High-frequency Ultrasound Assessment of Systemic Sclerosis Skin Involvement: Intraobserver Repeatability and Relationship With Clinician Assessment and Dermal Collagen Content.

OBJECTIVE: The modified Rodnan skin score (mRSS) remains the preferred method for skin assessment in systemic sclerosis (SSc). There are concerns regarding high interobserver variability of mRSS and negative clinical trials utilizing mRSS as the primary endpoint. High-frequency ultrasound (HFUS) allows objective assessment of cutaneous fibrosis in SSc. We investigated the relationship between HFUS with both mRSS and dermal collagen. METHODS: Skin thickness (ST), echogenicity, and novel shear wave elastography (SWE) were assessed in 53 patients with SSc and 15 healthy controls (HCs) at the finger, hand, forearm, and abdomen. The relationship between HFUS parameters with mRSS (n = 53) and dermal collagen (10 patients with SSc and 10 HCs) was investigated. Intraobserver repeatability of HFUS was calculated using intraclass correlation coefficients (ICCs). RESULTS: HFUS assessment of ST (hand/forearm) and SWE (finger/hand) correlated with local mRSS at some sites. Subclinical abnormalities in ST, echogenicity, and SWE were present in clinically uninvolved SSc skin. Additionally, changes in echogenicity and SWE were sometimes apparent despite objectively normal ST on HFUS. ST, SWE, and local mRSS correlated strongly with collagen quantification (r = 0.697, 0.709, 0.649, respectively). Intraobserver repeatability was high for all HFUS parameters (ICCs for ST = 0.946-0.978; echogenicity = 0.648-0.865; and SWE = 0.953-0.973). CONCLUSION: Our data demonstrate excellent reproducibility and reassuring convergent validity with dermal collagen content. Detection of subclinical abnormalities is an additional benefit of HFUS. The observed correlations with collagen quantification support further investigation of HFUS as an alternative to mRSS in clinical trial settings.

A Multicenter Study of the Validity and Reliability of Responses to Hand Cold Challenge as Measured by Laser Speckle Contrast Imaging and Thermography: Outcome Measures for Systemic Sclerosis-Related Raynaud's Phenomenon.

OBJECTIVE: Reliable and objective outcome measures to facilitate clinical trials of novel treatments for systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) are badly needed. Laser speckle contrast imaging (LSCI) and thermography are noninvasive measures of perfusion that have shown excellent potential. This multicenter study was undertaken to determine the reliability and validity of a hand cold challenge protocol using LSCI, standard thermography, and low-cost cell phone/mobile phone thermography (henceforth referred to as mobile thermography) in patients with SSc-related RP. METHODS: Patients with RP secondary to SSc were recruited from 6 UK tertiary care centers. The patients underwent cold challenge on 2 consecutive days. Changes in cutaneous blood flow/skin temperature at each visit were imaged simultaneously using LSCI, standard thermography, and mobile thermography. Measurements included area under the curve (AUC) for reperfusion/rewarming and maximum blood flow rate/skin temperature after rewarming (MAX). Test-retest reliability was assessed using intraclass correlation coefficients (ICCs). Estimated latent correlations (estimated from multilevel models, taking values between -1 and 1; denoted as rho values) were used to assess the convergent validity of LSCI and thermography. RESULTS: In total, 159 patients (77% with limited cutaneous SSc) were recruited (84% female, median age 63.3 years). LSCI and standard thermography both had substantial reliability, with ICCs for the reperfusion/rewarming AUC of 0.67 (95% confidence interval [95% CI] 0.54, 0.76) and 0.68 (95% CI 0.58, 0.80), respectively, and ICCs for the MAX of 0.64 (95% CI 0.52, 0.75) and 0.72 (95% CI 0.64, 0.81), respectively. Very high latent correlations were present for the AUCs of LSCI and thermography (ρ = 0.94; 95% CI 0.87, 1.00) and for the AUCs of standard and mobile thermography (ρ = 0.98; 95% CI 0.94, 1.00). CONCLUSION: This is the first multicenter study to examine the reliability and validity of cold challenge using LSCI and thermography in patients with SSc-related RP. LSCI and thermography both demonstrated good potential as outcome measures. LSCI, standard thermography, and mobile thermography had very high convergent validity.

Use of Laser Speckle Contrast Imaging to Assess Digital Microvascular Function in Primary Raynaud Phenomenon and Systemic Sclerosis: A Comparison Using the Raynaud Condition Score Diary.

OBJECTIVE: Evaluate objective assessment of digital microvascular function using laser speckle contrast imaging (LSCI) in a cross-sectional study of patients with primary Raynaud phenomenon (RP) and systemic sclerosis (SSc), comparing LSCI with both infrared thermography (IRT) and subjective assessment using the Raynaud Condition Score (RCS) diary. METHODS: Patients with SSc (n = 25) and primary RP (n = 18) underwent simultaneous assessment of digital perfusion using LSCI and IRT with a cold challenge on 2 occasions, 2 weeks apart. The RCS diary was completed between assessments. The relationship between objective and subjective assessments of RP was evaluated. Reproducibility of LSCI/IRT was assessed, along with differences between primary RP and SSc, and the effect of sex. RESULTS: There was moderate-to-good correlation between LSCI and IRT (Spearman rho 0.58-0.84, p < 0.01), but poor correlation between objective assessments and the RCS diary (p > 0.05 for all analyses). Reproducibility of IRT and LSCI was moderate at baseline (ICC 0.51-0.63) and immediately following cold challenge (ICC 0.56-0.86), but lower during reperfusion (ICC 0.3-0.7). Neither subjective nor objective assessments differentiated between primary RP and SSc. Men reported lower median daily frequency of RP attacks (0.82 vs 1.93, p = 0.03). Perfusion using LSCI/IRT was higher in men for the majority of assessments. CONCLUSION: Objective and subjective methods provide differing information on microvascular function in RP. There is good convergent validity of LSCI with IRT and acceptable reproducibility of both modalities. Neither subjective nor objective assessments could differentiate between primary RP and SSc. Influence of sex on subjective and objective assessment of RP warrants further evaluation.

Use of infrared thermography as an endpoint in therapeutic trials of Raynaud's phenomenon and systemic sclerosis.

OBJECTIVES: To perform a systematic review evaluating the use of infrared thermography (IRT) as an endpoint in clinical trials of Raynaud's phenomenon (RP). METHODS: Articles reporting the use of IRT and Raynaud's phenomenon were identified following systematic searches of PubMed, EMBase, MEDLINE and AMED databases. Articles incorporating IRT as an endpoint in a therapeutic trial were selected for full text analysis. Data extracted from articles included study design, study size, intervention, clinical and thermographic endpoints, and outcomes. Studies were scored on their methodological quality. Data analysis involved a descriptive analysis of the studies, along with a secondary analysis focusing on agreement between clinical and thermographic outcomes in the larger, better-described studies. RESULTS: Thirty-two studies evaluating 654 patients with RP were assessed. Significant heterogeneity between studies precluded any attempt at formal meta-analysis. Most studies were small (median 15.5 patients) and open-label design (19/32, 59.4%). The majority of studies (18/32, 56.3%) reported improvements in both clinical and thermographic endpoints. Thermographic parameters showing agreement with clinical endpoints in therapeutic trials included baseline hand/finger absolute temperature and parameters derived following local cold challenge, including longitudinal thermal gradients and percent re-warming. CONCLUSIONS: No single thermographic parameter has emerged as the preferred endpoint for clinical trials of RP. Objective microvascular imaging tools such as IRT have the potential to overcome the limitations of self-report assessment of RP. Future studies should continue to evaluate IRT, alongside recommended self-reports, in an attempt to validate objective microvascular assessment tools in therapeutic trials of RP.

Three-dimensional ultrasound imaging of mammary ducts in lactating women: a feasibility study.

OBJECTIVE: The main function of the breast is to produce milk for offspring. As such, the ductal system, which carries milk from the milk-secreting glands (alveoli) to the nipple, is central to the natural function of the breast. The ductal system is also the region in which many malignancies originate and spread. In this study, we aimed to assess the feasibility of manual mapping of ductal systems from 3-dimensional (3D) ultrasound data and to evaluate the structures found with respect to conventional understanding of breast anatomy and physiology. METHODS: Three-dimensional ultrasound data of the breast were acquired using a mechanical system, which captures data in a conical shape covering most of the breast without excessive compression. Manual mapping of the ductal system was performed using custom software for data from 4 lactating volunteers. RESULTS: Observational results are presented for ultrasound data from the 4 lactating volunteers. For all volunteers, only a small number of ductal structures were engorged with milk, suggesting that the lactiferous activity of the breast may be localized. These enlarged ducts were predominantly found in the inferior lateral quadrant of each breast. The observation was also made that the enlarged, milk-storing parts of the duct were spread throughout the ductal system and not directly below the nipple as conventional anatomy suggests. CONCLUSIONS: Ultrasound visualization of the 3D structure of milk-laden ducts in an uncompressed breast has been shown. Using manual tracing, it was possible to track milk-laden ducts of diameters less than 1 mm.

Transient elastography using impulsive ultrasound radiation force: a preliminary comparison with surface palpation elastography.

The use of impulsive acoustic radiation force for transient strain imaging was investigated and compared with conventional elastography. A series of experiments were performed to evaluate the performances of the technique on gelatine phantoms containing inclusions and to determine a range of applications where radiation force elastography may be useful compared with static elastography. Slip boundaries and cylindrical inclusions of varying elastic modulus were placed in background materials. A focused ultrasound transducer was used to apply localised radiation force to a small volume of tissue mimic (100 mm3) for durations of 8 ms. A conventional real-time ultrasound imaging probe was used to obtain radio- frequency echo signals. The resulting strains were mapped using ultrasound correlation-based methods. The instantaneous strain immediately following cessation of the radiation force was observed at depth within homogeneous gels and within stiff inclusions. The highly localised and transient strain that is produced at depth permits the sensing of variations in tissue elastic properties that are difficult to detect with conventional elastography, due to greater independence from boundary conditions. In particular, radiation force elastograms were more homogeneous in the background and within the inclusions and displayed a superior contrast-transfer-efficiency, particularly for regions that had negative modulus contrast or that were disconnected from the background or the anterior medium by a low friction boundary.

Elastography for breast cancer diagnosis using radiation force: system development and performance evaluation.

The use of impulsive acoustic radiation force for strain imaging was investigated. A focused ultrasound transducer was used to apply localized radiation force to a small volume of tissue mimic (100 mm3) for durations of 8 ms. A conventional real-time ultrasound imaging probe was used to obtain echo signals. The resulting strains were mapped using ultrasound correlation-based methods. The instantaneous strain immediately following cessation of the radiation force was observed at depth within homogeneous gels and within stiff inclusions, and was seen to vary approximately linearly with Young's modulus of the material. The highly localized and transient strain that is produced may permit the sensing of variations in tissue elastic properties that are difficult to detect with conventional elastography because of greater independence from boundary conditions. For example, the characteristic, bi-directional, high strain artefacts attributable to stress concentration, often seen with static elastography at tissue-inclusion interfaces, do not appear using the transient radiation force strain imaging technique.

Automatic mammary duct detection in 3D ultrasound.

This paper presents a method for the initial detection of ductal structures within 3D ultrasound images using second-order shape measurements. The desire to detect ducts is motivated in a number of way, principally as step in the detection and assessment of ductal carcinoma in-situ. Detection is performed by measuring the variation of the local second-order shape from a prototype shape corresponding to a perfect tube. We believe this work is the first demonstration of the ability to detect sections of duct automatically in ultrasound images. The detection is performed with a view to employing vessel tracking method to delineate the full ductal structure.

Visualisation of 4-D colour and power Doppler data.

Mechanically scanned, cardiac-gated, 4-D colour Doppler and power Doppler data were acquired and rendered using multiplanar slice display, surface-fitting (S-F) and direct volume rendering (DVR), with interactive viewpoint control or tool command language (Tcl)-scripted generation of animation sequences across the cardiac cycle. S-F applied the marching cubes algorithm within a YCbCr colour space to extract time-varying Doppler regions; supplementally generated surfaces enclosed all regions across the full cardiac cycle, partially to alleviate the problem of incomplete vessel filling. DVR used integrated intensity, maximum intensity and front-to-back projection; the latter applied an opacity function to the Cb, Cr and Y colour channels to control the appearance of the blood flow signal relative to the background B-mode image. Our most detailed display was a hybrid approach that combined multiplanar slicing and DVR.