Equilibrium Contrast Imaging for Extracellular Volume Quantification

In disease and senescence, the balance between cells and the surrounding interstitium is altered. Cell injury and inflammation induce fibrosis, with collagen deposition leading to expansion of the interstitium. When diffuse, this expansion can affect the structure and function of the whole organ. Examples of diffuse fibrosis include liver cirrhosis and myocardial fibrosis, which are becoming more prevalent as the population ages. Traditional assessment of such diseases involves invasive biopsy, but for many tissues, biopsy is poorly tolerated and carries a significant complication risk. Recently our group has developed a new technique (equilibrium imaging) that utilises the extracellular contrast agents employed widely in MRI and CT to quantify tissue fractional extracellular volume (ECV). Early work demonstrated a significant elevation in myocardial ECV in hypertrophic cardiomyopathy and aortic stenosis. Equilibrium contrast imaging potentially offers a powerful new non-invasive tissue biomarker for ‘extracellular disease’, and promises new insights into the biology of these conditions. In this thesis I develop the equilibrium imaging technique, beginning with an evaluation of the basic principles of extracellular volume estimation by EQ-MRI - using a 3-dimensional engineered tissue model. I show an association between ECV quantified during construction of six engineered models with ECV measured using EQ-MRI (R2=0.77, p=0.02). I then explore the use of equilibrium imaging in quantifying two disease processes that alter the extracellular volume – diffuse fibrosis and amyloidosis. EQ-MRI is used in systemic amyloidosis to demonstrate significant elevation in ECV within the liver (0.32) and spleen (0.39) compared with healthy volunteers (p<0.01). I then translate the basic EQ method to a new modality – computed tomography, a potentially simpler and more widely available imaging platform. EQ-CT is used to show an association between ECV and a histological comparator in cardiac valve disease (r=0.71); and in liver cirrhosis (r=0.64). EQ-MRI is also used as a reference test to investigate diffuse 99mTc-DPD skeletal muscle uptake in systemic ATTR amyloidosis. Using a novel scoring system to quantify uptake, I show that skeletal muscle ECV increases with 99mTc-DPD soft tissue score (R2=0.34) - suggesting that skeletal muscle is a significant target organ for amyloid deposition. Technical development of the CT technique required the optimisation of image acquisition and processing for quantitative attenuation measurement within tissues, and advancement of the contrast protocol to allow rapid ECV estimation using a bolus only dynamic equilibrium technique. In summary, this research thesis presents methological development and validation of EQ imaging for tissue extracellular volume fraction quantification

Long-term biopsy outcomes in prostate cancer patients treated with external beam radiotherapy: a systematic review and meta-analysis

Background: Biopsy after external beam radiotherapy (EBRT) for localised prostate cancer (PCa) is an infrequently used but potentially valuable technique to evaluate local recurrence and predict long-term outcomes. Methods: We performed a meta-analysis of studies until March 2020 where a post-EBRT biopsy was performed on patients with low-to intermediate risk PCa, according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The primary outcome was the aggregate post-EBRT positive biopsy rate (≥2 years after EBRT) and the associated odds ratio (OR) of a positive biopsy on biochemical failure (BCF), distant metastasis-free survival (DMFS) and prostate cancer-specific mortality (PCSM). A sensitivity analysis was performed which examined biopsy rate as a function of post-EBRT biopsy protocol, PCa risk, ADT usage and radiation dose. Results: A total of 22 studies were included, of which 10 were randomised controlled trials and 12 were cohort studies. Nine out of the 22 studies used dosing regimens consistent with the 2020 NCCN radiotherapy guidelines. The weighted-average positive biopsy rate across all 22 studies was 32% (95%-CI: 25–39%, n = 3017). In studies where post-treatment biopsy was part of the study protocol, the rate was 35% (95%-CI: 21–38%, n = 2450). In the subgroup of studies that conformed to the 2020 NCCN radiotherapy guidelines, this rate was 22% (95% CI: 19–41%, n = 832). Patients with positive biopsy had a 10-fold higher odds of developing BCF (OR of 10.3, 95%-CI: 3.7–28.7, p < 0.00001), 3-fold higher odds of developing distant metastasis (OR 3.1, 95%-CI: 2.1–4.7, p < 0.00001) and 5-fold higher odds of dying from their PCa (OR 5.1, 95%-CI: 2.6–10, p < 0.00001). Conclusion: A positive biopsy after EBRT is associated with a poor prognosis compared to a negative biopsy. The post-EBRT positive biopsy rate is an important measure which provides additional insight when comparing EBRT to other treatment modalities for PCa

Prostatic calcifications: Quantifying occurrence, radiodensity, and spatial distribution in prostate cancer patients

Background: To evaluate the prevalence, density, and distribution of prostate calcification in patients with prostate cancer. / Methods: Patients who underwent both Gallium-68 PSMA PET/CT and MRI of the prostate over the course of a year were selected for analysis. The CT images with visible calcifications within the prostate were included and calcifications automatically isolated using a threshold of 130 HU. The corresponding multiparametric MRI was assessed and the peripheral zone, transition zone, MRI-visible tumor, and urethra manually contoured. The contoured MRI and CT images were registered using rigid registration, and calcifications mapped automatically to the MRI contours. / Results: A total of 85 men (age range 50–88, mean 69 years, standard deviation 7.2 years) were assessed. The mean serum Prostate Specific Antigen PSA was 16.7, range 0.12 to 94.4. Most patients had intermediate-risk disease (68%; Gleason grade group 2 and 3), 26% had high-risk disease (Gleason grade group 4 and 5), and 6% had low-risk disease (Gleason grade group 1). Forty-six patients out of 85 (54%) had intraprostatic calcification. Calcification occurred more in transition zone than the peripheral zone (65% vs. 35%). The mean density of the calcification was 227 HU (min 133, max 1,966 HU). In 12 patients, the calcification was within an MRI-visible tumor, in 24 patients, there were calcifications within a 9 mm distance of the tumor border, and in 9 patients, there were calcifications located between the urethra and tumor. / Conclusions: Calcifications are common in patients with prostate cancer. Their density and location may make them a significant consideration when planning treatment or retreatment with some types of minimally invasive therapy

High-Frequency Jet Ventilation During Cryoablation of Small Renal Tumours

AIM: To evaluate the effect of high-frequency jet ventilation (HFJV) in place of standard intermittent positive-pressure ventilation (IPPV) on procedure duration, patient radiation dose, complication rates, and outcomes during CT-guided cryoablation of small renal tumours. MATERIALS AND METHODS: One hundred consecutive CT-guided cryoablation procedures to treat small renal tumours under general anaesthesia were evaluated-50 with standard IPPV and 50 after the introduction of HFJV as standard practice. Anaesthesia and procedural times, ionising radiation dose, complications, and 1-month post-treatment outcomes were collected. RESULTS: HFJV was feasible and safe in all cases. Mean procedure time and total anaesthetic time were shorter with HFJV (p = <0.0001). The number of required CT acquisitions (p = 0.0002) and total procedure patient radiation dose (p = 0.0027) were also lower in the HFJV group compared with the IPPV group. There were a total of four complications of Clavien-Dindo classification 3 or above-three in the IPPV group and one in the HFJV group. At 1-month follow-up, two cases (both in the IPPV group) demonstrated subtotal treatment. Both cases were subsequently successfully retreated with cryoablation. CONCLUSION: By reducing target tumour motion during CT-guided renal cryoablation, HFJV can reduce procedure times and exposure to ionising radiation. HFJV provides an important adjunct to complex image-guided interventions, with potential to improve safety and treatment outcomes

The role of multidisciplinary meetings for benign pancreatobiliary diseases: a tertiary centre experience

Multidisciplinary meetings are central to the management of chronic and complex diseases and they have become widely established across the modern healthcare. Patients with pancreatobiliary diseases can often present with complex clinical dilemmas, which fall out with the scope of current guidelines. Therefore, these patients require a personalised management approach discussed in a multidisciplinary meeting

Automatic Multi-organ Segmentation on Abdominal CT with Dense V-networks

Automatic segmentation of abdominal anatomy on computed tomography (CT) images can support diagnosis, treatment planning and treatment delivery workflows. Segmentation methods using statistical models and multi-atlas label fusion (MALF) require inter-subject image registrations which are challenging for abdominal images, but alternative methods without registration have not yet achieved higher accuracy for most abdominal organs. We present a registration-free deeplearning- based segmentation algorithm for eight organs that are relevant for navigation in endoscopic pancreatic and biliary procedures, including the pancreas, the GI tract (esophagus, stomach, duodenum) and surrounding organs (liver, spleen, left kidney, gallbladder). We directly compared the segmentation accuracy of the proposed method to existing deep learning and MALF methods in a cross-validation on a multi-centre data set with 90 subjects. The proposed method yielded significantly higher Dice scores for all organs and lower mean absolute distances for most organs, including Dice scores of 0.78 vs. 0.71, 0.74 and 0.74 for the pancreas, 0.90 vs 0.85, 0.87 and 0.83 for the stomach and 0.76 vs 0.68, 0.69 and 0.66 for the esophagus. We conclude that deep-learning-based segmentation represents a registration-free method for multi-organ abdominal CT segmentation whose accuracy can surpass current methods, potentially supporting image-guided navigation in gastrointestinal endoscopy procedures

Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis.

Cardiac involvement determines outcome in patients with systemic amyloidosis. There is major unmet need for quantification of cardiac amyloid burden, which is currently only met in part through semi-quantitative bone scintigraphy or Cardiovascular Magnetic Resonance (CMR), which measures ECVCMR. Other accessible tests are needed

Towards image-guided pancreas and biliary endoscopy: Automatic multi-organ segmentation on abdominal CT with dense dilated networks

Segmentation of anatomy on abdominal CT enables patient-specific image guidance in clinical endoscopic procedures and in endoscopy training. Because robust interpatient registration of abdominal images is necessary for existing multi-atlas- and statistical-shape-model-based segmentations, but remains challenging, there is a need for automated multi-organ segmentation that does not rely on registration. We present a deep-learning-based algorithm for segmenting the liver, pancreas, stomach, and esophagus using dilated convolution units with dense skip connections and a new spatial prior. The algorithm was evaluated with an 8-fold cross-validation and compared to a joint-label-fusion-based segmentation based on Dice scores and boundary distances. The proposed algorithm yielded more accurate segmentations than the joint-label-fusion-ba sed algorithm for the pancreas (median Dice scores 66 vs 37), stomach (83 vs 72) and esophagus (73 vs 54) and marginally less accurate segmentation for the liver (92 vs 93). We conclude that dilated convolutional networks with dense skip connections can segment the liver, pancreas, stomach and esophagus from abdominal CT without image registration and have the potential to support image-guided navigation in gastrointestinal endoscopy procedures

Cardiac computed tomography for the detection of cardiac amyloidosis

A 67-year-old Caucasian man presented with atrial flutter on routine 12-lead electrocardiography (ECG). Following appropriate anticoagulation, he successfully underwent atrial flutter ablation. Echocardiography during the admission showed concentric left ventricular (LV) hypertrophy with severely impaired LV systolic function, particularly longitudinal (Figure 1A, video 1), and biatrial dilatation. Due to episodes of non-sustained ventricular tachycardia, he was fitted with an implantable cardioverter-defibrillator (ICD). The ECG QRS complexes on peripheral leads were small compared to the structural wall thickening on echocardiography (Figure 1B) raising the suspicion of cardiac amyloidosis. Preliminary evaluation excluded a plasma cell dyscrasia (negative serum free light chains changes and urinary Bence-Jones protein). Serum amyloid P component (SAP) scintigraphy was negative for visceral organ uptake and bone tracer scintigraphy (Technetium-DPD) was positive with Perugini Grade 2-3 uptake (Figure 1C), consistent with a diagnosis of cardiac transthyretin amyloidosis (ATTR). Cardiac magnetic resonance (CMR) was contra-indicated due to the non-conditional ICD (Figure 1D). After giving fully informed written consent, cardiac computed tomography (CCT) was performed as part of a research study, using a three step protocol (Figure 1E) as previously described1, allowing calculation of the extracellular volume fraction (ECV) from pre- and 5-minutes post-contrast images. The septal ECV, calculated from a co-registered, segmented myocardial mask displaying pixel-by-pixel ECV values, was in the amyloid spectrum elevated at 63% (Figure 1F), Gene sequencing revealed a heterozygous V122I mutation, confirming the diagnosis of familial amyloid cardiomyopathy (ATTR)

Radiopaque drug-eluting embolisation beads as fiducial markers for stereotactic liver radiotherapy

OBJECTIVE: To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE). METHODS: A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepatocellular carcinoma or liver metastases from colorectal cancer. Following TACE, patients underwent simulated radiotherapy imaging with 4-dimensional computed tomography (4D-CT) and cone-beam CT (CBCT) imaging. RO beads were contoured using automated thresholding, and feasibility of matching between the simulated radiotherapy planning dataset (AVE-IP image from 4D data) and CBCT scans assessed. Additional kV, MV, helical CT and CBCT images of RO beads were obtained using an in-house phantom. Stability of RO bead position was assessed by comparing 4D-CT imaging to CT scans taken 6-20 days following TACE. RESULTS: Eight patients were treated and 4D-CT and CBCT images acquired. RO beads were visible on 4D-CT and CBCT images in all cases and matching successfully performed. Differences in centre of mass of RO beads between CBCT and simulated radiotherapy planning scans (AVE-IP dataset) were: 2.0 mm mediolaterally, 1.7 mm anteroposteriorally, 3.5 mm craniocaudally. RO beads in the phantom were visible on all imaging modalities assessed. RO bead position remained stable up to 29 days post-TACE. CONCLUSION: RO beads are visible on IGRT imaging modalities, showing minimal artefact. They can be used for on-set matching with CBCT and remain stable over time. ADVANCES IN KNOWLEDGE: The role of RO beads as fiducial markers for stereotactic liver radiotherapy is feasible and warrants further exploration as a combination therapy approach