jui Ho
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Francisco J Sánchez-Rivera
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Judith Feucht
- iFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany
- Department I-General Paediatrics, Haematology/Oncology, University Children's Hospital Tuebingen, Tuebingen, Germany
| | - Timour Baslan
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Biomedical Sciences, School of Veterinary Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | - Hsuan-An Chen
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sha Tian
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Janelle Simon
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexandra Wuest
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - John E Wilkinson
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Scott W Lowe
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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11
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Yamai D, Shimada Y, Ozeki H, Matsumoto A, Abe K, Tajima Y, Nakano M, Ichikawa H, Sakata J, Wakai T. Axillary cutaneous metastasis of colon cancer with microsatellite instability-high and BRAF V600E mutation treated with curative-intent surgery: a case report. Surg Case Rep 2023; 9:196. [PMID: 37962682 PMCID: PMC10646071 DOI: 10.1186/s40792-023-01780-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 11/07/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) metastasizes to various organs, while cutaneous metastases are rare. Although there have been several previous reports of axillary cutaneous metastases with other metastases of CRC, there has never been a report of axillary cutaneous metastasis of CRC that could be treated with curative-intent surgery. CASE PRESENTATION A 68-year-old female was diagnosed with an axillary cutaneous tumor and ascending colon cancer with invasion to the duodenum. Histopathological and immunohistochemical analysis revealed that the axillary cutaneous tumor showed adenocarcinoma and the same expression pattern for cytokeratin 7, cytokeratin 20, and CDX2 as the ascending colon cancer, and that proved to be KRAS-NRAS wild type, MSI-H, and with a BRAF V600E mutation. The patient underwent a two-stage resection with curative intent after receiving neoadjuvant chemotherapy which consisted of one cycle of modified FOLFOX6 followed by two cycles of FOLFOXIRI. During and after the two operations, the patient received a total of nine cycles of modified FOLFOX6 as adjuvant chemotherapy. Two years after the initial surgery, and 1 year and 8 months after the second surgery, the patient is alive without recurrence. CONCLUSIONS To the best of our knowledge, this is the first report of axillary cutaneous metastasis of CRC with microsatellite instability-high and BRAF V600E mutation that could be treated with curative-intent surgery. It is important to recognize the presence of such cases for the accurate diagnosis and treatment of CRC with cutaneous metastasis.
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Affiliation(s)
- Daisuke Yamai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yoshifumi Shimada
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
- Medical Genome Center, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata, Japan.
| | - Hikaru Ozeki
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Akio Matsumoto
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Kaoru Abe
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yosuke Tajima
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Mae Nakano
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
- Medical Genome Center, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata, Japan
| | - Hiroshi Ichikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Jun Sakata
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
- Medical Genome Center, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata, Japan
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12
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Gao Y, Wu A. Organ Preservation in MSS Rectal Cancer. Clin Colon Rectal Surg 2023; 36:430-440. [PMID: 37795468 PMCID: PMC10547535 DOI: 10.1055/s-0043-1767710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
Rectal cancer is a heterogeneous disease with complex genetic and molecular subtypes. Emerging progress of neoadjuvant therapy has led to increased pathological and clinical complete response (cCR) rates for microsatellite stable (MSS) rectal cancer, which responds poorly to immune checkpoint inhibitor alone. As a result, organ preservation of MSS rectal cancer as an alternative to radical surgery has gradually become a feasible option. For patients with cCR or near-cCR after neoadjuvant treatment, organ preservation can be implemented safely with less morbidity. Patient selection can be done either before the neoadjuvant treatment for higher probability or after with careful assessment for a favorable outcome. Those patients who achieved a good clinical response are managed with nonoperative management, organ preservation surgery, or radiation therapy alone followed by strict surveillance. The oncological outcomes of patients with careful selection and organ preservation seem to be noninferior compared with those of radical surgery, with lower postoperative morbidity. However, more studies should be done to seek better regression of tumor and maximize the possibility of organ preservation in MSS rectal cancer.
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Affiliation(s)
- Yuye Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Unit III, Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
| | - Aiwen Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Unit III, Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
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13
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Møller P, Seppälä TT, Ahadova A, Crosbie EJ, Holinski-Feder E, Scott R, Haupt S, Möslein G, Winship I, Broeke SWBT, Kohut KE, Ryan N, Bauerfeind P, Thomas LE, Evans DG, Aretz S, Sijmons RH, Half E, Heinimann K, Horisberger K, Monahan K, Engel C, Cavestro GM, Fruscio R, Abu-Freha N, Zohar L, Laghi L, Bertario L, Bonanni B, Tibiletti MG, Lino-Silva LS, Vaccaro C, Valle AD, Rossi BM, da Silva LA, de Oliveira Nascimento IL, Rossi NT, Dębniak T, Mecklin JP, Bernstein I, Lindblom A, Sunde L, Nakken S, Heuveline V, Burn J, Hovig E, Kloor M, Sampson JR, Dominguez-Valentin M. Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement. Hered Cancer Clin Pract 2023; 21:19. [PMID: 37821984 PMCID: PMC10568908 DOI: 10.1186/s13053-023-00263-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 09/29/2023] [Indexed: 10/13/2023] Open
Abstract
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
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Affiliation(s)
- Pal Møller
- Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, PO Box 4950, 0424, NydalenOslo, Norway.
| | - Toni T Seppälä
- Faculty of Medicine and Health Technology, Cancer Centre, Tampere University and Tays, Tampere University Hospital, Tampere, Finland
- Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
- Applied Tumor Genomics, Research Program Unit, University of Helsinki, Helsinki, Finland
| | - Aysel Ahadova
- Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Operation Unit Applied Tumour Biology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Emma J Crosbie
- Gynaecological Oncology Research Group, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Elke Holinski-Feder
- Medizinische Klinik Und Poliklinik IV, Klinikum Der Universität München, Campus Innenstadt, 80336, Munich, Germany
- Center of Medical Genetics, 80335, Munich, Germany
| | - Rodney Scott
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
| | - Saskia Haupt
- Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
- Data Mining and Uncertainty Quantification (DMQ), Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
| | - Gabriela Möslein
- Surgical Center for Hereditary Tumors, Academic Hospital University, Ev. Bethesda Khs Duisburg, Düsseldorf, Germany
| | - Ingrid Winship
- Genomic Medicine, The Royal Melbourne Hospital, Melbourne, Australia
- Department of Medicine, University of Melbourne, Melbourne, Australia
| | - Sanne W Bajwa-Ten Broeke
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Kelly E Kohut
- Centre for Psychosocial Research in Cancer, Health Sciences, University of Southampton, Southampton, UK
| | - Neil Ryan
- Medical School, University of Edinburgh, Edinburgh, UK
- Department of Gynaecology Oncology, Royal Infirmary of Edinburgh, Edinburgh, UK
| | | | - Laura E Thomas
- Institute of Life Science, Swansea University, Swansea, SA28PP, UK
| | - D Gareth Evans
- Manchester Centre for Genomic Medicine, Division of Evolution Infection and Genomic Sciences, University of Manchester, Manchester, M13 9WL, UK
| | - Stefan Aretz
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, 53127, Bonn, Germany
| | - Rolf H Sijmons
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Elizabeth Half
- Gastrointestinal Cancer Prevention Unit, Gastroenterology Department, Rambam Health Care Campus, Haifa, Israel
| | - Karl Heinimann
- Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Karoline Horisberger
- Department of General, Visceral and Transplatation Surgery, University Hospital of Mainz, Mainz, Germany
| | - Kevin Monahan
- Lynch Syndrome & Family Cancer Clinic, Centre for Familial Intestinal Cancer, St Mark's Hospital, London, HA1 3UJ, Harrow, UK
| | - Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Robert Fruscio
- Clinic of Obstetrics and Gynecology, Department of Medicine and Surgery, University of Milan-Bicocca, Fondazione IRCCS San Gerardo, Monza, Italy
| | - Naim Abu-Freha
- Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Levi Zohar
- Service High Risk GI Cancer Gastroenterology, Department Rabin Medical Center, Rabin, Israel
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Parma, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Lucio Bertario
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, IRCCS, 20141, Milan, Italy
| | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy
| | - Maria Grazia Tibiletti
- Ospedale di Circolo ASST Settelaghi, Università dell'Insubria, Centro di Ricerca tumori eredo-familiari, Varese, Italy
| | | | - Carlos Vaccaro
- Instituo Medicina Translacional e Ingenieria Biomedica - Hospital Italiano Bs As. - CONICET, Buenos Aires, Argentina
| | - Adriana Della Valle
- Hospital Central de las Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay
| | | | | | | | - Norma Teresa Rossi
- Fundación para el Progreso de la Medicina y Sanatorio Allende, Córdoba, Argentina
| | - Tadeusz Dębniak
- Department of Genetics and Pathology, Pomeranian Medical University, ul. Unii Lubelskiej 1, 71-252, Szczecin, Poland
| | - Jukka-Pekka Mecklin
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
- Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland
| | - Inge Bernstein
- Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg University, 9000, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University Hospital, Aalborg University, 9000, Aalborg, Denmark
- The Danish HNPCC-register, Hvidovre Hospital, Hvidovre, Denmark
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden
- Clinical Genetics, Karolinska University Hospital, Solna, Sweden
| | - Lone Sunde
- Department of Clinical Genetics, Aalborg University Hospital, 9000, Aalborg, Denmark
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus, Denmark
| | - Sigve Nakken
- Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, PO Box 4950, 0424, NydalenOslo, Norway
- Centre for bioinformatics, University of Oslo, Postbox 1080 Blindern, 0316, Oslo, Norway
- Centre for Cancer Cell Reprogramming (CanCell), Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Vincent Heuveline
- Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
- Data Mining and Uncertainty Quantification (DMQ), Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
| | - John Burn
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| | - Eivind Hovig
- Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, PO Box 4950, 0424, NydalenOslo, Norway
- Centre for bioinformatics, University of Oslo, Postbox 1080 Blindern, 0316, Oslo, Norway
| | - Matthias Kloor
- Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Operation Unit Applied Tumour Biology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Julian R Sampson
- Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK
| | - Mev Dominguez-Valentin
- Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, PO Box 4950, 0424, NydalenOslo, Norway
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14
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Woischke C, Michl M, Neumann J. [Molecular pathology of colorectal cancer]. PATHOLOGIE (HEIDELBERG, GERMANY) 2023; 44:279-286. [PMID: 37277480 DOI: 10.1007/s00292-023-01201-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/20/2023] [Indexed: 06/07/2023]
Abstract
In recent years, the treatment of colorectal carcinoma has experienced increasing individualization. In addition to RAS and BRAF mutational status that is firmly established in routine diagnostics, new therapeutic options evolved based on MSI and HER2 status as well as primary tumour localization. Offering the best targeted options in therapy requires new evidence-based decision-making algorithms regarding timing and scope of molecular pathological diagnostics in order for patients to receive an optimized therapy according to current treatment guidelines. New targeted therapies, some of which are about to be approved and for which pathology has to provide new molecular pathological biomarkers, will also play an increasingly important role in the future.
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Affiliation(s)
- Christine Woischke
- Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, 80337, München, Deutschland
| | - Marlies Michl
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Ludwig-Maximilians-Universität München, München, Deutschland
- Facharztpraxis für Innere Medizin, Hämatologie und Onkologie mit Tagesklinik, Praxis Dr. Michl, München, Deutschland
| | - Jens Neumann
- Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, 80337, München, Deutschland.
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15
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Liu QL, Zhou H, Zhou ZG, Chen HN. Colorectal cancer liver metastasis: genomic evolution and crosstalk with the liver microenvironment. Cancer Metastasis Rev 2023; 42:575-587. [PMID: 37061644 DOI: 10.1007/s10555-023-10107-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023]
Abstract
Colorectal cancer (CRC) patients frequently develop liver metastases, which are the major cause of cancer-related mortality. The molecular basis and management of colorectal liver metastases (CRLMs) remain a challenging clinical issue. Recent genomic evidence has demonstrated the liver tropism of CRC and the presence of a stricter evolutionary bottleneck in the liver as a target organ compared to lymph nodes. This bottleneck challenging CRC cells in the liver is organ-specific and requires adaptation not only at the genetic level, but also at the phenotypic level to crosstalk with the hepatic microenvironment. Here, we highlight the emerging evidence on the clonal evolution of CRLM and review recent insights into the molecular mechanisms orchestrating the bidirectional interactions between metastatic CRC cells and the unique liver microenvironment.
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Affiliation(s)
- Qiu-Luo Liu
- Department of General Surgery, Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Huijie Zhou
- Department of Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zong-Guang Zhou
- Department of General Surgery, Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Hai-Ning Chen
- Department of General Surgery, Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
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16
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Greco L, Rubbino F, Dal Buono A, Laghi L. Microsatellite Instability and Immune Response: From Microenvironment Features to Therapeutic Actionability-Lessons from Colorectal Cancer. Genes (Basel) 2023; 14:1169. [PMID: 37372349 DOI: 10.3390/genes14061169] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Microsatellite instability (MSI) can be found in 15-20% of all colorectal cancers (CRC) and is the key feature of a defective DNA mismatch repair (MMR) system. Currently, MSI has been established as a unique and pivotal biomarker in the diagnosis, prognosis, and treatment of CRC. MSI tumors display a strong lymphocytic activation and a shift toward a tumoral microenvironment restraining metastatic potential and ensuing in a high responsiveness to immunotherapy of MSI CRC. Indeed, neoplastic cells with an MMR defect overexpress several immune checkpoint proteins, such as programmed death-1 (PD-1) and programmed death-ligand 1(PD-L1), that can be pharmacologically targeted, allowing for the revival the cytotoxic immune response toward the tumor. This review aims to illustrate the role of MSI in the tumor biology of colorectal cancer, focusing on the immune interactions with the microenvironment and their therapeutic implications.
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Affiliation(s)
- Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Arianna Dal Buono
- Division of Gastroenterology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
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17
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Paula Simedan Vila A, Helena Rodrigues G, Leite Marzochi L, Garcia de Oliveira-Cucolo J, Lívia Silva Galbiatti-Dias A, Felipe Maciel Andrade R, de Santi Neto D, Gomes Netinho J, Castiglioni L, Cristina Pavarino É, Maria Goloni-Bertollo E. EPIDEMIOLOGICAL AND MOLECULAR EVALUATION OF BRAF, KRAS, NRAS GENES, AND MSI IN THE DEVELOPMENT OF COLORECTAL CANCER. Gene 2023; 870:147395. [PMID: 36990254 DOI: 10.1016/j.gene.2023.147395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/16/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023]
Abstract
BACKGROUND AND OBJECTIVES KRAS, NRAS, BRAF Mutations and microsatellite instability (MSI) can be associated with Colorectal Cancer (CRC) development. MATERIAL AND METHODS We evaluated 828 medical records of CRC patients from a school hospital from January/2016 to December/2020. Variables such as age, gender, ethnicity, literacy level, smoking, alcoholism, primary anatomical site, tumor staging, presence of BRAFV600E, KRAS, NRAS and MSI mutations, survival and metastasis were identified. The statistical analyses were performed (p<0.05 is significant. RESULTS There was a predominance of males (51.93%), whites (90.70%), low education (72.34%), smokers (73.79%), and non- alcoholics (79.10%). Rectum was the most affected site (42.14%), advanced tumor stage was most prevalent (62.07%), and metastasis occurred in (64.61%). Of the enrolled patients; 204 were investigated for BRAF mutation and detected in (2.94%); 216 for KRAS gene and detected in (26.08%); 210 for NRAS gene, and detected in (25.36%); 370 for MSI, and detected in (44.68%). A significant association of CRC with NRAS mutation and alcohol habit (p = 0.043) was observed. The presence of MSI was associated with primary site proximal colon (p<0.000), distal colon (p=0.001) and rectum (p=0.010). CONCLUSION Patients with CRC are male, over 64 years old, white, with low education, smokers and non-alcoholics. The most affected primary site is rectum in advanced stage with metastasis. CRC is associated with NRAS mutation and alcohol habit, there is increased risk for primary site of proximal colon and MSI; decreased risk for distal colon and rectum in the presence of MSI mutation.
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Hartwig M, Bräuner KB, Vogelsang R, Gögenur I. Preoperative prediction of lymph node status in patients with colorectal cancer. Developing a predictive model using machine learning. Int J Colorectal Dis 2022; 37:2517-2524. [PMID: 36435940 DOI: 10.1007/s00384-022-04284-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/09/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE Develop a prediction model to determine the probability of no lymph node metastasis (pN0) in patients with colorectal cancer. METHODS We used data from four Danish health databases on patients with colorectal cancer diagnosed between 2001 and 2019. The registries were harmonized into one common data model (CDM). Patients with clinical T4 tumors, undergoing palliative or acute surgery, and patients undergoing neoadjuvant therapy were excluded. Preoperative data was used to train the model. A postoperative model including tumor-specific variables potentially available after local tumor resection was also developed. Additionally, both models were compared with a model based on age, sex, and clinical N stage to resemble current standards. A Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression analysis for prediction was used. RESULTS In total, 35,812 patients with 16,802 variables were identified in the CDM, and 194 variables affected the probability of pN0 preoperative. The area under the receiver operating characteristic curve (AUROC) was 0.64 (95% CI 0.63-0.66), and the area under the precision-recall curve (AUPRC) was 0.75 (95% CI 0.74-0.76). The mean predicted risk was 0.649, observed risk was 0.650, and calibration-in-large was 0.998. Adding histopathological data from the tumor improved the model slightly by increasing AUROC to 0.69. In comparison, the AUROC of the current standard clinical staging model was 0.57. CONCLUSION Using Danish National Patient Registry data in a machine learning-based predictive model showed acceptable results and outperforms current tools for clinical staging in predicting pN0 status in patients scheduled for CRC surgery.
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Affiliation(s)
- Morten Hartwig
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koege, Lykkebaekvej 1, 4600, Koege, Denmark.
| | - Karoline Bendix Bräuner
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koege, Lykkebaekvej 1, 4600, Koege, Denmark
| | - Rasmus Vogelsang
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koege, Lykkebaekvej 1, 4600, Koege, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koege, Lykkebaekvej 1, 4600, Koege, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Yunlong W, Tongtong L, Hua Z. The efficiency of neoadjuvant chemotherapy in colon cancer with mismatch repair deficiency. Cancer Med 2022; 12:2440-2452. [PMID: 35904113 PMCID: PMC9939115 DOI: 10.1002/cam4.5076] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 07/06/2022] [Accepted: 07/13/2022] [Indexed: 11/09/2022] Open
Abstract
Colon cancers with mismatch repair deficiency (dMMR) have specific clinicopathologic characteristics compared with mismatch repair proficiency (pMMR); however, the effect of MMR status on the efficiency of neoadjuvant chemotherapy (NCT) remains unclear. In our study, 439 dMMR and 26 pMMR colon cancer patients with or without NCT from 2010 to 2017 were retrospectively collected. Clinicopathological features, treatment response, and survival were compared between different groups. In the dMMR group, patients with NCT were likely to have higher CEA (abnormal CEA: 51.6% vs. 17.4%, p < 0.001), more multiorgan resection (38.7% vs. 16.8%, p = 0.006), and larger postoperative tumor diameter (7.26 vs. 6.21, p = 0.033) than those without NCT, but nearly half of cT4b patients who had NCT (42.9%, 9/21) avoid multiorgan resection. pT4 stage (HR, 14.97; 95% CI, 1.88-118.92; p = 0.010), number of positive lymph nodes (HR, 1.17; 95% CI, 1.09-1.26; p < 0.001), and tumor deposit (HR, 6.73; 95% CI, 2.08-21.74; p = 0.001) were independent prognosis factors of disease-free survival (DFS). For the advanced tumor subset, there is no significant difference between patients with or without NCT for OS (p = 0.13) and DFS (p = 0.11), although the survival rate of NCT was higher than non-NCT patients. Moreover, tumor regression grade was similar between dMMR and pMMR patients who had NCT. This study showed that NCT was more likely to be employed in dMMR patients with advanced tumors and may reduce the rate of multiorgan resection for cT4b dMMR patients. More large-scaled researches are needed to further explore if MMR status could predict the efficacy of neoadjuvant chemotherapy in patients with colon cancer.
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Affiliation(s)
- Wu Yunlong
- Department of General SurgeryBeijing Chao‐Yang Hospital, Capital Medical UniversityBeijingChina
| | - Liu Tongtong
- Department of RadiologyBeijing Chao‐Yang Hospital, Capital Medical UniversityBeijingChina
| | - Zeng Hua
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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20
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REACCT Collaborative, Zaborowski AM, Adamina AAM, Aigner F, d'Allens L, Allmer C, Álvarez A, Anula R, Andric M, Bach SAS, Bala M, Barussaud M, Bausys A, Beggs A, Bellolio F, Bennett MR, Berdinskikh A, Bevan V, Biondo S, Bislenghi G, Bludau M, Brouwer N, Brown C, Bruns C, Buchanan DD, Buchwald P, Burger JW, Burlov N, Campanelli M, Capdepont M, Carvello M, Chew HH, Christoforidis D, Clark D, Climent M, Collinson R, Cologne KG, Contreras T, Croner R, Daniels IR, Dapri G, Davies J, Delrio P, Denost Q, Deutsch M, Dias A, D’Hoore A, Drozdov E, Duek D, Dunlop M, Dziki A, Edmundson A, Efetov S, El-Hussuna A, Elliot B, Emile S, Espin E, Evans M, Faes S, Faiz O, Figueiredo N, Fleming F, Foppa C, Fowler G, Frasson M, Forgan T, Frizelle F, Gadaev S, Gellona J, Glyn T, Goran B, Greenwood E, Guren MG, Guillon S, Gutlic I, Hahnloser D, Hampel H, Hanly A, Hasegawa H, Iversen LH, Hill A, Hill J, Hoch J, Hompes R, Hurtado L, Iaquinandi F, Imbrasaite U, Islam R, Jafari MD, Salido AJ, Jiménez-Toscano M, Kanemitsu Y, Karachun A, Karimuddin AA, Keller DS, Kelly J, Kennelly R, Khrykov G, Kocian P, Koh C, et alREACCT Collaborative, Zaborowski AM, Adamina AAM, Aigner F, d'Allens L, Allmer C, Álvarez A, Anula R, Andric M, Bach SAS, Bala M, Barussaud M, Bausys A, Beggs A, Bellolio F, Bennett MR, Berdinskikh A, Bevan V, Biondo S, Bislenghi G, Bludau M, Brouwer N, Brown C, Bruns C, Buchanan DD, Buchwald P, Burger JW, Burlov N, Campanelli M, Capdepont M, Carvello M, Chew HH, Christoforidis D, Clark D, Climent M, Collinson R, Cologne KG, Contreras T, Croner R, Daniels IR, Dapri G, Davies J, Delrio P, Denost Q, Deutsch M, Dias A, D’Hoore A, Drozdov E, Duek D, Dunlop M, Dziki A, Edmundson A, Efetov S, El-Hussuna A, Elliot B, Emile S, Espin E, Evans M, Faes S, Faiz O, Figueiredo N, Fleming F, Foppa C, Fowler G, Frasson M, Forgan T, Frizelle F, Gadaev S, Gellona J, Glyn T, Goran B, Greenwood E, Guren MG, Guillon S, Gutlic I, Hahnloser D, Hampel H, Hanly A, Hasegawa H, Iversen LH, Hill A, Hill J, Hoch J, Hompes R, Hurtado L, Iaquinandi F, Imbrasaite U, Islam R, Jafari MD, Salido AJ, Jiménez-Toscano M, Kanemitsu Y, Karachun A, Karimuddin AA, Keller DS, Kelly J, Kennelly R, Khrykov G, Kocian P, Koh C, Kok N, Knight KA, Knol J, Kontovounisios C, Korner H, Krivokapic Z, Kronberger I, Kroon HM, Kryzauskas M, Kural S, Kusters M, Lakkis Z, Lankov T, Larson D, Lázár G, Lee KY, Lee SH, Lefèvre JH, Lepisto A, Lieu C, Loi L, Lynch C, Maillou-Martinaud H, Maroli A, Martin S, Martling A, Matzel KE, Mayol J, McDermott F, Meurette G, Millan M, Mitteregger M, Moiseenko A, Monson JRT, Morarasu S, Moritani K, Möslein G, Munini M, Nahas C, Nahas S, Negoi I, Novikova A, Ocares M, Okabayashi K, Olkina A, Oñate-Ocaña L, Otero J, Ozen C, Pace U, Julião GPS, Panaiotti L, Panis Y, Papamichael D, Patel S, Uriburu JCP, Peng SL, Pera M, Perez RO, Petrov A, Pfeffer F, Phang TP, Poskus T, Pringle H, Proud D, Raguz I, Rama N, Rasheed S, Raval MJ, Rega D, Reissfelder C, Meneses JCR, Ris F, Riss S, Rodriguez-Zentner H, Roxburgh CS, Saklani A, Sammour T, Saraste D, Schneider M, Seishima R, Sekulic A, Seppala T, Sheahan K, Shlomina A, Sigismondo G, Singnomklao T, Siragusa L, Smart N, Solis-Peña A, Spinelli A, Staiger RD, Stamos MJ, Steele S, Tan KK, Tanis PJ, Tekkis P, Teklay B, Tengku S, Tsarkov P, Turina M, Ulrich A, Vailati BB, van Harten M, Verhoef C, Warrier S, Wexner S, de Wilt H, Weinberg BA, Wells C, Wolthuis A, Xynos E, You N, Zakharenko A, Zeballos J, Zhou J, Winter DC. Impact of microsatellite status in early-onset colonic cancer. Br J Surg 2022; 109:632-636. [PMID: 35522613 DOI: 10.1093/bjs/znac108] [Show More Authors] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/04/2022] [Accepted: 03/11/2022] [Indexed: 11/14/2022]
Abstract
BACKGROUND The molecular profile of early-onset colonic cancer is undefined. This study evaluated clinicopathological features and oncological outcomes of young patients with colonic cancer according to microsatellite status. METHODS Anonymized data from an international collaboration were analysed. Criteria for inclusion were patients younger than 50 years diagnosed with stage I-III colonic cancer that was surgically resected. Clinicopathological features, microsatellite status, and disease-specific outcomes were evaluated. RESULTS A total of 650 patients fulfilled the criteria for inclusion. Microsatellite instability (MSI) was identified in 170 (26.2 per cent), whereas 480 had microsatellite-stable (MSS) tumours (relative risk of MSI 2.5 compared with older patients). MSI was associated with a family history of colorectal cancer and lesions in the proximal colon. The proportions with pathological node-positive disease (45.9 versus 45.6 per cent; P = 1.000) and tumour budding (20.3 versus 20.5 per cent; P = 1.000) were similar in the two groups. Patients with MSI tumours were more likely to have BRAF (22.5 versus 6.9 per cent; P < 0.001) and KRAS (40.0 versus 24.2 per cent; P = 0.006) mutations, and a hereditary cancer syndrome (30.0 versus 5.0 per cent; P < 0.001; relative risk 6). Five-year disease-free survival rates in the MSI group were 95.0, 92.0, and 80.0 per cent for patients with stage I, II, and III tumours, compared with 88.0, 88.0, and 65.0 per cent in the MSS group (P = 0.753, P = 0.487, and P = 0.105 respectively). CONCLUSION Patients with early-onset colonic cancer have a high risk of MSI and defined genetic conditions. Those with MSI tumours have more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers.
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Waidhauser J, Nerlinger P, Sommer F, Wolf S, Eser S, Löhr P, Rank A, Märkl B. Circulating Lymphocytes Reflect the Local Immune Response in Patients with Colorectal Carcinoma. Diagnostics (Basel) 2022; 12:diagnostics12061408. [PMID: 35741218 PMCID: PMC9221878 DOI: 10.3390/diagnostics12061408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/03/2022] [Accepted: 06/04/2022] [Indexed: 12/04/2022] Open
Abstract
Tumor-infiltrating lymphocytes (TILs) correlate with the number and size of the surrounding lymph nodes in patients with colorectal carcinoma (CRC) and reflect the quality of the antitumor immune response. In this prospective study, we analyzed whether this response correlated with the circulating lymphocytes in peripheral blood (PB). In 47 patients with newly diagnosed CRC, flow cytometry was performed to analyze the B cells, T cells, NK cells, and a variety of their subsets in PB. The results were correlated with TILs in the resected tumor and with the number and size of the surrounding lymph nodes in nodal negative (N- patients (LN5: number of lymph nodes measuring ≥5 mm) and the metastasis-to-lymph node size ratio (MSR) in nodal positive patients (N+). Differences between the number of TILs could be seen between N+ and N- patients, dependent on the LN5 and MSR categories, with higher values in N- cases and in patients with a higher LN5 category or a lower MSR. Additionally, higher values of various circulating lymphocyte subgroups were observed in these patients. For the total PB lymphocytes, CD8 cells, and some of their subgroups, a positive correlation with the TILs was found. This study shows that circulating lymphocytes—in particular, cytotoxic T cells—correlate with the local antitumor immune response displayed by TILs and lymph node activation. Our findings indicate that local and generalized antitumor immune responses are concordant with their different components.
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Affiliation(s)
- Johanna Waidhauser
- Department of Hematology and Oncology, Medical Faculty, University of Augsburg, 86156 Augsburg, Germany; (P.N.); (P.L.); (A.R.)
- Correspondence:
| | - Pia Nerlinger
- Department of Hematology and Oncology, Medical Faculty, University of Augsburg, 86156 Augsburg, Germany; (P.N.); (P.L.); (A.R.)
| | - Florian Sommer
- Department of General, Visceral and Transplant Surgery, Medical Faculty, University of Augsburg, 86156 Augsburg, Germany; (F.S.); (S.W.)
| | - Sebastian Wolf
- Department of General, Visceral and Transplant Surgery, Medical Faculty, University of Augsburg, 86156 Augsburg, Germany; (F.S.); (S.W.)
| | - Stefan Eser
- Department of Gastroenterology and Infectious Diseases, Medical Faculty, University of Augsburg, 86156 Augsburg, Germany;
| | - Phillip Löhr
- Department of Hematology and Oncology, Medical Faculty, University of Augsburg, 86156 Augsburg, Germany; (P.N.); (P.L.); (A.R.)
| | - Andreas Rank
- Department of Hematology and Oncology, Medical Faculty, University of Augsburg, 86156 Augsburg, Germany; (P.N.); (P.L.); (A.R.)
| | - Bruno Märkl
- General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, 86156 Augsburg, Germany;
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22
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The Association between Platelet Glycocalicin and High Microsatellite Instability in Colorectal Cancer. Gastroenterol Res Pract 2022; 2022:9012063. [PMID: 35432525 PMCID: PMC9010183 DOI: 10.1155/2022/9012063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 03/23/2022] [Indexed: 11/17/2022] Open
Abstract
Background. Elevated platelet volume is the risk factor for the development and poor overall survival of colorectal cancer (CRC) patients. Both microsatellite status and platelet glycoprotein Ibα (GPIbα) are related to platelet volume in CRC patients. This study aimed to investigate platelet GPIbα ectodomain (termed glycocalicin) levels among CRC patients and the association between the glycocalicin levels and microsatellite status in CRC. Methods. The clinical and laboratory data of 430 CRC patients between January 2018 and December 2018 in Harbin Medical University Cancer Hospital were collected. The microsatellite status was determined with a polymerase chain reaction. The participants were separated into high microsatellite instability (MSI-H) and microsatellite stable (MSS) groups according to microsatellite status. The glycocalicin levels were measured with an enzyme-linked immunosorbent assay, and the cut-off point was determined with the receiver-operating characteristics curve. The clinical and pathological characteristics were collected via electronic medical records. Logistic regression was used to explore the association between glycocalicin and microsatellite status. Results. Among the 430 CRC patients enrolled, 64 patients (14.9%) were identified as MSI-H and others as MSS CRC. Glycocalicin levels were significantly reduced in patients with MSI-H than those with MSS. After controlling for potential confounders, logistic regression analysis revealed that glycocalicin levels were independently associated with MSI-H CRC. Conclusions. Reduced glycocalicin levels are associated with the MSI-H subtype of CRC. Further research is needed to elucidate the mechanisms of the association between glycocalicin and MSI-H in CRC patients.
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23
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Yan XL, Wang K, Bao Q, Wang HW, Jin KM, Su YM, Xing BC. Prognostic value of the combination of primary tumor location and RAS mutational status on patients with colorectal liver metastasis undergoing hepatectomy. J Surg Oncol 2022; 125:1002-1012. [PMID: 35171534 DOI: 10.1002/jso.26816] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 12/23/2021] [Accepted: 01/17/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To assess prognostic influences of RAS mutational status and primary tumor site on cases with colorectal liver metastasis (CRLM) who underwent hepatectomy. METHODS Clinicopathological data of 762 patients with CRLM who underwent hepatectomy between January 2000 and November 2018 were retrospectively analyzed. The left-sided tumors (LST) included tumors located in the splenic flexure, descending colon, sigmoid colon, and rectum; while right-sided tumors (RST) included those located in the cecum, ascending colon, and transverse colon. RAS mutational status was determined using Sanger sequencing or next-generation sequencing, including KRAS (Codons 12, 13, and 61) and NRAS (Codons 12, 13, and 61), which were defined as wild-type (RASwt) and mutant-type (RASmut), respectively. Survival curves were plotted using the Kaplan-Meier plotter and compared by the log rank test. The clinicopathological data were analyzed using univariate and multivariate analyses. RESULTS The 5-year overall survival (OS) in the LST group was longer than that in the RST group (OS: 47.1% vs. 31.0%, p = 0.000, respectively), and the OS in the RASwt group was longer compared with that in the RASmut group (OS: 53.6% vs. 24.0%, p = 0.000). Besides, overall survival of the patients after hepatectomy was alternative, which was stratified by primary tumor site, with the 1-, 3-, and 5-year survival rates of 93.1%, 62.1%, and 47.1% for patients with LST, and 91.1%, 42.8%, and 31.0% for patients with RST, respectively. OS and disease-free survival (DFS) were significantly different stratified by RAS mutational status, with the 1-, 3-, and 5-year rates of 96.9%, 67.9%, and 53.6% for patients with RASwt tumors, and 85.7%, 41.5%, and 24.0% for patients with RASmut tumors, respectively. The 1-, 3-, and 5-year DFS rates were 51.9%, 30.0%, and 26.7% for patients with RASwt tumors, and 35.8%, 18.2%, and 14.9% for patients with RASmut tumors, respectively. The results of multivariate analysis showed that RAS mutational status and primary tumor site were both independent influencing factors of OS. CONCLUSION RAS mutational status and primary tumor site affect OS independently in CRLM patients undergoing hepatectomy. The worse prognosis of RST cannot be simply attributed to the imbalance of RAS mutational status in different primary tumor sites.
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Affiliation(s)
- Xiao-Luan Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatobiliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Kun Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatobiliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Quan Bao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatobiliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hong-Wei Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatobiliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ke-Min Jin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatobiliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yu-Ming Su
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatobiliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Bao-Cai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatobiliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
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Adhikari C, Bandyopadhyay R, Bandyopadhyay U, Sarkar S, Basu K. Mismatch repair protein deficiency assessed by immunohistochemistry in sporadic colorectal carcinoma. INDIAN J PATHOL MICR 2022; 66:252-257. [PMID: 37077064 DOI: 10.4103/ijpm.ijpm_531_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Context Globally, colorectal carcinoma (CRC) ranks the third most commonly diagnosed malignant disease, one of the leading causes of cancer deaths. Aims To study the spectrum of clinicopathological characteristics of sporadic colorectal carcinoma and to assess mismatch repair gene deficiency by the expression pattern of the proteins assessed by immunohistochemistry. Setting and Design Observational study conducted in a tertiary care hospital in West Bengal. Materials and Methods Fifty-two surgically resected specimens of CRC received from January 2018 to May 2019 were studied for clinical, morphological, MSI status. Statistical Analysis Used IBM SPSS 23. Results A total of 50% of the cases belonged to younger and 50% to the older population, with male predominance being 53.8%. The most common histologic type was adenocarcinoma (88.5%). The majority was found to be well-differentiated carcinoma (50%). The majority cases were of the T3 stage accounting to 38.5%. A total of 24 out of 52 cases (46.15%) had an absent expression of at least one mismatch repair (MMR) protein. A significant correlation was found between the young age group and microsatellite instability (MSI) with a P value of 0.001. A significant association was found between MSI and tumor differentiation with P value of 0.018. A significant association was found between MSH6 and histological type with P value of 0.012. A significant association was found between MSI and tumor stage with P value of 0.032. Conclusions This study shows a significantly higher number of sporadic colon cancers involving the young age group, and younger cases showed significant association with MSI. This alarming trend needs validation by studies involving larger populations and can be helpful prognostically as well as in formulating chemotherapeutic regimens.
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Zaborowski AM, Winter DC, Lynch L. The therapeutic and prognostic implications of immunobiology in colorectal cancer: a review. Br J Cancer 2021; 125:1341-1349. [PMID: 34302062 PMCID: PMC8575924 DOI: 10.1038/s41416-021-01475-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/13/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer represents the second leading cause of cancer-related death worldwide. The therapeutic field of immuno-oncology has rapidly gained momentum, with strikingly promising results observed in clinical practice. Increasing emphasis has been placed on the role of the immune response in tumorigenesis, therapy and predicting prognosis. Enhanced understanding of the dynamic and complex tumour-immune microenvironment has enabled the development of molecularly directed, individualised treatment. Analysis of intra-tumoural lymphocyte infiltration and the dichotomisation of colorectal cancer into microsatellite stable and unstable disease has important therapeutic and prognostic implications, with potential to capitalise further on this data. This review discusses the latest evidence surrounding the tumour biology and immune landscape of colorectal cancer, novel immunotherapies and the interaction of the immune system with each apex of the tripartite of cancer management (oncotherapeutics, radiotherapy and surgery). By utilising the synergy of chemotherapeutic agents and immunotherapies, and identifying prognostic and predictive immunological biomarkers, we may enter an era of unprecedented disease control, survivorship and cure rates.
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Affiliation(s)
- Alexandra M. Zaborowski
- grid.412751.40000 0001 0315 8143Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin 4, Ireland ,grid.8217.c0000 0004 1936 9705School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Des C. Winter
- grid.412751.40000 0001 0315 8143Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin 4, Ireland ,grid.7886.10000 0001 0768 2743School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Lydia Lynch
- grid.8217.c0000 0004 1936 9705School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland ,grid.38142.3c000000041936754XHarvard Institutes of Medicine, Harvard Medical School, Boston, MA USA
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Greco L, Rubbino F, Morelli A, Gaiani F, Grizzi F, de’Angelis GL, Malesci A, Laghi L. Epithelial to Mesenchymal Transition: A Challenging Playground for Translational Research. Current Models and Focus on TWIST1 Relevance and Gastrointestinal Cancers. Int J Mol Sci 2021; 22:11469. [PMID: 34768901 PMCID: PMC8584071 DOI: 10.3390/ijms222111469] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022] Open
Abstract
Resembling the development of cancer by multistep carcinogenesis, the evolution towards metastasis involves several passages, from local invasion and intravasation, encompassing surviving anoikis into the circulation, landing at distant sites and therein establishing colonization, possibly followed by the outgrowth of macroscopic lesions. Within this cascade, epithelial to mesenchymal transition (EMT) works as a pleiotropic program enabling cancer cells to overcome local, systemic, and distant barriers against diffusion by replacing traits and functions of the epithelial signature with mesenchymal-like ones. Along the transition, a full-blown mesenchymal phenotype may not be accomplished. Rather, the plasticity of the program and its dependency on heterotopic signals implies a pendulum with oscillations towards its reversal, that is mesenchymal to epithelial transition. Cells in intermixed E⇔M states can also display stemness, enabling their replication together with the epithelial reversion next to successful distant colonization. If we aim to include the EMT among the hallmarks of cancer that could modify clinical practice, the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers needs to be filled. We review the knowledge on EMT, derived from models and mechanistic studies as well as from translational studies, with an emphasis on gastrointestinal cancers (GI).
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Affiliation(s)
- Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Alessandra Morelli
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Fabio Grizzi
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy;
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy;
| | - Gian Luigi de’Angelis
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Alberto Malesci
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy;
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
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Foppa C, Francesca Bertuzzi A, Cianchi F, Carvello M, Maroli A, Wolthuis AM, Rimassa L, Laghi L, Montorsi M, D'Hoore AJL, Spinelli A. Rectal Cancer in Adolescent and Young Adult Patients: Pattern of Clinical Presentation and Case-Matched Comparison of Outcomes. Dis Colon Rectum 2021; 64:1064-1073. [PMID: 34397557 DOI: 10.1097/dcr.0000000000002022] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Rectal cancer in adolescents and young adults (age ≤39) is increasing. Early diagnosis is a challenge in this subset of patients. OBJECTIVE This study aims to analyze the presentation pattern and outcomes of sporadic rectal cancer in adolescents and young adults. DESIGN This is a retrospective study. SETTING This study was conducted at 3 European tertiary centers. PATIENTS Data on adolescents and young adults operated on for sporadic rectal cancer (January 2008 through October 2019) were analyzed. To compare outcomes, adolescents and young adults were matched to a group of patients aged ≥40 operated on during the same period. MAIN OUTCOME MEASURES The primary outcomes measured were clinical presentation and long-term outcomes. RESULTS Sporadic rectal cancers occurred in 101 adolescents and young adults (2.4%; mean age, 33.5; range, 18-39); 51.5% were male, and a smoking habit was reported by 17.8% of patients. The rate of a family history for colorectal cancer was 25.7%, and of these patients, 24.7% were obese. Diagnosis based on symptoms was reported in 92.1% patients, and the mean time from first symptoms to diagnosis was 13.7 months. The most common symptom at diagnosis was rectal bleeding (68.8%), and 12% and 34% of the adolescents and young adults presented with locally advanced or metastatic disease at diagnosis. Consequently, 68.3% and 62.4% adolescents and young adults received neoadjuvant and adjuvant treatments. The rate of complete pathological response was 24.1%; whereas 38.6% patients had stage IV disease, and 93.1% were microsatellite stable. At a mean follow-up of 5 years, no difference in cancer-specific survival, but a lower disease-free survival was reported in adolescents and young adults (p < 0.0001) vs the matched group. Adolescents and young adults with stages I to II disease had shorter cancer-specific survival and disease-free survival (p = 0.006; p < 0.0001); with stage III disease, they had a shorter disease-free survival (p = 0.01). LIMITATIONS This study was limited by its observational, retrospective design. CONCLUSIONS The significantly delayed diagnosis in adolescents and young adults may have contributed to the advanced disease at presentation and lower disease-free survival, even at earlier stages, suggesting a higher metastatic potential than in older patients. See Video Abstract at http://links.lww.com/DCR/B537. CNCER DE RECTO EN PACIENTES ADOLESCENTES Y ADULTOS JVENES CUADRO DE PRESENTACIN CLNICA Y COMPARACIN DE DESENLACES POR CASOS EMPAREJADOS ANTECEDENTES:El cáncer de recto en adolescentes y adultos jóvenes (edad ≤ 39) está aumentando. El diagnóstico temprano es un desafío en este subgrupo de pacientes.OBJETIVO:Analizar el cuadro de presentación y los desenlaces en adolescentes y adultos jóvenes con cáncer de recto esporádico.DISEÑO:Estudio retrospectivo.ÁMBITO:Tres centros europeos de tercer nivel.PACIENTES:Se analizaron los datos de adolescentes y adultos jóvenes operados de cáncer de recto esporádico (enero de 2008 - octubre de 2019). Para comparar los desenlaces se emparejó a adolescentes y adultos jóvenes con un grupo de pacientes mayores de 40 años operados en el mismo período de tiempo.PRINCIPALES VARIABLES ANALIZADAS:Cuadro clínico, resultados a largo plazo.RESULTADOS:Los cánceres de recto esporádicos en adolescentes y adultos jóvenes fueron 101 (2,4%, edad media: 33,5, rango 18-39). El 51,5% eran hombres, el 17,8% de los pacientes fumaba. El 25,7% tentía antecedentes familiares de cáncer colorrectal. El 24,7% eran obesos. El diagnóstico con base en los síntomas se informó en el 92,1% de los pacientes, el tiempo promedio desde los primeros síntomas hasta el diagnóstico fue de 13,7 meses. El síntoma más común en el momento del diagnóstico fue el sangrado rectal (68,8%). 12% y 34% de adolescentes y adultos jóvenes presentaron enfermedad localmente avanzada o metastásica en el momento del diagnóstico. Por lo tanto, el 68,3% y el 62,4% de adolescentes y adultos jóvenes recibieron neoadyuvancia y adyuvancia. La tasa de respuesta patológica completa fue del 24,1%; mientras que el 38,6% estaban en estadio IV. El 93,1% eran microsatelite estable. Con una media de seguimiento de 5 años, no se observaron diferencias en la sobrevida específica del cáncer, pero se informó una menor sobrevida libre de enfermedad en adolescentes y adultos jóvenes (p <0,0001) frente al grupo emparejado. Los adolescentes y adultos jóvenes en estadios I-II tuvieron una sobrevida específica por cáncer y una sobrevida libre de enfermedad más corta (p = 0,006; p <0,0001); el estadio III tuvo una sobrevida libre de enfermedad más baja (p = 0,01).LIMITACIONES:Diseño observacional y retrospectivo.CONCLUSIONES:El diagnóstico notablemente demorado en adolescentes y adultos jóvenes puede contribuir a la presentación de una enfermedad avanzada y a una menor sobrevida libre de enfermedad, incluso en estadios más tempranas, lo cual implica un mayor potencial metastásico en comparación con pacientes mayores. Consulte Video Resumen en http://links.lww.com/DCR/B537.
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Affiliation(s)
- Caterina Foppa
- IRCCS Humanitas Research Hospital, Division of Colon and Rectal Surgery, Rozzano, Milan, Italy
| | - Alexia Francesca Bertuzzi
- IRCCS Humanitas Research Hospital, Medical Oncology and Hematology Unit, Humanitas Cancer Center, Rozzano, Milan, Italy
| | - Fabio Cianchi
- Division of Digestive Surgery, Careggi University Hospital, Florence, Italy
| | - Michele Carvello
- IRCCS Humanitas Research Hospital, Division of Colon and Rectal Surgery, Rozzano, Milan, Italy
| | - Annalisa Maroli
- IRCCS Humanitas Research Hospital, Division of Colon and Rectal Surgery, Rozzano, Milan, Italy
| | - Albert M Wolthuis
- Department of Abdominal Surgery, University Hospital Leuven, Belgium
| | - Lorenza Rimassa
- IRCCS Humanitas Research Hospital, Medical Oncology and Hematology Unit, Humanitas Cancer Center, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Luigi Laghi
- IRCCS Humanitas Research Hospital, Division of Gastroenterology, Rozzano, Milan, Italy
| | - Marco Montorsi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IRCCS Humanitas Research Hospital, Division of General and Digestive Surgery, Rozzano, Milan, Italy
| | - André J L D'Hoore
- Department of Abdominal Surgery, University Hospital Leuven, Belgium
| | - Antonino Spinelli
- IRCCS Humanitas Research Hospital, Division of Colon and Rectal Surgery, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
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Kastrinos F, Ingram MA, Silver ER, Oh A, Laszkowska M, Rustgi AK, Hur C. Gene-Specific Variation in Colorectal Cancer Surveillance Strategies for Lynch Syndrome. Gastroenterology 2021; 161:453-462.e15. [PMID: 33839100 PMCID: PMC9330543 DOI: 10.1053/j.gastro.2021.04.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance with colonoscopy every 1-2 years starting at age 25 years for all carriers of Lynch syndrome-associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost. METHODS Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25-40 years), and surveillance intervals (1-5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold. RESULTS Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively. CONCLUSIONS We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome-associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome-associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.
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Affiliation(s)
- Fay Kastrinos
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York.
| | - Myles A Ingram
- Division of General Medicine, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York
| | - Elisabeth R Silver
- Division of General Medicine, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York
| | - Aaron Oh
- Division of General Medicine, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York
| | - Monika Laszkowska
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York
| | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York
| | - Chin Hur
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York; Division of General Medicine, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York
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Toh JWT, Phan K, Reza F, Chapuis P, Spring KJ. Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis. Int J Colorectal Dis 2021; 36:1573-1596. [PMID: 33604737 DOI: 10.1007/s00384-021-03874-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
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Affiliation(s)
- James W T Toh
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia. .,Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. .,Discipline of Surgery, The University of New South Wales, Sydney, NSW, Australia. .,Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia.
| | - Kevin Phan
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Faizur Reza
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Pierre Chapuis
- Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kevin J Spring
- Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia
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Schrecker C, Behrens S, Schönherr R, Ackermann A, Pauli D, Plotz G, Zeuzem S, Brieger A. SPTAN1 Expression Predicts Treatment and Survival Outcomes in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13143638. [PMID: 34298848 PMCID: PMC8305611 DOI: 10.3390/cancers13143638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/07/2021] [Accepted: 07/15/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is a common and deadly form of cancer. Non-erythroid spectrin αII (SPTAN1), a protein of the cytoskeleton, is thought to be involved in CRC development and progression. In this study, we explore whether measuring SPTAN1 levels in resected CRC specimens might help to predict patient survival outcomes and response to chemotherapy. Indeed, we find that higher SPTAN1 protein and mRNA levels in CRC specimens associate with longer patient survival times. Using cell culture experiments, we then show that cells with lower SPTAN1 levels are less susceptible to FOLFOX chemotherapy, a standard treatment regimen for patients with CRC. Overall, our study underscores the importance of cytoskeletal proteins in shaping tumour biology and treatment responses and nominates SPTAN1 as a biomarker to improve patient stratification and refine therapeutic decisions in CRC. Abstract Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality. In a cohort of 189 patients with CRC, we recently showed that expression of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1) was lower in advanced metastatic tumours. The aim of the present study was to clarify the association of intratumoural SPTAN1 expression levels with treatment and survival outcomes in patients with CRC. The analysis was based on histologic assessment of SPTAN1 protein levels in our own CRC cohort, and transcriptome data of 573 CRC cases from The Cancer Genome Atlas (TCGA). We first establish that high intratumoural levels of SPTAN1 protein and mRNA associate with favourable survival outcomes in patients with CRC. Next, a response prediction signature applied to the TCGA data reveals a possible link between high SPTAN1 transcript levels and improved patient responses to FOLFOX chemotherapy. Complementary in vitro experiments confirm that SPTAN1 knockdown strains of the colon cancer cell lines HT-29, HCT116 mlh1-2 and Caco-2 are less responsive to FOLFOX chemotherapy compared with SPTAN1-proficient control strains. Taken together, we identify SPTAN1 as a novel prognostic biomarker in CRC and show that SPTAN1 expression levels may predict patient responses to chemotherapy. These investigations illustrate how an affordable, histology-based diagnostic test could directly impact therapeutic decision-making at the bedside.
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Affiliation(s)
- Christopher Schrecker
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
- Correspondence: (C.S.); (A.B.); Tel.: +49-69-6301-6218 (A.B.)
| | - Sophia Behrens
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Rebecca Schönherr
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
- Faculty of Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria
| | - Anne Ackermann
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Daniel Pauli
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Guido Plotz
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Stefan Zeuzem
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Angela Brieger
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
- Correspondence: (C.S.); (A.B.); Tel.: +49-69-6301-6218 (A.B.)
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Cao Y, Zhang G, Zhang J, Yang Y, Ren J, Yan X, Wang Z, Zhao Z, Huang X, Bao H, Zhou J. Predicting Microsatellite Instability Status in Colorectal Cancer Based on Triphasic Enhanced Computed Tomography Radiomics Signatures: A Multicenter Study. Front Oncol 2021; 11:687771. [PMID: 34178682 PMCID: PMC8222982 DOI: 10.3389/fonc.2021.687771] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/17/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND This study aimed to develop and validate a computed tomography (CT)-based radiomics model to predict microsatellite instability (MSI) status in colorectal cancer patients and to identify the radiomics signature with the most robust and high performance from one of the three phases of triphasic enhanced CT. METHODS In total, 502 colorectal cancer patients with preoperative contrast-enhanced CT images and available MSI status (441 in the training cohort and 61 in the external validation cohort) were enrolled from two centers in our retrospective study. Radiomics features of the entire primary tumor were extracted from arterial-, delayed-, and venous-phase CT images. The least absolute shrinkage and selection operator method was used to retain the features closely associated with MSI status. Radiomics, clinical, and combined Clinical Radiomics models were built to predict MSI status. Model performance was evaluated by receiver operating characteristic curve analysis. RESULTS Thirty-two radiomics features showed significant correlation with MSI status. Delayed-phase models showed superior predictive performance compared to arterial- or venous-phase models. Additionally, age, location, and carcinoembryonic antigen were considered useful predictors of MSI status. The Clinical Radiomics nomogram that incorporated both clinical risk factors and radiomics parameters showed excellent performance, with an AUC, accuracy, and sensitivity of 0.898, 0.837, and 0.821 in the training cohort and 0.964, 0.918, and 1.000 in the validation cohort, respectively. CONCLUSIONS The proposed CT-based radiomics signature has excellent performance in predicting MSI status and could potentially guide individualized therapy.
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Affiliation(s)
- Yuntai Cao
- Department of Radiology, Affiliated Hospital of Qinghai University, Xining, China
- Second Clinical School, Lanzhou University, Lanzhou, China
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Medical Imaging, Lanzhou, China
| | - Guojin Zhang
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China
- Sichuan Academy of Medical Sciences Sichuan Provincial People's Hospital, Chengdu, China
| | - Jing Zhang
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China
- The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, China
| | - Yingjie Yang
- Department of Radiology, Second People’s Hospital of Lanzhou City, Lanzhou, China
| | - Jialiang Ren
- Department of Pharmaceuticals Diagnosis, GE Healthcare, Beijing, China
| | - Xiaohong Yan
- Department of Critical Medicine, Affiliated Hospital of Qinghai University, Xining, China
| | - Zhan Wang
- Department of Biomedical Engineering, Tsinghua University, Beijing, China
| | - Zhiyong Zhao
- Second Clinical School, Lanzhou University, Lanzhou, China
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Medical Imaging, Lanzhou, China
| | - Xiaoyu Huang
- Second Clinical School, Lanzhou University, Lanzhou, China
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Medical Imaging, Lanzhou, China
| | - Haihua Bao
- Department of Radiology, Affiliated Hospital of Qinghai University, Xining, China
| | - Junlin Zhou
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Medical Imaging, Lanzhou, China
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Bai J, Chen H, Bai X. Relationship between microsatellite status and immune microenvironment of colorectal cancer and its application to diagnosis and treatment. J Clin Lab Anal 2021; 35:e23810. [PMID: 33938589 PMCID: PMC8183910 DOI: 10.1002/jcla.23810] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/09/2021] [Accepted: 04/11/2021] [Indexed: 12/13/2022] Open
Abstract
Due to advances in understanding the immune microenvironment of colorectal cancer (CRC), microsatellite classification (dMMR/MSI-H and pMMR/MSS) has become a key biomarker for the diagnosis and treatment of CRC patients and therefore has important clinical value. Microsatellite status is associated with a variety of clinicopathological features and affects drug resistance and the prognosis of patients. CRC patients with different microsatellite statuses have different compositions and distributions of immune cells and cytokines within their tumor microenvironments (TMEs). Therefore, there is great interest in reversing or reshaping CRC TMEs to transform immune tolerant "cold" tumors into immune sensitive "hot" tumors. This requires a thorough understanding of differences in the immune microenvironments of MSI-H and MSS type tumors. This review focuses on the relationship between CRC microsatellite status and the immune microenvironment. It focuses on how this relationship has value for clinical application in diagnosis and treatment, as well as exploring the limitations of its current application.
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Affiliation(s)
- Junge Bai
- The Fourth Hospital of Harbin Medical UniversityHarbinChina
| | - Hongsheng Chen
- Department of General SurgeryThe Fourth Hospital of Harbin Medical UniversityHarbinChina
| | - Xuefeng Bai
- Department of Colorectal SurgeryHarbin Medical University Cancer HospitalHarbinChina
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Gaiani F, Marchesi F, Negri F, Greco L, Malesci A, de’Angelis GL, Laghi L. Heterogeneity of Colorectal Cancer Progression: Molecular Gas and Brakes. Int J Mol Sci 2021; 22:5246. [PMID: 34063506 PMCID: PMC8156342 DOI: 10.3390/ijms22105246] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/11/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
The review begins with molecular genetics, which hit the field unveiling the involvement of oncogenes and tumor suppressor genes in the pathogenesis of colorectal cancer (CRC) and uncovering genetic predispositions. Then the notion of molecular phenotypes with different clinical behaviors was introduced and translated in the clinical arena, paving the way to next-generation sequencing that captured previously unrecognized heterogeneity. Among other molecular regulators of CRC progression, the extent of host immune response within the tumor micro-environment has a critical position. Translational sciences deeply investigated the field, accelerating the pace toward clinical transition, due to its strong association with outcomes. While the perturbation of gut homeostasis occurring in inflammatory bowel diseases can fuel carcinogenesis, micronutrients like vitamin D and calcium can act as brakes, and we discuss underlying molecular mechanisms. Among the components of gut microbiota, Fusobacterium nucleatum is over-represented in CRC, and may worsen patient outcome. However, any translational knowledge tracing the multifaceted evolution of CRC should be interpreted according to the prognostic and predictive frame of the TNM-staging system in a perspective of clinical actionability. Eventually, we examine challenges and promises of pharmacological interventions aimed to restrain disease progression at different disease stages.
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Affiliation(s)
- Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, via Gramsci 14, 43126 Parma, Italy
| | - Federica Marchesi
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy; (F.M.); (A.M.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20132 Milan, Italy
| | - Francesca Negri
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy;
| | - Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy;
| | - Alberto Malesci
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy; (F.M.); (A.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy
| | - Gian Luigi de’Angelis
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, via Gramsci 14, 43126 Parma, Italy
| | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy;
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Zheng H, Bai Y, Wang J, Chen S, Zhang J, Zhu J, Liu Y, Wang X. Weighted Gene Co-expression Network Analysis Identifies CALD1 as a Biomarker Related to M2 Macrophages Infiltration in Stage III and IV Mismatch Repair-Proficient Colorectal Carcinoma. Front Mol Biosci 2021; 8:649363. [PMID: 33996905 PMCID: PMC8116739 DOI: 10.3389/fmolb.2021.649363] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022] Open
Abstract
Immunotherapy has achieved efficacy for advanced colorectal cancer (CRC) patients with a mismatch-repair-deficient (dMMR) subtype. However, little immunotherapy efficacy was observed in patients with the mismatch repair-proficient (pMMR) subtype, and hence, identifying new immune therapeutic targets is imperative for those patients. In this study, transcriptome data of stage III/IV CRC patients were retrieved from the Gene Expression Omnibus database. The CIBERSORT algorithm was used to quantify immune cellular compositions, and the results revealed that M2 macrophage fractions were higher in pMMR patients as compared with those with the dMMR subtype; moreover, pMMR patients with higher M2 macrophage fractions experienced shorter overall survival (OS). Subsequently, weighted gene co-expression network analysis and protein–protein interaction network analysis identified six hub genes related to M2 macrophage infiltrations in pMMR CRC patients: CALD1, COL6A1, COL1A2, TIMP3, DCN, and SPARC. Univariate and multivariate Cox regression analyses then determined CALD1 as the independent prognostic biomarker for OS. CALD1 was upregulated specifically the in CMS4 CRC subtype, and single-sample Gene Set Enrichment Analysis (ssGSEA) revealed that CALD1 was significantly correlated with angiogenesis and TGF-β signaling gene sets enrichment scores in stage III/IV pMMR CRC samples. The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm and correlation analysis revealed that CALD1 was significantly associated with multiple immune and stromal components in a tumor microenvironment. In addition, GSEA demonstrated that high expression of CALD1 was significantly correlated with antigen processing and presentation, chemokine signaling, leukocyte transendothelial migration, vascular smooth muscle contraction, cytokine–cytokine receptor interaction, cell adhesion molecules, focal adhesion, MAPK, and TGF-beta signaling pathways. Furthermore, the proliferation, invasion, and migration abilities of cancer cells were suppressed after reducing CALD1 expression in CRC cell lines. Taken together, multiple bioinformatics analyses and cell-level assays demonstrated that CALD1 could serve as a prognostic biomarker and a prospective therapeutic target for stage III/IV pMMR CRCs.
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Affiliation(s)
- Hang Zheng
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yuge Bai
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Jingui Wang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Shanwen Chen
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Junling Zhang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Jing Zhu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yucun Liu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Xin Wang
- Department of General Surgery, Peking University First Hospital, Beijing, China
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Toh JWT, Ferguson AL, Spring KJ, Mahajan H, Palendira U. Cytotoxic CD8+ T cells and tissue resident memory cells in colorectal cancer based on microsatellite instability and BRAF status. World J Clin Oncol 2021; 12:238-248. [PMID: 33959477 PMCID: PMC8085513 DOI: 10.5306/wjco.v12.i4.238] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/14/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory (TRM) cells with improved patient survival. It is unknown if TRM plays a role in colorectal cancer (CRC).
AIM To examine the potential role of TRM cells in providing immunogenicity in CRC stratified by microsatellite instability (MSI) and BRAF status.
METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry (IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera (Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in inForm 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.
RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ TRM cells in the MSI (BRAF mutant and wild type) group over the microsatellite stable (MSS) group. There was a statistically significant difference in CD8+ TRM between high level MSI (MSI-H):BRAF mutant [22.57, 95% confidence interval (CI): 14.31-30.84] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0076 andMSI-H:BRAF wild type [16.18 (95%CI: 10.44-21.93)] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells (both CD8+CD103- and CD8+CD103+TRM) between MSI-H: BRAF mutant and wild type CRC.
CONCLUSION This study has shown that CD8+ TRM are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ TRM may play a role in the immunogenicity in MSI-H CRC (BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of TRM cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.
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Affiliation(s)
- James Wei Tatt Toh
- Division of Surgery and Anaesthesia, Department of Colorectal Surgery, Westmead Hospital, Westmead Clinical School, The University of Sydney, Ingham Institute for Applied Medical Research, Westmead 2145, NSW, Australia
| | - Angela L Ferguson
- Department of Infectious Diseases and Immunology, School of Medical Sciences, Faculty of Medicine and Health, Human Viral & Cancer Immunology, Centenary Institute, Charles Perkin Centre, The University of Sydney, Sydney 2000, NSW, Australia
| | - Kevin J Spring
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool Hospital, Liverpool Clinical School, University of Western Sydney, South Western Clinical School UNSW, Liverpool 2170, NSW, Australia
| | - Hema Mahajan
- Department of Anatomical Pathology, ICPMR, Westmead Hospital, Westmead 2145, NSW, Australia
| | - Umaimainthan Palendira
- Department of Immunology and Infectious Diseases, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney 2000, NSW, Australia
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Pramil E, Dillard C, Escargueil AE. Colorectal Cancer and Immunity: From the Wet Lab to Individuals. Cancers (Basel) 2021; 13:cancers13071713. [PMID: 33916641 PMCID: PMC8038567 DOI: 10.3390/cancers13071713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Tackling the current dilemma of colorectal cancer resistance to immunotherapy is puzzling and requires novel therapeutic strategies to emerge. However, characterizing the intricate interactions between cancer and immune cells remains difficult because of the complexity and heterogeneity of both compartments. Developing rationales is intellectually feasible but testing them can be experimentally challenging and requires the development of innovative procedures and protocols. In this review, we delineated useful in vitro and in vivo models used for research in the field of immunotherapy that are or could be applied to colorectal cancer management and lead to major breakthroughs in the coming years. Abstract Immunotherapy is a very promising field of research and application for treating cancers, in particular for those that are resistant to chemotherapeutics. Immunotherapy aims at enhancing immune cell activation to increase tumor cells recognition and killing. However, some specific cancer types, such as colorectal cancer (CRC), are less responsive than others to the current immunotherapies. Intrinsic resistance can be mediated by the development of an immuno-suppressive environment in CRC. The mutational status of cancer cells also plays a role in this process. CRC can indeed be distinguished in two main subtypes. Microsatellite instable (MSI) tumors show a hyper-mutable phenotype caused by the deficiency of the DNA mismatch repair machinery (MMR) while microsatellite stable (MSS) tumors show a comparatively more “stable” mutational phenotype. Several studies demonstrated that MSI CRC generally display good prognoses for patients and immunotherapy is considered as a therapeutic option for this type of tumors. On the contrary, MSS metastatic CRC usually presents a worse prognosis and is not responsive to immunotherapy. According to this, developing new and innovative models for studying CRC response towards immune targeted therapies has become essential in the last years. Herein, we review the in vitro and in vivo models used for research in the field of immunotherapy applied to colorectal cancer.
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Affiliation(s)
- Elodie Pramil
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Alliance Pour la Recherche en Cancérologie—APREC, Tenon Hospital, F-75012 Paris, France
| | - Clémentine Dillard
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Alliance Pour la Recherche en Cancérologie—APREC, Tenon Hospital, F-75012 Paris, France
| | - Alexandre E. Escargueil
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Correspondence: ; Tel.: +33-(0)1-49-28-46-44
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Akce M, Zakka K, Jiang R, Williamson S, Alese OB, Shaib WL, Wu C, Behera M, El-Rayes BF. Impact of Tumor Side on Clinical Outcomes in Stage II and III Colon Cancer With Known Microsatellite Instability Status. Front Oncol 2021; 11:592351. [PMID: 33859934 PMCID: PMC8042136 DOI: 10.3389/fonc.2021.592351] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 01/28/2021] [Indexed: 12/24/2022] Open
Abstract
Background Tumor sidedness as a prognostic factor in advanced stage colon cancer (CC) is well established. The impact of tumor sidedness on the clinical outcomes of stage II and III CC has not been well studied. Methods The National Cancer Database (NCDB) was utilized to identify patients with pathological stage II and III primary adenocarcinoma of the colon from 2010 to 2015 using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490 and C18.0, 18.2,18.3, 18.5,18.6, 18.7. Univariate (UVA) and multivariable (MVA) survival analyses and Kaplan–Meier Curves with Log-rank test were utilized to compare overall survival (OS) based on tumor location and treatment received. Results A total of 35,071 patients with stage II (n = 17,629) and III (n = 17,442) CC were identified. 51.3% female; 81.5% Caucasian; median age 66 (range, 18–90). Majority of stage II and III tumors were right sided, 61.2% (n = 10,794) and 56.0% (n = 9,763). Microsatellite instability high (MSI-H) was more common in stage II compared to III, 23.3% (n = 4,115) vs 18.2% (n = 3,171) (p < 0.0001). In stage II MSI-H CC right was more common than left, 78.3% (n = 3223) vs 21.7% (n = 892). There was no significant difference in survival between stage II MSI-H left vs right (5-year OS 76.2 vs 74.7%, p = 0.1578). Stage II MSS CC right was more common than left, 56.0% (n = 7571) vs 44.0% (n = 5943), and survival was better in the left vs right (5-year OS 73.2 vs 70.8%, p = 0.0029). Stage III MSI-H CC was more common in the right than in the left, 75.6% (n = 2,397) vs 24.4% (n = 774) and survival was better in the left (5-year OS 62.5 vs 56.5%, p = 0.0026). Stage III MSS CC was more common in the right than in the left, 51.6% (n = 7,366) vs 48.4% (n = 6,905), and survival was better in the left vs right (5-year OS 67.0 vs 54.4%, p < 0.001). Conclusion Survival was better in left sided tumors compared to right in stage II MSS, stage III MSS, and stage III MSI-H CC.
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Affiliation(s)
- Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Katerina Zakka
- Department of Internal Medicine, Wellstar Health System, Atlanta Medical Center, Atlanta, GA, United States
| | - Renjian Jiang
- Winship Research Informatics, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Shayla Williamson
- Winship Research Informatics, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Olatunji B Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Walid L Shaib
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Christina Wu
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Madhusmita Behera
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States.,Winship Research Informatics, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Bassel F El-Rayes
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
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Is the Effect of Tumor Localization on Prognosis Compatible with Real-life Data in Metastatic Colon Cancer? Single-Center Experience: A Retrospective Analysis. J Gastrointest Cancer 2021; 53:7-15. [PMID: 33665720 DOI: 10.1007/s12029-021-00615-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 10/22/2022]
Abstract
AIM In recent years, the prognostic and predictive value of primary tumor localization in colon cancer has become increasingly important. This study aimed to retrospectively analyze the effect of colon cancer tumor localization on progression-free survival, overall survival, and response to treatments and present real-life data. METHOD Retrospective evaluation was made of 465 patients who were diagnosed with metastatic colorectal carcinoma between 2010 and 2015 in our clinic. The effect of primary tumor localization on progression-free survival, overall survival, and response to therapy was investigated. RESULTS The right colon cancer (RCC) was determined in 66 patients, 14.2% of the whole group, and left colorectal cancer (LCRC) in 399 patients which is 85.8% of patients. Mucinous adenocarcinoma was 16.7% in RCC; however, only 6.4% of LCRC had a mucinous tumor (p < 0.05). Nodal involvement in any stage (N1 and N2) was 46.9% in right colon cancer whereas in LCRC, it was 41.2% (p < 0.05). Primary tumor surgery (74.2% vs. 70.2%) and metastasectomy (33.3% vs. 19.4%) were also more common in RCC(p < 0.05). k-ras mutation status was similar in both groups (28.8% in RCC vs 26.8% in LCRC, p > 0.05). Median progression-free survival was 12.6 months in RCC, and 15.5 in LCRC (p > 0.05). Median overall survival was 28.4 months in RCC and 33.5 months in LCRC (p > 0.05). In k-ras wild-type patients, the median overall survival was 32.3 months (95% CI 25.2-39.5) in the anti-VEGF antibody treatment group and 55.1 months (95% CI 36.5-73.7) in the anti-EGFR antibody treatment group (p < 0.05). CONCLUSION Although tumors located in the right colon have been considered to be worse in terms of progression-free and overall survival in clinical trials, the results of this study showed that in daily practice, there was no difference between left and right colon localized tumors in progression-free and overall survival. Further, in k-ras wild-type colon cancers, tumor localization predicts the treatment response. This study is important with the presentation of real-life data and compatibility with the data of the studies to daily life.
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Zou Y, Hu X, Zheng S, Yang A, Li X, Tang H, Kong Y, Xie X. Discordance of immunotherapy response predictive biomarkers between primary lesions and paired metastases in tumours: A systematic review and meta-analysis. EBioMedicine 2021; 63:103137. [PMID: 33310681 PMCID: PMC7736926 DOI: 10.1016/j.ebiom.2020.103137] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/20/2020] [Accepted: 11/06/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Several biomarkers predict the efficacy of immunotherapy, which is essential for selecting patients who would potentially benefit. Discordant status of these biomarkers between primary tumours and paired metastases has been increasingly revealed. We aimed to comprehensively summarize the incidence of this phenomenon. METHODS Databases were searched to identify studies reporting primary-to-metastatic conversion of biomarkers, including programmed death ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), PD-L2, tumour-infiltrating lymphocyte (TIL), tumour mutational burden (TMB), and microsatellite instability (MSI). FINDINGS 56 studies with 2739 patients were included. The pooled discordance rate of PD-L1 was 22%. The percentage of PD-L1 changed from positive to negative was 41%, whereas that from negative to positive was 16%. The discordance rate for PD-1 and PD-L2 was 26% and 22%, respectively. TIL level was found with a discordance rate of 39%, and changes from high to low (50%) occurred more than that from low to high (16%). No significant difference in TMB was observed between two sites in most studies. MSI status discordance was found in 6% patients, with a percentage of 9% from MSI-high to microsatellite instable (MSS) and 0% from MSS to MSI-high. INTERPRETATION Our study demonstrates that PD-L1, PD-1, PD-L2, and TIL level had high frequency of discordance, while TMB and MSI status were less likely to change between primary tumours and paired metastases. Therefore, evaluating those frequently altered biomarkers of both primary and metastatic tumours is strongly recommended for precise clinical decision of immune checkpoint treatment. FUND: The National Natural Science Foundation of China (81872152).
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Affiliation(s)
- Yutian Zou
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, People's Republic of China
| | - Xiaoqian Hu
- School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, People's Republic of China
| | - Shaoquan Zheng
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, People's Republic of China
| | - Anli Yang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, People's Republic of China
| | - Xing Li
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, People's Republic of China
| | - Hailin Tang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, People's Republic of China
| | - Yanan Kong
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, People's Republic of China.
| | - Xiaoming Xie
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, People's Republic of China.
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Laghi L, Negri F, Gaiani F, Cavalleri T, Grizzi F, de’ Angelis GL, Malesci A. Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer. Int J Mol Sci 2020; 21:9680. [PMID: 33353162 PMCID: PMC7766746 DOI: 10.3390/ijms21249680] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/21/2022] Open
Abstract
Understanding molecular features of colon cancer has shed light on its pathogenesis and progression. Over time, some of these features acquired clinical dignity and were incorporated in decision making. Namely, microsatellite instability (MSI) due to mismatch repair of defects, which primarily was adopted for the diagnosis of Lynch syndrome, became recognized as the biomarker of a different disease type, showing a less aggressive behavior. MSI tumors harbor high amounts of tumor infiltrating lymphocytes (TILs) due to their peculiar load in neoantigens. However, microsatellite stable colon cancer may also show high amounts of TILs, and this feature is as well associated with better outcomes. High TIL loads are in general associated with a favorable prognosis, especially in stage II colon cancer, and therein identifies a patient subset with the lowest probability of relapse. With respect to post-surgical adjuvant treatment, particularly in stage III, TILs predictive ability seems to weaken along with the progression of the disease, being less evident in high risk patients. Moving from cohort studies to the analysis of a series from clinical trials contributed to increase the robustness of TILs as a biomarker. The employment of high TIL densities as an indicator of good prognosis in early-stage colon cancers is strongly advisable, while in late-stage colon cancers the employment as an indicator of good responsiveness to post-surgical therapy requires refinement. It remains to be clarified whether TILs could help in identifying those patients with node-positive cancers to whom adjuvant treatment could be spared, at least in low-risk groups as defined by the TNM staging system.
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Affiliation(s)
- Luigi Laghi
- Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy; (F.G.); (G.L.d.A.)
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy;
| | - Francesca Negri
- Medical Oncology Unit, University Hospital of Parma, 43121 Parma, Italy;
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy; (F.G.); (G.L.d.A.)
| | - Tommaso Cavalleri
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy;
| | - Fabio Grizzi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy;
| | - Gian Luigi de’ Angelis
- Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy; (F.G.); (G.L.d.A.)
| | - Alberto Malesci
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy;
- Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy
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Ricke J, Westphalen CB, Seidensticker M. Therapeutic Concepts for Oligometastatic Gastrointestinal Tumours. Visc Med 2020; 36:359-363. [PMID: 33178732 DOI: 10.1159/000509897] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 07/02/2020] [Indexed: 12/25/2022] Open
Abstract
Background Clinical trials have proven a survival benefit from applying local therapies for oligometastatic cancers of various origin. Summary Today, the definition of oligometa-static disease is based on limited lesion numbers and organ systems involved. Treatment guidelines by the European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO) and several other groups suggest a threshold of up to 5 tumours. Established biological markers indicating the aggressiveness of a given tumour (and therefore suggesting local treatment only or the addition of or complete switch to systemic therapies) are missing, except for disease-free survival, the only recommended parameter for patient selection beyond lesion count. Key Message The following article discusses clinical implications as well as local techniques established for the treatment of oligometastatic disease.
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Affiliation(s)
- Jens Ricke
- Klinik und Poliklinik für Radiologie, LMU Klinikum, Munich, Germany
| | - Christoph Benedikt Westphalen
- Medizinische Klinik und Poliklinik III und CCC München, Klinikum der Universität München, LMU München, Munich, Germany
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Nakamura Y, Hokuto D, Koyama F, Matsuo Y, Nomi T, Yoshikawa T, Kamitani N, Sadamitsu T, Takei T, Matsumoto Y, Iwasa Y, Fukuoka K, Obara S, Nakamoto T, Kuge H, Sho M. The prognosis and recurrence pattern of right- and left- sided colon cancer in Stage II, Stage III, and liver metastasis after curative resection. Ann Coloproctol 2020; 37:326-336. [PMID: 32972100 PMCID: PMC8566149 DOI: 10.3393/ac.2020.09.14] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 09/14/2020] [Indexed: 11/18/2022] Open
Abstract
Purpose Primary tumor location of colon cancer has been reported to affect the prognosis after curative resection. However, some reports suggested the impact was varied by tumor stage. This study analyzed the prognostic impact of the sidedness of colon cancer in stages II, III, and liver metastasis after curative resection using propensity-matched analysis. Methods Right-sided colon cancer was defined as a tumor located from cecum to splenic flexure, while any more distal colon cancer was defined as left-sided colon cancer. Patients who underwent curative resection at Nara Medical University hospital between 2000 and 2016 were analyzed. Results There were 110 patients with stage II, 100 patients with stage III, and 106 patients with liver metastasis. After propensity matching, 28 pairs with stage II and 32 pairs with stage III were identified. In the patients with stage II, overall survival (OS) and recurrence-free survival (RFS) were not significantly different for right- and left-sided colon cancers. In the patients with stage III, OS and RFS were significantly worse in right-sided colon cancer. In those with liver metastasis, OS of right-sided colon cancer was significantly worse than left-sided disease, while RFS was similar. Regarding metachronous liver metastasis, the difference was observed only in the patients whose primary colon cancer was stage III. In each stage, significantly higher rate of peritoneal recurrence was found in those with right-sided colon cancer. Conclusion Sidedness of colon cancer had a significant and varied prognostic impact in patients with stage II, III, and liver metastasis after curative resection.
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Affiliation(s)
- Yasuyuki Nakamura
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Daisuke Hokuto
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Fumikazu Koyama
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Yasuko Matsuo
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Takeo Nomi
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Takahiro Yoshikawa
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Naoki Kamitani
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Tomomi Sadamitsu
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Takeshi Takei
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Yayoi Matsumoto
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Yosuke Iwasa
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Kohei Fukuoka
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Shinsaku Obara
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Takayuki Nakamoto
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Hiroyuki Kuge
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan
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Shaib WL, Zakka KM, Jiang R, Yan M, Alese OB, Akce M, Wu C, Behera M, El-Rayes BF. Survival outcome of adjuvant chemotherapy in deficient mismatch repair stage III colon cancer. Cancer 2020; 126:4136-4147. [PMID: 32697360 DOI: 10.1002/cncr.33049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/11/2020] [Accepted: 05/31/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND The prognostic impact of DNA mismatch repair (MMR) status remains controversial in patients with stage III colon cancer who are treated with adjuvant chemotherapy (AC). The aim of this study was to evaluate the survival outcome of AC in deficient mismatch repair (dMMR)/microsatellite instable (MSI) stage III CC. METHODS Patients with pathological stage III CC between 2010 and 2013 were identified from the National Cancer Database using International Classification of Diseases for Oncology (3rd Edition) morphology and topography codes 8140, 8480, and C18.0-18.8. Patients with pathologic stage T3N2, T4N1, or T4N were considered high risk; patients with stage T3N1 were considered low risk. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazards models were used to identify the association between AC and overall survival (OS). RESULTS A total of 9226 patients with pathological stage III CC were identified, of which 2384 (25.8%) were MSI-high (MSI-H) and met the inclusion criteria of the final analysis. MSI-low (MSI-L) patients (n = 6842) were excluded. There was a preponderance of women (55.0% [n = 1311]), and 76.6% (n = 1825) of patients were non-Hispanic white. The median age was 65 years (range, 19-90 years). The primary sites were the cecum (29.7% [n = 707]), ascending colon (26.0% [n = 620]), sigmoid colon (17.2% [n = 410]), and transverse colon (10.8% [n = 257]). The most common tumor grade was moderately differentiated (n = 50.4% [1202]), followed by poorly differentiated (34.1% [n = 813]) and well differentiated (5.1% [n = 121]). High-risk pathologic stage III CC (T4N1, TxN2) constituted 51.0% (n = 1215) of the study population. High-risk stage III was associated with worse OS compared with low-risk stage III on univariate (P < .001) analysis and displayed a similar trend on multivariable analysis, without a statistically significant difference. Multiagent AC was associated with improved OS compared with no treatment on univariate (P < .001) and multivariable (P < .001) analysis. When stratified by risk status, multiagent AC was associated with improved OS compared with no treatment for high-risk (P < .001) and low-risk (P < .001) stage III disease. CONCLUSION Adjuvant chemotherapy is associated with better OS in stage III dMMR/MSI-H CC. An enhanced benefit was shown for high-risk stage III disease.
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Affiliation(s)
- Walid L Shaib
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Katerina M Zakka
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Renjian Jiang
- Winship Research Informatics, Emory University, Atlanta, Georgia
| | - Ming Yan
- Winship Research Informatics, Emory University, Atlanta, Georgia
| | - Olatunji B Alese
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Mehmet Akce
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Christina Wu
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Madhusmita Behera
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.,Winship Research Informatics, Emory University, Atlanta, Georgia
| | - Bassel F El-Rayes
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
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Lou L, Lv F, Wu X, Li Y, Zhang X. Clinical implications of mismatch repair deficiency screening in patients with mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN). Eur J Surg Oncol 2020; 47:323-330. [PMID: 32907775 DOI: 10.1016/j.ejso.2020.08.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/28/2020] [Accepted: 08/24/2020] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are rare tumors, mainly encountered in the gastroenteropancreatic tract. Based on the limited available data, MiNEN is usually a highly aggressive neoplasm combining a high-grade neuroendocrine and a non-neuroendocrine component, associated with a poor prognostic outlook. Deficient DNA mismatch repair (MMR) results in microsatellite instability, which is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. Little information on MMR status in MiNEN is available in published studies. Therefore, the purpose of this study was to explore the status and putative role of MMR on MiNEN. METHODS We investigated the MMR status in 44 cases and characterized their clinicopathological features and prognoses. Immunohistochemistry was performed for four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). RESULTS Mean age at diagnosis was 61 years, and 75% of the patients were male. Lymph node metastases were observed in 14 (35.9%) patients. The most common tumor localizations were gastric (28 patients, 63.6%). Lack of immunohistochemical expression of MMR proteins was shown in 38.6% of cases. The common deletion rates of one or more proteins were 29.4% (5/17) for MLH1/PMS2 and 23.5% (4/17) for MLH1. Correlation between clinicopathological parameters showed that MMR deficiency was significantly associated with early TNM stage and better prognoses in patients with MiNEN. CONCLUSION MiNENs showed frequent losses of MMR protein expression, which contributes to the knowledge of the pathological and clinical aspects of MiNEN tumors.
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Affiliation(s)
- Lei Lou
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, PR China; Laboratory of Pathology, Hebei Medical University, Shijiazhuang, Hebei Province, Shijiazhuang, Hebei, 050017, PR China
| | - Fengzhu Lv
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, Hebei Province, Shijiazhuang, Hebei, 050017, PR China
| | - Xin Wu
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, Hebei Province, Shijiazhuang, Hebei, 050017, PR China
| | - Yuehong Li
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, PR China
| | - Xianghong Zhang
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, PR China; Laboratory of Pathology, Hebei Medical University, Shijiazhuang, Hebei Province, Shijiazhuang, Hebei, 050017, PR China.
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Mukherji R, Marshall JL, Seeber A. Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives. Cancers (Basel) 2020; 12:E2001. [PMID: 32707813 PMCID: PMC7465976 DOI: 10.3390/cancers12082001] [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: 07/01/2020] [Revised: 07/17/2020] [Accepted: 07/18/2020] [Indexed: 02/08/2023] Open
Abstract
The selection of treatment according to genomic alterations is a standard approach in metastatic colorectal cancer but is only starting to have an impact in the earlier stages of the disease. The status if genes like KRAS, BRAF, and MMR has substantial survival implications, and concerted research efforts have revolutionized treatment towards precision oncology. In contrast, a genomic-based approach has not changed the adjuvant setting after curative tumor-resection in the daily routine so far. This review focuses on the current knowledge regarding prognostic and predictive genomic biomarkers in patients with locally advanced nonmetastasized colorectal cancer. Furthermore, we provide an outlook on future challenges for a personalized adjuvant treatment approach in patients with colorectal cancer.
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Affiliation(s)
- Reetu Mukherji
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - John L. Marshall
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck A-6020, Austria;
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Cappellesso R, Nicolè L, Zanco F, Lo Mele M, Fassina A, Ventura L, Rosa-Rizzotto E, Guido E, De Lazzari F, Pilati P, Tonello M, Fassan M, Rugge M. Synchronous nodal metastatic risk in screening detected and endoscopically removed pT1 colorectal cancers. Pathol Res Pract 2020; 216:152966. [PMID: 32360247 DOI: 10.1016/j.prp.2020.152966] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 04/02/2020] [Accepted: 04/11/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The population screening campaigns have resulted in increasing the prevalence of endoscopically resected colorectal cancers (CRCs) invading the submucosa (pT1). Synchronous nodal involvement occurs in less than 15 % of these tumors. Histologic criteria currently used for selecting patients needing resection are imprecise and most patients could have been simply followed-up. Tumor infiltrating lymphocytes (TILs) and mismatch repair (MMR) status impact on CRC prognosis. To identify patients requiring completion surgery, the value of histologic variables, TILs and MMR status as risk factors of nodal metastasis was investigated in screening detected and endoscopically removed pT1 CRCs. METHODS In 102 endoscopically resected pT1 CRCs, the cancer phenotype, CD3+ and CD8+ TILs, and MMR status were assessed. Univariate and multivariate analyses were used to evaluate the correlation with nodal metastasis. RESULTS Positive resection margin, evidence of vascular invasion and tumor budding, wide area of submucosal invasion, and high number of CD3+ TILs were associated with nodal metastasis in univariate analyses. Vascular invasion was statistically independent in multivariate analysis. Evidence of neoplastic cells in the vessels and/or at the excision border featured 5 out of 5 metastatic tumors and 13 out of 97 non-metastatic ones. CONCLUSIONS Completion surgery should be recommended only in pT1 CRC with vascular invasion or with tumor cells reaching the margin. In all other cases, the treatment choice should result from a multidisciplinary discussion on the patient-centered evaluation of the risk-benefit ratio.
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Affiliation(s)
- Rocco Cappellesso
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua 35121, Italy
| | - Lorenzo Nicolè
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua 35121, Italy
| | - Francesca Zanco
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua 35121, Italy
| | - Marcello Lo Mele
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua 35121, Italy
| | - Ambrogio Fassina
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua 35121, Italy
| | - Laura Ventura
- Department of Statistics, University of Padua, Padua 35121, Italy
| | | | - Ennio Guido
- Gastroenterology Unit, S. Antonio Hospital, Padua 35128, Italy
| | | | - Pierluigi Pilati
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology - I.R.C.S.S, Padua 35128, Italy
| | - Marco Tonello
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology - I.R.C.S.S, Padua 35128, Italy; Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua 35128, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua 35121, Italy.
| | - Massimo Rugge
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua 35121, Italy
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Ahmad-Nielsen SA, Bruun Nielsen MF, Mortensen MB, Detlefsen S. Frequency of mismatch repair deficiency in pancreatic ductal adenocarcinoma. Pathol Res Pract 2020; 216:152985. [PMID: 32360245 DOI: 10.1016/j.prp.2020.152985] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/13/2020] [Accepted: 04/15/2020] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has an ominous prognosis and there are only few treatment options. It is therefore crucial to investigate possible predictive markers that may improve the treatment of this disease. Mismatch repair (MMR) deficiency (d-MMR), meaning MMR protein loss (l-MMR) and/or microsatellite instability (MSI), is predictive of response to immunotherapy, but its frequency has to our knowledge not been elucidated in Scandinavian PDACs. Our aims were to examine the frequency of d-MMR in a Danish cohort of PDACs. We constructed multi-punch tissue microarrays (TMAs) using primary tumor tissue. Immunohistochemistry (IHC) for the DNA MMR proteins MLH1, MSH2, MSH6 and PMS2 was performed, and their expression was evaluated using a scoring system from 0 to 4. If the overall score was between 0-2 or if IHC was inconclusive for technical reasons, IHC on whole-tissue sections and MSI using PCR was performed. A final score of 0, 1-2 or 3-4 defined the tumor as l-MMR, MMR reduced (r-MMR) or MMR proficient. In total, 4/164 (2.4 %), 2/164 (1.2 %) and 3/164 (1.8 %) were l-MMR, r-MMR, or inconclusive based on IHC. MSI testing of these specimens showed that two of the four l-MMR tumors were MSI-high, while the remaining cases were microsatellite stable (MSS). In conclusion, in this study of Danish PDACss, d-MMR was found in a small proportion of the tumors. For these patients, individualized treatment using immunotherapy could be considered.
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Affiliation(s)
- Soz Abdulrahman Ahmad-Nielsen
- Department of Pathology, Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | | | - Michael Bau Mortensen
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; HPB Section, Department of Surgery, Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
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Laporte GA, Leguisamo NM, Gloria HDCE, Azambuja DB, Kalil AN, Saffi J. The role of double-strand break repair, translesion synthesis, and interstrand crosslinks in colorectal cancer progression-clinicopathological data and survival. J Surg Oncol 2020; 121:906-916. [PMID: 31650563 DOI: 10.1002/jso.25737] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/08/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND OBJECTIVES DNA repair is a new and important pathway that explains colorectal carcinogenesis. This study will evaluate the prognostic value of molecular modulation of double-strand break repair (XRCC2 and XRCC5); DNA damage tolerance/translesion synthesis (POLH, POLK, and POLQ), and interstrand crosslink repair (DCLRE1A) in sporadic colorectal cancer (CRC). METHODS Tumor specimens and matched healthy mucosal tissues from 47 patients with CRC who underwent surgery were assessed for gene expression of XRCC2, XRCC5, POLH, POLK, POLQ, and DCLRE1A; protein expression of Polk, Ku80, p53, Ki67, and mismatch repair MLH1 and MSH2 components; CpG island promoter methylation of XRCC5, POLH, POLK, POLQ, and DCLRE1A was performed. RESULTS Neoplastic tissues exhibited induction of POLK (P < .001) and DCLRE1A (P < .001) expression and low expression of POLH (P < .001) and POLQ (P < .001) in comparison to healthy paired mucosa. Low expression of POLH was associated with mucinous histology and T1-T2 tumors (P = .038); low tumor expression of POLK was associated with distant metastases (P = .042). CRC harboring POLK promoter methylation exhibited better disease-free survival (DFS) (P = .005). CONCLUSIONS This study demonstrated that low expression or unmethylated POLH and POLK were related to worse biological behavior tumors. However, POLK methylation was associated with better DFS. POLK and POLH are potential prognostic biomarkers in CRC.
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Affiliation(s)
- Gustavo A Laporte
- Division of Surgical Oncology, Santa Rita Hospital/ISCMPA, Porto Alegre, Brazil
- Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre/UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil
| | - Natália M Leguisamo
- Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre/UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil
- Institute of Cardiology of Rio Grande do Sul, University Foundation of Cardiology, Porto Alegre, Brazil
| | - Helena de Castro E Gloria
- Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre/UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil
| | | | - Antonio N Kalil
- Division of Surgical Oncology, Santa Rita Hospital/ISCMPA, Porto Alegre, Brazil
| | - Jenifer Saffi
- Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre/UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil
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Jang SR, Truong H, Oh A, Choi J, Tramontano AC, Laszkowska M, Hur C. Cost-effectiveness Evaluation of Targeted Surgical and Endoscopic Therapies for Early Colorectal Adenocarcinoma Based on Biomarker Profiles. JAMA Netw Open 2020; 3:e1919963. [PMID: 32150269 PMCID: PMC7063501 DOI: 10.1001/jamanetworkopen.2019.19963] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
IMPORTANCE Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. The prognosis for patients with CRC varies widely, but new prognostic biomarkers provide the opportunity to implement a more individualized approach to treatment selection. OBJECTIVE To assess the cost-effectiveness of 3 therapeutic strategies, namely, endoscopic therapy (ET), laparoscopic colectomy (LC), and open colectomy (OC), for patients with T1 CRC with biomarker profiles that prognosticate varying levels of tumor progression in the US payer perspective. DESIGN, SETTING, AND PARTICIPANTS In this economic evaluation study, a Markov model was developed for the cost-effectiveness analysis. Risks of all-cause mortality and recurrent cancer after ET, LC, or OC were estimated with a 35-year time horizon. Quality of life was based on EuroQoL 5 Dimensions scores reported in the published literature. Hospital and treatment costs reflected Medicare reimbursement rates. Deterministic and probabilistic sensitivity analyses were performed. Data from patients with T1 CRC and 6 biomarker profiles that included adenomatous polyposis coli (APC), TP53 and/or KRAS, or BRAFV600E were used as inputs for the model. Data analyses were conducted from February 27, 2019, to May 13, 2019. EXPOSURES Endoscopic therapy, LC, and OC. MAIN OUTCOMES AND MEASURES The primary outcomes were unadjusted life-years, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) between competing treatment strategies. RESULTS Endoscopic therapy had the highest QALYs and the lowest cost and was the dominant treatment strategy for T1 CRC with the following biomarker profiles: BRAFV600E, APC(1)/KRAS/TP53, APC(2) or APC(2)/KRAS or APC(2)/TP53, or APC(1) or APC(1)/KRAS or APC(1)/TP53. The QALYs gained ranged from 16.97 to 17.22, with costs between $68 902.75 and $77 784.53 in these subgroups. For the 2 more aggressive biomarker profiles with worse prognoses (APC(2)/KRAS/TP53 and APCwt [wild type]), LC was the most effective strategy (with 16.45 and 16.61 QALYs gained, respectively) but was not cost-effective. Laparoscopic colectomy cost $65 234.87 for APC(2)/KRAS/TP53 and $71 250.56 for APCwt, resulting in ICERs of $113 290 per QALY and $178 765 per QALY, respectively. CONCLUSIONS AND RELEVANCE This modeling analysis found that ET was the most effective strategy for patients with T1 CRC with less aggressive biomarker profiles. For patients with more aggressive profiles, LC was more effective but was costly, rendering ET the cost-effective option. This study highlights the potential utility of prognostic biomarkers in T1 CRC treatment selection.
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Affiliation(s)
- Se Ryeong Jang
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
- now with College of Population Health, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Han Truong
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
| | - Aaron Oh
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
| | - Jin Choi
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
| | - Angela C. Tramontano
- Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School, Boston
| | - Monika Laszkowska
- Department of Medicine, New York Presbyterian/Columbia University Medical Center, New York, New York
| | - Chin Hur
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
- Department of Medicine, New York Presbyterian/Columbia University Medical Center, New York, New York
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Coupez D, Hulo P, Touchefeu Y, Bossard C, Bennouna J. Pembrolizumab for the treatment of colorectal cancer. Expert Opin Biol Ther 2020; 20:219-226. [PMID: 31952453 DOI: 10.1080/14712598.2020.1718095] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Colorectal cancer (CRC) is one of the most frequent and lethal cancers in the world, and therapies are still insufficient. Immune checkpoint inhibitors (ICI) in metastatic CRC (mCRC) have not revolutionized treatment to the extent that they have in melanoma or renal carcinoma. Their use is limited to a molecular niche of mCRC with microsatellite instability (MSI). This review summarizes clinical data published with pembrolizumab in mCRC and also tries to identify potential new strategies.Areas covered: This paper focuses on pembrolizumab in mCRC. We screened all trials on PubMed and ClinicalTrials.gov and describe the most significant ones in our opinion.Expert opinion: Pembrolizumab seems to be effective in tumors with MSI-high status. It defines a new horizon for therapeutic strategy called 'agnostic' medicine. For microsatellite stable (MSS) colorectal cancers, the future challenge will be to successfully redraw the immune microenvironment to make it immunogenic with new therapeutic combinations, including ICI.
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Affiliation(s)
- Dahna Coupez
- Digestive Oncology, Institut Des Maladies De l'Appareil Digestif, Centre Hospitalier Universitaire De Nantes, Nantes, France
| | - Pauline Hulo
- Digestive Oncology, Institut Des Maladies De l'Appareil Digestif, Centre Hospitalier Universitaire De Nantes, Nantes, France.,Centre De Recherche En Cancérologie Et Immunologie Nantes-Angers (CRCINA), INSERM, Université d'Angers, Université De Nantes, Nantes, France
| | - Yann Touchefeu
- Digestive Oncology, Institut Des Maladies De l'Appareil Digestif, Centre Hospitalier Universitaire De Nantes, Nantes, France
| | - Céline Bossard
- Service d'Anatomie Et Cytologie Pathologiques, Centre Hospitalier Universitaire, Nantes, France
| | - Jaafar Bennouna
- Digestive Oncology, Institut Des Maladies De l'Appareil Digestif, Centre Hospitalier Universitaire De Nantes, Nantes, France.,Centre De Recherche En Cancérologie Et Immunologie Nantes-Angers (CRCINA), INSERM, Université d'Angers, Université De Nantes, Nantes, France
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