Patients unfit for neoadjuvant therapy may still undergo resection of locally advanced esophageal or esophagogastric junctional cancer with acceptable oncological results

O’Neill, J. Robert; Kennedy, Ewan D.; Save, Vicki; Langdale-Brown, B.; Wall, Lucy; Skipworth, Richard J.E.; Paterson-Brown, Simon

doi:10.1097/ij9.0000000000000009

Cited by 5 publications

(7 citation statements)

References 34 publications

(35 reference statements)

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“…3 Defining the optimal neoadjuvant treatment regime is an area of active investigation, 4 as current treatments carry a significant risk of systemic toxicity, histologic response rates remain poor, 5 and only a limited subgroup of patients experience any survival benefit over surgery alone. 6,7 EAC is a highly heterogeneous disease, dominated by largescale genomic rearrangements and copy number alterations. 8 This has made clinically meaningful subgroups and wellvalidated therapeutic targets difficult to define.…”

Section: Introductionmentioning

confidence: 99%

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High-Content Phenotypic Profiling in Esophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery

et al. 2020

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Esophageal adenocarcinoma (EAC) is a highly heterogeneous disease, dominated by large-scale genomic rearrangements and copy number alterations. Such characteristics have hampered conventional target-directed drug discovery and personalized medicine strategies, contributing to poor outcomes for patients. We describe the application of a high-content Cell Painting assay to profile the phenotypic response of 19,555 compounds across a panel of six EAC cell lines and two tissue-matched control lines. We built an automated high-content image analysis pipeline to identify compounds that selectively modified the phenotype of EAC cell lines. We further trained a machine-learning model to predict the mechanism of action of EAC selective compounds using phenotypic fingerprints from a library of reference compounds. We identified a number of phenotypic clusters enriched with similar pharmacological classes, including methotrexate and three other antimetabolites that are highly selective for EAC cell lines. We further identify a small number of hits from our diverse chemical library that show potent and selective activity for EAC cell lines and that do not cluster with the reference library of compounds, indicating they may be selectively targeting novel esophageal cancer biology. Overall, our results demonstrate that our EAC phenotypic screening platform can identify existing pharmacologic classes and novel compounds with selective activity for EAC cell phenotypes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High-Content Phenotypic Profiling in Esophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery

et al. 2020

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“…In the UK, 95% of patients diagnosed with EAC will die from metastatic disease and the majority are resistant, at presentation, to current platinum-based chemotherapy regimens (4–6). …”

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confidence: 99%

Quantitative Shotgun Proteomics Unveils Candidate Novel Esophageal Adenocarcinoma (EAC)-specific Proteins

O’Neill

Pak

Pairo-Castineira

et al. 2017

Molecular & Cellular Proteomics

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Esophageal cancer is the eighth most common cancer worldwide and the majority of patients have systemic disease at presentation. Esophageal adenocarcinoma (OAC), the predominant subtype in western countries, is largely resistant to current chemotherapy regimens. Selective markers are needed to enhance clinical staging and to allow targeted therapies yet there are minimal proteomic data on this cancer type. After histological review, lysates from OAC and matched normal esophageal and gastric samples from seven patients were subjected to LC MS/MS after tandem mass tag labeling and OFFGEL fractionation. Patient matched samples of OAC, normal esophagus, normal stomach, lymph node metastases and uninvolved lymph nodes were used from an additional 115 patients for verification of expression by immunohistochemistry (IHC).Over six thousand proteins were identified and quantified across samples. Quantitative reproducibility was excellent between technical replicates and a moderate correlation was seen across samples with the same histology. The quantitative accuracy was verified across the dynamic range for seven proteins by immunohistochemistry (IHC) on the originating tissues. Multiple novel tumor-specific candidates are proposed and EPCAM was verified by IHC.This shotgun proteomic study of OAC used a comparative quantitative approach to reveal proteins highly expressed in specific tissue types. Novel tumor-specific proteins are proposed and EPCAM was demonstrated to be specifically overexpressed in primary tumors and lymph node metastases compared with surrounding normal tissues. This candidate and others proposed in this study could be developed as tumor-specific targets for novel clinical staging and therapeutic approaches.

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“…The tumors were staged according to the seventh edition of the TNM classification system for both gastric and esophageal cancer [23]. Some patients with clinical stage II or III according to the esophageal cancer staging system, received neoadjuvant chemotherapy to accelerate curability [24]. All patients were fully involved in the decision-making process, and informed consent was obtained from all patients.…”

Section: Examination Of Excised Specimensmentioning

confidence: 99%

Requiring Multi-Steps During Minimally Invasive Surgery to Achieve Optimal Proximal Resection Margin for Siewert-Types II and III Esophagogastric Junctional Cancer

Uchiyama¹,

Noshirο²,

Iwasaki³

et al. 2019

ACO

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Background: Transection of the esophagus at a cancer-negative proximal surgical margin and alimentary tract reconstruction through the hiatus during minimally invasive surgery (MIS) may be complicated and difficult in some patients with Siewert type II or III esophagogastric junctional cancer (EGJC). In this study, we retrospectively determined requiring multi-steps during MIS for Siewert types II and III EGJC. Study Design: Fifty-one consecutive patients with surgically treated Siewert type II or III EGJC were reviewed from July 2006 to October 2016. Five patients were excluded, and the remaining forty-six patients were divided into four groups based on the combination of laparoscopic and thoracoscopic surgical procedures performed, according to Siewert classification and TNM-staging: one-step surgery (n = 16), twostep surgery without novel transection of the esophagus (n = 8), two-step surgery with novel transection of the esophagus (n = 13), and three-step surgery (n = 9). Results: The esophagus was transected successfully with a cancer-free proximal margin in all but one patient. However, only 16 patients (35 %) were treated successfully by laparoscopic surgery alone, and the remaining 30 patients needed one or more additional steps to complete the anastomosis after transection of the esophagus according to the extent of esophageal invasion of the tumor. Conclusion: Multi-step procedures may be needed to achieve a cancer-negative proximal margin followed by alimentary reconstruction during MIS in patients with Siewert type II or III EGJC.

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Patients unfit for neoadjuvant therapy may still undergo resection of locally advanced esophageal or esophagogastric junctional cancer with acceptable oncological results

Abstract: Supplemental Digital Content is available in the text.

Cited by 5 publications

References 34 publications

High-Content Phenotypic Profiling in Esophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery

High-Content Phenotypic Profiling in Esophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery

Quantitative Shotgun Proteomics Unveils Candidate Novel Esophageal Adenocarcinoma (EAC)-specific Proteins

Requiring Multi-Steps During Minimally Invasive Surgery to Achieve Optimal Proximal Resection Margin for Siewert-Types II and III Esophagogastric Junctional Cancer

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