1,721,201 research outputs found
Comprehensive imaging characterization of colorectal liver metastases
No full textColorectal liver metastases (CRLM) have heterogenous histopathological and immunohistochemical phenotypes, which are associated with variable responses to treatment and outcomes. However, this information is usually only available after resection, and therefore of limited value in treatment planning. Improved techniques for in vivo disease assessment, which can characterise the variable tumour biology, would support further personalization of management strategies. Advanced imaging of CRLM including multiparametric MRI and functional imaging techniques have the potential to provide clinically-actionable phenotypic characterisation. This includes assessment of the tumour-liver interface, internal tumour components and treatment response. Advanced analysis techniques, including radiomics and machine learning now have a growing role in assessment of imaging, providing high-dimensional imaging feature extraction which can be linked to clinical relevant tumour phenotypes, such as a the Consensus Molecular Subtypes (CMS). In this review, we outline how imaging techniques could reproducibly characterize the histopathological features of CRLM, with several matched imaging and histology examples to illustrate these features, and discuss the oncological relevance of these features. Finally, we discuss the future challenges and opportunities of CRLM imaging, with a focus on the potential value of advanced analytics including radiomics and artificial intelligence, to help inform future research in this rapidly moving field
The role of thoracic ultrasonography in the assessment of extravascular lung water and breathlessness
Full text linkPatients with respiratory failure and breathlessness frequently present clinicians with a unique diagnostic and therapeutic challenge. These patients may be acutely unwell and in need of rapid intervention with limited information available to guide the responsible clinician. The range of different conditions that can present with breathlessness is broad, and differentiating one from another may be extremely difficult in a patient with multiple overlapping co-morbidities. Even when the cause of a patient’s breathlessness appears obvious, as can be the case with malignant pleural disease, identifying the best treatment option for that individual may not always be a straightforward process.
The use of bedside, or point-of-care ultrasound has become increasingly common over the past decade; moving away from a traditional home in the radiology department and entering the hands of clinicians who are responsible for diagnosing and treating patients on a day-to-day basis. The most widely accepted role for thoracic ultrasound is as an adjunct to pleural procedures, but as clinicians have become more familiar with its use the ways in which thoracic ultrasound is utilized have begun to diversify. As a result, there is growing interest in how thoracic ultrasonography might be used as a diagnostic tool in patients who are breathless, and in turn have a positive impact on their treatment and key clinical outcomes.
The purpose of this thesis is to evaluate some of the differing roles that thoracic ultrasonography might have in the clinical assessment and management of the patient with breathlessness and respiratory failure, and to focus on areas that are outside what is currently regarded as conventional practice. This thesis will begin to answer, through a series of clinical studies, specific questions that have the potential to change the way clinicians use bedside thoracic ultrasound examination to diagnose and treat their patients.
Malignant pleural effusion is an increasingly common problem, traditionally managed by chest tube drainage and intrapleural administration of a chemical sclerosant such as talc with the aim of achieving pleurodesis and preventing fluid recurrence. This treatment strategy is however unsuccessful in up to 30% of patients. The first study presented in this thesis examined the ability of thoracic ultrasound to predict long-term pleurodesis success in the immediate aftermath of talc slurry administration via an intercostal chest tube to treat recurrent symptomatic malignant pleural effusion, recognizing the ability of thoracic ultrasound to identify the presence of pleural adhesions in other clinical scenarios through the loss of the normal “lung sliding” artefact. 18 participants were recruited to a prospective observational cohort feasibility study, undergoing a standardised nine-point thoracic ultrasound examination immediately before, and 24 hours after talc slurry administration in order to derive a pleural adherence score for the affected hemithorax at each of these timepoints. The ultrasound scans were reported by the primary bedside operator and two independent assessors blinded to the participant’s clinical status. Study participants who went on to suffer pleurodesis failure had a lower pleural adherence score at 24 hours post-talc instillation than those who were successful. This novel association between a thoracic ultrasound-derived pleural adherence score and long-term pleurodesis success and failure should now be evaluated in further research to assess its utility in supporting decision making in the treatment of patients with malignant pleural effusion.
The second study looked at whether thoracic ultrasound examination prior to any intervention for a symptomatic pleural effusion could predict the presence of unexpandable lung and the subsequent relief of breathlessness; two clinical outcomes that are of great relevance to both patients and clinicians in determining longer-term management strategies, such as a decision to proceed with an attempt at chemical pleurodesis. 92 participants were recruited to this prospective observational study assessing whether any parameters included in a standardised in-depth thoracic ultrasound examination were associated with the outcomes of interest described above. A reduction in the excursion of atelectatic lung with cardiac pulse transmission, as measured by motion (M-) mode ultrasound, was associated with the presence of unexpandable lung; as were the presence of anechoic pleural fluid and pleural fluid septations in a subsequent exploratory regression model. Future studies should explore these candidate parameters in greater depth with a view to validating an ultrasound-based model that can predict the presence of unexpandable lung prior to any pleural intervention, with potential implications for personalized care of patients with symptomatic pleural effusion.
The presence of extravascular lung water, for example in the form of pulmonary oedema secondary to congestive cardiac failure, is among the most common causes of breathlessness that may result in a patient presenting for medical treatment. The third study presented in this thesis assessed the ability of thoracic ultrasound to detect the presence of, and identify real-time changes in extravascular lung water in patients with end-stage renal failure undergoing haemodialysis. Computed tomography was utilized to provide a gold-standard radiologic reference test to correlate with the findings on thoracic ultrasound in this patient population. 30 participants were recruited to this prospective observational study, undergoing a standardised 20-point thoracic ultrasound examination to derive a total lung ultrasound B-line score before, during and after haemodialysis. The ultrasound scans were reported by the primary bedside operator and two independent assessors blinded to the participant’s clinical status. The results suggest an association between a reduction in total B-line score and an increasing volume of fluid removed during haemodialysis, with potentially greater sensitivity to this physiological change in total body fluid status and extravascular lung water than computed tomography. Further research is needed to further evaluate the potential capability of thoracic ultrasound in both this controlled setting and other relevant clinical scenarios as a point-of-care diagnostic tool, with a view to how this might influence the management of acutely breathless patients and/or those with excess lung water
Functional lung assessment using hyperpolarised xenon gas magnetic resonance imaging
Full text linkPurpose
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. The standard method for assessing lung function in COPD is spirometry, which provides global lung function information but is a poor predictor of disability and quality of life. The overall aim of this thesis is to develop utility of hyperpolarised xenon gas magnetic resonance imaging (HP 129Xe-MRI) as a technique to evaluate regional lung function.
Methods
Studies were approved by the National Research Ethics Service (NRES). Eleven volunteers and 25 patients with COPD underwent HP 129Xe-MRI, pulmonary function tests (PFTs) and quantitative computerised tomography (QCT).
Gravitational-dependent gradients of HP 129Xe-MRI were compared between prone and supine postures in healthy volunteers. Lobar quantification of HP 129Xe-MRI was completed in COPD patients, who also underwent time-resolved HP 129Xe-MRI and HP 129Xe-MRI pre- and post-salbutamol to determine feasibility of detecting regional delayed ventilation and post-intervention change. The relationship between study measures was assessed using Pearsonâs correlation coefficient.
Results
HP 129Xe-MR ventilation gradients were more marked in the supine than prone posture in healthy volunteers, whereas diffusion-weighted gradients were more uniform. HP 129Xe-MRI was successfully quantified according to pulmonary lobes and correlated with lobar lung anatomy (QCT) and global functional transfer capability (TLCO) (r=-0.61, p<0.005). Delayed ventilation was observed with time-resolved breath-hold HP 129Xe-MRI. Differential regional ventilation change was detected with HP 129Xe-MRI post-salbutamol.
Conclusion
These data demonstrate technical optimisation of HP 129Xe-MRI in healthy volunteers and COPD patients. Successful generation of lobar HP 129Xe-MRI parameters offers an automated analysis method that can be adopted into the clinical workflow. Finally proof-of-principle data have identified roles for HP 129Xe-MRI in evaluating regional treatments and assessing therapeutic response. Future work will evaluate the role of HP 129Xe-MRI in patient selection for lung volume reduction therapy and as a surrogate end-point in drug development studies. </p
Cancer imaging with fluciclovine (18F)
Full text link[18F]1-amino-3-fluorocyclobutane 1-carboxylic acid (18F-fluciclovine) is a synthetic amino acid developed as a PET radiotracer for cancer imaging. Upon project commencement, 18F-fluciclovine was in late phase of pharmaceutical development for recurrent prostate cancer imaging, requiring validation of clinical utility. Growing prospect in targeting of tumour metabolism in breast cancer treatment set the premise to investigate the role of amino acid imaging in this prevalent disease. The aims of this project were to: (1) establish the transport mechanisms of fluciclovine in breast cancer;; (2) explore the utility of fluciclovine in early assessment of response to treatments of related metabolic and biological targets;; (3) run a clinical study to investigate how 18F-fluciclovine uptake can be used to characterise breast cancer biology;; and (4) run a multicentre clinical trial to investigate the impact of 18F-fluciclovine imaging on clinical management of men with recurrent prostate cancer. Fluciclovine transport in breast cancer was found to be predominantly mediated by the high-affinity glutamine transporter ASCT2. Increased fluciclovine uptake was demonstrated in cell lines sensitive to glutaminase inhibition with CB-839 (known to result in build-up of intra-cellular glutamine);; and the opposite with bithionol and metformin which are known to reduce intra-cellular glutamine. These results were recapitulated in animal models, and collectively raise the potential for fluciclovine to be used as an imaging biomarker of glutamine pool, in addition to early response assessment in therapies augmenting glutamine metabolism. The FRONTIER study was established to investigate how 18F-fluciclovine can be used to characterise breast cancer biology and is ongoing. Initial data demonstrate a trend of highest uptake in triple-receptor negative, followed by ER+ then HER2+ tumours, complementing in vitro data. The FALCON multicentre trial investigated the impact of 18F-fluciclovine imaging on clinical management of recurrent prostate cancer. In the 32-patient Oxford cohort, 44% of patients had their intended management plan revised following 18F-fluciclovine PET/CT. Initial short term follow-up data demonstrate a higher proportion of short-term responders to 18F-fluciclovine guided radiotherapy (71%, 5/7) compared to standard radiotherapy (53%, 8/15). This encouraging trend will require ratification with trial-wide data. Across the trial, interim analysis found management was revised post-scan in 52/85 (61%) patients, exceeding a pre- set criteria for overwhelming effectiveness (45/85), leading to early closure
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Imaging biomarkers for oligometastatic colorectal cancer
Full text linkOligometastatic colorectal cancer represents an intermediate disease state potentially treatable with curative intent. Novel treatment strategies are expanding the opportunity to offer local treatment for limited metastatic disease. It is therefore increasingly important to define patients likely to benefit from these targeted treatments. Diagnostic imaging is central to patient management, to establish the burden and distribution of metastatic disease. This thesis explores the potential value of novel imaging biomarkers in patients with colorectal liver metastases (CRLM). In a prospective study, perfusion CT (pCT) and dynamic contrast-enhanced MRI (DCE-MRI) were performed prior to resection, and a retrospective series of patients with resected CRLM was collated. Resected metastases were analysed for relevant morphological features and IHC expression. Novel and conventional imaging variables were derived based on CT, MRI, pCT, DCE-MRI and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET), and their associations with histopathological features, immunohistochemical expression and patient outcomes analysed. A novel subregion analysis based on DCE-MRI data was developed to classify tumour subregions, using a histological reference standard. The results presented in this thesis confirm that the number and distribution of hepatic metastases are prognostic markers for patients with resected CRLM, and that higher SUVmean of liver metastases, and higher SUVmax of the background liver, are potential prognostic biomarkers. Histopathological assessment of resected CRLM highlighted that there is significant between and within patient variability of clinically relevant histopathological features and IHC expression, which would support the potential utility of imaging biomarkers to characterise multi- site disease. Analysis of functional imaging data demonstrated positive correlations between imaging variables and clinically relevant markers of tumour vascularity and metabolism, while subregion analysis of DCE-MRI data produced good spatial correlation with viable and non-viable tumour based on histopathology, with significant differences in derived phamacokinetic parameters between subregions.</p
Novel imaging and circulating biomarkers in hepatic malignancies
Full text linkColorectal cancer (CRC) that has metastasised to the liver has a median survival of less than 24 months unless patients have resectable disease. Liver-directed therapies target disease to improve hepatic disease-control. Selective internal radiation therapy (SIRT) exploits the arterial blood supply to the liver to deliver yttrium-90 (90Y) microspheres. Optimising radiation delivery whilst sparing normal liver is an important part of the work-up. Imaging biomarkers to determine vascularity and microcirculation may improve patient selection for liver-directed therapies. This research project studied the following imaging modalities to optimise patient selection for liver-directed therapy: perfusion computerized tomography (pCT); dynamic contrast enhanced magnetic resonance imaging (DCE MRI); T1 mapping (native and oxygen-enhanced) MRI.
Patients were recruited in three clinical trials, each exploring tissue and imaging biomarkers of potential response to therapy: FOXFIRE; PERFORM and NICOLA studies. The PERFORM trial investigated the feasibility of multi-parametric imaging to measure hepatic perfusion and generate parameter maps pre- and post-SIRT treatment through pCT and DCE MRI. The distribution and location of microspheres were described through the histopathological analysis of patients from the FOXFIRE study in patients who had hepatic resection post-SIRT. T1 mapping pre- and during high flow oxygen inhalation in the NICOLA study explored the role of this emerging technique for the characterisation of liver lesions having a hepatic resection.
The potential role of complimenting imaging biomarkers with circulating biomarkers was also explored. Circulating tumour DNA (ctDNA) was extracted at three time-points having pCT and DCE MRI after SIRT. Ion Torrent Amplicon sequencing detected multiple somatic mutations associated with CRC and the quantification of these mutations over time. This was also expanded to include patients with intrahepatic cholangiocarcinomas (ICC) and included some measurements of circulating metabolites with liquid chromatography mass spectrometry.
The PERFORM study recruited 58 patients to examine the feasibility of pCT and DCE MRI to generate perfusion parameters pre- and post-SIRT. The hypothesis was that baseline perfusion parameters reflecting high blow flow would increase delivery of SIRT microspheres and would predict for response. The second hypothesis was that a reduction in perfusion parameters would act as a biomarker for the response to the targeted delivery of 90Y, at four weeks rather than the standard imaging at 12 weeks.
The acquisition and analysis of pCT parameters was completed via 4D perfusion software. Specific parameters measured were – blood flow; blood volume; mean transit time and permeability surface area product. Pharmacokinetic modelling post DCE MRI acquisition supported the generation of Ktrans, Kep and Vep mapping. Measurement of each parameter at a range of time intervals failed to demonstrate a specific imaging predictive biomarker of response to SIRT. DCE MRI analysis did reveal parameter changes over time, although the mean values did not discriminate treatment responders from non-responders.
Quantitative T1 mapping using shortened Modified Look-Locker Inversion recovery (shMOLLI) was performed on 11 patients and explored oxygen as a non-invasive contrast agent. The feasibility of this technique for quantitative T1 mapping in malignant hepatic lesions was demonstrated for the first time and analysis of data supported the need for further research into the role of T1 mapping pre and post oxygen-enhancement for patients receiving neo-adjuvant chemotherapy.
The analysis of the resected tumour specimens from the FOXFIRE study demonstrated that the density of microspheres was highest 0-1 mm within the tumour margin. The location of microspheres also showed clustering around the endothelium. The analysis of macrophages revealed giant cell reactions around microspheres with increased numbers of tumour-associated macrophages.
The results from the ctDNA revealed high concordance of KRAS status up to 1127 days from primary CRC to ctDNA results. Variant allele frequencies were measured during treatment with SIRT and detected common genes associated with CRC including APC, AKT and BRAF. The exploration of ctDNA and metabolites in four patients with ICC confirmed the presence of elevated circulating 2-hydroxyglutarate in a patient with an IDH1 mutation.
In summary, the feasibility of pCT and DCE MRI is shown, but further work is required to validate these techniques as a measure of vascularity that will predict for SIRT delivery. The findings from FOXFIRE resection analysis confirmed the changes and deposition from microsphere delivery. T1 mapping has been used for one of the first times to assist in the characterisation of suspected hepatic malignancies and suggests that the role of oxygen as a non-injectable contrast agent is worth pursuing. The addition of circulating biomarkers in helps to integrate multiple biomarkers into cancer care, pairing biology with imaging. It is likely a combined approach like this may need to be adopted in this emerging era of precision medicine
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