Fergus Noble

• MB BS BSC (Hons) PhD FRCS (Gen. Surg)
• Consultant at University Hospital Southampton NHS Foundation Trust

Background Oesophago-gastric cancer surgery negatively affects quality of life with a high postoperative symptom burden. Several conditions that may be diagnosed and treated after surgery are recognised. However, consensus regarding their definition and management is lacking. This study aimed to develop consensus regarding the definition, investiga...

Objective This study investigated if hybrid oesophagectomy with minimally invasive gastric mobilization and thoracotomy enabled faster recovery than open surgery. Methods In eight UK centres, this pragmatic RCT recruited patients for oesophagectomy to treat localized cancer. Participants were randomly allocated to hybrid or open surgery, stratifie...

Introduction: Complications are frequent after oesophagectomy, and there is evidence these adversely impact long-term prognosis. However, the effect of multiple complications, and the absolute magnitude of effect on survival is unclear. This study aimed to examine these effects in a single high-volume UK unit. Methods: Patients undergoing oesoph...

Gastro-esophageal reflux disease (GERD) is a common, significant health burden. United Kingdom guidance states that surgery should be considered for patients with a diagnosis of GERD not suitable for long-term acid suppression. There is no consensus on many aspects of patient pathways and optimal surgical technique, and an absence of information on...

Background Globally, oesophageal cancer incidence continues to increase. In recent years, surgical and oncological advancements have increased survival rates. Despite this, survival remains <50% at five-years for patients treated with curative oesophagectomy. Previous data has suggested post-operative complications may play a role in long-term incr...

Introduction In oesophageal adenocarcinoma with an apparent pathological complete response (pCR) to neoadjuvant therapy (NAT) there remains debate as to whether oesophagectomy is required. Single Cell RNA sequencing (scRNAseq) enables identification and characterisation of cell populations at higher resolution than diagnostic techniques. Method Sc...

Introduction: Boerhaave's syndrome is a life-threatening spontaneous perforation of the esophagus associated with significant morbidity and mortality. Historically, thoracotomy has been the mainstay of treatment, but is associated with high morbidity and pain. Minimally invasive approaches provide alternative treatment possibilities. This systemati...

In esophageal adenocarcinoma (EAC) with apparent pathological complete response (pCR) to neoadjuvant therapy (NAT) debate remains as to whether esophagectomy is required. Recurrence after pCR is not limited to distant metastases outside radiation or resection fields. It is unknown if cancer persists below the lower detection limit of current diagno...

Background: esophageal cancer is increasingly common and carries a poor prognosis. The optimal treatment modality for locally advanced cancer is unknown, with current guidance recommending either neoadjuvant chemotherapy (CT) or chemoradiotherapy (CRT) followed by surgery. There is a lack of adequately powered trials comparing CT against CRT. We re...

Introduction Surgery (oesophagectomy), with neoadjuvant chemo(radio)therapy, is the main curative treatment for patients with oesophageal cancer. Several surgical approaches can be used to remove an oesophageal tumour. The Ivor Lewis (two-phase procedure) is usually used in the UK. This can be performed as an open oesophagectomy (OO), a laparoscopi...

Background The prediction of a difficult cholecystectomy has traditionally been based on certain pre-operative clinical and imaging factors. Most of the previous literature reported small patient cohorts and have not used an objective measure of operative difficulty. The aim of this study was to develop a pre-operative score to predict difficult ch...

Introduction Acute pancreatitis is a common surgical emergency. Identifying variations in presentation, incidence and management may assist standardisation and optimisation of care. The objective of the study was to document the current incidence management and outcomes of acute pancreatitis against international guidelines, and to assess temporal...

Introduction: Acute pancreatitis is a common surgical emergency. Identifying variations in presentation, incidence and management may assist standardisation and optimisation of care. The objective of the study was to document the current incidence management and outcomes of acute pancreatitis against international guidelines, and to assess tempora...

Background: Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preop...

Objective Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. Design Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endos...

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Objective: To investigate differences in methylation between patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma and those who do not. Background: Identifying patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma remains a challenge. Previous studies have demonstrated the potentia...

Background: Cancer–associated fibroblasts (CAFs) form the major stromal component of the tumour microenvironment (TME). The present study aimed to examine the proteomic profiles of CAFs vs. normal fibroblasts (NOFs) from patients with oesophageal adenocarcinoma to gain insight into their pro-oncogenic phenotype. Methods: CAFs/NOFs from four patient...

Table S2 Effect of chemotherapy regimen on tumour regression grade, lymph node downstaging and resection margins

Appendix S1 Site‐specific questionnaire

Fig. S1 Responses to questionnaire sent to 11 UK cancer centres to determine current use of pathological response information in clinical decision‐making

Fig. S2 Kaplan–Meier curves for patients treated with cisplatin and 5‐fluorouracil or platinum‐based triplet chemotherapy

Table S1 Resection margin involvement in relation to tumour regression grade (Word document)

BACKGROUND: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. METHODS: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Re...

Background: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. Methods: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy....

Background: Programmed Death-1 Receptor (PD-1) and its ligand (PD-L1) downregulate T cell activation and suppress tumor killing. This study investigated the role of PD-L1 and tumor infiltrating lymphocytes (TILs) in response to neo-adjuvant therapy and prognosis in esophageal adenocarcinoma (EAC). Methods: Transcriptional profiling of 273 formali...

4026 Background: Current strategies to guide the selection of neo-adjuvant or adjuvant therapy in esophageal and gastric adenocarcinomas (EAC/GAC) are inadequate. We assessed a clinically validated 44 gene DNA Damage Response Deficiency (DDRD) assay to predict prognosis following neo-adjuvant DNA damaging chemotherapy (CT) in EAC and adjuvant CT or...

4030 Background: Prognostication for cancer patients is based upon factors determined at baseline and becomes less relevant over time. Conditional survival (CS) estimates future prognosis based upon survival to a specific time point after treatment. We analyzed CS for patients in the United Kingdom (UK) undergoing surgery and neoadjuvant chemothera...

Background: Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed. Methods: CAF accumulation and prognostic significance in head and neck...

The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-ge...

Background: Hiatal hernia (HH) after esophagectomy is becoming more relevant due to improvements in survival. This study evaluated and compared the occurrence and clinical course of HH after open and minimally invasive esophagectomy (MIE). Methods: The prospectively recorded characteristics of patients treated with esophagectomy for cancer at 2...

Background: Enhanced recovery programmes improve outcomes in surgery, but their implementation after upper gastrointestinal resection has been limited. The aim of this study was to compare short-term outcomes for patients undergoing oesophagogastric surgery in an enhanced recovery programme (EROS). Methods: EROS was developed after a multidiscip...

BACKGROUND: Hiatal hernia (HH) after esophagectomy is becoming more relevant due to improvements in survival. This study evaluated and compared the occurrence and clinical course of HH after open and minimally invasive esophagectomy (MIE). METHODS: The prospectively recorded characteristics of patients treated with esophagectomy for cancer at 2 te...

Abstract Background: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy (NAC) in oesophageal adenocarcinoma (OAC). Methods: A questionnaire was distributed to 11 UK Upper GI cancer centres to assess the current use of neoadjuvant response assessment. The reco...

BACKGROUND: The aims of this prospective population-based cohort study were to identify the patient and hospital characteristics associated with emergency cholecystectomy, and the influences of these in determining variations between hospitals. METHODS: Data were collected for consecutive patients undergoing cholecystectomy in acute UK and Irish ho...

Background: The optimal timing of cholecystectomy for patients admitted with acute gallbladder pathology is unclear. Some studies have shown that emergency cholecystectomy during the index admission can reduce length of hospital stay with similar rates of conversion to open surgery, complications and mortality compared with a 'delayed' operation f...

New biological tools are required to understand the functional significance of genetic events revealed by whole genome sequencing (WGS) studies in oesophageal adenocarcinoma (OAC). The MFD-1 cell line was isolated from a 55-year-old male with OAC without recombinant-DNA transformation. Somatic genetic variations from MFD-1, tumour, normal oesophagu...

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-ampl...

Background: Laparoscopic cholecystectomy is commonly performed, and several factors increase the risk of open conversion, prolonging operating time and hospital stay. Preoperative stratification would improve consent, scheduling and identify appropriate training cases. The aim of this study was to develop a validated risk score for conversion for...

Background: The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all-cause 30-day readmissions and complications in a prospective population-based cohort. Methods: Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and...

Background: Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10-15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing...

Collagen structure has been shown to influence tumor cell invasion, metastasis and clinical outcome in breast cancer. However, it remains unclear how it affects other solid cancers. Here we utilized multi-photon laser scanning microscopy and Second Harmonic Generation to identify alterations to collagen fiber structure within the tumor stroma of he...

Gallstones are common, but most are asymptomatic and need no treatment. Typical presentations include biliary colic and acute cholecystitis. Chronic symptoms overlap with irritable bowel syndrome and non-ulcer dyspepsia, which may lead to uncertainty in identifying the cause of the symptoms. Complications of gallstones include empyema and mucocele...

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insi...

Oesophageal adenocarcinoma (OAC) is one of the fastest rising malignancies with continued poor prognosis. Many studies have proposed novel biomarkers but, to date, no immunohistochemical markers of survival after oesophageal resection have entered clinical practice. Here, we systematically review and meta-analyse the published literature, to identi...

Introduction Enhanced recovery is an accepted mechanism to improve perioperative outcomes in surgery. The generalisablity of outcomes after enhanced recovery for oesophagogastric surgery (EROS) has been limited because the majority of series come from a single surgeon or have excluded patients based on surgeon preference. There have been few report...

Introduction The optimal neoadjuvant therapy regime for cancers of the oesophagus and OGJ remains controversial. In the UK preoperative chemotherapy is the standard of care, and we have been slow to adopt chemoradiotherapy (CRT) fearing increased surgical morbidity and under-treatment of systemic disease. The CROSS trial has led to a renewed intere...

Introduction The 2014 report of the National OesopahgoGastric Cancer Audit (NOGCA) identified an increasing number of patients who were treated with minimally invasive (MIO) or hybrid operations (41.5%). Overall complications were similar to open surgery, but a significant increase in anastomotic leak (AL) after MIO was identified (11.7% vs. 6.7%)....

Introduction The United Kingdom has the highest age-standardised incidence of oesophageal adenocarcinoma (EAC) in the world. EAC has a narrow window for medical intervention and 2/3 of patients present with incurable disease. Even after potentially curative surgery survival rates are at best 50% at 5 years. The oesophageal International Cancer Geno...

Further characterization of primary oesophageal fibroblasts

Additional organotypic and mouse xenograft model

KME values for all of the proteins clustered in the ECM module

Integrin αvβ3 and αvβ5 expressions were analysed in FLO-1 and OE33 cells using western blot, FACs and MTS proliferation assay

Clinicopathological characteristics of patient cohort for immunohistochemistry

Interactions between cancer cells and cancer-associated fibroblasts (CAF) play an important role in tumour development and progression. In this study we investigated the functional role of CAF in oesophageal adenocarcinoma (EAC). We used immunochemistry to analyse a cohort of EAC patients (183 patients) for CAF markers related to disease mortality....

Thoracoabdominal hernias are uncommon following blunt trauma. If diaphragmatic rupture does occur, the abdominal viscera can herniate into the thorax through the diaphragm. We report a rare case of thoracoabdominal herniation in which the bowel herniated through the lateral abdominal wall, migrating cranially and entering the thorax through an inte...

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes a...

Esophageal adenocarcinoma is one of the fastest rising cancers in Western society. Incidence has increased by 600% within the last 30 years. Rates of diagnosis and death run parallel due to the poor prognosis and a lack of effective treatments. Potentially curative treatments are followed by high rates of disease recurrence. For the majority of pat...

The Siewert classification has been used to plan treatment for tumours of the gastro-oesophageal junction since its proposal in the 1980s. The purpose of this study was to assess its continued relevance by evaluating whether there were differences in the biology and clinical characteristics of adenocarcinomas by Siewert type, in a contemporary coho...

To assess tumour regression grade (TRG) and lymph node downstaging to help define patients who benefit from neoadjuvant chemotherapy. Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005 and 2011 at a single in...

The aim of this study was to interrogate whether blood-borne inflammatory and nutritional markers predict long-term survival and response to neoadjuvant chemotherapy in radically treated oesophagogastric cancer patients. This retrospective study included 246 patients who underwent oesophageal resection for high-grade dysplasia or carcinoma between...

The majority of esophagectomies in Western parts of the world are performed by a transthoracic approach reflecting the prevalence of adenocarcinoma of the lower esophagus or esophagogastric junction. Minimally invasive esophagectomy (MIE) has been reported in a variety of formats, but there are no series that directly compare totally minimally inva...

Introduction Since the early 1980s the Siewert classification has been used to plan treatment for tumours of the gastro-oesophageal junction. However, the relationship between tumour site and survival has not been conclusively demonstrated, with conflicting outcomes in the largest series, before the widespread application of neoadjuvant chemotherap...

Introduction Patients with oesophagogastric cancer are at high risk of malnutrition.1 The aim of this study was to assess the effect of advice provided by a dietitian peri-operatively on nutritional status at first surgical follow-up. The period studied was prior to specialist dietetic services being funded, resulting in lack of capacity to see all...

Introduction Stromal and other non-malignant cells have the potential to undergo modifications that can synergistically create a supportive microenvironment for tumour growth, invasion and metastasis. Oesophageal adenocarcinoma (EAC) is characterised by early invasion, leading to metastatic disease and therefore only 20% of patients are suitable fo...

Oesophagectomy is associated with significant morbidity and mortality. A simple score to define a patient's risk of developing major complications would be beneficial. Patients who underwent upper gastrointestinal resections with an oesophageal anastomosis between 2005 and 2010 were reviewed and formed the development dataset with resections perfor...

Background: the aim of this study was to establish a numerical scoring system that categorises a patients’ risk of developing major post-operative complications after oesophageal resection based on routine blood tests. Methods: a prospective database of all upperGI resectionswith an oesophageal anastomosis between 2005 and 2010 was reviewed. C-reac...

Background information: Carcinoma of the oesophagus is the sixth leading cause of cancer death in the western world and is associated with a 5-year survival of less than 15%. Recent evidence suggests that stromal-epithelial interactions are fundamental in carcinogenesis. The advent of co-culture techniques permits the investigation of cross-talk b...