CT colonography: external clinical validation of an algorithm for computer-assisted prone and supine registration

Purpose To perform external validation of a computer-assisted registration algorithm for prone and supine computed tomographic (CT) colonography and to compare the results with those of an existing centerline method. Materials and Methods All contributing centers had institutional review board approval; participants provided informed consent. A validation sample of CT colonographic examinations of 51 patients with 68 polyps (6–55 mm) was selected from a publicly available, HIPAA compliant, anonymized archive. No patients were excluded because of poor preparation or inadequate distension. Corresponding prone and supine polyp coordinates were recorded, and endoluminal surfaces were registered automatically by using a computer algorithm. Two observers independently scored three-dimensional endoluminal polyp registration success. Results were compared with those obtained by using the normalized distance along the colonic centerline (NDACC) method. Pairwise Wilcoxon signed rank tests were used to compare gross registration error and McNemar tests were used to compare polyp conspicuity. Results Registration was possible in all 51 patients, and 136 paired polyp coordinates were generated (68 polyps) to test the algorithm. Overall mean three-dimensional polyp registration error (mean ± standard deviation, 19.9 mm ± 20.4) was significantly less than that for the NDACC method (mean, 27.4 mm ± 15.1; P = .001). Accuracy was unaffected by colonic segment (P = .76) or luminal collapse (P = .066). During endoluminal review by two observers (272 matching tasks, 68 polyps, prone to supine and supine to prone coordinates), 223 (82%) polyp matches were visible (120° field of view) compared with just 129 (47%) when the NDACC method was used (P < .001). By using multiplanar visualization, 48 (70%) polyps were visible after scrolling ± 15 mm in any multiplanar axis compared with 16 (24%) for NDACC (P < .001). Conclusion Computer-assisted registration is more accurate than the NDACC method for mapping the endoluminal surface and matching the location of polyps in corresponding prone and supine CT colonographic acquisitions

Facilitating Colorectal Cancer Diagnosis with Computed Tomographic Colonography

Computed tomographic colonography (CTC) is a diagnostic technique involving helical volume acquisition of the cleansed, distended colorectum to detect colorectal cancer or potentially premalignant polyps. This Thesis summarises the evidence base, identifies areas in need of further research, quantifies sources of bias and presents novel techniques to facilitate colorectal cancer diagnosis using CTC. CTC literature is reviewed to justify the rationale for current implementation and to identify fruitful areas for research. This confirms excellent diagnostic performance can be attained providing CTC is interpreted by trained, experienced observers employing state-of-the-art implementation. The technique is superior to barium enema and consequently, it has been embraced by radiologists, clinicians and health policy-makers. Factors influencing generalisability of CTC research are investigated, firstly with a survey of European educational workshop participants which revealed limited CTC experience and training, followed by a systematic review exploring bias in research studies of diagnostic test accuracy which established that studies focussing on these aspects were lacking. Experiments to address these sources of bias are presented, using novel methodology: Conjoint analysis is used to ascertain patients‘ and clinicians’ attitudes to false-positive screening diagnoses, showing that both groups overwhelmingly value sensitivity over specificity. The results inform a weighted statistical analysis for CAD which is applied to the results of two previous studies showing the incremental benefit is significantly higher for novices than experienced readers. We have employed eye-tracking technology to establish the visual search patterns of observers reading CTC, demonstrated feasibility and developed metrics for analysis. We also describe development and validation of computer software to register prone and supine endoluminal surface locations demonstrating accurate matching of corresponding points when applied to a phantom and a generalisable, publically available, CTC database. Finally, areas in need of future development are suggested

Eye-tracking the moving medical image: Development and investigation of a novel investigational tool for CT Colonography

Colorectal cancer remains the third most common cancer in the UK but the second leading cause of cancer death with >16,000 dying per year. Many advances have been made in recent years in all areas of investigation for colorectal cancer, one of the more notable being the widespread introduction of CT Colonography (CTC). CTC has rapidly established itself as a cornerstone of diagnosis for colonic neoplasia and much work has been done to standardise and assure quality in practice in both the acquisition and interpretation of the technique. A novel feature of CTC is the presentation of imaging in both traditional 2D and the ‘virtual’ 3D endoluminal formats. This thesis looks at expanding our understanding of and improving our performance in utilizing the endoluminal 3D view. We present and develop novel metrics applicable to eye-tracking the moving image, so that the complex dynamic nature of 3D endoluminal fly-through interpretation can be captured. These metrics are then applied to assess the effect of important elements of image interpretation, namely, reader experience, the effect of the use Computer Aided Detection (CAD) and the influence of the expected prevalence of abnormality. We review our findings with reference to the literature of eye tracking within medical imaging. In the co-registration section we apply our validated computer-assisted registration algorithm to the matching of 3D endoluminal colonic locations between temporally separate datasets, assessing its accuracy as an aid to colonic polyp surveillance with CTC

Registration of prone and supine CT colonography images and its clinical application

Computed tomographic (CT) colonography is a technique for detecting bowel cancer and potentially precancerous polyps. CT imaging is performed on the cleansed and insufflated bowel in order to produce a virtual endoluminal representation similar to optical colonoscopy. Because fluids and stool can mimic pathology, images are acquired with the patient in both prone and supine positions. Radiologists then match endoluminal locations visually between the two acquisitions in order to determine whether pathology is real or not. This process is hindered by the fact that the colon can undergo considerable deformation between acquisitions. Robust and accurate automated registration between prone and supine data acquisitions is therefore pivotal for medical interpretation, but a challenging problem. The method proposed in this thesis reduces the complexity of the registration task of aligning the prone and supine CT colonography acquisitions. This is done by utilising cylindrical representations of the colonic surface which reflect the colon's specific anatomy. Automated alignment in the cylindrical domain is achieved by non-rigid image registration using surface curvatures, applicable even when cases exhibit local luminal collapses. It is furthermore shown that landmark matches for initialisation improve the registration's accuracy and robustness. Additional performance improvements are achieved by symmetric and inverse-consistent registration and iteratively deforming the surface in order to compensate for differences in distension and bowel preparation. Manually identified reference points in human data and fiducial markers in a porcine phantom are used to validate the registration accuracy. The potential clinical impact of the method has been evaluated using data that reflects clinical practise. Furthermore, correspondence between follow-up CT colonography acquisitions is established in order to facilitate the clinical need to investigate polyp growth over time. Accurate registration has the potential to both improve the diagnostic process and decrease the radiologist's interpretation time. Furthermore, its result could be integrated into algorithms for improved computer-aided detection of colonic polyps

Feature extraction to aid disease detection and assessment of disease progression in CT and MR colonography

Computed tomographic colonography (CTC) is a technique employed to examine the whole colon for cancers and premalignant adenomas (polyps). Oral preparation is taken to fully cleanse the colon, and gas insufflation maximises the attenuation contrast between the enoluminal colon surface and the lumen. The procedure is performed routinely with the patient both prone and supine to redistribute gas and residue. This helps to differentiate fixed colonic pathology from mobile faecal residue and also helps discover pathology occluded by retained fluid or luminal collapse. Matching corresponding endoluminal surface locations with the patient in the prone and supine positions is therefore an essential aspect of interpretation by radiologists; however, interpretation can be difficult and time consuming due to the considerable colonic deformations that occur during repositioning. Hence, a method for automated registration has the potential to improve efficiency and diagnostic accuracy. I propose a novel method to establish correspondence between prone and supine CT colonography acquisitions automatically. The problem is first simplified by detecting haustral folds which are elongated ridgelike endoluminal structures and can be identified by curvature based measurements. These are subsequently matched using appearance based features, and their relative geometric relationships. It is shown that these matches can be used to find correspondence along the full length of the colon, but may also be used in conjunction with other registration methods to achieve a more robust and accurate result, explicitly addressing the problem of colonic collapse. The potential clinical value of this method has been assessed in an external clinical validation, and the application to follow-up CTC surveillance has been investigated. MRI has recently been applied as a tool to quantitatively evaluate the therapeutic response to therapy in patients with Crohn's disease, and is the preferred choice for repeated imaging. A primary biomarker for this evaluation is the measurement of variations of bowel wall thickness on changing from the active phase of the disease to remission; however, a poor level of interobserver agreement of measured thickness is reported and therefore a system for accurate, robust and reproducible measurements is desirable. I propose a novel method which will automatically track sections of colon, by estimating the positions of elliptical cross sections. Subsequently, estimation of the positions of the inner and outer bowel walls are made based on image gradient information and therefore a thickness measurement value can be extracted

Performance and Evaluation in Computed Tomographic Colonography Screening for Colorectal Cancer

Each year over 20,000 people die from colorectal cancer (CRC). However, despite causing the second highest number of cancer deaths, CRC is not only curable if detected early but can be prevented by population screening. The detection and removal of pre-malignant polyps in the colon prevents cancer from ever developing. As such, screening of the at-risk population (those over 45-50 years) confers protection against CRC incidence and mortality. Although the principles and benefit of screening are well established, the adequate provision of screening is a complex process requiring robust healthcare infrastructure, evidence-based quality assurance and resources. The success of any screening programme is dependent on the accuracy of the screening investigations deployed and sufficiently high uptake by the target population. In England, the Bowel Cancer Screening Programme (BCSP) delivers screening via initial stool testing to triage patients for the endoscopic procedure, colonoscopy, or the radiological investigation CT colonography (CTC) in some patients. There has been considerable investment in colonoscopy accreditation processes which contribute to high quality services, suitable access for patients and a competent endoscopy workforce. The performance of colonoscopists in the BCSP is tightly monitored and regulated; however, the same is not true for CTC. Comparatively, there has been little investment in CTC services, and in fact there is no mandatory accreditation or centralised training. Instead, CTC reporting radiologists must learn ad hoc on the job, or at self-funded commercial workshops. This inevitably leads to variability in quality and expertise, inequity in service provision, and could negatively impact patient outcomes. To address this disparity and develop evidence-based training, one must determine what factors affect the performance of CTC reporting radiologists, what CTC training is necessary, and what training works. This thesis investigates these topics and is structured as follows: Section A reviews the background literature, describing the public health burden of CRC and the role of screening. Aspects of CTC screening and its role in the BCSP are explored. The importance of performance monitoring and value of accreditation are examined and the disparity between CTC, colonoscopy and other imaging-based screening programmes is discussed. Section B expands on radiologist performance by determining the post-imaging CRC (or interval cancer) rate through systematic review and meta-analysis. Factors contributing to the interval cancer rate are evaluated, and an observational study assessing factors affecting CTC accuracy is presented. The impact of CTC training is assessed via a structured review and best principles for training delivery are discussed. Section C presents a multicentre, cluster-randomised control trial developed from the data and understanding described in Sections A and B. Section D summarises the thesis and discusses future recommendations and research

An investigation into the relationship between mode of presentation, clinicopathological factors and outcomes in colon cancer

Colorectal cancer is the 4th most common cancer in the United Kingdom and the second most common cause of cancer related death after lung cancer. Resectional surgery remains the cornerstone of treatment with curative intent however, despite this, a large proportion of patients eventually succumb due to recurrent or metastatic disease. Despite the widespread introduction of bowel cancer screening programmes, a significant proportion of cases of colorectal cancer continues to require investigation and treatment on an emergency basis. Emergency presentations have been reported to have significantly worse short-term and long-term outcomes than elective presentations even after adjustment for disease stage. It seems likely that as opposed to emergency presentations per se being associated with adverse outcomes in colorectal cancer, clinicopathological factors – tumour, host and other factors – are likely to be associated with emergency presentation and that it is these factors that are associated with adverse oncological outcomes. The work presented in this thesis examines the impact of emergency presentation on short-term and long-term outcomes of patients with colorectal cancer. It examines, in detail, the association between mode of presentation and tumour and host factors in patients undergoing treatment with curative intent for colon cancer and subsequently the association between these factors and long-term oncological outcomes. Chapter 1 provides an overview of colorectal cancer including epidemiology, risk factors, routes to presentation, presenting symptoms and signs and the investigation and management of patients with colorectal cancer. Chapter 2 examines 30 years of published literature in a systematic review and meta-analysis and summarises the existing literature regarding the association between mode of presentation and tumour and host factors in patients with colorectal cancer. The results conclude that there are multiple differences in tumour and host factors between elective and emergency presentations of colorectal cancer. However, the studies identified were heterogenous, and it was not possible to carry out a review of the effect of these factors on short-term and long-term outcomes. Chapter 3 examines the association between mode of presentation and basic clinicopathological factors within a regional cohort of patients presenting with colon or rectal cancer in the West of Scotland regardless of disease stage or treatment received. The results show that patients with colon cancer are more likely to undergo investigation and definitive treatment on an emergency basis in comparison to rectal cancer. Patients presenting emergently with colorectal cancer were more likely to have advanced disease at diagnosis. Furthermore, in a subgroup analysis of patients undergoing curative resectional surgery for TNM Stage I-III colon cancer, emergency presentation was associated with adverse short-term and long-term outcomes even after adjustment for disease stage. Chapter 4 examines the association between basic clinicopathological factors (tumour and host factors identified within Chapter 2), mode of presentation and short-term and long-term survival within a regional cohort of patients undergoing resectional surgery with curative intent for TNM I-III colon cancer. Younger age, increased comorbidity (as measured by ASA classification), lower BMI, more advanced T stage and extramural venous invasion were associated with both emergency presentation and with adverse oncological outcomes. However, emergency presentation remained independently associated with both adverse short-term survival and long-term oncological outcomes despite adjustment for these factors. Increased co-morbidity as measured by the Charlson Co-morbidity index was not associated with emergency presentation. When the association between mode of presentation and individual components of the Charlson Index was examined, only Diabetes Mellitus was associated with mode of presentation and was protective against emergency presentation. Within a subgroup analysis of patients with Diabetes Mellitus, no clear association between diabetic factors (Type 1 vs Type 2 Diabetes, type of diabetic control, metformin/sulfonylurea/insulin use) and mode of presentation was identified. Chapter 5 examines the association between the systemic inflammatory response, mode of presentation and short-term and long-term survival in a regional cohort of patients undergoing resectional surgery with curative intent for TNM I-III colon cancer. Both the neutrophil-lymphocyte ratio and the modified Glasgow Prognostic Score were independently prognostic and combined into a Systemic Inflammatory Grade. This Systemic Inflammatory Grade was independently associated with emergency presentation. When the association between clinicopathological factors, including mode of presentation and Systemic Inflammatory Grade, and short-term and long-term outcomes were analysed, Systemic Inflammatory Grade remained independently associated with short-term and long-term survival. Mode of presentation remained associated with short-term but not long-term survival. Chapter 6 examines the association between mode of presentation and CTderived body composition. High subcutaneous fat index and low skeletal muscle index were independently associated with emergency presentation and were associated with Systemic Inflammatory Grade even after adjustment for TNM Stage. Chapter 7 examines the prior interaction with the bowel screening programme of a regional cohort of patients diagnosed with colorectal cancer. Only 19% of patients were diagnosed through screening. Screening diagnosis was associated with significantly improved long-term outcomes. The most common reasons for failure to diagnosis through screening were non-invitation to screening (either above or below routine screening age), non-return of screening test (associated with male sex, increased socio-economic deprivation, increased comorbid status and current smokers) and negative screening test (associated with female sex, preoperative anaemia, less comorbid status, right-sided tumours and screening with gFOBT testing). Chapter 8 examines the association between tumour mutational status, mode of presentation and long-term outcomes in patients undergoing resectional surgery with curative intent for TNM I-III colon cancer. The results show that on unadjusted analysis, APC wild-type, KRAS mutant and BRAF wild-type colon cancer were associated with improved long-term outcomes. There may be an association between KRAS mutant status and an elevated systemic inflammatory response. On adjusted analysis, KRAS mutational status was independently associated with adverse long-term outcomes after adjustment for other clinicopathological factors. In this study, no statistically significant associations were seen between mutational status and mode of presentation however there were trends between P53 wild-type, KRAS mutant and PIK3CA mutant status and emergency presentation. Chapter 9 examines the association between the preoperative systemic inflammatory response, emergency presentation and short-term and long-term outcomes in patients undergoing resectional surgery with curative intent for TNM Stage II colon cancer when controlled for the established high-risk factors of TNM Stage II disease. The results show that after adjustment for these factors, emergency presentation was not independently associated with either shortterm or long-term outcomes however a significant association was seen between the preoperative systemic inflammatory response and outcomes. Chapter 10 presents the results from a national survey with regards to attitudes towards and the use of perioperative steroids in patients undergoing resectional surgery with colorectal cancer. The results show that perioperative steroids are widely used at the discretion of the anaesthetist with the primary aim of preventing postoperative nausea and vomiting. The results show that there is sufficient equipoise to carry out a randomised controlled trial examining the impact of single dose corticosteroid administration at induction of anaesthesia on the postoperative systemic inflammatory response and outcomes following colorectal resection