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Scanlon E, Lavery A, Albraikat M, Stevenson L, Kennedy C, Byrne R, Walker A, Mullan-Young B, McManus DT, Virdee PS, Elhussein L, Turbitt J, Collinson D, Miedzybrodzka Z, Van Schaeybroeck S, McQuaid S, James JA, Craig SG, Blayney JK, Petty RD, Harkin DP, Kennedy RD, Eatock MM, Middleton MR, Thomas A, Turkington RC. Immune microenvironment modulation following neoadjuvant therapy for oesophageal adenocarcinoma: a translational analysis of the DEBIOC clinical trial. ESMO Open 2024; 9:103930. [PMID: 39395265 PMCID: PMC11693431 DOI: 10.1016/j.esmoop.2024.103930] [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: 05/23/2024] [Revised: 08/21/2024] [Accepted: 09/05/2024] [Indexed: 10/14/2024] Open
Abstract
BACKGROUND The Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant oxaliplatin and capecitabine (Xelox) ± AZD8931 in oesophageal adenocarcinoma (OAC) but limited efficacy. We evaluated the impact of neoadjuvant Xelox ± AZD8931, a novel small-molecule inhibitor with equipotent activity against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2 and HER3, on biological pathways using a unique software-driven solution. PATIENTS AND METHODS Transcriptomic profiles from 25 pre-treatment formalin-fixed paraffin-embedded OAC biopsies and 18 matched resection specimens, treated with Xelox + AZD8931 (n = 16) and Xelox alone (n = 9), were analysed using the Almac claraT total mRNA report analysing 92 gene signatures, 100 unique single-gene drug targets and 7337 single genes across 10 hallmarks of cancer. Gene-set enrichment analysis (GSEA) was utilised to investigate pathways governing pathological response. Tumour-infiltrating lymphocytes (TILs) were assessed digitally using the QuPath software. RESULTS Hierarchical clustering identified three molecular subgroups classified by activation of innate immune signalling. The immune-high subgroup was associated with HER2 positivity, increased pathological response and a marked reduction in immune signalling and TILs following neoadjuvant therapy. The immune-low cluster was predominantly HER2/EGFR-negative, and EGFR positivity was associated with the immune-mixed subgroup. Treatment with neoadjuvant therapy induced common resistance mechanisms, such as angiogenesis and epithelial-mesenchymal transition signalling, and a reduction in DNA repair signatures. Addition of AZD8931 was associated with reduction of expression of EGFR, HER2 and AKT pathways and also promoted an immunosuppressive microenvironment. GSEA showed that patients with a pathological response to treatment had increased immune signalling, whereas non-responders to neoadjuvant therapy were enriched for nucleotide repair and cellular growth through the action of E2F transcription factors. CONCLUSION OAC may be subdivided into three immune-related subgroups which undergo modulation in response to neoadjuvant therapy with marked suppression of the immune microenvironment in HER2-positive/immune-high tumours.
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Affiliation(s)
- E Scanlon
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - A Lavery
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - M Albraikat
- Precision Medicine Centre of Excellence, The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - L Stevenson
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - C Kennedy
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - R Byrne
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - A Walker
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - B Mullan-Young
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - D T McManus
- Department of Pathology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast
| | - P S Virdee
- Centre for Statistics in Medicine, University of Oxford, Oxford
| | - L Elhussein
- Centre for Statistics in Medicine, University of Oxford, Oxford
| | - J Turbitt
- Medical Genetics, School of Medicine, Medical Sciences, Nutrition and Dentistry, University of Aberdeen, Aberdeen
| | - D Collinson
- Medical Genetics, School of Medicine, Medical Sciences, Nutrition and Dentistry, University of Aberdeen, Aberdeen
| | - Z Miedzybrodzka
- Medical Genetics, School of Medicine, Medical Sciences, Nutrition and Dentistry, University of Aberdeen, Aberdeen
| | - S Van Schaeybroeck
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - S McQuaid
- Precision Medicine Centre of Excellence, The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast; Department of Pathology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast; Northern Ireland Biobank, The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - J A James
- Precision Medicine Centre of Excellence, The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast; Department of Pathology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast; Northern Ireland Biobank, The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - S G Craig
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - J K Blayney
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast
| | - R D Petty
- Division of Molecular and Clinical Medicine, Ninewells Hospital and School of Medicine, University of Dundee, Dundee
| | - D P Harkin
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast; Almac Diagnostic Services Ltd, Craigavon
| | - R D Kennedy
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast; Almac Diagnostic Services Ltd, Craigavon
| | - M M Eatock
- Northern Ireland Cancer Centre, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast
| | - M R Middleton
- Department of Oncology, University of Oxford, Oxford
| | - A Thomas
- University of Leicester, Leicester, UK
| | - R C Turkington
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast.
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Wu H, Liu Q, Li J, Leng X, He Y, Liu Y, Zhang X, Ouyang Y, Liu Y, Liang W, Xu C. Tumor-Resident Microbiota-Based Risk Model Predicts Neoadjuvant Therapy Response of Locally Advanced Esophageal Squamous Cell Carcinoma Patients. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2309742. [PMID: 39268829 PMCID: PMC11538710 DOI: 10.1002/advs.202309742] [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: 12/12/2023] [Revised: 07/11/2024] [Indexed: 09/15/2024]
Abstract
Few predictive biomarkers exist for identifying patients who may benefit from neoadjuvant therapy (NAT). The intratumoral microbial composition is comprehensively profiled to predict the efficacy and prognosis of patients with esophageal squamous cell carcinoma (ESCC) who underwent NAT and curative esophagectomy. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis is conducted to screen for the most closely related microbiota and develop a microbiota-based risk prediction (MRP) model on the genera of TM7x, Sphingobacterium, and Prevotella. The predictive accuracy and prognostic value of the MRP model across multiple centers are validated. The MRP model demonstrates good predictive accuracy for therapeutic responses in the training, validation, and independent validation sets. The MRP model also predicts disease-free survival (p = 0.00074 in the internal validation set and p = 0.0017 in the independent validation set) and overall survival (p = 0.00023 in the internal validation set and p = 0.11 in the independent validation set) of patients. The MRP-plus model basing on MRP, tumor stage, and tumor size can also predict the patients who can benefit from NAT. In conclusion, the developed MRP and MRP-plus models may function as promising biomarkers and prognostic indicators accessible at the time of diagnosis.
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Affiliation(s)
- Hong Wu
- Department of Oncology & Cancer InstituteSichuan Academy of Medical SciencesSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan610072P. R. China
- Sichuan Cancer Hospital & InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduSichuan610041P. R. China
- Jinfeng LaboratoryChongqing400039P. R. China
- Yu‐Yue Pathology Scientific Research CenterChongqing400039P. R. China
| | - Qianshi Liu
- Department of Oncology & Cancer InstituteSichuan Academy of Medical SciencesSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan610072P. R. China
- Sichuan Cancer Hospital & InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduSichuan610041P. R. China
- Jinfeng LaboratoryChongqing400039P. R. China
- Yu‐Yue Pathology Scientific Research CenterChongqing400039P. R. China
| | - Jingpei Li
- Thoracic Surgery DepartmentThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong510230P. R. China
| | - Xuefeng Leng
- Sichuan Cancer Hospital & InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduSichuan610041P. R. China
| | - Yazhou He
- Department of OncologyWest China School of Public Health and West China Fourth HospitalSichuan UniversityChengduSichuan610041P. R. China
| | - Yiqiang Liu
- Department of Oncology & Cancer InstituteSichuan Academy of Medical SciencesSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan610072P. R. China
- Jinfeng LaboratoryChongqing400039P. R. China
| | - Xia Zhang
- Sichuan Cancer Hospital & InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduSichuan610041P. R. China
- Institute of Pathology and Southwest Cancer CenterMinistry of Education of ChinaSouthwest HospitalThird Military Medical University (Army Medical University) and Key Laboratory of Tumor ImmunopathologyChongqing400038P. R. China
| | - Yujie Ouyang
- Acupuncture and Massage CollegeChengdu University of Traditional Chinese MedicineChengduSichuan610072P. R. China
| | - Yang Liu
- Sichuan Cancer Hospital & InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduSichuan610041P. R. China
| | - Wenhua Liang
- Thoracic Surgery DepartmentThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong510230P. R. China
| | - Chuan Xu
- Department of Oncology & Cancer InstituteSichuan Academy of Medical SciencesSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan610072P. R. China
- Jinfeng LaboratoryChongqing400039P. R. China
- Yu‐Yue Pathology Scientific Research CenterChongqing400039P. R. China
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Chen P, Chen M, Bu Y, Che G, Cheng C, Wang Y. Prognostic role of lymph node regression in patients with esophageal cancer undergoing neoadjuvant therapy. Pathol Oncol Res 2024; 30:1611844. [PMID: 39464231 PMCID: PMC11502349 DOI: 10.3389/pore.2024.1611844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 09/19/2024] [Indexed: 10/29/2024]
Abstract
Purpose To clarify the prognostic value of lymph node regression (LNR) status including the lymph node regression grade (LNRG) and N downstaging in patients with esophageal cancer receiving neoadjuvant therapy based on available evidence. Methods Several databases were searched up to 25 March 2024. The main outcomes included overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were combined. Subgroup analyses based on the neoadjuvant therapy and pathological type were also conducted. Results In total, 14 retrospective studies with 3,212 participants were included. Nine and five studies explored the relationship between LNRG and N downstaging and survival, respectively. Pooled results indicated that complete LNR predicted significantly improved OS (HR = 0.47, 95% CI: 0.41-0.55, P < 0.001) and DFS (HR = 0.42, 95% CI: 0.32-0.55, P < 0.001) and subgroup analysis based on neoadjuvant therapy and pathological type manifested similar results. Besides, N downstaging was also significantly related to improved OS (HR = 0.40, 95% CI: 0.21-0.77, P = 0.006) and CSS (HR = 0.27, 95% CI: 0.12-0.60, P < 0.001). Conclusion LNR could serve as a novel and reliable prognostic factor in patients with esophageal cancer receiving neoadjuvant therapy and complete LNR and N downstaging predict better survival.
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Affiliation(s)
- Pingrun Chen
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Maojia Chen
- Animal Experiment Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yijie Bu
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Guowei Che
- Department of Thoracic Surgery/Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Chao Cheng
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Wang
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
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Gao B, Zhao Z, Gao X, Zhang T, Zhang N, Zhang Y, Zhu Y. Role of pathological tumor regression grade of lymph node metastasis following neoadjuvant chemotherapy in locally advanced gastric cancer. Dig Liver Dis 2024; 56:1768-1775. [PMID: 38811246 DOI: 10.1016/j.dld.2024.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 05/07/2024] [Accepted: 05/09/2024] [Indexed: 05/31/2024]
Abstract
AIMS To confirm whether the pathological response of lymph node metastasis (LNM) to neoadjuvant chemotherapy (NCT) can predict the prognosis of patients with gastric cancer (GC). METHODS A total of 979 patients with locally advanced GC were included. χ2 test was used to analyze the relationship between LNM TRG and clinicopathological factors. Cox proportional hazards model was used to analyze the relationship between LNM TRG, clinicopathological factors, and overall survival (OS). RESULTS A total of 21,162 lymph nodes were evaluated, with 237 patients (35.4%) in the response group and 433 patients (64.6%) in the non-response group. The non-responsive group was strongly associated with higher ypT, ypN, ypTNM, primary tumor (PT) TRG (all p < 0.001), positive cancer nodules (p = 0.001), and more distant LNM location (p < 0.001). Patients with the same PT TRG but different LNM TRG had different prognosis. There was no difference in OS between the responding and non-responding groups of LNM at location 2, 3, and M. YpN, tumor location, and LNM location were independent prognostic factors. CONCLUSIONS The combination of LNM TRG and PT TRG could better predict patient prognosis. Lymph node dissection should be routinely performed after NCT to provide the reference of radical resection.
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Affiliation(s)
- Bo Gao
- Department of Pathology, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital &Institute, Shenyang, China
| | - Zehua Zhao
- Department of Pathology, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital &Institute, Shenyang, China
| | - Xiaozhuo Gao
- Department of Pathology, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital &Institute, Shenyang, China
| | - Tao Zhang
- Department of Gastric Surgery,Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital &Institute, Shenyang, China
| | - Ning Zhang
- Department of Pathology, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital &Institute, Shenyang, China
| | - Yong Zhang
- Department of Pathology, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital &Institute, Shenyang, China.
| | - Yanmei Zhu
- Department of Pathology, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital &Institute, Shenyang, China.
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West MA, Rahman S, Jack S, Grocott MP, Levett DZ, Rashid Y, Griffiths J, Ezra M, Ayres L, Neville-Webbe H, Javed MS, Shrotri M, Khan I, Whitmore D, Prabhu P, Timbrell D, Allen S, Packham AO, Sharpe D, Anderson H, Minto G, McAleer S, McPhail S, Alasmar M, Hartley RA, Sultan J, Grace B, Underwood TJ, Byrne J, Noble F, Kelly J, Ansell G, Edwards M. Cardiopulmonary exercise variables and their association with postoperative morbidity and mortality after major oesophagogastric cancer surgery-a multicentre observational study. BJA OPEN 2024; 10:100289. [PMID: 38947220 PMCID: PMC11214286 DOI: 10.1016/j.bjao.2024.100289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/01/2024] [Indexed: 07/02/2024]
Abstract
Background Outcomes after oesophagogastric cancer surgery remain poor. Cardiopulmonary exercise testing (CPET) used for risk stratification before oesophagogastric cancer surgery is based on conflicting evidence. This study explores the relationship between CPET and postoperative outcomes, specifically for patients undergoing neoadjuvant treatment. Methods Patients undergoing oesophagogastric cancer resection and CPET (pre- or post-neoadjuvant treatment, or both) were retrospectively enrolled into a multicentre pooled cohort study. Oxygen uptake at peak exercise (VO2 peak) was compared with 1-yr postoperative survival. Secondary analyses explored relationships between patient characteristics, tumour pathology characteristics, CPET variables (absolute, relative to weight, ideal body weight, and body surface area), and postoperative outcomes (morbidity, 1-yr and 3-yr survival) were assessed using logistic regression analyses. Results Seven UK centres recruited 611 patients completing a 3-yr postoperative follow-up period. Oesophagectomy was undertaken in 475 patients (78%). Major complications occurred in 25%, with 18% 1-yr and 43% 3-yr mortality. No association between VO2 peak or other selected CPET variables and 1-yr survival was observed in the overall cohort. In the overall cohort, the anaerobic threshold relative to ideal body weight was associated with 3-yr survival (P=0.013). Tumour characteristics (ypT/ypN/tumour regression/lymphovascular invasion/resection margin; P<0.001) and Clavien-Dindo ≥3a (P<0.001) were associated with 1-yr and 3-yr survival. On subgroup analyses, pre-neoadjuvant treatment CPET; anaerobic threshold (absolute; P=0.024, relative to ideal body weight; P=0.001, body surface area; P=0.009) and VE/VCO2 at anaerobic threshold (P=0.026) were associated with 3-yr survival. No other CPET variables (pre- or post-neoadjuvant treatment) were associated with survival. Conclusions VO2 peak was not associated with 1-yr survival after oesophagogastric cancer resection. Tumour characteristics and major complications were associated with survival; however, only some selected pre-neoadjuvant treatment CPET variables were associated with 3-yr survival. CPET in this cohort of patients demonstrates limited outcome predictive precision. Clinical trial registration NCT03637647.
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Affiliation(s)
- Malcolm A. West
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Perioperative and Critical Care Theme, NIHR Southampton Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK
| | - Saqib Rahman
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Sandy Jack
- Perioperative and Critical Care Theme, NIHR Southampton Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Michael P.W. Grocott
- Perioperative and Critical Care Theme, NIHR Southampton Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Denny Z.H. Levett
- Perioperative and Critical Care Theme, NIHR Southampton Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - the Perioperative Exercise Testing and Training Society (POETTS)
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Perioperative and Critical Care Theme, NIHR Southampton Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Nuffield Department of Anaesthetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Departments of Anaesthesia and Critical Care, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
- Department of General Surgery, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
- Countess of Chester Hospital NHS Foundation Trust, Chester, UK
- Department of Anaesthetics, The Royal Surrey Foundation NHS Trust, Guildford, UK
- Anaesthetic Department, Frimley Park Hospital, Frimley Health NHS Foundation Trust, UK
- Department of General Surgery, The Royal Surrey NHS Foundation Trust Hospital, Minimal Access Therapy Training Unit (MATTU), Guildford, UK
- Department of Anaesthesia, University Hospitals of Leicester NHS Trust, Leicester, UK
- Department of Gastro-Intestinal Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK
- Directorate of Anaesthesia, University Hospitals Plymouth NHS Trust, Plymouth, UK
- Emergency Medical Retrieval and Transfer Service, Cymru, Joint Hospital Group (Southwest), UK
- Institute of Naval Medicine, Alverstoke, UK
- Salford Royal NHS Foundation Trust, Salford Royal, Salford, UK
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, UK
- University Hospitals Southampton, Department of Surgery, Southampton, UK
| | - Yasir Rashid
- Nuffield Department of Anaesthetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - John Griffiths
- Nuffield Department of Anaesthetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Martin Ezra
- Nuffield Department of Anaesthetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Lyndsay Ayres
- Departments of Anaesthesia and Critical Care, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Helen Neville-Webbe
- Departments of Anaesthesia and Critical Care, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
- Department of General Surgery, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Muhammad Shafiq Javed
- Department of General Surgery, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Milind Shrotri
- Department of General Surgery, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Iftikhar Khan
- Department of General Surgery, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - David Whitmore
- Departments of Anaesthesia and Critical Care, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
- Countess of Chester Hospital NHS Foundation Trust, Chester, UK
| | - Pradeep Prabhu
- Department of Anaesthetics, The Royal Surrey Foundation NHS Trust, Guildford, UK
| | - David Timbrell
- Department of Anaesthetics, The Royal Surrey Foundation NHS Trust, Guildford, UK
- Anaesthetic Department, Frimley Park Hospital, Frimley Health NHS Foundation Trust, UK
| | - Sophie Allen
- Department of General Surgery, The Royal Surrey NHS Foundation Trust Hospital, Minimal Access Therapy Training Unit (MATTU), Guildford, UK
| | - Andrew O. Packham
- Department of Anaesthesia, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - David Sharpe
- Department of Gastro-Intestinal Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Helen Anderson
- Directorate of Anaesthesia, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Gary Minto
- Directorate of Anaesthesia, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Samuel McAleer
- Directorate of Anaesthesia, University Hospitals Plymouth NHS Trust, Plymouth, UK
- Emergency Medical Retrieval and Transfer Service, Cymru, Joint Hospital Group (Southwest), UK
| | - Stuart McPhail
- Directorate of Anaesthesia, University Hospitals Plymouth NHS Trust, Plymouth, UK
- Institute of Naval Medicine, Alverstoke, UK
| | - Mohamed Alasmar
- Salford Royal NHS Foundation Trust, Salford Royal, Salford, UK
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, UK
| | - Robert A. Hartley
- Salford Royal NHS Foundation Trust, Salford Royal, Salford, UK
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, UK
| | - Javed Sultan
- Department of General Surgery, The Royal Surrey NHS Foundation Trust Hospital, Minimal Access Therapy Training Unit (MATTU), Guildford, UK
- Salford Royal NHS Foundation Trust, Salford Royal, Salford, UK
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, UK
| | - Ben Grace
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Timothy J. Underwood
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Perioperative and Critical Care Theme, NIHR Southampton Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK
- University Hospitals Southampton, Department of Surgery, Southampton, UK
| | - James Byrne
- University Hospitals Southampton, Department of Surgery, Southampton, UK
| | - Fergus Noble
- University Hospitals Southampton, Department of Surgery, Southampton, UK
| | - Jamie Kelly
- University Hospitals Southampton, Department of Surgery, Southampton, UK
| | - Gillian Ansell
- Perioperative and Critical Care Theme, NIHR Southampton Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- University Hospitals Southampton, Department of Surgery, Southampton, UK
| | - Mark Edwards
- Perioperative and Critical Care Theme, NIHR Southampton Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- University Hospitals Southampton, Department of Surgery, Southampton, UK
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Nie Y, Yao G, Wei Y, Wu S, Zhang W, Xu X, Li Q, Zhou F, Yang Z. Single-cell transcriptome sequencing analysis reveals intra-tumor heterogeneity in esophageal squamous cell carcinoma. ENVIRONMENTAL TOXICOLOGY 2024. [PMID: 38572681 DOI: 10.1002/tox.24243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 02/29/2024] [Accepted: 03/14/2024] [Indexed: 04/05/2024]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor of the digestive system that poses a significant threat to human life and health. It is crucial to thoroughly investigate the mechanisms of esophageal carcinogenesis and identify potential key molecular events in its carcinogenesis. Single-cell transcriptome sequencing is an emerging technology that has gained prominence in recent years for studying molecular mechanisms, which may help to further explore the underlying mechanisms of the ESCC tumor microenvironment in depth. The single-cell dataset was obtained from GSE160269 in the Gene Expression Omnibus database, including 60 tumor samples and four paracancer samples. The single-cell data underwent dimensional reduction clustering analysis to identify clusters and annotate expression profiles. Subcluster analysis was conducted for each cellular taxon. Copy number variation analysis of tumor cell subpopulations was performed to primarily identify malignant cells within them. A proposed chronological analysis was performed to obtain the process of cell differentiation. In addition, cell communication, transcription factor analysis, and tumor pathway analysis were also performed. Relevant risk models and key genes were established by univariate COX regression and LASSO analysis. The key genes obtained from the screen were subjected to appropriate silencing and cellular assays, including CCK-8, 5-ethynyl-2'-deoxyuridine, colony formation, and western blot. Single-cell analysis revealed that normal samples contained a large number of fibroblasts, T cells, and B cells, with fewer other cell types, whereas tumor samples exhibited a relatively balanced distribution of cell types. Subclassification analysis of immune cells, fibroblasts, endothelial cells, and epithelial cells revealed their specific spatial characteristics. The prognostic risk model, we constructed successfully, achieved accurate prognostic stratification for ESCC patients. The screened key gene, UPF3A, was found to be significantly associated with the development of ESCC by cellular assays. This process might be linked to the phosphorylation of ERK and P38. Single-cell transcriptome analysis successfully revealed the distribution of cell types and major expressed factors in ESCC patients, which could facilitate future in-depth studies on the therapeutic mechanisms of ESCC.
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Affiliation(s)
- Yuanliu Nie
- Tumor Research and Therapy Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, People's Republic of China
| | - Guangyue Yao
- Tumor Research and Therapy Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, People's Republic of China
| | - Yanjun Wei
- Department of Radiation Oncology, Weifang People's Hospital, Weifang, China
| | - Sheng Wu
- The Fourth Clinical College of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, People's Republic of China
| | - Wentao Zhang
- Postgraduate School, Shandong First Medical University(Shandong Academy of Medical Sciences), Jinan, Shandong, People's Republic of China
| | - Xiaoying Xu
- Shandong First Medical University, College of Basic Medicine, Shandong First Medical University-Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Qiang Li
- Tumor Research and Therapy Center，Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People's Republic of China
| | - Fengge Zhou
- Tumor Research and Therapy Center，Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People's Republic of China
| | - Zhe Yang
- Tumor Research and Therapy Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, People's Republic of China
- Tumor Research and Therapy Center，Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People's Republic of China
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7
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Yang Z, Guan F, Bronk L, Zhao L. Multi-omics approaches for biomarker discovery in predicting the response of esophageal cancer to neoadjuvant therapy: A multidimensional perspective. Pharmacol Ther 2024; 254:108591. [PMID: 38286161 DOI: 10.1016/j.pharmthera.2024.108591] [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: 08/23/2023] [Revised: 12/02/2023] [Accepted: 01/04/2024] [Indexed: 01/31/2024]
Abstract
Neoadjuvant chemoradiotherapy (NCRT) followed by surgery has been established as the standard treatment strategy for operable locally advanced esophageal cancer (EC). However, achieving pathologic complete response (pCR) or near pCR to NCRT is significantly associated with a considerable improvement in survival outcomes, while pCR patients may help organ preservation for patients by active surveillance to avoid planned surgery. Thus, there is an urgent need for improved biomarkers to predict EC chemoradiation response in research and clinical settings. Advances in multiple high-throughput technologies such as next-generation sequencing have facilitated the discovery of novel predictive biomarkers, specifically based on multi-omics data, including genomic/transcriptomic sequencings and proteomic/metabolomic mass spectra. The application of multi-omics data has shown the benefits in improving the understanding of underlying mechanisms of NCRT sensitivity/resistance in EC. Particularly, the prominent development of artificial intelligence (AI) has introduced a new direction in cancer research. The integration of multi-omics data has significantly advanced our knowledge of the disease and enabled the identification of valuable biomarkers for predicting treatment response from diverse dimension levels, especially with rapid advances in biotechnological and AI methodologies. Herein, we summarize the current status of research on the use of multi-omics technologies in predicting NCRT response for EC patients. Current limitations, challenges, and future perspectives of these multi-omics platforms will be addressed to assist in experimental designs and clinical use for further integrated analysis.
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Affiliation(s)
- Zhi Yang
- Department of Radiation Oncology, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi'an, China
| | - Fada Guan
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510, United States of America
| | - Lawrence Bronk
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States of America
| | - Lina Zhao
- Department of Radiation Oncology, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi'an, China.
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8
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Clements HA, Underwood TJ, Petty RD. Total neoadjuvant therapy in oesophageal and gastro-oesophageal junctional adenocarcinoma. Br J Cancer 2024; 130:9-18. [PMID: 37898721 PMCID: PMC10781745 DOI: 10.1038/s41416-023-02458-w] [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: 04/01/2023] [Revised: 09/07/2023] [Accepted: 09/28/2023] [Indexed: 10/30/2023] Open
Abstract
Adenocarcinoma of the oesophagus and gastro-oesophageal junction represent a large burden of cancer death in the Western World with an increasing incidence. In the past two decades, the overall survival of patients on a potentially curative treatment pathway has more than doubled due to the addition of perioperative oncological therapies to surgery. However, patients often fail to respond to oncological treatment or struggle to complete their treatment after surgery. In this review, we discuss the current evidence for total neoadjuvant therapy and options for assessment of treatment response.
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Affiliation(s)
- Hollie A Clements
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
| | - Tim J Underwood
- School of Cancer Sciences, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Russell D Petty
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
- Tayside Cancer Centre, Ninewells Hospital and Medical School, NHS Tayside, Dundee, UK
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9
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Withey SJ, Owczarczyk K, Grzeda MT, Yip C, Deere H, Green M, Maisey N, Davies AR, Cook GJ, Goh V. Association of dynamic contrast-enhanced MRI and 18F-Fluorodeoxyglucose PET/CT parameters with neoadjuvant therapy response and survival in esophagogastric cancer. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:106934. [PMID: 37183047 PMCID: PMC10769883 DOI: 10.1016/j.ejso.2023.05.009] [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: 07/27/2022] [Revised: 04/17/2023] [Accepted: 05/09/2023] [Indexed: 05/16/2023]
Abstract
INTRODUCTION Better predictive markers are needed to deliver individualized care for patients with primary esophagogastric cancer. This exploratory study aimed to assess whether pre-treatment imaging parameters from dynamic contrast-enhanced MRI and 18F-fluorodeoxyglucose (18F-FDG) PET/CT are associated with response to neoadjuvant therapy or outcome. MATERIALS AND METHODS Following ethical approval and informed consent, prospective participants underwent dynamic contrast-enhanced MRI and 18F-FDG PET/CT prior to neoadjuvant chemotherapy/chemoradiotherapy ± surgery. Vascular dynamic contrast-enhanced MRI and metabolic 18F-FDG PET parameters were compared by tumor characteristics using Mann Whitney U test and with pathological response (Mandard tumor regression grade), recurrence-free and overall survival using logistic regression modelling, adjusting for predefined clinical variables. RESULTS 39 of 47 recruited participants (30 males; median age 65 years, IQR: 54, 72 years) were included in the final analysis. The tumor vascular-metabolic ratio was higher in patients remaining node positive following neoadjuvant therapy (median tumor peak enhancement/SUVmax ratio: 0.052 vs. 0.023, p = 0.02). In multivariable analysis adjusted for age, gender, pre-treatment tumor and nodal stage, peak enhancement (highest gadolinium concentration value prior to contrast washout) was associated with pathological tumor regression grade. The odds of response decreased by 5% for each 0.01 unit increase (OR 0.95; 95% CI: 0.90, 1.00, p = 0.04). No 18F-FDG PET/CT parameters were predictive of pathological tumor response. No relationships between pre-treatment imaging and survival were identified. CONCLUSION Pre-treatment esophagogastric tumor vascular and metabolic parameters may provide additional information in assessing response to neoadjuvant therapy.
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Affiliation(s)
- Samuel J Withey
- Department of Radiology, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom
| | - Kasia Owczarczyk
- Department of Clinical Oncology, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom
| | - Mariusz T Grzeda
- School of Biomedical Engineering & Imaging Sciences, King's College London, United Kingdom
| | - Connie Yip
- Department of Radiation Oncology, National Cancer Centre, Singapore
| | - Harriet Deere
- Department of Pathology, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom
| | - Mike Green
- Department of Pathology, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom
| | - Nick Maisey
- Department of Medical Oncology, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom
| | - Andrew R Davies
- Department of Surgery, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom
| | - Gary J Cook
- School of Biomedical Engineering & Imaging Sciences, King's College London, United Kingdom; The King's College London and Guy's and St Thomas' PET Centre, St Thomas' Hospital, London, United Kingdom
| | - Vicky Goh
- Department of Radiology, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom; School of Biomedical Engineering & Imaging Sciences, King's College London, United Kingdom.
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10
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Moore JL, Green M, Santaolalla A, Deere H, Evans RPT, Elshafie M, Lavery A, McManus DT, McGuigan A, Douglas R, Horne J, Walker R, Mir H, Terlizzo M, Kamarajah SK, Van Hemelrijck M, Maisey N, Sita-Lumsden A, Ngan S, Kelly M, Baker CR, Kumar S, Lagergren J, Allum WH, Gossage JA, Griffiths EA, Grabsch HI, Turkington RC, Underwood TJ, Smyth EC, Fitzgerald RC, Cunningham D, Davies AR. Pathologic Lymph Node Regression After Neoadjuvant Chemotherapy Predicts Recurrence and Survival in Esophageal Adenocarcinoma: A Multicenter Study in the United Kingdom. J Clin Oncol 2023; 41:4522-4534. [PMID: 37499209 DOI: 10.1200/jco.23.00139] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/03/2023] [Accepted: 05/24/2023] [Indexed: 07/29/2023] Open
Abstract
PURPOSE There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma. METHODS Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index. RESULTS In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). CONCLUSION Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.
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Affiliation(s)
- Jonathan L Moore
- Department of Upper Gastrointestinal and General Surgery, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
| | - Michael Green
- Department of Histopathology, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Aida Santaolalla
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
| | - Harriet Deere
- Department of Histopathology, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Richard P T Evans
- Department of Upper Gastrointestinal Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Mona Elshafie
- Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Anita Lavery
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom
| | - Damian T McManus
- Department of Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom
| | - Andrew McGuigan
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom
| | - Rosalie Douglas
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom
| | - Joanne Horne
- Department of Histopathology, University Hospitals Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Robert Walker
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Hira Mir
- Department of Histopathology, The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Monica Terlizzo
- Department of Histopathology, The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Sivesh K Kamarajah
- Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Mieke Van Hemelrijck
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
| | - Nick Maisey
- Department of Medical Oncology, St Thomas' Hospital, London, United Kingdom
| | - Ailsa Sita-Lumsden
- Department of Medical Oncology, St Thomas' Hospital, London, United Kingdom
| | - Sarah Ngan
- Department of Medical Oncology, St Thomas' Hospital, London, United Kingdom
| | - Mark Kelly
- Department of Upper Gastrointestinal and General Surgery, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
| | - Cara R Baker
- Department of Upper Gastrointestinal and General Surgery, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
| | - Sacheen Kumar
- Department of Upper Gastrointestinal Surgery, The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Jesper Lagergren
- Department of Upper Gastrointestinal and General Surgery, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - William H Allum
- Department of Upper Gastrointestinal Surgery, The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - James A Gossage
- Department of Upper Gastrointestinal and General Surgery, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
| | - Ewen A Griffiths
- Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, the Netherlands
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Richard C Turkington
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom
| | - Tim J Underwood
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Elizabeth C Smyth
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Rebecca C Fitzgerald
- Early Cancer Institute, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University NHS Foundation Trust, Cambridge, United Kingdom
| | - David Cunningham
- Department of Medical Oncology, The Royal Marsden Hospital, London, United Kingdom
| | - Andrew R Davies
- Department of Upper Gastrointestinal and General Surgery, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
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11
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Takashima Y, Komatsu S, Ohashi T, Kiuchi J, Nishibeppu K, Kamiya H, Arakawa H, Ishida R, Shimizu H, Arita T, Konishi H, Shiozaki A, Kubota T, Fujiwara H, Otsuji E. Plasma miR-1254 as a predictive biomarker of chemosensitivity and a target of nucleic acid therapy in esophageal cancer. Cancer Sci 2023; 114:3027-3040. [PMID: 37190912 PMCID: PMC10323105 DOI: 10.1111/cas.15830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/06/2023] [Accepted: 04/09/2023] [Indexed: 05/17/2023] Open
Abstract
This study investigated novel tumor suppressor microRNAs (miRNAs) that decrease in plasma and predict chemosensitivity to neoadjuvant chemotherapy (NAC) for esophageal squamous cell carcinoma (ESCC) and revealed their usefulness as novel therapeutic agents. We selected four miRNA candidates (miR-323, 345, 409, and 1254) based on the microRNA microarray comparing pre-treatment plasma levels in ESCC patients with high and low histopathological responses to NAC and an NCBI database review. Among these miRNA candidates, miR-1254 was more highly elevated in pre-treatment plasma of ESCC patients with a high histopathological response than in those with a low histopathological response (P = 0.0021, area under the receiver-operating characteristic curve 0.7621). High plasma miR-1254 levels tended to correlate with the absence of venous invasion (P = 0.0710) and were an independent factor predicting a higher response to chemotherapy (P = 0.0022, odds ratio 7.86) and better prognosis (P = 0.0235, hazard ratio 0.23). Overexpressing miR-1254 in ESCC cells significantly enhanced chemosensitivity to cisplatin through the transcriptional regulation of ABCC1 in vitro. Moreover, increased plasma miR-1254 levels by subcutaneous injection significantly improved responses to cisplatin in mice. Plasma miR-1254 might be a useful biomarker for predicting responses to NAC, and the restoration of plasma miR-1254 levels might improve chemosensitivity in ESCC.
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Affiliation(s)
- Yusuke Takashima
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Shuhei Komatsu
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Takuma Ohashi
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Jun Kiuchi
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Keiji Nishibeppu
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hajime Kamiya
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hiroshi Arakawa
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Ryo Ishida
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hiroki Shimizu
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Tomohiro Arita
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hirotaka Konishi
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Atsushi Shiozaki
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Takeshi Kubota
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hitoshi Fujiwara
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Eigo Otsuji
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
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12
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Gujjuri RR, Clarke JM, Elliott JA, Rahman SA, Reynolds JV, Hanna GB, Markar SR. Predicting long-term survival and time-to-recurrence after esophagectomy in patients with esophageal cancer - Development and validation of a multivariate prediction model. Ann Surg 2023; 277:971-978. [PMID: 37193219 PMCID: PMC7614526 DOI: 10.1097/sla.0000000000005538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Rohan R Gujjuri
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Imperial College London, Department of Surgery and Cancer, St Mary’s Hospital Campus, Praed Street, W2 1NY, United Kingdom
| | - Jonathan M Clarke
- Centre for Mathematics of Precision Healthcare, Department of Mathematics, Imperial College London, SW7 2AZ, United Kingdom
| | - Jessie A Elliott
- Trinity St. James’s Cancer Institute, Trinity College Dublin, and St. James’s Hospital, Dublin, Ireland
| | - Saqib A Rahman
- School of Cancer Sciences, Faculty of Medicine, University of Southampton
| | - John V Reynolds
- Trinity St. James’s Cancer Institute, Trinity College Dublin, and St. James’s Hospital, Dublin, Ireland
| | - George B Hanna
- Imperial College London, Department of Surgery and Cancer, St Mary’s Hospital Campus, Praed Street, W2 1NY, United Kingdom
| | - Sheraz R Markar
- Imperial College London, Department of Surgery and Cancer, St Mary’s Hospital Campus, Praed Street, W2 1NY, United Kingdom
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
- Nuffield Department of Surgery, University of Oxford, United Kingdom
| | - ENSURE Group Study
- Young Investigator Division, European Society for Diseases of the Esophagus
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13
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Athauda A, Nankivell M, Langer R, Pritchard S, Langley RE, von Loga K, Starling N, Chau I, Cunningham D, Grabsch HI. Pathological regression of primary tumour and metastatic lymph nodes following chemotherapy in resectable OG cancer: pooled analysis of two trials. Br J Cancer 2023; 128:2036-2043. [PMID: 36966233 PMCID: PMC10206103 DOI: 10.1038/s41416-023-02217-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 12/12/2022] [Accepted: 02/23/2023] [Indexed: 03/27/2023] Open
Abstract
BACKGROUND No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy and the impact on survival. METHODS Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis. RESULTS Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable. CONCLUSIONS Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further.
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Affiliation(s)
- Avani Athauda
- Department of Gastrointestinal Oncology and Lymphoma, The Royal Marsden NHS Foundation Trust, London, UK
| | - Matthew Nankivell
- Medical Research Council Clinical Trials Unit, University College London, London, UK
| | - Rupert Langer
- Klinisches Institut fur Pathologie und Molekularpathologie, Kepler Universitatsklinikum, Linz, Austria
| | - Susan Pritchard
- Department of Pathology, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
| | - Ruth E Langley
- Medical Research Council Clinical Trials Unit, University College London, London, UK
| | - Katharina von Loga
- Department of Gastrointestinal Oncology and Lymphoma, The Royal Marsden NHS Foundation Trust, London, UK
| | - Naureen Starling
- Department of Gastrointestinal Oncology and Lymphoma, The Royal Marsden NHS Foundation Trust, London, UK
| | - Ian Chau
- Department of Gastrointestinal Oncology and Lymphoma, The Royal Marsden NHS Foundation Trust, London, UK
| | - David Cunningham
- Department of Gastrointestinal Oncology and Lymphoma, The Royal Marsden NHS Foundation Trust, London, UK.
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands.
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's University, University of Leeds, Leeds, UK.
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14
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Su P, Zhang Y, Yu T, Jiang L, Kang W, Liu Y, Yu J. Comparison of the predictive value of pathological response at primary tumor and lymph node status after neoadjuvant chemotherapy in locally advanced gastric cancer. Clin Transl Oncol 2023:10.1007/s12094-023-03130-8. [PMID: 37093455 DOI: 10.1007/s12094-023-03130-8] [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: 12/10/2022] [Accepted: 02/20/2023] [Indexed: 04/25/2023]
Abstract
BACKGROUND Preoperative chemotherapy has been increasingly used in locally advanced gastric cancer (LAGC). However, the prognostic factors are still insufficient. This study aimed to investigate the prognostic significance of pathological response of the primary tumor to neoadjuvant chemotherapy (NACT) and the lymph node status after NACT. METHODS Data from 160 patients with LAGC treated with NACT followed by gastrectomy and met the inclusion criteria between March 2016 and December 2019 were retrospectively reviewed. Pathological evaluation after NACT was based on the grade of pathological response of the primary tumor and the status of lymph node. Survival curves for overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival difference. Univariate and multivariate analyses for prognostic factors were based on the Cox regression. RESULTS Among 160 selected cases, 90 had pathological response (PR), while 70 had no pathological response (nPR) to NACT. Smaller tumor size was presented in PR group, which also had lower level of signet ring cell features, compared to nPR group (all p < 0.05). Based on the status of lymph nodes, nodal status (-) group showed smaller tumor size, lower depth of tumor invasion, better differentiated degree, lower level of signet ring cell features, lower rate of lymphatic and venous invasion and less advanced ypTNM stage (all p < 0.05). Survival was equivalent between PR and nPR group (all p > 0.05), while patients with no lymph node metastasis had better DFS than that with lymph node metastasis (HR 0.301, 95% CI 0.194-0.468, p = 0.002). Multivariable Cox regression analysis identified that lymph node status after NACT was an independent prognostic factor associated with survival (OS: hazard ratio 1.756, 95% CI 1.114-3.278, p = 0.029; DFS: hazard ratio 1.901, 95% CI 1.331-3.093, p = 0.012). CONCLUSION Lymph node status is a potential independent prognostic factor for LAGC patients treated with NACT and may be more efficient than pathological response in primary tumor.
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Affiliation(s)
- Pengfei Su
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Yingjing Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Tian Yu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Lin Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Weiming Kang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Yuqin Liu
- Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Jianchun Yu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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O’Connell F, Mylod E, Donlon NE, Heeran AB, Butler C, Bhardwaj A, Ramjit S, Durand M, Lambe G, Tansey P, Welartne I, Sheahan KP, Yin X, Donohoe CL, Ravi N, Dunne MR, Brennan L, Reynolds JV, Roche HM, O’Sullivan J. Energy Metabolism, Metabolite, and Inflammatory Profiles in Human Ex Vivo Adipose Tissue Are Influenced by Obesity Status, Metabolic Dysfunction, and Treatment Regimes in Patients with Oesophageal Adenocarcinoma. Cancers (Basel) 2023; 15:cancers15061681. [PMID: 36980567 PMCID: PMC10046380 DOI: 10.3390/cancers15061681] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/12/2023] Open
Abstract
Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (n = 32). Compared to visceral fat from non-obese patients (n = 16), visceral fat explants from obese OAC patients (n = 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (n = 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1α, IL-22, and TNF-β and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes.
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Affiliation(s)
- Fiona O’Connell
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Eimear Mylod
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity College Dublin, St. James’s Hospital, D08 W9RT Dublin, Ireland
| | - Noel E. Donlon
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity College Dublin, St. James’s Hospital, D08 W9RT Dublin, Ireland
| | - Aisling B. Heeran
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Christine Butler
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Sinead Ramjit
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Michael Durand
- Department of Radiology, St. James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Gerard Lambe
- Department of Radiology, St. James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Paul Tansey
- Department of Radiology, St. James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Ivan Welartne
- Department of Radiology, St. James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Kevin P. Sheahan
- Department of Radiology, Beaumont Hospital, D02 YN77 Dublin, Ireland
| | - Xiaofei Yin
- UCD School of Agriculture and Food Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland
| | - Claire L. Donohoe
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Margaret R. Dunne
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
- School of Chemical & Biopharmaceutical Sciences, Technological University Dublin, Tallaght, D07 EWV4 Dublin, Ireland
| | - Lorraine Brennan
- UCD School of Agriculture and Food Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland
| | - John V. Reynolds
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Helen M. Roche
- Nutrigenomics Research Group, UCD Conway Institute, School of Public Health, Physiotherapy and Sports Science, University College Dublin, D04 C1P1 Dublin, Ireland
- Institute for Global Food Security, School of Biological Sciences, Queens University Belfast, Belfast BT9 5DL, UK
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
- Correspondence:
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Rahman SA, Walker RC, Maynard N, Trudgill N, Crosby T, Cromwell DA, Underwood TJ. The AUGIS Survival Predictor: Prediction of Long-Term and Conditional Survival After Esophagectomy Using Random Survival Forests. Ann Surg 2023; 277:267-274. [PMID: 33630434 PMCID: PMC9831040 DOI: 10.1097/sla.0000000000004794] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE The aim of this study was to develop a predictive model for overall survival after esophagectomy using pre/postoperative clinical data and machine learning. SUMMARY BACKGROUND DATA For patients with esophageal cancer, accurately predicting long-term survival after esophagectomy is challenging. This study investigated survival prediction after esophagectomy using a RandomSurvival Forest (RSF) model derived from routine data from a large, well-curated, national dataset. METHODS Patients diagnosed with esophageal adenocarcinoma or squamous cell carcinoma between 2012 and 2018 in England and Wales who underwent an esophagectomy were included. Prediction models for overall survival were developed using the RSF method and Cox regression from 41 patient and disease characteristics. Calibration and discrimination (time-dependent area under the curve) were validated internally using bootstrap resampling. RESULTS The study analyzed 6399 patients, with 2625 deaths during follow-up. Median follow-up was 41 months. Overall survival was 47.1% at 5 years. The final RSF model included 14 variables and had excellent discrimination with a 5-year time-dependent area under the receiver operator curve of 83.9% [95% confidence interval (CI) 82.6%-84.9%], compared to 82.3% (95% CI 81.1%-83.3%) for the Cox model. The most important variables were lymph node involvement, pT stage, circumferential resection margin involvement (tumor at < 1 mm from cut edge) and age. There was a wide range of survival estimates even within TNM staging groups, with quintiles of prediction within Stage 3b ranging from 12.2% to 44.7% survival at 5 years. CONCLUSIONS An RSF model for long-term survival after esophagectomy exhibited excellent discrimination and well-calibrated predictions. At a patient level, it provides more accuracy than TNM staging alone and could help in the delivery of tailored treatment and follow-up.
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Affiliation(s)
- Saqib A Rahman
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK
| | - Robert C Walker
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Nigel Trudgill
- Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK
| | | | - David A Cromwell
- Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK
| | - Timothy J Underwood
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK
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17
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Thavanesan N, Vigneswaran G, Bodala I, Underwood TJ. The Oesophageal Cancer Multidisciplinary Team: Can Machine Learning Assist Decision-Making? J Gastrointest Surg 2023; 27:807-822. [PMID: 36689150 PMCID: PMC10073064 DOI: 10.1007/s11605-022-05575-8] [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: 08/30/2022] [Accepted: 12/10/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND The complexity of the upper gastrointestinal (UGI) multidisciplinary team (MDT) is continually growing, leading to rising clinician workload, time pressures, and demands. This increases heterogeneity or 'noise' within decision-making for patients with oesophageal cancer (OC) and may lead to inconsistent treatment decisions. In recent decades, the application of artificial intelligence (AI) and more specifically the branch of machine learning (ML) has led to a paradigm shift in the perceived utility of statistical modelling within healthcare. Within oesophageal cancer (OC) care, ML techniques have already been applied with early success to the analyses of histological samples and radiology imaging; however, it has not yet been applied to the MDT itself where such models are likely to benefit from incorporating information-rich, diverse datasets to increase predictive model accuracy. METHODS This review discusses the current role the MDT plays in modern UGI cancer care as well as the utilisation of ML techniques to date using histological and radiological data to predict treatment response, prognostication, nodal disease evaluation, and even resectability within OC. RESULTS The review finds that an emerging body of evidence is growing in support of ML tools within multiple domains relevant to decision-making within OC including automated histological analysis and radiomics. However, to date, no specific application has been directed to the MDT itself which routinely assimilates this information. CONCLUSIONS The authors feel the UGI MDT offers an information-rich, diverse array of data from which ML offers the potential to standardise, automate, and produce more consistent, data-driven MDT decisions.
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Affiliation(s)
- Navamayooran Thavanesan
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, University Hospitals Southampton, Southampton, UK.
| | - Ganesh Vigneswaran
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, University Hospitals Southampton, Southampton, UK
| | - Indu Bodala
- School of Electronics and Computer Science, University of Southampton, Southampton, UK
| | - Timothy J Underwood
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, University Hospitals Southampton, Southampton, UK
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18
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Fu C, Feng S, Wang S, Su X. Development and validation of a prognostic model for esophageal carcinoma based on immune microenvironment using system bioinformatics. Cancer Med 2023; 12:2089-2103. [PMID: 35771026 PMCID: PMC9883539 DOI: 10.1002/cam4.4985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 05/02/2022] [Accepted: 06/11/2022] [Indexed: 02/02/2023] Open
Abstract
Esophageal cancer (EC) is an aggressive malignancy that accounts for numerous cancer-related deaths worldwide. The multimodal combination therapy approach can be potentially used to treat EC effectively. However, distinct biomarker of significant specificity are still needed to develop individualized treatment strategies and provide accurate prognostic predictions. Therefore, we aimed to investigate the associated genes subtypes identified were, IFN-γDominant, Inflammatory, Lymphocyte Depleted, etc. and construct a risk model based on these genes to predict the overall survival (OS) of patients suffering from EC. Three immune subtypes were defined in the Cancer Genome Atlas (TCGA) cohort with different tumor microenvironment (TME) and clinical outcomes based on radio-differentiated immune genes. Subsequently, a risk model of immune characteristics included the immune cell infiltration levels and pathway activity was developed based on the genomic changes between the subtypes. In the TCGA dataset, as well as in subgroup analysis with different stages, gender, age, and pathological type, a high-risk score was identified as an adverse factor for OS using the method of the univariate Cox regression analysis and tROC analysis. Furthermore, it was observed that the high-risk group was characterized by depleted immunophenotype, active cell metabolism, and a high tumor mutation burden (TMB). The low-risk group was characterized by high TME abundance and active immune function. Differences in the biological genotypes may account for the differences in the prognosis and treatment response. Extensive research was carried out, and the results revealed that the low-risk group exhibited a significant level of therapeutic advantage in the field of immunotherapy. A risk model was developed based on the immune characteristics. It can be used to optimize risk stratification for patients suffering from EC. The results can potentially help provide new perspectives on treatment methods.
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Affiliation(s)
- Chenchun Fu
- Department of OncologyZhongda Hospital, Southeast UniversityNanjingChina
| | - Shicheng Feng
- Department of OncologyZhongda Hospital, Southeast UniversityNanjingChina
| | - Sheng Wang
- Department of OncologyZhongda Hospital, Southeast UniversityNanjingChina
| | - Xiangyu Su
- Department of OncologyZhongda Hospital, Southeast UniversityNanjingChina
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19
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Matani H, Sahu D, Paskewicz M, Gorbunova A, Omstead AN, Wegner R, Finley GG, Jobe BA, Kelly RJ, Zaidi AH, Goel A. Prognostic and predictive biomarkers for response to neoadjuvant chemoradiation in esophageal adenocarcinoma. Biomark Res 2022; 10:81. [PMCID: PMC9664643 DOI: 10.1186/s40364-022-00429-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/31/2022] [Indexed: 11/16/2022] Open
Abstract
Abstract
Background
Esophageal adenocarcinoma is a lethal disease. For locally advanced patients, neoadjuvant chemoradiotherapy followed by surgery is the standard of care. Risk stratification relies heavily on clinicopathologic features, particularly pathologic response, which is inadequate, therefore establishing the need for new and reliable biomarkers for risk stratification.
Methods
Thirty four patients with locally advanced esophageal adenocarcinoma were analyzed, of which 21 received a CROSS regimen with carboplatin, paclitaxel, and radiation. Capture-based targeted sequencing was performed on the paired baseline and post-treatment samples. Differentially mutated gene analysis between responders and non-responders of treatment was performed to determine predictors of response. A univariate Cox proportional hazard regression was used to examine associations between gene mutation status and overall survival.
Results
A 3-gene signature, based on mutations in EPHA5, BCL6, and ERBB2, was identified that robustly predicts response to the CROSS regimen. For this model, sensitivity was 84.6% and specificity was 100%. Independently, a 9 gene signature was created using APC, MAP3K6, ETS1, CSF3R, PDGFRB, GATA2, ARID1A, PML, and FGF6, which significantly stratifies patients into risk categories, prognosticating for improved relapse-free (p = 4.73E-03) and overall survival (p = 3.325E-06). The sensitivity for this model was 73.33% and the specificity was 94.74%.
Conclusion
We have identified a 3-gene signature (EPHA5, BCL6, and ERBB2) that is predictive of response to neoadjuvant chemoradiotherapy and a separate prognostic 9-gene classifier that predicts survival outcomes. These panels provide significant potential for personalized management of locally advanced esophageal cancer.
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20
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da Costa WL, Gu X, Farjah F, Groth SS, Burt BM, Ripley RT, Massarweh NN. Clinical Understaging, Treatment Response, and Survival Among Esophageal Adenocarcinoma Patients. J Surg Res 2022; 279:256-264. [PMID: 35797753 DOI: 10.1016/j.jss.2022.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/09/2022] [Accepted: 06/04/2022] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Selecting appropriate management for patients with esophageal adenocarcinoma (EA) is predicated on accurate clinical staging information. Inaccurate information could lead to inappropriate treatment and suboptimal survival. We investigated the relationship between staging accuracy, treatment, and survival. METHODS This was a national cohort study of EA patients in the National Cancer Data Base (2006-2015) treated with upfront resection or neoadjuvant therapy (NAT). Clinical and pathological staging information was used to ascertain staging concordance for each patient. For NAT patients, Bayesian analysis was used to account for potential downstaging. We evaluated the association between staging concordance, receipt of NAT, and survival through hierarchical logistic regression and multivariable Cox regression. RESULTS Among 7635 EA patients treated at 877 hospitals, 3038 had upfront resection and 4597 NAT followed by surgery. Relative to accurately staged patients, understaging was associated with a lower likelihood (odds ratio [OR] 0.04 95% confidence interval [CI] 0.02-0.05) while overstaging was associated with a greater likelihood of receiving NAT (OR 1.98 [1.53-2.56]). Relative to upfront surgery, treatment of cT1N0 patients with NAT was associated with a higher risk of death (HR 3.08 [2.36-4.02]). For accurately or overstaged cT3-T4 patients, NAT was associated with a lower risk of death whether downstaging occurred (ypN0 disease-HR 0.67 [0.49-0.92]; N+ disease-HR 0.55 [0.45-0.66]) or not (ypN + disease-HR 0.78 [95% CI 0.65-0.93]). CONCLUSIONS Clinical understaging is associated with receipt of NAT which in turn may have a stage-specific impact on patients' survival regardless of treatment response. Guidelines should account for the possibility of inaccurate clinical staging.
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Zyla RE, Kalimuthu SN. Barrett’s Esophagus and Esophageal Adenocarcinoma: A Histopathological Perspective. Thorac Surg Clin 2022; 32:413-424. [DOI: 10.1016/j.thorsurg.2022.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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22
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Withey SJ, Goh V, Foley KG. State-of-the-art imaging in oesophago-gastric cancer. Br J Radiol 2022; 95:20220410. [PMID: 35671095 PMCID: PMC10996959 DOI: 10.1259/bjr.20220410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 11/05/2022] Open
Abstract
Radiological investigations are essential in the management of oesophageal and gastro-oesophageal junction cancers. The current multimodal combination of CT, 18F-fluorodeoxyglucose positron emission tomography combined with CT (PET/CT) and endoscopic ultrasound (EUS) has limitations, which hinders the prognostic and predictive information that can be used to guide optimum treatment decisions. Therefore, the development of improved imaging techniques is vital to improve patient management. This review describes the current evidence for state-of-the-art imaging techniques in oesophago-gastric cancer including high resolution MRI, diffusion-weighted MRI, dynamic contrast-enhanced MRI, whole-body MRI, perfusion CT, novel PET tracers, and integrated PET/MRI. These novel imaging techniques may help clinicians improve the diagnosis, staging, treatment planning, and response assessment of oesophago-gastric cancer.
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Affiliation(s)
- Samuel J Withey
- Department of Radiology, The Royal Marsden NHS Foundation
Trust, London,
UK
| | - Vicky Goh
- Cancer Imaging, School of Biomedical Engineering & Imaging
Sciences, King’s College London,
London, UK
- Department of Radiology, Guy’s and St Thomas’ NHS
Foundation Trust, London,
UK
| | - Kieran G Foley
- Division of Cancer & Genetics, School of Medicine, Cardiff
University, Wales,
UK
- Department of Radiology, Velindre Cancer Centre,
Cardiff, UK
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23
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McCabe NH, Stevenson L, Scanlon E, Douglas R, Kennedy S, Keminer O, Windshügel B, Zisterer D, Kennedy RD, Blayney JK, Turkington RC. Identification of Src as a Therapeutic Target in Oesophageal Adenocarcinoma through Functional Genomic and High-Throughput Drug Screening Approaches. Cancers (Basel) 2022; 14:cancers14153726. [PMID: 35954391 PMCID: PMC9367554 DOI: 10.3390/cancers14153726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/15/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
Drug resistance limits the effectiveness of oesophageal adenocarcinoma (OAC) chemotherapies, leading to a poor prognosis for this disease. Elucidation of the underlying resistance mechanisms is key to enabling the identification of more effective treatments. This study, therefore, aims to identify novel therapeutic and/or chemotherapy sensitising drug targets in OAC. Transcriptional data from a cohort of 273 pre-treatment OAC biopsies, from patients who received neoadjuvant chemotherapy followed by surgical resection, were analysed using gene set enrichment analysis (GSEA) to determine differential gene expression between responding and non-responding OAC tumours. From this, 80 genes were selected for high-throughput siRNA screening in OAC cell lines with or without standard chemotherapy treatment. In parallel, cell viability assays were performed using a panel of FDA-approved drugs and combination index (CI) values were calculated to evaluate drug synergy with standard chemotherapy. Mechanisms of synergy were investigated using western blot, propidium iodide flow cytometry, and proliferation assays. Taken together, the screens identified that targeting Src, using either siRNA or the small molecule inhibitor dasatinib, enhanced the efficacy of chemotherapy in OAC cells. Further in vitro functional analysis confirmed Src inhibition to be synergistic with standard OAC chemotherapies, 5-fluorouracil (5-FU), and cisplatin (CDDP). In conclusion, a compound screen together with a functional genomic approach identified Src as a potential chemosensitising target in OAC, which could be assessed in a clinical study for poor prognosis OAC patients.
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Affiliation(s)
- Niamh H. McCabe
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK; (N.H.M.); (L.S.); (E.S.); (R.D.); (S.K.); (J.K.B.)
| | - Leanne Stevenson
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK; (N.H.M.); (L.S.); (E.S.); (R.D.); (S.K.); (J.K.B.)
| | - Enya Scanlon
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK; (N.H.M.); (L.S.); (E.S.); (R.D.); (S.K.); (J.K.B.)
| | - Rosalie Douglas
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK; (N.H.M.); (L.S.); (E.S.); (R.D.); (S.K.); (J.K.B.)
| | - Susanna Kennedy
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK; (N.H.M.); (L.S.); (E.S.); (R.D.); (S.K.); (J.K.B.)
| | - Oliver Keminer
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany; (O.K.); (B.W.)
- Department of Life Sciences and Chemistry, Jacobs University Bremen, 28759 Bremen, Germany
| | - Björn Windshügel
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany; (O.K.); (B.W.)
- Department of Life Sciences and Chemistry, Jacobs University Bremen, 28759 Bremen, Germany
| | - Daniela Zisterer
- Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, D08 XW7X Dublin, Ireland;
| | | | - Jaine K. Blayney
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK; (N.H.M.); (L.S.); (E.S.); (R.D.); (S.K.); (J.K.B.)
| | - Richard C. Turkington
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK; (N.H.M.); (L.S.); (E.S.); (R.D.); (S.K.); (J.K.B.)
- Correspondence: ; Tel.: +44-(0)28-9097-2756
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24
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Tomás TC, Eiriz I, Vitorino M, Vicente R, Gramaça J, Oliveira AG, Luz P, Baleiras M, Spencer AS, Costa LL, Liu P, Mendonça J, Dinis M, Padrão T, Correia M, Atalaia G, Silva M, Fiúza T. Neutrophile-to-lymphocyte, lymphocyte-to-monocyte, and platelet-to-lymphocyte ratios as prognostic and response biomarkers for resectable locally advanced gastric cancer. World J Gastrointest Oncol 2022; 14:1307-1323. [PMID: 36051098 PMCID: PMC9305575 DOI: 10.4251/wjgo.v14.i7.1307] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/19/2021] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Perioperative fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) improves prognosis in locally advanced gastric cancer (LAGC). Neutrophil-to-lymphocyte (NLR), lymphocyte-to-monocyte (LMR), and platelet-to-lymphocyte (PLR) ratios are prognostic biomarkers but not predictive factors.
AIM To assess blood ratios’ (NLR, LMR and PLR) potential predictive response to FLOT and survival outcomes in resectable LAGC patients.
METHODS This was a multicentric retrospective study investigating the clinical potential of NLR, LMR, and PLR in resectable LAGC patients, treated with at least one preoperative FLOT cycle, from 12 Portuguese hospitals. Means were compared through non-parametric Mann-Whitney tests. Receiver operating characteristic curve analysis defined the cut-off values as: High PLR > 141 for progression and > 144 for mortality; high LMR > 3.56 for T stage regression (TSR). Poisson and Cox regression models the calculated relative risks/hazard ratios, using NLR, pathologic complete response, TSR, and tumor regression grade (TRG) as independent variables, and overall survival (OS) as the dependent variable.
RESULTS This study included 295 patients (mean age, 63.7 years; 59.7% males). NLR was correlated with survival time (r = 0.143, P = 0.014). PLR was associated with systemic progression during FLOT (P = 0.022) and mortality (P = 0.013), with high PLR patients having a 2.2-times higher risk of progression [95% confidence interval (CI): 0.89-5.26] and 1.5-times higher risk of mortality (95%CI: 0.92-2.55). LMR was associated with TSR, and high LMR patients had a 1.4-times higher risk of achieving TSR (95%CI: 1.01-1.99). OS benefit was found with TSR (P = 0.015) and partial/complete TRG (P < 0.001). Patients without TSR and with no evidence of pathological response had 2.1-times (95%CI: 1.14-3.96) and 2.8-times (95%CI: 1.6-5) higher risk of death.
CONCLUSION Higher NLR is correlated with longer survival time. High LMR patients have a higher risk of decreasing T stage, whereas high PLR patients have higher odds of progressing under FLOT and dying. Patients with TSR and a pathological response have better OS and lower risk of dying.
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Affiliation(s)
- Tiago Cruz Tomás
- Department of Medical Oncology, Hospital Professor Doutor Fernando Fonseca EPE, Amadora 2720-276, Portugal
| | - Inês Eiriz
- Department of Medical Oncology, Hospital Professor Doutor Fernando Fonseca EPE, Amadora 2720-276, Portugal
| | - Marina Vitorino
- Department of Medical Oncology, Hospital Professor Doutor Fernando Fonseca EPE, Amadora 2720-276, Portugal
| | - Rodrigo Vicente
- Department of Medical Oncology, Hospital Professor Doutor Fernando Fonseca EPE, Amadora 2720-276, Portugal
| | - João Gramaça
- Department of Medical Oncology, Centro Hospitalar Barreiro-Montijo EPE, Barreiro 2830-003, Portugal
| | | | - Paulo Luz
- Department of Medical Oncology, Centro Hospitalar Universitário do Algarve EPE, Algarve 8000-386, Portugal
| | - Mafalda Baleiras
- Department of Medical Oncology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental EPE, Lisboa 1449-005, Portugal
| | - Ana Sofia Spencer
- Department of Medical Oncology, Hospital Santo António dos Capuchos, Centro Hospital Lisboa Central EPE, Lisboa 1169-050, Portugal
| | - Luísa Leal Costa
- Department of Medical Oncology, Hospital Beatriz Ângelo, Loures 2674-514, Portugal
| | - Patrícia Liu
- Department of Medical Oncology, Centro Hospitalar de Trás-os-Montes e Alto Douro EPE, Vila Real 5000-508, Portugal
| | - Joana Mendonça
- Department of Medical Oncology, Hospital da Senhora da Oliveira EPE, Guimarães 4835-044, Portugal
| | - Magno Dinis
- Department of Medical Oncology, Hospital Garcia de Orta EPE, Almada 2805-267, Portugal
| | - Teresa Padrão
- Department of Medical Oncology, Hospital da Luz, Lisboa 1500-650, Portugal
| | - Marisol Correia
- Department of Medical Oncology, Hospital Distrital de Santarém EPE, Santarém 2005-177, Portugal
| | - Gonçalo Atalaia
- Department of Medical Oncology, Hospital Professor Doutor Fernando Fonseca EPE, Amadora 2720-276, Portugal
| | - Michelle Silva
- Department of Medical Oncology, Hospital Professor Doutor Fernando Fonseca EPE, Amadora 2720-276, Portugal
| | - Teresa Fiúza
- Department of Medical Oncology, Hospital Professor Doutor Fernando Fonseca EPE, Amadora 2720-276, Portugal
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Prognostic, Diagnostic and Predictive Biomarkers in the Barrett’s Oesophagus-Adenocarcinoma Disease Sequence. Cancers (Basel) 2022; 14:cancers14143427. [PMID: 35884487 PMCID: PMC9315596 DOI: 10.3390/cancers14143427] [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: 05/11/2022] [Revised: 06/16/2022] [Accepted: 07/12/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Oesophageal adenocarcinoma (OAC) is a type of cancer of the oesophagus (food pipe) which is associated with poor patient outcomes. Barrett’s oesophagus (BO) is a precancerous condition of the oesophagus associated with chronic heartburn. Currently, surveillance programs exist which monitor patients with BO to prevent it from developing into OAC. However, these surveillance programs are expensive and unpleasant for patients. Prognostic biomarkers are signs which could be measured to determine the chance of someone with BO developing OAC, allowing more targeted surveillance. Similarly, diagnostic biomarkers are indicators which could be measured to see if someone has OAC. Developing new diagnostic biomarkers could allow wider population testing. Only a small proportion of patients with OAC respond to treatment before surgery. Predictive biomarkers could be measured to predict whether someone would respond to the treatments, allowing more individualized therapy. This review focuses on potential biomarkers which could improve patient outcomes in BO/OAC. Abstract Oesophageal adenocarcinoma (OAC) incidence has increased dramatically in the developed world, yet outcomes remain poor. Extensive endoscopic surveillance programs among patients with Barrett’s oesophagus (BO), the precursor lesion to OAC, have aimed to both prevent the development of OAC via radiofrequency ablation (RFA) and allow earlier detection of disease. However, given the low annual progression rate and the costs of endoscopy/RFA, improvement is needed. Prognostic biomarkers to stratify BO patients based on their likelihood to progress would enable a more targeted approach to surveillance and RFA of high-risk precursor lesions, improving the cost–risk–benefit ratio. Similarly, diagnostic biomarkers for OAC could enable earlier diagnosis of disease by allowing broader population screening. Current standard treatment for locally advanced OAC includes neoadjuvant chemotherapy (+/− radiotherapy) despite only a minority of patients benefiting from neoadjuvant treatment. Accordingly, biomarkers predictive of response to neoadjuvant therapy could improve patient outcomes by reducing time to surgery and unnecessary toxicity for the patients who would have received no benefit from the therapy. In this mini-review, we will discuss the emerging biomarkers which promise to dramatically improve patient outcomes along the BO-OAC disease sequence.
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da Costa WL, Tran Cao HS, Gu X, Massarweh NN. Understanding the association between clinical staging accuracy, treatment response, and survival among gastric cancer patients through Bayesian analysis. J Surg Oncol 2022; 126:986-994. [PMID: 35819061 DOI: 10.1002/jso.27016] [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: 03/15/2022] [Revised: 05/31/2022] [Accepted: 07/04/2022] [Indexed: 11/08/2022]
Abstract
BACKGROUND Neoadjuvant therapy (NAT) improves survival among patients with locally advanced gastric cancer (GC), but it remains unclear whether its benefit is contingent on treatment response. METHODS This is a national cohort study of stage Ib-III GC patients in the National Cancer Data Base (2006-2015) treated with upfront resection or NAT followed by surgery. Bayesian analysis was used for NAT patients to ascertain staging concordance and to account for down-staging. We used multivariable Cox regression to evaluate the association between staging concordance, treatment, response to NAT, and survival. RESULTS The cohort included 13 340 patients treated at 1124 hospitals. Staging concordance ranged from 86.1% for cT3-4N+ to 34.7% for cT2N0 patients. Relative to accurately staged patients treated with upfront surgery, NAT was associated with a decreased risk of death if there was disease down-staging among those with cT1-2N+ (hazard ratio [HR]: 0.43 [0.30-0.61]), cT3-4N0 (HR: 0.69 [0.54-0.88]), and cT3-4N+ (HR: 0.51 [0.48-0.58]) tumors, and in the absence of down-staging among cT3-4N+ patients (HR: 0.83 [0.74-0.92]). Conversely, NAT without down-staging increased the risk of death among those with intermediate-stage disease. CONCLUSIONS NAT is associated with improved survival for GC, but it seems to be contingent on treatment response among patients with intermediate-stage disease.
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Affiliation(s)
- Wilson Luiz da Costa
- Department of Medicine, Epidemiology, and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Hop S Tran Cao
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xiangjun Gu
- Department of Medicine, Epidemiology, and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Nader N Massarweh
- Surgical and Perioperative Care, Atlanta VA Health Care System, Decatur, Georgia, USA.,Department of Surgery, Division of Surgical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.,Department of Surgery, Morehouse School of Medicine, Atlanta, Georgia, USA
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A Transcriptomic Liquid Biopsy Assay for Predicting Resistance to Neoadjuvant Therapy in Esophageal Squamous Cell Carcinoma. Ann Surg 2022; 276:101-110. [PMID: 35703443 PMCID: PMC9276630 DOI: 10.1097/sla.0000000000005473] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The aim of this study was to establish a liquid-biopsy assay to predict response to neoadjuvant therapy (NAT) in esophageal squamous cell carcinoma (ESCC) patients. SUMMARY BACKGROUND DATA Pretreatment prediction of resistance to NAT is of great significance for the selection of treatment options in ESCC patients. In this study, we comprehensively translated tissue-based microRNA (miRNA) and messenger RNA (mRNA) expression biomarkers into a liquid biopsy assay. METHODS We analyzed 186 clinical ESCC samples, which included 128 formalin-fixed paraffin-embedded and a matched subset of 58 serum samples, from 2 independent institutions. We performed quantitative reverse-transcription polymerase chain reaction, and developed a resistance-prediction model using the logistic regression analyses. RESULTS We first evaluated the potential of 4-miRNAs and 3-mRNAs panel, which robustly predicted resistance to NAT [area under the curve (AUC): 0.85]. Moreover, addition of tumor size to this panel increased predictive potential to establish a combination signature (AUC: 0.92). We successfully validated this signature performance in independent cohort, and our model was more accurate when the signature was combined with clinical predictors (AUC: 0.81) to establish a NAT resistance risk (NATRR) model. Finally, we successfully translated our NATRR model into a liquid biopsy assay (AUC: 0.78), and a multivariate regression analysis revealed this model as an independent predictor for response to NAT (odds ratio: 6.10; P < 0.01). CONCLUSIONS We successfully developed a liquid biopsy-based assay that allows robust prediction of response to NAT in ESCC patients, and our assay provides fundamentals of developing precision-medicine.
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Sharpe BP, Hayden A, Manousopoulou A, Cowie A, Walker RC, Harrington J, Izadi F, Breininger SP, Gibson J, Pickering O, Jaynes E, Kyle E, Saunders JH, Parsons SL, Ritchie AA, Clarke PA, Collier P, Mongan NP, Bates DO, Yacqub-Usman K, Garbis SD, Walters Z, Rose-Zerilli M, Grabowska AM, Underwood TJ. Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts. Cell Rep Med 2022; 3:100541. [PMID: 35732148 PMCID: PMC9244979 DOI: 10.1016/j.xcrm.2022.100541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/14/2021] [Accepted: 01/28/2022] [Indexed: 12/03/2022]
Abstract
The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.
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Affiliation(s)
- Benjamin P Sharpe
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Annette Hayden
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | | | - Andrew Cowie
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Robert C Walker
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Jack Harrington
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Fereshteh Izadi
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK; Centre for NanoHealth, Swansea University Medical School, Singleton Campus, Swansea SA2 8PP, UK
| | - Stella P Breininger
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Jane Gibson
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Oliver Pickering
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Eleanor Jaynes
- University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Ewan Kyle
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - John H Saunders
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK; Salford Royal NHS Foundation Trust, Salford M6 8HD, UK
| | - Simon L Parsons
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK; Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK
| | - Alison A Ritchie
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Philip A Clarke
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Pamela Collier
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Nigel P Mongan
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA; Biodiscovery Institute, School of Veterinary Medicine and Science, University of Nottingham, Nottingham NG5 1PB, UK
| | - David O Bates
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Kiren Yacqub-Usman
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | | | - Zoë Walters
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Matthew Rose-Zerilli
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Anna M Grabowska
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Timothy J Underwood
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK.
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Donlon NE, Davern M, O’Connell F, Sheppard A, Heeran A, Bhardwaj A, Butler C, Narayanasamy R, Donohoe C, Phelan JJ, Lynam-Lennon N, Dunne MR, Maher S, O’Sullivan J, Reynolds JV, Lysaght J. Impact of radiotherapy on the immune landscape in oesophageal adenocarcinoma. World J Gastroenterol 2022; 28:2302-2319. [PMID: 35800186 PMCID: PMC9185220 DOI: 10.3748/wjg.v28.i21.2302] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/19/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the contemporary era of cancer immunotherapy, an abundance of clinical and translational studies have reported radiotherapy (RT) and immunotherapies as a viable option for immunomodulation of many cancer subtypes, with many related clinical trials ongoing. In locally advanced disease, chemotherapy or chemoradiotherapy followed by surgical excision of the tumour remain the principal treatment strategy in oesophageal adenocarcinoma (OAC), however, the use of the host immune system to improve anti-tumour immunity is rapidly garnering increased support in the curative setting. AIM To immunophenotype OAC patients' immune checkpoint (IC) expression with and without radiation and evaluate the effects of checkpoint blockade on cell viability. METHODS In the contemporary era of cancer immunotherapy, an abundance of studies have demonstrated that combination RT and IC inhibitors (ICIs) are effective in the immunomodulation of many cancer subtypes, with many related clinical trials ongoing. Although surgical excision and elimination of tumour cells by chemotherapy or chemoradiotherapy remains the gold standard approach in OAC, the propagation of anti-tumour immune responses is rapidly garnering increased support in the curative setting. The aim of this body of work was to immunophenotype OAC patients' IC expression with and without radiation and to establish the impact of checkpoint blockade on cell viability. This study was a hybrid combination of in vitro and ex vivo models. Quantification of serum immune proteins was performed by enzyme-linked immunosorbent assay. Flow cytometry staining was performed to evaluate IC expression for in vitro OAC cell lines and ex vivo OAC biopsies. Cell viability in the presence of radiation with and without IC blockade was assessed by a cell counting kit-8 assay. RESULTS We identified that conventional dosing and hypofractionated approaches resulted in increased IC expression (PD-1, PD-L1, TIM3, TIGIT) in vitro and ex vivo in OAC. There were two distinct subcohorts with one demonstrating significant upregulation of ICs and the contrary in the other cohort. Increasing IC expression post RT was associated with a more aggressive tumour phenotype and adverse features of tumour biology. The use of anti-PD-1 and anti-PD-L1 immunotherapies in combination with radiation resulted in a significant and synergistic reduction in viability of both radiosensitive and radioresistant OAC cells in vitro. Interleukin-21 (IL-21) and IL-31 significantly increased, with a concomitant reduction in IL-23 as a consequence of 4 Gray radiation. Similarly, radiation induced an anti-angiogenic tumour milieu with reduced expression of vascular endothelial growth factor-A, basic fibroblast growth factor, Flt-1 and placental growth factor. CONCLUSION The findings of the current study demonstrate synergistic potential for the use of ICIs and ionising radiation to potentiate established anti-tumour responses in the neoadjuvant setting and is of particular interest in those with advanced disease, adverse features of tumour biology and poor treatment responses to conventional therapies.
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Affiliation(s)
- Noel E Donlon
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Maria Davern
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Fiona O’Connell
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Andrew Sheppard
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Aisling Heeran
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Christine Butler
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Ravi Narayanasamy
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Claire Donohoe
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - James J Phelan
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Margaret R Dunne
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Stephen Maher
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - John V Reynolds
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Joanne Lysaght
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
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Kamarajah SK, Markar SR, Phillips AW, Kunene V, Fackrell D, Salti GI, Dahdaleh FS, Griffiths EA. Survival benefit of adjuvant chemotherapy following neoadjuvant therapy and oesophagectomy in oesophageal adenocarcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:1980-1987. [PMID: 35718676 DOI: 10.1016/j.ejso.2022.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 03/31/2022] [Accepted: 05/16/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND The evidence assessing the additional benefits of adjuvant chemotherapy (AC) following neoadjuvant therapy (NAT; i.e. chemotherapy or chemoradiotherapy) and oesophagectomy for oesophageal adenocarcinoma (EAC) are limited. This study aimed to determine whether AC improves long-term survival in patients receiving NAT and oesophagectomy. METHODS Patients receiving oesophagectomy for EAC following NAT from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). To account for immortality bias, patients with survival ≤3 months were excluded to account for immortality bias. Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of AC on overall survival. RESULTS Overall, 12,972 (91%) did not receive AC and 1,255 (9%) received AC. After PSM there were 2,485 who did not receive AC and 1,254 who did. After matching, AC was associated with improved survival (median: 38.5 vs 32.3 months, p < 0.001), which remained after multivariable adjustment (HR: 0.78, CI95%: 0.71-0.87). On multivariable interaction analyses, this benefit persisted in subgroup analysis for nodal status: N0 (HR: 0.85, CI95%: 0.69-0.96), N1 (HR: 0.66, CI95%: 0.56-0.78), N2/3 (HR: 0.80, CI95%: 0.66-0.97) and margin status: R0 (HR: 0.77, CI95%: 0.69-0.86), R1 (HR: 0.60, CI95%: 0.43-0.85). Further, patients with stable disease following NAT (HR: 0.60, CI95%: 0.59-0.80) or downstaged (HR: 0.80, CI95%: 0.68-0.95) disease had significant survival benefit after AC, but not patients with upstaged disease. CONCLUSION AC following NAT and oesophagectomy is associated with improved survival, even in node-negative and margin-negative disease. NAT response may be crucial in identifying patients who will benefit maximally from AC, and thus future research should be focused on identifying molecular phenotype of tumours that respond to chemotherapy to improve outcomes.
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Can Gastric Cancer Patients with High Mandard Score Benefit from Neoadjuvant Chemotherapy? Can J Gastroenterol Hepatol 2022; 2022:8178184. [PMID: 35369117 PMCID: PMC8975703 DOI: 10.1155/2022/8178184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 11/18/2022] Open
Abstract
A high Mandard score may indicate the tumor is insensitive to chemotherapy. We analyzed tumor regression and lymph node response under different Mandard scores to assess the impact of Mandard score on prognosis. Methods. Mandard scores and ypN stage of postoperative pathological reports were recorded. The results were reviewed by a professional pathologist. The radiologist compared the tumor regression before and after chemotherapy by computed tomography (CT). The survival of all patients was obtained by telephone follow-up. Multivariate Cox regression was used to assess the relationship between overall risk of death and Mandard score, imaging evaluation, and ypN stage. Results. In the Mandard score (4-5) group, the median survival time for PR and ypN0 patients was 68.5 and 76.7 months. While in the Mandard score (1-2) group, the median survival time for PD and ypN3a patients was 15.6 and 14.5 months. Imaging evaluation of tumor regression (PR 68.5 months, SD 27.8 months, and PD 10.2 months) and lymph node remission (ypN0 76.7 months, ypN1 61.6 months, ypN2 18.0 months, ypN3a 18.7 months, and ypN3b 18.3 months) showed improved survival. Mandard score, imaging evaluation, and ypN stage are important prognostic factors affecting prognosis. Conclusion. A high Mandard score does not mean neoadjuvant chemotherapy is ineffective in gastric cancer. Patients with imaging evaluation of tumor regression and ypN stage reduction may benefit from neoadjuvant chemotherapy.
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Lang CCJ, Lloyd M, Alyacoubi S, Rahman S, Pickering O, Underwood T, Breininger SP. The Use of miRNAs in Predicting Response to Neoadjuvant Therapy in Oesophageal Cancer. Cancers (Basel) 2022; 14:1171. [PMID: 35267476 PMCID: PMC8909542 DOI: 10.3390/cancers14051171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Oesophageal cancer (OC) is the ninth most common cancer worldwide. Patients receive neoadjuvant therapy (NAT) as standard of care, but less than 20% of patients with oesophageal adenocarcinoma (OAC) or a third of oesophageal squamous cell carcinoma (OSCC) patients, obtain a clinically meaningful response. Developing a method of determining a patient's response to NAT before treatment will allow rational treatment decisions to be made, thus improving patient outcome and quality of life. (1) Background: To determine the use and accuracy of microRNAs as biomarkers of response to NAT in patients with OAC or OSCC. (2) Methods: MEDLINE, EMBASE, Web of Science and the Cochrane library were searched to identify studies investigating microRNAs in treatment naïve biopsies to predict response to NAT in OC patients. (3) Results: A panel of 20 microRNAs were identified as predictors of good or poor response to NAT, from 15 studies. Specifically, miR-99b, miR-451 and miR-505 showed the strongest ability to predict response in OAC patients along with miR-193b in OSCC patients. (4) Conclusions: MicroRNAs are valuable biomarkers of response to NAT in OC. Research is needed to understand the effects different types of chemotherapy and chemoradiotherapy have on the predictive value of microRNAs; studies also require greater standardization in how response is defined.
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Affiliation(s)
| | | | | | | | | | | | - Stella P. Breininger
- Cancer Research UK Center, Faculty of Medicine, School of Cancer Science, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (C.C.J.L.); (M.L.); (S.A.); (S.R.); (O.P.); (T.U.)
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Jiang W, de Jong JM, van Hillegersberg R, Read M. Predicting Response to Neoadjuvant Therapy in Oesophageal Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14040996. [PMID: 35205743 PMCID: PMC8869950 DOI: 10.3390/cancers14040996] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/07/2022] [Accepted: 02/12/2022] [Indexed: 12/20/2022] Open
Abstract
(1) Background: Oesophageal cancers are often late-presenting and have a poor 5-year survival rate. The standard treatment of oesophageal adenocarcinomas involves neoadjuvant chemotherapy with or without radiotherapy followed by surgery. However, less than one third of patients respond to neoadjuvant therapy, thereby unnecessarily exposing patients to toxicity and deconditioning. Hence, there is an urgent need for biomarkers to predict response to neoadjuvant therapy. This review explores the current biomarker landscape. (2) Methods: MEDLINE, EMBASE and ClinicalTrial databases were searched with key words relating to “predictive biomarker”, “neoadjuvant therapy” and “oesophageal adenocarcinoma” and screened as per the inclusion and exclusion criteria. All peer-reviewed full-text articles and conference abstracts were included. (3) Results: The search yielded 548 results of which 71 full-texts, conference abstracts and clinical trials were eligible for review. A total of 242 duplicates were removed, 191 articles were screened out, and 44 articles were excluded. (4) Discussion: Biomarkers were discussed in seven categories including imaging, epigenetic, genetic, protein, immunologic, blood and serum-based with remaining studies grouped in a miscellaneous category. (5) Conclusion: Although promising markers and novel methods have emerged, current biomarkers lack sufficient evidence to support clinical application. Novel approaches have been recommended to assess predictive potential more efficiently.
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Affiliation(s)
- William Jiang
- Upper Gastrointestinal Surgery Department, St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia
- Correspondence: (W.J.); (M.R.)
| | - Jelske M. de Jong
- Gastrointestinal Oncology Department, The University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (J.M.d.J.); (R.v.H.)
| | - Richard van Hillegersberg
- Gastrointestinal Oncology Department, The University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (J.M.d.J.); (R.v.H.)
| | - Matthew Read
- Upper Gastrointestinal Surgery Department, St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia
- Correspondence: (W.J.); (M.R.)
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Rahman S, Thomas B, Maynard N, Park MH, Wahedally M, Trudgill N, Crosby T, Cromwell DA, Underwood TJ. Impact of postoperative chemotherapy on survival for oesophagogastric adenocarcinoma after preoperative chemotherapy and surgery. Br J Surg 2022; 109:227-236. [PMID: 34910129 PMCID: PMC10364695 DOI: 10.1093/bjs/znab427] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Perioperative chemotherapy is widely used in the treatment of oesophagogastric adenocarcinoma (OGAC) with a substantial survival benefit over surgery alone. However, the postoperative part of these regimens is given in less than half of patients, reflecting uncertainty among clinicians about its benefit and poor postoperative patient fitness. This study estimated the effect of postoperative chemotherapy after surgery for OGAC using a large population-based data set. METHODS Patients with adenocarcinoma of the oesophagus, gastro-oesophageal junction or stomach diagnosed between 2012 and 2018, who underwent preoperative chemotherapy followed by surgery, were identified from a national-level audit in England and Wales. Postoperative therapy was defined as the receipt of systemic chemotherapy within 90 days of surgery. The effectiveness of postoperative chemotherapy compared with observation was estimated using inverse propensity treatment weighting. RESULTS Postoperative chemotherapy was given to 1593 of 4139 patients (38.5 per cent) included in the study. Almost all patients received platinum-based triplet regimens (4004 patients, 96.7 per cent), with FLOT used in 3.3 per cent. Patients who received postoperative chemotherapy were younger, with a lower ASA grade, and were less likely to have surgical complications, with similar tumour characteristics. After weighting, the median survival time after postoperative chemotherapy was 62.7 months compared with 50.4 months without chemotherapy (hazard ratio 0.84, 95 per cent c.i. 0.77 to 0.94; P = 0.001). CONCLUSION This study has shown that postoperative chemotherapy improves overall survival in patients with OGAC treated with preoperative chemotherapy and surgery.
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Affiliation(s)
- Saqib Rahman
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK
| | - Betsan Thomas
- Department of Oncology, Velindre University NHS Trust, Cardiff, UK
| | - Nick Maynard
- Department of Upper Gastrointestinal Surgery, Oxford University Hospitals NHS Trust, Oxford, UK
| | - Min Hae Park
- Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK
| | - Muhammad Wahedally
- Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK
| | - Nigel Trudgill
- Department of Gastroenterology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK
| | - Tom Crosby
- Department of Oncology, Velindre University NHS Trust, Cardiff, UK
| | - David A. Cromwell
- Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK
| | - Tim J. Underwood
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
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Hagens E, Tukanova K, Jamel S, van Berge Henegouwen M, Hanna GB, Gisbertz S, Markar SR. Prognostic relevance of lymph node regression on survival in esophageal cancer: a systematic review and meta-analysis. Dis Esophagus 2022; 35:doab021. [PMID: 33893494 PMCID: PMC8752080 DOI: 10.1093/dote/doab021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 03/02/2021] [Accepted: 03/27/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The prognostic value of histomorphologic regression in primary esophageal cancer has been previously established, however the impact of lymph node (LN) response on survival still remains unclear. The aim of this review was to assess the prognostic significance of LN regression or downstaging following neoadjuvant therapy for esophageal cancer. METHODS An electronic search was performed to identify articles evaluating LN regression or downstaging after neoadjuvant therapy. Random effects meta-analyses were performed to assess the influence of regression in the LNs and nodal downstaging on overall survival. Histomorphologic tumor regression in LNs was defined by the absence of viable cells or degree of fibrosis on histopathologic examination. Downstaged LNs were defined as pN0 nodes by the tumor, node, and metastasis classification, which were positive prior to treatment neoadjuvant. RESULTS Eight articles were included, three of which assessed tumor regression (number of patients = 292) and five assessed downstaging (number of patients = 1368). Complete tumor regression (average rate of 29.1%) in the LNs was associated with improved survival, although not statistically significant (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.26-1.06; P = 0.17). LNs downstaging (average rate of 32.2%) was associated with improved survival compared to node positivity after neoadjuvant treatment (HR = 0.41, 95%CI = 0.22-0.77; P = 0.005). DISCUSSION The findings of this meta-analysis have shown a survival benefit in patients with LN downstaging and are suggestive for considering LN downstaging to ypN0 as an additional prognostic marker in staging and in the comparative evaluation of differing neoadjuvant regimens in clinical trials. No statistically significant effect of histopathologic regression in the LNs on long-term survival was seen.
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Affiliation(s)
- Eliza Hagens
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Karina Tukanova
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Sara Jamel
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Mark van Berge Henegouwen
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - George B Hanna
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Suzanne Gisbertz
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Sheraz R Markar
- Department of Surgery and Cancer, Imperial College London, London, UK
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Evans RP, Kamarajah SK, Kunene V, Zardo D, Elshafie M, Griffiths EA. Impact of neoadjuvant chemotherapy on nodal regression and survival in oesophageal adenocarcinoma. Eur J Surg Oncol 2021; 48:1001-1010. [PMID: 34974947 DOI: 10.1016/j.ejso.2021.12.021] [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: 08/16/2021] [Revised: 11/02/2021] [Accepted: 12/17/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND The prognostic value of lymph node regression (LNR) following neoadjuvant chemotherapy (nCT) for oesophageal and gastro-oeosphageal adenocarcinoma remains unclear. This study aimed to characterise the long-term survival outcomes of LNR in patients having resectional surgery after nCT. METHODS This study included patients undergoing oesophagectomy or extended total gastrectomy for oesophageal and junctional tumours (Siewert types 1,2,3) at the Queen Elizabeth Hospital Birmingham from 2012 to 2018. Lymph nodes retrieved at surgery were examined for evidence of a response to chemotherapy. Patients were classified as lymph node-negative (either negative nodes with no evidence of previous tumour involvement or negative with evidence of complete regression) or positive with either partial or no response. RESULTS This study identified 183 patients who received nCT, of which 71% (130/183) had positive lymph nodes. Of these 130 patients, 44% (57/130) had a lymph node response and 56% (73/130) did not. The remaining 53 patients (29.0%) had negative lymph nodes with no evidence of tumour. Lymph node responders had a significant survival benefit compared to patients without lymph node response, but shorter than those with negative lymph nodes (median: 27 vs 18 vs NR months, p < 0·001). On multivariable analysis, lymph node responders had an improved overall (Hazard ratio (HR): 0.86, 95% CI: 0.80-0.92, p < 0.001) and recurrence-free (HR: 0.90, 95% CI: 0.82-0.98, p = 0.030) survival. CONCLUSION Lymph node regression is an important prognostic factor, warranting closer evaluation over primary tumour response to help with planning further adjuvant therapy in these patients.
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Affiliation(s)
- Richard Pt Evans
- Department of Upper Gastrointestinal Surgery, University Hospitals Birmingham NHS Foundation Trust, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Sivesh K Kamarajah
- Department of Upper Gastrointestinal Surgery, University Hospitals Birmingham NHS Foundation Trust, UK; Institute of Cancer and Genomic Science, University of Birmingham, UK
| | - Victoria Kunene
- Department of Oncology, University Hospitals Birmingham NHS Foundation Trust, UK
| | - Davide Zardo
- Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Department of Pathology, San Bortolo Hospital, Vicenza, Italy
| | - Mona Elshafie
- Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ewen A Griffiths
- Department of Upper Gastrointestinal Surgery, University Hospitals Birmingham NHS Foundation Trust, UK; Institute of Cancer and Genomic Science, University of Birmingham, UK.
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Pucher PH, White A, Padfield O, Davies AR, Maisey N, Qureshi A, Subesinghe M, Baker C, Gossage JA. Incidence and relevance of clinically indeterminate nonregional lymph nodes in the treatment of oesophageal cancer. Nucl Med Commun 2021; 42:1270-1276. [PMID: 34347657 DOI: 10.1097/mnm.0000000000001457] [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: 11/26/2022]
Abstract
OBJECTIVES Metastatic involvement of nonregional supraclavicular or superior mediastinal lymph nodes in distal oesophageal cancer is rare but has important implications for prognosis and management. The management of nonregional lymph nodes which appear indeterminate on CT and FDG PET-CT (subcentimeter nodes or those with preserved normal morphology, but increased FDG avidity) can present a diagnostic dilemma. This study investigates the incidence, work-up and clinical significance of nonregional clinically indeterminate FDG avid lymph nodes. METHODS A single-centre retrospective review of all FDG PET-CT scans conducted over 5 years was conducted. Patients with mid- or distal oesophageal cancer with nonregional FDG avid nodes were identified. Subsequent work-up, management and outcomes were retrieved from electronic health records. RESULTS Reports for 1189 PET-CT scans were reviewed. A total of 79 patients met the inclusion criteria. Of these, 18 (23%) were deemed to have disease and performance status potentially amenable to radical surgery and underwent further assessment. The indeterminate lymph nodes were successfully sampled via endobronchial ultrasound (EBUS) or ultrasound-guided fine-needle aspiration (US-FNA) in 100% of cases. 15/18 (83.3%) of samples were benign and proceeded to surgery. Outcomes for patients who proceeded to surgery were similar to other cohorts. None had pathology suggesting false-negative lymph node sampling. CONCLUSIONS EBUS and US-FNA are effective means of sampling clinically indeterminate nonregional lymph nodes, and can significantly impact prognosis, and management. Further investigations in this context are of value in this cohort and should be pursued. Nonregional clinically indeterminate lymph nodes represent a diagnostic dilemma in oesophageal cancer staging. Additional investigations in the form of endobronchial ultrasound are effective at providing additional staging information, and can substantially influence patient care.
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Affiliation(s)
- Philip H Pucher
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London
- Department of General Surgery, Portsmouth University Hospital NHS Trust, Portsmouth
| | - Annabelle White
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London
| | - Olivia Padfield
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London
| | - Andrew R Davies
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London
- Division of Cancer Sciences, King's College London
| | - Nick Maisey
- Department of Oncology, Guys and St Thomas' Hospital NHS Foundation Trust
| | - Asad Qureshi
- Department of Oncology, Guys and St Thomas' Hospital NHS Foundation Trust
| | - Manil Subesinghe
- King's College London & Guy's and St. Thomas' PET Centre
- Department of Cancer Imaging, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
| | - Cara Baker
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London
| | - James A Gossage
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London
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Tong Y, Zhu Y, Zhao Y, Jiang C, Wang W, Shan Z, Sun F, Liu D, Zhang J. CA724 Predicts Tumor Regression Grade in Locally Advanced Gastric Cancer Patients with Neoadjuvant Chemotherapy. J Cancer 2021; 12:6465-6472. [PMID: 34659537 PMCID: PMC8489128 DOI: 10.7150/jca.60694] [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: 03/21/2021] [Accepted: 08/23/2021] [Indexed: 12/16/2022] Open
Abstract
Purpose: Tumor regression grade (TRG) is widely used to evaluate the efficacy of neoadjuvant chemotherapy (NCT) and it is related to many clinicopathological factors. However, whether TRG can be predicted by clinical characteristics is unknown. Methods: 141 locally advanced gastric cancer (GC) patients who underwent NCT and curative operation were retrospectively analyzed. TRG is reevaluated according to the CAP guideline. The values of CA199, CA125 and CA724 before NCT (pre-) and after NCT (post-) were extracted from our database. Survival curves on overall survival (OS) were obtained by Kaplan-Meier method, and differences were analyzed by log-rank test. Associations between categorical variables were explored by chi-square test or Fisher's exact method. Univariable and multivariate analyses were performed by logistic regression model or Cox proportional hazard regression model. Results: TRG was related to OS (P < 0.001), especially when divided into responders (TRG 0-1) and non-responders (TRG 2-3). Pre-CA724 (p = 0.029) and post-CA199 (p = 0.038) were related to OS. In multivariable analysis, pre-CA724 (p = 0.015) and post-CA199 (p = 0.007) were independent prognostic factors for OS, respectively. The changes (diff-) of all tumor markers were not related to OS. Among the clinical characteristics, pre-CA724 (P = 0.047) and tumor size (P = 0.012) were related to TRG, while pre-CA199 (P = 0.377) and pre-CA125 (P = 0.856) were not. In logistics analysis, pre-CA724 (P = 0.032), tumor size (P = 0.011) and tumor location (P = 0.047) were independent risk factors to pathological response. Conclusion: CA724 was an independent prognostic factor for OS and could be used to predict pathological response.
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Affiliation(s)
- Yilin Tong
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Yanmei Zhu
- Department of Pathology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Yan Zhao
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Chengyao Jiang
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Wentao Wang
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Zexing Shan
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Fan Sun
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Dong Liu
- Department of Pathology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Jianjun Zhang
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
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Spitzner M, Emons G, Schütz KB, Wolff HA, Rieken S, Ghadimi BM, Schneider G, Grade M. Inhibition of Wnt/β-Catenin Signaling Sensitizes Esophageal Cancer Cells to Chemoradiotherapy. Int J Mol Sci 2021; 22:ijms221910301. [PMID: 34638639 PMCID: PMC8509072 DOI: 10.3390/ijms221910301] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/26/2022] Open
Abstract
The standard treatment of locally advanced esophageal cancer comprises multimodal treatment concepts including preoperative chemoradiotherapy (CRT) followed by radical surgical resection. However, despite intensified treatment approaches, 5-year survival rates are still low. Therefore, new strategies are required to overcome treatment resistance, and to improve patients’ outcome. In this study, we investigated the impact of Wnt/β-catenin signaling on CRT resistance in esophageal cancer cells. Experiments were conducted in adenocarcinoma and squamous cell carcinoma cell lines with varying expression levels of Wnt proteins and Wnt/β-catenin signaling activities. To investigate the effect of Wnt/β-catenin signaling on CRT responsiveness, we genetically or pharmacologically inhibited Wnt/β-catenin signaling. Our experiments revealed that inhibition of Wnt/β-catenin signaling sensitizes cell lines with robust pathway activity to CRT. In conclusion, Wnt/β-catenin activity may guide precision therapies in esophageal carcinoma patients.
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Affiliation(s)
- Melanie Spitzner
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany; (M.S.); (G.E.); (K.B.S.); (B.M.G.); (G.S.)
| | - Georg Emons
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany; (M.S.); (G.E.); (K.B.S.); (B.M.G.); (G.S.)
| | - Karl Burkhard Schütz
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany; (M.S.); (G.E.); (K.B.S.); (B.M.G.); (G.S.)
- Department of Urology and Andrology, Sankt Georg Medical Centre and Hospital, 04129 Leipzig, Germany
| | - Hendrik A. Wolff
- Department of Radiotherapy and Radiooncology, University Medical Center Goettingen, 37075 Goettingen, Germany; (H.A.W.); (S.R.)
- Department of Radiology, Nuclear Medicine and Radiotherapy, Radiology Munich, 80331 Munich, Germany
| | - Stefan Rieken
- Department of Radiotherapy and Radiooncology, University Medical Center Goettingen, 37075 Goettingen, Germany; (H.A.W.); (S.R.)
| | - B. Michael Ghadimi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany; (M.S.); (G.E.); (K.B.S.); (B.M.G.); (G.S.)
| | - Günter Schneider
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany; (M.S.); (G.E.); (K.B.S.); (B.M.G.); (G.S.)
| | - Marian Grade
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany; (M.S.); (G.E.); (K.B.S.); (B.M.G.); (G.S.)
- Correspondence: ; Tel.: +49-551-39-67809
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Levenson G, Voron T, Paye F, Balladur P, Debove C, Chafai N, De Dios AG, Lefevre JH, Parc Y. Tumor downstaging after neoadjuvant chemotherapy determines survival after surgery for gastric adenocarcinoma. Surgery 2021; 170:1711-1717. [PMID: 34561115 DOI: 10.1016/j.surg.2021.08.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 07/20/2021] [Accepted: 08/15/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Since 2006, surgery combined with perioperative chemotherapy is the standard of care for resectable gastric adenocarcinoma in Europe. Specific effects of neoadjuvant chemotherapy remain unknown. The aim was to evaluate the rate of tumor downstaging and its impact on survival in patients undergoing curative resection after neoadjuvant chemotherapy (NeoCT) for gastric adenocarcinoma. MATERIAL AND METHODS All patients treated in a curative intent for gastric or esophagogastric junction adenocarcinomas between 1996 and 2016 in our high-volume center were retrospectively included. Tumor downstaging after NeoCT was defined as ypTN inferior to cTN. The accuracy of clinical staging was evaluated in patients treated by upfront surgery before 2006. RESULTS During the study period, 491 patients were operated for gastric adenocarcinoma, and 449 patients were finally analyzed. Among the 163 (36.3%) patients who received NeoCT, 61 (37.4%) had tumor downstaging. Overall survival and disease-free survival were longer in patients with tumor downstaging compared to patients without it (5-year survival: 84.8% vs 49.7%; P = .002 and 61.7% vs 43.4%; P = .054). In multivariate analysis tumor downstaging was an independent prognosis factor for better overall survival (HR = 5.258; P = .002) and disease-free survival (HR = 2.286; P = .028). Moreover, 45.5% of patients staged cT1-T2N0, in whom upfront surgery was performed, were understaged and ultimately had a more advanced tumor on pathological analysis. CONCLUSION Response to neoadjuvant chemotherapy constitutes a major prognostic factor for overall and disease-free survival. In the absence of predictive factors for tumor downstaging, the indication for perioperative chemotherapy should remain broad, in particular because of the low accuracy of pretherapeutic staging and therefore the high risk of understaging tumors.
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Affiliation(s)
- Guillaume Levenson
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France
| | - Thibault Voron
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France; Sorbonne Université, France.
| | - François Paye
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France; Sorbonne Université, France
| | - Pierre Balladur
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France; Sorbonne Université, France
| | - Clotilde Debove
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France; Sorbonne Université, France
| | - Najim Chafai
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France; Sorbonne Université, France
| | - Alba Gallego De Dios
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France
| | - Jeremie H Lefevre
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France; Sorbonne Université, France
| | - Yann Parc
- Department of General and Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France; Sorbonne Université, France
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Pickering OJ, Breininger SP, Underwood TJ, Walters ZS. Histone Modifying Enzymes as Targets for Therapeutic Intervention in Oesophageal Adenocarcinoma. Cancers (Basel) 2021; 13:4084. [PMID: 34439236 PMCID: PMC8392153 DOI: 10.3390/cancers13164084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/03/2021] [Accepted: 08/10/2021] [Indexed: 12/24/2022] Open
Abstract
Oesophageal adenocarcinoma (OAC) has a dismal prognosis, where curable disease occurs in less than 40% of patients, and many of those with incurable disease survive for less than a year from diagnosis. Despite the widespread use of systematic chemotherapy in OAC treatment, many patients receive no benefit. New treatments are urgently needed for OAC patients. There is an emerging interest in epigenetic regulators in cancer pathogenesis, which are now translating into novel cancer therapeutic strategies. Histone-modifying enzymes (HMEs) are key epigenetic regulators responsible for dynamic covalent histone modifications that play roles in both normal and dysregulated cellular processes including tumorigenesis. Several HME inhibitors are in clinical use for haematological malignancies and sarcomas, with numerous on-going clinical trials for their use in solid tumours. This review discusses the current literature surrounding HMEs in OAC pathogenesis and their potential use in targeted therapies for this disease.
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Affiliation(s)
| | | | | | - Zoë S. Walters
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (O.J.P.); (S.P.B.); (T.J.U.)
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42
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Pucher PH, Allum WH, Bateman AC, Green M, Maynard N, Novelli M, Petty R, Underwood TJ, Gossage J. Consensus recommendations for the standardized histopathological evaluation and reporting after radical oesophago-gastrectomy (HERO consensus). Dis Esophagus 2021; 34:doab033. [PMID: 33969411 DOI: 10.1093/dote/doab033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/12/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Variation in the approach, radicality, and quality of gastroesophageal surgery impacts patient outcomes. Pathological outcomes such as lymph node yield are routinely used as surrogate markers of surgical quality, but are subject to significant variations in histopathological evaluation and reporting. A multi-society consensus group was convened to develop evidence-based recommendations for the standardized assessment of gastroesophageal cancer specimens. METHODS A consensus group comprised of surgeons, pathologists, and oncologists was convened on behalf of the Association of Upper Gastrointestinal Surgery of Great Britain & Ireland. Literature was reviewed for 17 key questions. Draft recommendations were voted upon via an anonymous Delphi process. Consensus was considered achieved where >70% of participants were in agreement. RESULTS Consensus was achieved on 18 statements for all 17 questions. Twelve strong recommendations regarding preparation and assessment of lymph nodes, margins, and reporting methods were made. Importantly, there was 100% agreement that the all specimens should be reported using the Royal College of Pathologists Guidelines as the minimum acceptable dataset. In addition, two weak recommendations regarding method and duration of specimen fixation were made. Four topics lacked sufficient evidence and no recommendation was made. CONCLUSIONS These consensus recommendations provide explicit guidance for gastroesophageal cancer specimen preparation and assessment, to provide maximum benefit for patient care and standardize reporting to allow benchmarking and improvement of surgical quality.
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Affiliation(s)
- Philip H Pucher
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London, UK
- Department of General Surgery, Portsmouth University Hospital NHS Trust, Portsmouth, UK
| | - William H Allum
- Department of Academic Surgery, The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Adrian C Bateman
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Michael Green
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Nick Maynard
- Department of General Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK
| | - Marco Novelli
- Department of Histopathology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Russell Petty
- Department of Medical Oncology, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Timothy J Underwood
- Royal College of Surgeons of England and Association of Upper Gastrointestinal Surgery of GB&I (AUGIS) Surgical Specialty Lead for Oesophageal Cancer, UK
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - James Gossage
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London, UK
- Oesophagogastric Cancer Lead, AUGIS, UK
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Donlon NE, Davern M, Sheppard A, Power R, O’Connell F, Heeran AB, King R, Hayes C, Bhardwaj A, Phelan JJ, Dunne MR, Ravi N, Donohoe CL, O’Sullivan J, Reynolds JV, Lysaght J. The Prognostic Value of the Lymph Node in Oesophageal Adenocarcinoma; Incorporating Clinicopathological and Immunological Profiling. Cancers (Basel) 2021; 13:4005. [PMID: 34439160 PMCID: PMC8391676 DOI: 10.3390/cancers13164005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/24/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022] Open
Abstract
Response rates to the current gold standards of care for treating oesophageal adenocarcinoma (OAC) remain modest with 15-25% of patients achieving meaningful pathological responses, highlighting the need for novel therapeutic strategies. This study consists of immune, angiogenic, and inflammatory profiling of the tumour microenvironment (TME) and lymph node microenvironment (LNME) in OAC. The prognostic value of nodal involvement and clinicopathological features was compared using a retrospective cohort of OAC patients (n = 702). The expression of inhibitory immune checkpoints by T cells infiltrating tumour-draining lymph nodes (TDLNs) and tumour tissue post-chemo(radio)therapy at surgical resection was assessed by flow cytometry. Nodal metastases is of equal prognostic importance to clinical tumour stage and tumour regression grade (TRG) in OAC. The TME exhibited a greater immuno-suppressive phenotype than the LNME. Our data suggests that blockade of these checkpoints may have a therapeutic rationale for boosting response rates in OAC.
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Affiliation(s)
- Noel E. Donlon
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Maria Davern
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Andrew Sheppard
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Robert Power
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Fiona O’Connell
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Aisling B. Heeran
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Ross King
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Conall Hayes
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
| | - James J. Phelan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Margaret R. Dunne
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Claire L. Donohoe
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - John V. Reynolds
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
| | - Joanne Lysaght
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, D08 W9RT Dublin, Ireland; (M.D.); (A.S.); (R.P.); (F.O.); (A.B.H.); (R.K.); (C.H.); (A.B.); (J.J.P.); (M.R.D.); (N.R.); (C.L.D.); (J.O.); (J.V.R.); (J.L.)
- Trinity St James’s Cancer Institute, St James’s Hospital, D08 W9RT Dublin, Ireland
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Izadi F, Sharpe BP, Breininger SP, Secrier M, Gibson J, Walker RC, Rahman S, Devonshire G, Lloyd MA, Walters ZS, Fitzgerald RC, Rose-Zerilli MJJ, Underwood TJ. Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma. Cancers (Basel) 2021; 13:3394. [PMID: 34298611 PMCID: PMC8308111 DOI: 10.3390/cancers13143394] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 06/28/2021] [Accepted: 07/01/2021] [Indexed: 01/04/2023] Open
Abstract
Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20-37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n = 27) and non-responders classified as TRG4-5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.
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Affiliation(s)
- Fereshteh Izadi
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
- Centre for NanoHealth, Swansea University Medical School, Singleton Campus, Swansea SA2 8PP, UK
| | - Benjamin P. Sharpe
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Stella P. Breininger
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
| | - Maria Secrier
- UCL Genetics Institute, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK;
| | - Jane Gibson
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Robert C. Walker
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
| | - Saqib Rahman
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
| | - Ginny Devonshire
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK;
| | - Megan A. Lloyd
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
| | - Zoë S. Walters
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Rebecca C. Fitzgerald
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge CB2 OXZ, UK;
| | - Matthew J. J. Rose-Zerilli
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Tim J. Underwood
- School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; (F.I.); (B.P.S.); (S.P.B.); (J.G.); (R.C.W.); (S.R.); (M.A.L.); (Z.S.W.); (M.J.J.R.-Z.)
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
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Pucher PH, Wijnhoven BPL, Underwood TJ, Reynolds JV, Davies AR. Thinking through the multimodal treatment of localized oesophageal cancer: the point of view of the surgeon. Curr Opin Oncol 2021; 33:353-361. [PMID: 33966001 DOI: 10.1097/cco.0000000000000751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
PURPOSE OF REVIEW This review examines current developments and controversies in the multimodal management of oesophageal cancer, with an emphasis on surgical dilemmas and outcomes from the surgeon's perspective. RECENT FINDINGS Despite the advancement of oncological neoadjuvant treatments, there is still no consensus on what regimen is superior. The majority of patients may still fail to respond to neoadjuvant therapy and suffer potential harm without any survival advantage as a result. In patients who do not respond, adjuvant therapy is still often recommended after surgery despite any evidence for its benefit. We examine the implications of different regimens and treatment approaches for both squamous cell cancer and adenocarcinoma of the oesophagus. SUMMARY The efficacy of neoadjuvant treatment is highly variable and likely relates to variability of tumour biology. Ongoing work to identify responders, or optimize treatment on an individual patient, should increase the efficacy of multimodal therapy and improve patient outcomes.
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Affiliation(s)
- Philip H Pucher
- Department of Surgery, Guy's and St Thomas' NHS Foundation Trust, London
- Department of Surgery, Portsmouth University Hospitals NHS Trust, Portsmouth, UK
| | - Bas P L Wijnhoven
- Department of Surgery, Erasmus MC-Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Timothy J Underwood
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, UK
| | - John V Reynolds
- Department of Surgery, National Oesophageal and Gastric Center, St. James's Hospital and Trinity College, Dublin, Ireland
| | - Andrew R Davies
- Department of Surgery, Guy's and St Thomas' NHS Foundation Trust, London
- King's College London, London, UK
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Foley KG, Lavery A, Napier E, Campbell D, Eatock MM, Kennedy RD, Bradley KM, Turkington RC. A DNA-damage immune response assay combined with PET biomarkers predicts response to neo-adjuvant chemotherapy and survival in oesophageal adenocarcinoma. Sci Rep 2021; 11:13061. [PMID: 34158588 PMCID: PMC8219719 DOI: 10.1038/s41598-021-92545-w] [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: 12/08/2020] [Accepted: 06/07/2021] [Indexed: 11/24/2022] Open
Abstract
18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26–0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26–0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.
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Affiliation(s)
| | | | - Eoin Napier
- Belfast Health and Social Care Trust, Belfast, UK
| | | | - Martin M Eatock
- Queen's University Belfast, Belfast, UK.,Belfast Health and Social Care Trust, Belfast, UK
| | | | - Kevin M Bradley
- Wales Research & Diagnostic Positron Emission Tomography Imaging Centre (PETIC), Cardiff University, Cardiff, UK
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West MA, Anastasiou Z, Ambler G, Loughney L, Mythen MG, Owen T, Danjoux G, Levett DZ, Calverley PM, Kelly JJ, Jack S, Grocott MP. The effects of cancer therapies on physical fitness before oesophagogastric cancer surgery: a prospective, blinded, multi-centre, observational, cohort study. NIHR OPEN RESEARCH 2021; 1:1. [PMID: 35106479 PMCID: PMC7612293 DOI: 10.3310/nihropenres.13217.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 05/31/2021] [Indexed: 12/05/2022]
Abstract
Background Neoadjuvant cancer treatment is associated with improved survival following major oesophagogastric cancer surgery. The impact of neoadjuvant chemo/chemoradiotherapy on physical fitness and operative outcomes is however unclear. This study aims to investigate the impact of neoadjuvant chemo/chemoradiotherapy on fitness and post-operative mortality. Methods Patients with oesophagogastric cancer scheduled for chemo/chemoradiotherapy and surgery were recruited to a prospective, blinded, multi-centre, observational cohort study. Primary outcomes were changes in fitness with chemo/chemoradiotherapy, measured using cardiopulmonary exercise testing and its association with mortality one-year after surgery. Patients were followed up for re-admission at 30-days, in-hospital morbidity and quality of life (exploratory outcomes). Results In total, 384 patients were screened, 217 met the inclusion criteria, 160 consented and 159 were included (72% male, mean age 65 years). A total of 132 patients (83%) underwent chemo/chemoradiotherapy, 109 (71%) underwent chemo/chemoradiotherapy and two exercise tests, 100 (63%) completed surgery and follow-up. A significant decline in oxygen uptake at anaerobic threshold and oxygen uptake peak was observed following chemo/chemoradiotherapy: -1.25ml.kg -1.min -1 (-1.80 to -0.69) and -3.02ml.kg -1.min -1 (-3.85 to -2.20); p<0.0001). Baseline chemo/chemoradiotherapy anaerobic threshold and peak were associated with one-year mortality (HR=0.72, 95%CI 0.59 to 0.88; p=0.001 and HR=0.85, 0.76 to 0.95; p=0.005). The change in physical fitness was not associated with one-year mortality. Conclusions Chemo/chemoradiotherapy prior to oesophagogastric cancer surgery reduced physical fitness. Lower baseline fitness was associated with reduced overall survival at one-year. Careful consideration of fitness prior to chemo/chemoradiotherapy and surgery is urgently needed.
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Affiliation(s)
- Malcolm A. West
- Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
- Acute Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
| | - Zachos Anastasiou
- Department of Statistical Science, University College London, London, W1T 7PJ, UK
| | - Gareth Ambler
- Department of Statistical Science, University College London, London, W1T 7PJ, UK
| | - Lisa Loughney
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
- Acute Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
| | - Michael G. Mythen
- Centre for Anaesthesia, Institute of Sport Exercise and Health, University College London Hospitals NIHR Biomedical Research Centre, London, W1T 7HA, UK
| | - Thomas Owen
- Department of Critical Care and Anaesthesia, Lancashire Teaching Hospitals NHS Foundation Trust, Lancashire, PR7 1PP, UK
| | - Gerard Danjoux
- Department of Critical Care and Anaesthesia, The James Cook University Hospital, Middlesborough, TS4 3BW, UK
| | - Denny Z.H. Levett
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
- Acute Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
| | - Peter M.A. Calverley
- Department of Respiratory Research, University of Liverpool, University Hospitals Aintree, Liverpool, L9 7AL, UK
| | - Jamie J. Kelly
- Department of Upper Gastro-intestinal Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
| | - Sandy Jack
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
- Acute Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
| | - Michael P.W. Grocott
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
- Acute Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
| | - Fit4Surgery Consortium
- Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
- Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
- Acute Perioperative and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
- Department of Statistical Science, University College London, London, W1T 7PJ, UK
- Centre for Anaesthesia, Institute of Sport Exercise and Health, University College London Hospitals NIHR Biomedical Research Centre, London, W1T 7HA, UK
- Department of Critical Care and Anaesthesia, Lancashire Teaching Hospitals NHS Foundation Trust, Lancashire, PR7 1PP, UK
- Department of Critical Care and Anaesthesia, The James Cook University Hospital, Middlesborough, TS4 3BW, UK
- Department of Respiratory Research, University of Liverpool, University Hospitals Aintree, Liverpool, L9 7AL, UK
- Department of Upper Gastro-intestinal Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
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Foley KG, Jeffries J, Hannon C, Coles B, Bradley KM, Smyth E. Response rate and diagnostic accuracy of early PET-CT during neo-adjuvant therapies in oesophageal adenocarcinoma: A systematic review and meta-analysis. Int J Clin Pract 2021; 75:e13906. [PMID: 33300222 DOI: 10.1111/ijcp.13906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/03/2020] [Indexed: 11/28/2022] Open
Abstract
PURPOSE Only 25% of oesophageal adenocarcinoma (OAC) patients have a pathological response to neo-adjuvant therapy (NAT) before oesophagectomy. Early response assessment using PET imaging may help guide management of these patients. We performed a systematic review and meta-analysis to synthesise the evidence detailing response rate and diagnostic accuracy of early PET-CT assessment. METHODS We systematically searched several databases including MEDLINE and Embase. Studies with mixed cohorts of histology, tumour location and a repeat PET-CT assessment after more than one cycle of NAT were excluded. Reference standard was pathological response defined by Becker or Mandard classifications. Primary outcome was metabolic response rate after one cycle of NAT defined by a reduction in maximum standardised uptake value (SUVmax) of 35%. Secondary outcome was diagnostic accuracy of treatment response prediction, defined as the sensitivity and specificity of early PET-CT using this threshold. Quality of evidence was also assessed. Random-effects meta-analysis pooled response rates and diagnostic accuracy. This study was registered with PROSPERO (CRD42019147034). RESULTS Overall, 1341 articles were screened, and 6 studies were eligible for analysis. These studies reported data for 518 patients (aged 27-78 years; 452 [87.3%] were men) between 2005 and 2020. Pooled sensitivity of early metabolic response to predict pathological response was 77.2% (95% CI 53.2%-100%). Significant heterogeneity existed between studies (I2 = 80.6% (95% CI 38.9%-93.8%), P = .006). Pooled specificity was 75.0% (95% CI 68.2%-82.5%), however, no significant heterogeneity between studies existed (I2 = 0.0% (95% CI 0.0%-67.4%), P = .73). CONCLUSION High-quality evidence is lacking, and few studies met the inclusion criteria of this systematic review. The sensitivity of PET using a SUVmax reduction threshold of 35% was suboptimal and varied widely. However, specificity was consistent across studies with a pooled value of 75.0%, suggesting early PET assessment is a better predictor of treatment resistance than of pathological response. Further research is required to define optimal PET-guided treatment decisions in OAC.
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Affiliation(s)
- Kieran G Foley
- Royal Glamorgan Hospital & Velindre Cancer Centre, Cardiff, UK
| | | | - Clare Hannon
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Kevin M Bradley
- Wales Diagnostic and Research Positron Emission Tomography Imaging Centre, Cardiff University, Cardiff, UK
| | - Elizabeth Smyth
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Predictive value of NLR, TILs (CD4+/CD8+) and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer. Cancer Immunol Immunother 2021; 71:45-55. [PMID: 34009410 PMCID: PMC8738448 DOI: 10.1007/s00262-021-02960-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/06/2021] [Indexed: 12/24/2022]
Abstract
The combination of perioperative chemotherapy plus complete surgical resection is currently accounted as the first-choice strategy in patients with locally advanced Gastric Cancer (LAGC). Nevertheless, the partial response rate makes it necessary to search biological parameters useful to select patients who would benefit most from neoadjuvant chemotherapy (NAD-CT). We performed a retrospective analysis on a cohort of 65 LAGC cases, EBV negative and without MMR defect, submitted to perioperative chemotherapy plus surgical resection. We evaluated the neutrophil-lymphocytes ratio (NLR) in peripheral blood, the TILs density (reported as CD4/CD8 tissue ratio) and PD-L1 expression by immunohistochemistry on bioptic tissues before the treatment. Results were correlated with the biological features, histological response (TRG) and clinical outcome (PFS and OS). We found that NLR, TILs and PD-L1 expression showed a significant correlation with TNM stage, lymphovascular invasion and response to NAD-CT (TRG). Correlating the NLR, TILs and PD-L1 expression with PFS and OS, we found that patients with lower NLR levels (< 2.5 ratio), lower TILs (< 0.2 ratio) and higher PD-L1 level (CPS ≥ 1) had a significantly better PFS and OS than those with higher NLR, higher TILs and lower PD-L1 expression (p < 0.0001). Multivariate and multiple regression analyses confirmed the predictive and prognostic role of all three parameters, especially when all three parameters are combined. Our study demonstrated that pre-treatment NLR, TILs and PD-L1 expression are predictive and prognostic parameters in NAD-CT-treated LAGC suggesting a pivotal role of the systemic and tumor microenvironment immunological profile in the response to chemotherapy.
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Lam AK, Bourke MJ, Chen R, Fiocca R, Fujishima F, Fujii S, Jansen M, Kumarasinghe P, Langer R, Law S, Meijer SL, Muldoon C, Novelli M, Shi C, Tang L, Nagtegaal ID. Dataset for the reporting of carcinoma of the esophagus in resection specimens: recommendations from the International Collaboration on Cancer Reporting. Hum Pathol 2021; 114:54-65. [PMID: 33992659 DOI: 10.1016/j.humpath.2021.05.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/06/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND OBJECTIVES A standardized data set for esophageal carcinoma pathology reporting was developed based on the approach of the International Collaboration on Cancer Reporting (ICCR) for the purpose of improving cancer patient outcomes and international benchmarking in cancer management. MATERIALS AND METHODS The ICCR convened a multidisciplinary international expert panel to identify the best evidence-based clinical and pathological parameters for inclusion in the data set for esophageal carcinoma. The data set incorporated the current edition of the World Health Organization Classification of Tumours of the Digestive System, and Tumour-Node-Metastasis staging systems. RESULTS The scope of the data set encompassed resection specimens of the esophagus and esophagogastric junction with tumor epicenter ≤20 mm into the proximal stomach. Core reporting elements included information on neoadjuvant therapy, operative procedure used, tumor focality, tumor site, tumor dimensions, distance of tumor to resection margins, histological tumor type, presence and type of dysplasia, tumor grade, extent of invasion in the esophagus, lymphovascular invasion, response to neoadjuvant therapy, status of resection margin, ancillary studies, lymph node status, distant metastases, and pathological staging. Additional non-core elements considered useful to report included clinical information, specimen dimensions, macroscopic appearance of tumor, and coexistent pathology. CONCLUSIONS This is the first international peer-reviewed structured reporting data set for surgically resected specimens of the esophagus. The ICCR carcinoma of the esophagus data set is recommended for routine use globally and is a valuable tool to support standardized reporting, to benefit patient care by providing diagnostic and prognostic best-practice parameters.
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Affiliation(s)
- Alfred K Lam
- Pathology, School of Medicine and Dentistry, Gold Coast Campus, Griffith University, Gold Coast, Queensland, 4222, Australia; Pathology Queensland, Gold Coast University Hospital, Southport, Queensland, 4222, Australia; Faculty of Medicine, The University of Queensland, Herston, Queensland, 4006, Australia.
| | - Michael J Bourke
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, 2145, Australia; University of Sydney, Westmead Clinical School, Sydney, New South Wales, 2145, Australia.
| | - Renyin Chen
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, Henan Province, PR China.
| | - Roberto Fiocca
- Department of Pathology, University of Genova and IRCCS Policlinico San Martino, 16132, Genova, Italy.
| | - Fumiyoshi Fujishima
- Department of Pathology, Tohoku University Hospital, Aoba-ku, Sendai, 980-8574, Japan.
| | - Satoshi Fujii
- Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan; Department of Pathology and Clinical Laboratories, National Cancer Centre Hospital East, Kashiwa, 6-5-1, Japan.
| | - Marnix Jansen
- University College London (UCL) Cancer Institute, London, United Kingdom; University College London Hospitals NHS Trust, London, WC1E 6DD, United Kingdom.
| | - Priyanthi Kumarasinghe
- PathWest Laboratory Medicine, PathWest QEII Medical Centre, Perth, 6009, Western Australia, Australia.
| | - Rupert Langer
- Institute of Pathology, University of Bern, 3012 Bern, Switzerland.
| | - Simon Law
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
| | - Sybren L Meijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105, AZ, the Netherlands.
| | - Cian Muldoon
- Histopathology Department, St James's Hospital, Dublin, D08 NHY1, Ireland.
| | - Marco Novelli
- Research Department of Pathology, University College London Medical School, London, WC1E 6DD, United Kingdom.
| | - Chanjuan Shi
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27708, United States.
| | - Laura Tang
- Department of Pharmacy, Memorial Sloan Kettering Cancer Centre, New York City, NY, 10065, United States.
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, 6500, the Netherlands.
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