SPECT/CT imaging of inflammation and calcification in human carotid atherosclerosis to identify the plaque at risk of rupture.

BACKGROUND: Calcification and inflammation are atherosclerotic plaque compositional biomarkers that have both been linked to stroke risk. The aim of this study was to evaluate their co-existing prevalence in human carotid plaques with respect to plaque phenotype to determine the value of hybrid imaging for the detection of these biomarkers. METHODS: Human carotid plaque segments, obtained from endarterectomy, were incubated in [111In]In-DOTA-butylamino-NorBIRT ([111In]In-Danbirt), targeting Leukocyte Function-associated Antigen-1 (LFA-1) on leukocytes. By performing SPECT/CT, both inflammation from DANBIRT uptake and calcification from CT imaging were assessed. Plaque phenotype was classified using histology. RESULTS: On a total plaque level, comparable levels of calcification volume existed with different degrees of inflammation and vice versa. On a segment level, an inverse relationship between calcification volume and inflammation was evident in highly calcified segments, which classify as fibrocalcific, stable plaque segments. In contrast, segments with little or no calcification presented with a moderate to high degree of inflammation, often coinciding with the more dangerous fibrous cap atheroma phenotype. CONCLUSION: Calcification imaging alone can only accurately identify highly calcified, stable, fibrocalcific plaques. To identify high-risk plaques, with little or no calcification, hybrid imaging of calcification and inflammation could provide diagnostic benefit.

British Association of Dermatologists (BAD) National Audit on Non-Melanoma Skin Cancer Excision 2016 in collaboration with the Royal College of Pathologists.

BACKGROUND: We conducted a re-audit of the surgical practice of UK dermatologists for the treatment of nonmelanoma skin cancer and examined changes with reference to our previous audit in 2014. The audit was supplemented by a detailed assessment of completeness of the histopathology reports for each tumour. METHODS: UK dermatologists collected data on 10 consecutive nonmicrographic excisions for basal cell carcinoma (BCC) and 5 for squamous cell carcinoma (SCC). Data were collected on site, preoperative diagnosis, histological diagnosis, proximity to previous scars, and histological deep and peripheral margins. RESULTS: In total, 222 responses were received from 135 centres, reporting on 3290 excisions. Excisions from the head and neck accounted for 56.7% of cases. Tumour diameter (mean ± SD) was 11.4 ± SD 7.1 mm (maximum size 100 mm) and 97% of cases were primary excisions. BCCs and SCCs respectively accounted for 65.7% and 26.8% of total cases. Of the suspected BCCs and SCCs, 95.8% and 80.4%, respectively, were confirmed histologically. All margins for any tumour were clear in 97.0% of cases, and complication rate in the audit was < 1%. Of the 2864 histology reports evaluated, only 706 (24.6%) contained all core data items; 95% of these were structure (synoptic) reports. Commonly omitted items were level of invasion, risk and T stage, which were absent from 35.7%, 64.2% and 44.1% of reports, respectively. CONCLUSIONS: Diagnostic accuracy and complete excision rates remain high. Complication rates may be under-reported owing to lack of follow-up. Histopathology reporting has a greater chance of being complete if reports are generated on a field-based platform (synoptic reporting).

Perspectives on Small Animal Radionuclide Imaging; Considerations and Advances in Atherosclerosis.

This review addresses nuclear SPECT and PET imaging in small animals in relation to the atherosclerotic disease process, one of our research topics of interest. Imaging of atherosclerosis in small animal models is challenging, as it operates at the limits of current imaging possibilities regarding sensitivity, and spatial resolution. Several topics are discussed, including technical considerations that apply to image acquisition, reconstruction, and analysis. Moreover, molecules developed for or applied in these small animal nuclear imaging studies are listed, including target-directed molecules, useful for imaging organs or tissues that have elevated expression of the target compared to other tissues, and molecules that serve as substrates for metabolic processes. Differences between animal models and human pathophysiology that should be taken into account during translation from animal to patient as well as differences in tracer behavior in animal vs. man are also described. Finally, we give a future outlook on small animal radionuclide imaging in atherosclerosis, followed by recommendations. The challenges and solutions described might be applicable to other research fields of health and disease as well.

On the effect of computed tomography resolution to distinguish between abdominal aortic aneurysm wall tissue and calcification: A proof of concept.

PURPOSE: The purpose of this study is to determine the optimal target CT spatial resolution for accurately imaging abdominal aortic aneurysm (AAA) wall characteristics, distinguishing between tissue and calcification components, for an accurate assessment of rupture risk. MATERIALS AND METHODS: Ruptured and non-ruptured AAA-wall samples were acquired from eight patients undergoing open surgical aneurysm repair upon institutional review board approval and informed consent was obtained from all patients. Physical measurements of AAA-wall cross-section were made using scanning electron microscopy. Samples were scanned using high resolution micro-CT scanning. A resolution range of 15.5-155µm was used to quantify the influence of decreasing resolution on wall area measurements, in terms of tissue and calcification. A statistical comparison between the reference resolution (15.5µm) and multi-detector CT resolution (744µm) was also made. RESULTS: Electron microscopy examination of ruptured AAAs revealed extremely thin outer tissue structure <200µm in radial distribution which is supporting the aneurysm wall along with large areas of adjacent medial calcifications far greater in area than the tissue layer. The spatial resolution of 155µm is a significant predictor of the reference AAA-wall tissue and calcification area measurements (r=0.850; p<0.001; r=0.999; p<0.001 respectively). The tissue and calcification area at 155µm is correct within 8.8%±1.86 and 26.13%±9.40 respectively with sensitivity of 87.17% when compared to the reference. CONCLUSION: The inclusion of AAA-wall measurements, through the use of high resolution-CT will elucidate the variations in AAA-wall tissue and calcification distributions across the wall which may help to leverage an improved assessment of AAA rupture risk.

Calcification Volume Reduces Stretch Capability and Predisposes Plaque to Rupture in an in vitro Model of Carotid Artery Stenting.

OBJECTIVE/BACKGROUND: Carotid artery stenting (CAS) in calcified arteries carries a higher peri-operative risk. This study investigates the relationship between the stretching limits of carotid plaque samples and calcification in order to determine a stretch tolerance criterion for endovascular intervention. METHODS: Seventeen carotid plaque samples were acquired from standard endarterectomy procedures. The maximum stretch capability of the global plaque was determined by circumferentially extending the tissue to complete failure. Quantitative assessment of calcification was performed using high resolution computed tomography, including measures of percent calcification volume fraction (%CVF) and calcification configuration. Maximum stretch properties were then related to calcification measures in order to evaluate the predictive power of calcification for determining plaque stretching limits. RESULTS: A strong negative correlation was found between %CVF and stretch ratio with respect to specific calcification configuration types. All plaques with < 70% stenosis superseded the minimum required stretch threshold. Severe stenosis (> 70%) warrants a stretch of at least 2.33 during revascularisation and only plaques containing concentric calcifications with < 20% CVF successfully reached this minimum required stretch threshold. CONCLUSION: The addition of calcification measures to the stenosis classification may help in guiding endovascular intervention techniques to achieve a balance between an acceptable residual patency level while avoiding plaque rupture in calcified carotid plaques.

Towards the characterisation of carotid plaque tissue toughness: Linking mechanical properties to plaque composition.

UNLABELLED: The morphological manifestation of calcification within an atherosclerotic plaque is diverse and the response to cutting balloon angioplasty remains an elusive target to predict in the presence of extensive calcification. This study examines the resistance of plaque tissue to blade penetration by characterising the underlying toughness properties and stratifying the upper and lower scale toughness limits based on the strong mechanical influence of calcification. Mechanical toughness properties of the common, bifurcation and internal carotid artery (n=62) were determined using guillotine-cutting tests measuring the energy required to pass a surgical blade through a unit length of plaque tissue. The corresponding structural composition of the dissected plaque segments was characterised using Fourier transform infrared analysis, electron microscopy and energy dispersive x-ray spectroscopy. Mechanical results reveal a clear distinction in toughness properties within each region of the carotid vessel with significantly tougher properties localised in the bifurcation (p=0.004) and internal region (p=0.0003) compared to the common. The severity of the intra-plaque variance is highest in plaques with high toughness localised in the bifurcation region (p<0.05). Structural examination reveals that the diverse mechanical influence of the level of calcification present is characteristic of specific regions within the carotid plaque. The energy required to overcome the calcific resistance and propagate a controlled cut in the calcified tissue at each region varies further with the degree of plaque progression. The identification of the localised calcification characteristics is a key determinant in achieving successful dissection of the severely toughened plaque segments during cutting balloon angioplasty. STATEMENT OF SIGNIFICANCE: Calcification plays a fundamental role in plaque tissue mechanics and demonstrates a diverse range of material moduli properties. This work addresses the characterisation of the toughness properties in human carotid plaque tissue using a fracture mechanics approach. Toughness determines the energy required to propagate a controlled cut in the plaque material. This parameter is crucial for predicting the cutting forces required during endovascular cutting balloon angioplasty intervention. Results demonstrate that a strong relationship exists between the structural calcification configurations, fracture mechanisms and associated toughness properties that are characteristic of specific regions within the carotid artery plaque. The identification of the morphological characteristics of localised calcification may serve as a valuable quantitative measure for cutting balloon angioplasty treatment.

On the effect of calcification volume and configuration on the mechanical behaviour of carotid plaque tissue.

Vascular calcification is a complex molecular process that exhibits a number of relatively characteristic morphology patterns in atherosclerotic plaques. Treatment of arterial stenosis by endovascular intervention, involving forceful circumferential expansion of the plaque, can be unpredictable in calcified lesions. The aim of this study was to determine the mechanical stretching mechanisms and define the mechanical limits for circumferentially expanding carotid plaque lesions under the influence of distinct calcification patterns. Mechanical and structural characterisation was performed on 17 human carotid plaques acquired from patients undergoing endarterectomy procedures. The mechanical properties were determined using uniaxial extension tests that stretch the lesions to complete failure along their circumferential axis. Calcification morphology of mechanically ruptured plaque lesions was characterised using high resolution micro computed tomography imaging. Scanning electron microscopy was used to examine the mechanically induced failure sites and to identify the interface boundary conditions between calcified and non-calcified tissue. The mechanical tests produced four distinct trends in mechanical behaviour which corresponded to the calcification patterns that structurally defined each mechanical group. Each calcification pattern produced unique mechanical restraining effects on the plaque tissue stretching properties evidenced by the variation in degree of stretch to failure. Resistance to failure appears to rely on interactions between calcification and non-calcified tissue. Scanning electron microscopy examination revealed structural gradations at interface boundary conditions to facilitate the transfer of stress. This study emphasises the mechanical influence of distinct calcification configurations on plaque expansion properties and highlights the importance of pre-operative lesion characterisation to optimise treatment outcomes.

The influence of composition and location on the toughness of human atherosclerotic femoral plaque tissue.

The toughness of femoral atherosclerotic tissue is of pivotal importance to understanding the mechanism of luminal expansion during cutting balloon angioplasty (CBA) in the peripheral vessels. Furthermore, the ability to relate this parameter to plaque composition, pathological inclusions and location within the femoral vessels would allow for the improvement of existing CBA technology and for the stratification of patient treatment based on the predicted fracture response of the plaque tissue to CBA. Such information may lead to a reduction in clinically observed complications, an improvement in trial results and an increased adoption of the CBA technique to reduce vessel trauma and further endovascular treatment uptake. This study characterises the toughness of atherosclerotic plaque extracted from the femoral arteries of ten patients using a lubricated guillotine cutting test to determine the critical energy release rate. This information is related to the location that the plaque section was removed from within the femoral vessels and the composition of the plaque tissue, determined using Fourier Transform InfraRed spectroscopy, to establish the influence of location and composition on the toughness of the plaque tissue. Scanning electron microscopy (SEM) is employed to examine the fracture surfaces of the sections to determine the contribution of tissue morphology to toughness. Toughness results exhibit large inter and intra patient and location variance with values ranging far above and below the toughness of healthy porcine arterial tissue (Range: 1330-3035 for location and 140-4560J/m(2) for patients). No significant difference in mean toughness is observed between patients or location. However, the composition parameter representing the calcified tissue content of the plaque correlates significantly with sample toughness (r=0.949, p<0.001). SEM reveals the presence of large calcified regions in the toughest sections that are absent from the least tough sections. Regression analysis highlights the potential of employing the calcified tissue content of the plaque as a preoperative tool for predicting the fracture response of a target lesion to CBA (R(2)=0.885, p<0.001). STATEMENT OF SIGNIFICANCE: This study addresses a gap in current knowledge regarding the influence of plaque location, composition and morphology on the toughness of human femoral plaque tissue. Such information is of great importance to the continued improvement of endovascular treatments, particularly cutting balloon angioplasty (CBA), which require experimentally derived data as a framework for assessing clinical cases and advancing medical devices. This study identifies that femoral plaque tissue exhibits large inter and intra patient and location variance regarding tissue toughness. Increasing calcified plaque content is demonstrated to correlate significantly with increasing toughness. This highlights the potential for predicting target lesion toughness which may lead to an increased adoption of the CBA technique and also further the uptake of endovascular treatment.

Mechanical, biological and structural characterization of human atherosclerotic femoral plaque tissue.

The failure of endovascular treatments of peripheral arterial disease represents a critical clinical issue. Specialized data are required to tailor such procedures to account for the mechanical response of the diseased femoral arterial tissue to medical device deployment. The purpose of this study is to characterize the mechanical response of atherosclerotic femoral arterial tissue to large deformation, the conditions typical of angioplasty and stenting, and also to determine the mechanically induced failure properties and to relate this behaviour to biological content and structural composition using uniaxial testing, Fourier transform infrared spectroscopy and scanning electron microscopy. Mechanical and biological characterization of 20 plaque samples obtained from femoral endarterectomy identified three distinct classifications. "Lightly calcified" samples display linear mechanical responses and fail at relatively high stretch. "Moderately calcified" samples undergo an increase in stiffness and ultimate strength coupled with a decrease in ductility. Structural characterization reveals calcified nodules within this group that may be acting to reinforce the tissue matrix, thus increasing the stiffness and ultimate strength. "Heavily calcified" samples account for the majority of samples tested and exhibit significantly reduced ultimate strength and ductility compared to the preceding groups. Structural characterization of this group reveals large areas of calcified tissue dominating the failure cross-sections of the samples. The frequency and structural dominance of these features solely within this group offers an explanation as to the reduced ultimate strength and ductility and highlights the need for modern peripheral endovascular devices to account for this behaviour during novel medical device design.