National Institute for Health and Care Excellence (NICE) guidance on monitoring and management of Barrett's oesophagus and stage I oesophageal adenocarcinoma.

Barrett's oesophagus is the only known precursor to oesophageal adenocarcinoma, a cancer with very poor prognosis. The main risk factors for Barrett's oesophagus are a history of gastro-oesophageal acid reflux symptoms and obesity. Men, smokers and those with a family history are also at increased risk. Progression from Barrett's oesophagus to cancer occurs via an intermediate stage, known as dysplasia. However, dysplasia and early cancer usually develop without any clinical signs, often in individuals whose symptoms are well controlled by acid suppressant medications; therefore, endoscopic surveillance is recommended to allow for early diagnosis and timely clinical intervention. Individuals with Barrett's oesophagus need to be fully informed about the implications of this diagnosis and the benefits and risks of monitoring strategies. Pharmacological treatments are recommended for control of symptoms, but not for chemoprevention. Dysplasia and stage 1 oesophageal adenocarcinoma have excellent prognoses, since they can be cured with endoscopic or surgical therapies. Endoscopic resection is the most accurate staging technique for early Barrett's-related oesophageal adenocarcinoma. Endoscopic ablation is effective and indicated to eradicate Barrett's oesophagus in patients with dysplasia. Future research should focus on improved accuracy for dysplasia detection via new technologies and providing more robust evidence to support pathways for follow-up and treatment.

SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma.

Metastasis in oesophageal adenocarcinoma (OAC) is an important predictor of survival. Radiological staging is used to stage metastases in patients, and guide treatment selection, but is limited by the accuracy of the approach. Improvements in staging will lead to improved clinical decision making and patient outcomes. Sequencing studies on primary tumours and pre-cancerous tissue have revealed the mutational landscape of OAC, and increasingly cheap and widespread sequencing approaches offer the potential to improve staging assessment. In this work we present an analysis of lymph node metastases found by radiological and pathological sampling, identifying new roles of the genes SMAD4 and KCNQ3 in metastasis. Through transcriptomic analysis we find that both genes are associated with canonical Wnt pathway activity, but KCNQ3 is uniquely associated with changes in planar cell polaritiy associated with non-canonical Wnt signalling. We go on to validate our observations in KCNQ3 in cell line and xenograph systems, showing that overexpression of KCNQ3 reduces wound closure and the number of metastases observed. Our results suggest both genes as novel biomarkers of metastatic risk and offer new potential routes to drug targeting.

Modelling lung cancer diagnostic pathways using discrete event simulation.

The United Kingdom has one of the poorest lung cancer survival rates in Europe. In this study, to help design and evaluate a single lung cancer pathway (SCP) for Wales, existing diagnostic pathways and processes have been mapped and then modelled with a discrete event simulation. The validated models have been used to provide key performance indicators and to examine different diagnostic testing strategies. Under the current diagnostic pathways, the mean time to treatment was 72 days for surgery patients, 56 days for chemotherapy patients, and 61 days for radiotherapy patients. Our research demonstrated that by ensuring that the patient attends their first outpatient appointment within 7 days and streamlining the diagnostic tests would have the potential to remove approximately 11 days from the current lung cancer pathway resulting in a 21% increase in patients receiving treatment within the Welsh Government set target of 62 days.

Gallbladder polyps and adenomyomatosis.

Incidental findings are commonly detected during examination of the gallbladder. Differentiating benign from malignant lesions is critical because of the poor prognosis associated with gallbladder malignancy. Therefore, it is important that radiologists and sonographers are aware of common incidental gallbladder findings, which undoubtedly will continue to increase with growing medical imaging use. Ultrasound is the primary imaging modality used to examine the gallbladder and biliary tree, but contrast-enhanced ultrasound and MRI are increasingly used. This review article focuses on two common incidental findings in the gallbladder; adenomyomatosis and gallbladder polyps. The imaging features of these conditions will be reviewed and compared between radiological modalities, and the pathology, epidemiology, natural history, and management will be discussed.

Imaging standardisation in metastatic colorectal cancer: A joint EORTC-ESOI-ESGAR expert consensus recommendation.

BACKGROUND: Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on reporting and interpretation of imaging findings yet offer no guidance on a standardised imaging protocol tailored to patients with mCRC. Imaging protocol heterogeneity remains a challenge for the reproducibility of conventional imaging end-points and is an obstacle for research on novel imaging end-points. PATIENTS AND METHODS: Acknowledging the recently highlighted potential of radiomics and artificial intelligence tools as decision support for patient care in mCRC, a multidisciplinary, international and expert panel of imaging specialists was formed to find consensus on mCRC imaging protocols using the Delphi method. RESULTS: Under the guidance of the European Organisation for Research and Treatment of Cancer (EORTC) Imaging and Gastrointestinal Tract Cancer Groups, the European Society of Oncologic Imaging (ESOI) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the EORTC-ESOI-ESGAR core imaging protocol was identified. CONCLUSION: This consensus protocol attempts to promote standardisation and to diminish variations in patient preparation, scan acquisition and scan reconstruction. We anticipate that this standardisation will increase reproducibility of radiomics and artificial intelligence studies and serve as a catalyst for future research on imaging end-points. For ongoing and future mCRC trials, we encourage principal investigators to support the dissemination of these imaging standards across recruiting centres.

The impact of baseline 18F-FDG PET-CT on the management and outcome of patients with gastric cancer: a systematic review.

OBJECTIVE: CT and staging laparoscopy are routinely used to stage patients with gastric cancer, however the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with CT (PET-CT) is uncertain. This systematic review synthesised the evidence regarding the impact of baseline PET-CT staging on treatment decisions and patient outcomes. METHODS: Systematic database searches were performed without date restriction. Studies reporting data in patients with gastric adenocarcinoma who underwent radiological staging were included. One reviewer screened titles and abstracts for suitability and two reviewers extracted data from included articles. Primary outcome was the reported change in management after PET-CT. Secondary outcomes were the rates of recurrence and overall survival between patients staged with and without PET-CT. Risk of bias was assessed using the ROBINS-I tool. PROSPERO registration (CRD42022304314). RESULTS: Data from 11 studies recruiting 2101 patients between 2012 and 2021 were included. PET-CT was performed in 1422 patients. Change of management varied between 3% and 29% of cases. No studies compared recurrence or survival rates between patients staged with or without PET-CT. Adenocarcinoma of intestinal subtype tended to be more FDG-avid compared to diffuse or signet-ring subtypes. No randomised data existed, and studies were considered low quality with high risk of bias. CONCLUSION: Evidence for the additional value of PET-CT in the gastric cancer staging pathway is limited. All studies reported a positive impact by preventing those with undetected metastatic disease on CT undergoing futile surgery. Future national guidelines should consider routine staging PET-CT in gastric cancer. ADVANCES IN KNOWLEDGE: Studies indicated that FDG PET-CT added benefit in gastric cancer staging by detecting more distant metastases, but these studies were generally of low quality and at high risk of bias. Intestinal subtype of gastric adenocarcinoma tended to be more FDG-avid and therefore more distant metastases were subsequently detected.

Risk of developing gallbladder cancer in patients with gallbladder polyps detected on transabdominal ultrasound: a systematic review and meta-analysis.

OBJECTIVE: To estimate the risk of malignancy in gallbladder polyps of incremental sizes detected during transabdominal ultrasound (TAUS). METHODS: We searched databases including MEDLINE, Embase, and Cochrane Library for eligible studies recording the polyp size from which gallbladder malignancy developed, confirmed following cholecystectomy, or by subsequent follow-up. Primary outcome was the risk of gallbladder cancer in patients with polyps. Secondary outcome was the effect of polyp size as a prognostic factor for cancer. Risk of bias was assessed using the Quality in Prognostic Factor Studies (QUIPS) tool. Bayesian meta-analysis estimated the median cancer risk according to polyp size. This study is registered with PROSPERO (CRD42020223629). RESULTS: 82 studies published since 1990 reported primary data for 67,837 patients. 67,774 gallbladder polyps and 889 cancers were reported. The cumulative median cancer risk of a polyp measuring 10 mm or less was 0.60% (99% credible range 0.30-1.16%). Substantial heterogeneity existed between studies (I2 = 99.95%, 95% credible interval 99.86-99.98%). Risk of bias was generally high and overall confidence in evidence was low. 13 studies (15.6%) were graded with very low certainty, 56 studies (68.3%) with low certainty, and 13 studies (15.6%) with moderate certainty. In studies considered moderate quality, TAUS monitoring detected 4.6 cancers per 10,000 patients with polyps less than 10 mm. CONCLUSION: Malignant risk in gallbladder polyps is low, particularly in polyps less than 10 mm, however the data are heterogenous and generally low quality. International guidelines, which have not previously modelled size data, should be informed by these findings. ADVANCES IN KNOWLEDGE: This large systematic review and meta-analysis has shown that the mean cumulative risk of small gallbladder polyps is low, but heterogeneity and missing data in larger polyp sizes (>10 mm) means the risk is uncertain and may be higher than estimated.Studies considered to have better methodological quality suggest that previous estimates of risk are likely to be inflated.

State-of-the-art imaging in oesophago-gastric cancer.

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.

Management and follow-up of gallbladder polyps: updated joint guidelines between the ESGAR, EAES, EFISDS and ESGE.

MAIN RECOMMENDATIONS: 1. Primary investigation of polypoid lesions of the gallbladder should be with abdominal ultrasound. Routine use of other imaging modalities is not recommended presently, but further research is needed. In centres with appropriate expertise and resources, alternative imaging modalities (such as contrast-enhanced and endoscopic ultrasound) may be useful to aid decision-making in difficult cases. Strong recommendation, low-moderate quality evidence. 2. Cholecystectomy is recommended in patients with polypoid lesions of the gallbladder measuring 10 mm or more, providing the patient is fit for, and accepts, surgery. Multidisciplinary discussion may be employed to assess perceived individual risk of malignancy. Strong recommendation, low-quality evidence. 3. Cholecystectomy is suggested for patients with a polypoid lesion and symptoms potentially attributable to the gallbladder if no alternative cause for the patient's symptoms is demonstrated and the patient is fit for, and accepts, surgery. The patient should be counselled regarding the benefit of cholecystectomy versus the risk of persistent symptoms. Strong recommendation, low-quality evidence. 4. If the patient has a 6-9 mm polypoid lesion of the gallbladder and one or more risk factors for malignancy, cholecystectomy is recommended if the patient is fit for, and accepts, surgery. These risk factors are as follows: age more than 60 years, history of primary sclerosing cholangitis (PSC), Asian ethnicity, sessile polypoid lesion (including focal gallbladder wall thickening > 4 mm). Strong recommendation, low-moderate quality evidence. 5. If the patient has either no risk factors for malignancy and a gallbladder polypoid lesion of 6-9 mm, or risk factors for malignancy and a gallbladder polypoid lesion 5 mm or less, follow-up ultrasound of the gallbladder is recommended at 6 months, 1 year and 2 years. Follow-up should be discontinued after 2 years in the absence of growth. Moderate strength recommendation, moderate-quality evidence. 6. If the patient has no risk factors for malignancy, and a gallbladder polypoid lesion of 5 mm or less, follow-up is not required. Strong recommendation, moderate-quality evidence. 7. If during follow-up the gallbladder polypoid lesion grows to 10 mm, then cholecystectomy is advised. If the polypoid lesion grows by 2 mm or more within the 2-year follow-up period, then the current size of the polypoid lesion should be considered along with patient risk factors. Multidisciplinary discussion may be employed to decide whether continuation of monitoring, or cholecystectomy, is necessary. Moderate strength recommendation, moderate-quality evidence. 8. If during follow-up the gallbladder polypoid lesion disappears, then monitoring can be discontinued. Strong recommendation, moderate-quality evidence. SOURCE AND SCOPE: These guidelines are an update of the 2017 recommendations developed between the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), European Association for Endoscopic Surgery and other Interventional Techniques (EAES), International Society of Digestive Surgery-European Federation (EFISDS) and European Society of Gastrointestinal Endoscopy (ESGE). A targeted literature search was performed to discover recent evidence concerning the management and follow-up of gallbladder polyps. The changes within these updated guidelines were formulated after consideration of the latest evidence by a group of international experts. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence. KEY POINT: • These recommendations update the 2017 European guidelines regarding the management and follow-up of gallbladder polyps.

A DNA-damage immune response assay combined with PET biomarkers predicts response to neo-adjuvant chemotherapy and survival in oesophageal adenocarcinoma.

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.

Factors influencing the delivery of cancer pathways: a summary of the literature.

PURPOSE: The study aims to summarise the literature on cancer care pathways at the diagnostic and treatment phases. The objectives are to find factors influencing the delivery of cancer care pathways; to highlight any interrelating factors; to find gaps in the literature concerning areas of research; to summarise the strategies and recommendations implemented in the studies. DESIGN/METHODOLOGY/APPROACH: The study used a qualitative approach and developed a causal loop diagram to summarise the current literature on cancer care pathways, from screening and diagnosis to treatment. A total of 46 papers was finally included in the analysis, which highlights the recurring themes in the literature. FINDINGS: The study highlights the myriad areas of research applied to cancer care pathways. Factors influencing the delivery of cancer care pathways were classified into different albeit interrelated themes. These include access barriers to care, hospital emergency admissions, fast track diagnostics, delay in diagnosis, waiting time to treatment and strategies to increase system efficiency. ORIGINALITY/VALUE: As far as the authors know, this is the first study to present a visual representation of the complex relationship between factors influencing the delivery of cancer care pathways.

Examining the diagnostic pathway for lung cancer patients in Wales using discrete event simulation.

BACKGROUND: UK's National Health Service (NHS) has one of the poorest lung cancer survival rates in Europe. To improve patient outcomes, a single cancer pathway was introduced in the NHS. In this study, a Discrete Event Simulation was developed to understand bottlenecks during lung cancer treatment. METHODS: This study focused on the lung cancer diagnostic pathways at two Welsh hospitals. Discrete Event Simulation is a computer-based method that has been effectively used in demand and capacity planning. In this study, simulation models were developed for the current and proposed single cancer pathways. The validated models were used to provide Key Performance Indicators. Several "what-if" scenarios were considered for the current and proposed pathways. RESULTS: Under the current diagnostic pathway, the mean time to treatment for a surgery patient was 68 days at the Royal Glamorgan Hospital and 79 days at Prince Charles Hospital. For chemotherapy patients, the mean time to treatment was 52 days at the Royal Glamorgan Hospital and 57 days at Prince Charles Hospital. For radiotherapy patients, the mean time to treatment was 44 days at Royal Glamorgan Hospital and 54 days at Prince Charles Hospital. Ensuring that the patient attends their first outpatient appointment within 7 days and streamlining the diagnostic tests would have the potential to remove approximately 20 days from the current lung cancer pathway resulting in a 20-25% increase of patients receiving treatment within 62 days. Ensuring that patients begin their treatment within 21 days of diagnosis sees almost all patients comply with the 62-day target. CONCLUSIONS: Discrete Event Simulation coupled with a detailed statistical analysis provides a useful decision support tool which can be used to examine the current and proposed lung cancer pathways in terms of time spent on the pathway.

Response rate and diagnostic accuracy of early PET-CT during neo-adjuvant therapies in oesophageal adenocarcinoma: A systematic review and meta-analysis.

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.

Prediction of lymph node metastases using pre-treatment PET radiomics of the primary tumour in esophageal adenocarcinoma: an external validation study.

OBJECTIVES: To improve clinical lymph node staging (cN-stage) in oesophageal adenocarcinoma by developing and externally validating three prediction models; one with clinical variables only, one with positron emission tomography (PET) radiomics only, and a combined clinical and radiomics model. METHODS: Consecutive patients with fluorodeoxyglucose (FDG) avid tumours treated with neoadjuvant therapy between 2010 and 2016 in two international centres (n = 130 and n = 60, respectively) were included. Four clinical variables (age, gender, clinical T-stage and tumour regression grade) and PET radiomics from the primary tumour were used for model development. Diagnostic accuracy, area under curve (AUC), discrimination and calibration were calculated for each model. The prognostic significance was also assessed. RESULTS: The incidence of lymph node metastases was 58% in both cohorts. The areas under the curve of the clinical, radiomics and combined models were 0.79, 0.69 and 0.82 in the developmental cohort, and 0.65, 0.63 and 0.69 in the external validation cohort, with good calibration demonstrated. The area under the curve of current cN-stage in development and validation cohorts was 0.60 and 0.66, respectively. For overall survival, the combined clinical and radiomics model achieved the best discrimination performance in the external validation cohort (X2 = 6.08, df = 1, p = 0.01). CONCLUSION: Accurate diagnosis of lymph node metastases is crucial for prognosis and guiding treatment decisions. Despite finding improved predictive performance in the development cohort, the models using PET radiomics derived from the primary tumour were not fully replicated in an external validation cohort. ADVANCES IN KNOWLEDGE: This international study attempted to externally validate a new prediction model for lymph node metastases using PET radiomics. A model combining clinical variables and PET radiomics improved discrimination of lymph node metastases, but these results were not externally replicated.

Discordant nodal staging identifies intermediate-risk group for overall survival in patients with cT3 oesophageal adenocarcinoma.

OBJECTIVES: Oesophageal adenocarcinoma has a poor prognosis and relies on multi-modality assessment for accurate nodal staging. The aim of the study was to determine the prognostic significance of nodal concordance between PET/CT and EUS in oesophageal adenocarcinoma. METHODS: Consecutive patients with oesophageal adenocarcinoma staged between 2010 and 2016 were included. Groups comprising concordant node-negative (C-ve), discordant (DC), and concordant node-positive (C+ve) patients were analysed. Survival analysis using log-rank tests and Cox proportional hazards model was performed. The primary outcome was overall survival. A p value < 0.05 was considered statistically significant. RESULTS: In total, 310 patients (median age = 66.0; interquartile range 59.5-72.5, males = 264) were included. The median overall survival was 23.0 months (95% confidence intervals (CI) 18.73-27.29). There was a significant difference in overall survival between concordance groups (X2 = 44.91, df = 2, p < 0.001). The hazard ratios for overall survival of DC and C+ve patients compared with those of C-ve patients with cT3 tumours were 1.21 (95% CI 0.81-1.79) and 1.79 (95% CI 1.23-2.61), respectively. On multivariable analysis, nodal concordance was significantly and independently associated with overall survival (HR 1.44, 95% CI 1.12-1.83, p = 0.004) and performed better than age at diagnosis (HR 1.02, 95% CI 1.003-1.034, p = 0.016) and current cN-staging methods (HR 1.20, 95% CI 0.978-1.48, p = 0.080). CONCLUSIONS: Patients with discordant nodal staging on PET/CT and EUS represent an intermediate-risk group for overall survival. This finding was consistent in patients with cT3 tumours. These findings will assist optimum treatment decisions based upon perceived prognosis for each patient. KEY POINTS: • Clinicians are commonly faced with results of discordant nodal staging in oesophageal adenocarcinoma. • There is a significant difference in overall survival between patients with negative, discordant, and positive lymph node staging. • Patients with discordant lymph node staging between imaging modalities represent an intermediate-risk group for overall survival.

Discovery of stable and prognostic CT-based radiomic features independent of contrast administration and dimensionality in oesophageal cancer.

The aim of this work was to investigate radiomic analysis of contrast and non-contrast enhanced planning CT images of oesophageal cancer (OC) patients in terms of stability, dimensionality and contrast agent dependency. The prognostic significance of CT-based radiomic features was also evaluated. Different 2D and 3D radiomic features were extracted from contrast and non-contrast enhanced CT images of 213 patients from the multi-centre SCOPE1 randomised controlled trial (RCT) in OC. Feature stability was evaluated by randomly dividing patients into three groups and identifying textures with similar distributions among groups with a Kruskal-Wallis analysis. A paired two-sided Wilcoxon signed rank test was used to assess for significant differences in the remaining corresponding 2D and 3D stable features. A prognostic model was constructed using clinical characteristics and remaining filtered features. The discriminative ability of significant variables was tested using Kaplan-Meier analysis. A total of 238 2D and 3D radiomic features were computed from oesophageal CT images. More than 75 features were stable if extracted from homogeneous cohort (contrast or non-contrast enhanced CT images) and inhomogeneous cohort (contrast and non-contrast enhanced CT images). Among the remaining corresponding stable features computed from both cohorts, only 4 features did not show a statistically significant difference if obtained in 2D or in 3D (p-value < 0.05). A Cox regression model constructed using 5 clinical variables (age, sex, tumour, node and metastasis (TNM) stage, WHO performance status and contrast administration) and 4 radiomic variables (inverse varianceGLCM, large distance emphasisGLDZM, zone distance non uniformity normGLDZM, zone distance varianceGLDZM), identified one radiomic feature (zone distance varianceGLDZM) that was significantly associated with overall survival (p-value = 0.032, HR = 1.25, 95% CI = 1.02-1.52). A significant difference in overall survival between groups was found when considering a threshold of zone distance varianceGLDZM equals to 1.70 (X2 = 7.692, df = 1, p-value = 0.006). Zone distance varianceGLDZM was identified as the only stable CT radiomic feature statistically correlated with overall survival, independent of dimensionality and contrast administration. This feature was able to identify high-risk patients and if validated, could be the subject of a future clinical trial aiming to improve clinical decision making and personalise OC treatment.

Assessing radiomic feature robustness to interpolation in 18F-FDG PET imaging.

Radiomic studies link quantitative imaging features to patient outcomes in an effort to personalise treatment in oncology. To be clinically useful, a radiomic feature must be robust to image processing steps, which has made robustness testing a necessity for many technical aspects of feature extraction. We assessed the stability of radiomic features to interpolation processing and categorised features based on stable, systematic, or unstable responses. Here, 18F-fluorodeoxyglucose (18F-FDG) PET images for 441 oesophageal cancer patients (split: testing = 353, validation = 88) were resampled to 6 isotropic voxel sizes (1.5 mm, 1.8 mm, 2.0 mm, 2.2 mm, 2.5 mm, 2.7 mm) and 141 features were extracted from each volume of interest (VOI). Features were categorised into four groups with two statistical tests. Feature reliability was analysed using an intraclass correlation coefficient (ICC) and patient ranking consistency was assessed using a Spearman's rank correlation coefficient (ρ). We categorised 93 features robust and 6 limited robustness (stable responses), 34 potentially correctable (systematic responses), and 8 not robust (unstable responses). We developed a correction technique for features with potential systematic variation that used surface fits to link voxel size and percentage change in feature value. Twenty-nine potentially correctable features were re-categorised to robust for the validation dataset, after applying corrections defined by surface fits generated on the testing dataset. Furthermore, we found the choice of interpolation algorithm alone (spline vs trilinear) resulted in large variation in values for a number of features but the response categorisations remained constant. This study attempted to quantify the diverse response of radiomics features commonly found in 18F-FDG PET clinical modelling to isotropic voxel size interpolation.

Cyclo-oxygenase-2 expression is associated with mean standardised uptake value on 18F-Fluorodeoxyglucose positron emission tomography in oesophageal adenocarcinoma.

OBJECTIVES: This pilot study investigated the association of four PET image features and cyclo-oxygenase-2 (COX-2) expression in patients with oesophageal adenocarcinoma. The prognostic significance of these biomarkers was also assessed. METHODS: 50 consecutive patients [median age = 68 (range 47 - 84), males = 45) with oesophageal adenocarcinoma had PET/CT staging between January 2011 and July 2015. The maximum and mean standardised uptake values (SUVmax and SUVmean), metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG) were calculated from the primary tumour. Their association with COX-2 status was assessed using Mann-Whitney U tests. Kaplan-Meier and Cox regression analysis tested their prognostic significance. A p-value < 0.05 was considered statistically significant. RESULTS: 32 tumours (64.0%) were COX-2 positive. There was a significant association between SUVmean and COX-2 status (p = 0.019). TLG (hazard ratio (HR) 1.001, 95 % confidence intervals (CI) 1.000 - 1.002, p = 0.018) was significantly associated with overall survival on multivariable analysis. CONCLUSIONS: This study investigated the association between PET image features and COX-2 expression in oesophageal adenocarcinoma. The preliminary results signal that a combination of TLG (calculated as product of MTV and SUVmean) and COX-2 status may be a strong and clinically important prognostic biomarker. Our research group are planning a prospective, multi-centre study to validate these findings. ADVANCES IN KNOWLEDGE: Mean standardised uptake value (SUVmean) on PET imaging is associated with COX-2 expression in oesophageal adenocarcinoma.

External Validation of Radiation-Induced Dyspnea Models on Esophageal Cancer Radiotherapy Patients.

Purpose: Radiation-induced lung disease (RILD), defined as dyspnea in this study, is a risk for patients receiving high-dose thoracic irradiation. This study is a TRIPOD (Transparent Reporting of A Multivariable Prediction Model for Individual Prognosis or Diagnosis) Type 4 validation of previously-published dyspnea models via secondary analysis of esophageal cancer SCOPE1 trial data. We quantify the predictive performance of these two models for predicting the maximal dyspnea grade ≥ 2 within 6 months after the end of high-dose chemo-radiotherapy for primary esophageal cancer. Materials and methods: We tested the performance of two previously published dyspnea risk models using baseline, treatment and follow-up data on 258 esophageal cancer patients in the UK enrolled into the SCOPE1 multi-center trial. The tested models were developed from lung cancer patients treated at MAASTRO Clinic (The Netherlands) from the period 2002 to 2011. The adverse event of interest was dyspnea ≥ Grade 2 (CTCAE v3) within 6 months after the end of radiotherapy. As some variables were missing randomly and cannot be imputed, 212 patients in the SCOPE1 were used for validation of model 1 and 255 patients were used for validation of model 2. The model parameter Forced Expiratory Volume in 1 s (FEV1), as a predictor to both validated models, was imputed using the WHO performance status. External validation was performed using an automated, decentralized approach, without exchange of individual patient data. Results: Out of 258 patients with esophageal cancer in SCOPE1 trial data, 38 patients (14.7%) developed radiation-induced dyspnea (≥ Grade 2) within 6 months after chemo-radiotherapy. The discrimination performance of the models in esophageal cancer patients treated with high-dose external beam radiotherapy was moderate, area under curve (AUC) of 0.68 (95% CI 0.55-0.76) and 0.70 (95% CI 0.58-0.77), respectively. The curves and AUCs derived by distributed learning were identical to the results from validation on a local host. Conclusion: We have externally validated previously published dyspnea models using an esophageal cancer dataset. FEV1 that is not routinely measured for esophageal cancer was imputed using WHO performance status. Prediction performance was not statistically different from previous training and validation sets. Risk estimates were dominated by WHO score in Model 1 and baseline dyspnea in Model 2. The distributed learning approach gave the same answer as local processing, and could be performed without accessing a validation site's individual patients-level data.

Propensity score analysis of 18-FDG PET/CT-enhanced staging in patients undergoing surgery for esophageal cancer.

PURPOSE: PET/CT is now integral to the staging pathway for potentially curable esophageal cancer (EC), primarily to identify distant metastases undetected by computed tomography. The aim of this study was to analyze the effect of PET/CT introduction on survival and assess patterns of recurrence after esophagectomy. METHODS: A longitudinal cohort of EC patients staged between 1998 and 2016 were considered for inclusion. After co-variate adjustment using propensity scoring, a cohort of 496 patients (273 pre-PET/CT and 223 post-PET/CT) who underwent esophagectomy [median age 63 years (31-80), 395 males, 425 adenocarcinomas, 71 squamous cell carcinomas, 325 neoadjuvant therapy] were included. The primary outcome measure was overall survival (OS) based on intention to treat. RESULTS: Three-year OS pre-PET/CT was 42.5% compared with 57.8% post-PET/CT (Chi2 6.571, df 1, p = 0.004). On multivariable analysis, pT stage (HR 1.496 [95% CI 1.28-1.75], p < 0.0001), pN stage (HR 1.114 [95% CI 1.04-1.19], p = 0.001) and PET/CT staging (HR 0.688 [95% CI 0.53-0.89] p = 0.004) were independently associated with OS. Recurrent cancer was observed in 125 patients (51.4%) pre-PET/CT, compared with 74 patients post-PET/CT (37.8%, p = 0.004), and was less likely to be distant recurrence after PET/CT introduction (39.5 vs. 27.0%, p = 0.006). CONCLUSIONS: Enhanced PET/CT staging is an important modality and independent factor associated with improved survival in patients undergoing esophagectomy for cancer.