Intra-operative Assessment of Breast Tumor Margins Using Diffuse Reflectance Spectroscopy

<p>Breast cancer is one of the leading causes of death every year in the United States for women. Breast conserving surgery (BCS) is one treatment option for these patients where achieving tumor-free surgical margins is desired to avoid local recurrence [1, 2]. Unfortunately, as many as 17.7-72% of patients undergoing BCS require repeat surgeries due to a close or positive surgical margin diagnosed post-operatively [3-11]. Histopathology is the current gold standard for determining surgical margin status; however, given the large volumes of resected breast tissue it is not feasible to section the entire specimen. High re-excision rates and limited histopathological sampling of the tissue represent a significant unmet clinical need for margin assessment for both the surgeon and pathologist. Quantitative diffuse reflectance (DR) spectral imaging has been shown to be a promising tool for interrogating tumor margins but patient and surgical factors have to be accounted for in order to fully exploit the discriminatory capability of the technology. The objective of this work was to characterize an instrument for margin assessment and to evaluate the effects of inter-patient variability and surgical and excisional factors on quantitative tissue optical properties, to devise strategies to exploit optical contrast for the detection of positive (<2mm) tumor margins. In addition, the performance of the spectral imaging platform was evaluated.</p><p>The DR spectral imaging device utilized in these studies consisted of a Xenon lamp, a multi-channel imaging fiber-optic probe, an imaging spectrograph, and a 2D charge-coupled device (CCD) [12]. The instrument was found to extract quantitative optical parameters related to tissue micro-morphology with <15% error. Cross-talk at the tissue surface was <1% when the spacing between adjacent channels was 10mm and the sensing depth of each channel was found to be 0.5-2.2mm, an appropriate depth for identifying close and positive tumor margins. Reproducibility of the imaging protocol was best when the probe was interfaced with lumpectomy specimens from the side; this methodology was maintained for all measurements from lumpectomies in this dissertation.</p><p>DR spectral images were acquired from lumpectomy margins and converted into composition maps of quantitative optical parameters. Mammographic breast density was found to have the greatest impact on the optical data with &#946;-carotene concentration ([&#946;-carotene]) and the ratio of [&#946;-carotene] to the wavelength-averaged reduced scattering coefficient from 450-600nm (<&#956;s'>) being significantly higher in the negative margins of high-density patients (p=0.017 and p=0.038, respectively). We originally hypothesized that increased [&#946;-carotene] would be associated with an increase in fat; however the significant increase in [&#946;-carotene] cannot be attributed to differences in the percentage of adipose tissue since low-density patients should theoretically have higher percentages of this tissue type. Hematoxylin and eosin analysis of the adipose sites (n=25) showed increased [&#946;-carotene] (p=0.066), increased adipocyte density (p=0.034), and smaller adipocyte sizes (p=0.051) in the adipose tissues (where &#946;-carotene is stored) of high-density patients. This analysis suggests that increased [&#946;-carotene] is associated with smaller adipocytes and that high-density breasts overall have smaller adipocytes, thus affecting optical contrast. This increase in [&#946;-carotene] actually served to increase contrast between negative and positive margins which resulted in better classification accuracy in the high-density patients with a conditional inference tree model (77% in low-density and 80% in high-density). </p><p>If the purpose of the spectroscopy tool is to provide a differential diagnosis of benign versus malignant tissue, there must be an understanding of how excision of the tissue affects the optical properties over time, and how differences in surgical techniques affect optical properties. DR spectra were acquired 17±4 minutes post-excision from 12 incised mastectomies and from the surface of 10 lumpectomies 7±3 minutes post-excision. A linear longitudinal model was used to fit the data and obtain a rate of change for the tissue parameters. In lumpectomies, [&#946;-carotene], <&#956;s'>, and [&#946;-carotene]/<&#956;s'> had the lowest percent change (<14%) over 30 minutes; total hemoglobin concentration ([THb]) and [THb]/<&#956;s'> had higher percent changes (>40%) over 30 minutes; hemoglobin saturation (HbSat) showed non-linear changes making it a poor variable for ex vivo margin assessment; and Lymphazurin^TM concentration (denoted as [Lymphazurin^TM]) changed more than 200% in 30 minutes. Although the percent error in [Lymphazurin^TM] was high, all other tissue parameters could be quantified with <3.3% error even when Lymphazurin^TM was 80&#956;M. No significant difference was found between benign and malignant rates of change, and baseline values were not significantly correlated with elapsed time post-excision. Initial values from benign non-cauterized mastectomy (n=13) and cauterized lumpectomy (n=59) sites were compared to assess the effect of cautery. [THb] was the only parameter that was significantly higher in the cauterized lumpectomies (p=0.013) compared to non-cauterized mastectomies. </p><p>The work in this dissertation shows the feasibility of using an optical device for margin assessment and that [&#946;-carotene] and [&#946;-carotene]/<&#956;s'> emerge as important variables for differentiating negative and close/positive margins. These two parameters were likely most important since they were least affected by kinetics, cautery, and the presence of Lymphazurin^TM.</p>Dissertatio

3D Visualisation of Navigation Catheters for Endovascular Procedures Using a 3D Hub and Fiber Optic RealShape Technology: Phantom Study Results

Objective: Fiber Optic RealShape (FORS) is a new technology that visualises the full three dimensional (3D) shape of guidewires using an optical fibre embedded in the device. Co-registering FORS guidewires with anatomical images, such as a digital subtraction angiography (DSA), provides anatomical context for navigating these devices during endovascular procedures. The objective of this study was to demonstrate the feasibility and usability of visualising compatible conventional navigation catheters, together with the FORS guidewire, in phantom with a new 3D Hub technology and to understand potential clinical benefits. Methods: The accuracy of localising the 3D Hub and catheter in relation to the FORS guidewire, was evaluated using a translation stage test setup and a retrospective analysis of prior clinical data. Catheter visualisation accuracy and navigation success was assessed in a phantom study where 15 interventionists navigated devices to three pre-defined targets in an abdominal aortic phantom using an Xray or computed tomography angiography (CTA) roadmap. Additionally, the interventionists were surveyed about the usability and potential benefits of the 3D Hub. Results: The location of the 3D Hub and catheter along the FORS guidewire was detected correctly 96.59% of the time. During the phantom study, all 15 interventionists successfully reached the target locations 100% of the time and the error in catheter visualisation was 0.69 mm. The interventionists agreed or strongly agreed that the 3D Hub was easy to use and the greatest potential clinical benefit over FORS is in offering interventionists choice over which catheter they used. Conclusion: This set of studies has shown that FORS guided catheter visualisation, enabled by a 3D Hub, is accurate and easy to use in a phantom setting. Further evaluation is needed to understand the benefits and limitations of the 3D Hub technology during endovascular procedures

Chromophore based analyses of steady-state diffuse reflectance spectroscopy: current status and perspectives for clinical adoption

Diffuse reflectance spectroscopy is a rapidly growing technology in the biophotonics community where it has shown promise in its ability to classify different tissues. In the steady-state domain a wide spectrum of clinical applications is supported with this technology ranging from diagnostic to guided interventions. Diffuse reflectance spectra provide a wealth of information about tissue composition; however, extracting biologically relevant information from the spectra in terms of chromophores may be more useful to gain acceptance into the clinical community. The chromophores that absorb light in the visible and near infrared wavelengths can provide information about tissue composition. The key characteristics of these chromophores and their relevance in different organs and clinical applications is the focus of this review, along with translating their use to the clini

Nerve detection using optical spectroscopy, an evaluation in four different models: In human and swine, in-vivo, and post mortem

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Optical spectral surveillance of breast tissue landscapes for detection of residual disease in breast tumor margins.

We demonstrate a strategy to "sense" the micro-morphology of a breast tumor margin over a wide field of view by creating quantitative hyperspectral maps of the tissue optical properties (absorption and scattering), where each voxel can be deconstructed to provide information on the underlying histology. Information about the underlying tissue histology is encoded in the quantitative spectral information (in the visible wavelength range), and residual carcinoma is detected as a shift in the histological landscape to one with less fat and higher glandular content. To demonstrate this strategy, fully intact, fresh lumpectomy specimens (n = 88) from 70 patients were imaged intra-operatively. The ability of spectral imaging to sense changes in histology over large imaging areas was determined using inter-patient mammographic breast density (MBD) variation in cancer-free tissues as a model system. We discovered that increased MBD was associated with higher baseline β-carotene concentrations (p = 0.066) and higher scattering coefficients (p = 0.007) as measured by spectral imaging, and a trend toward decreased adipocyte size and increased adipocyte density as measured by histological examination in BMI-matched patients. The ability of spectral imaging to detect cancer intra-operatively was demonstrated when MBD-specific breast characteristics were considered. Specifically, the ratio of β-carotene concentration to the light scattering coefficient can report on the relative amount of fat to glandular density at the tissue surface to determine positive margin status, when baseline differences in these parameters between patients with low and high MBD are taken into account by the appropriate selection of threshold values. When MBD was included as a variable a priori, the device was estimated to have a sensitivity of 74% and a specificity of 86% in detecting close or positive margins, regardless of tumor type. Superior performance was demonstrated in high MBD tissue, a population that typically has a higher percentage of involved margins

Spectral sensing for tissue diagnosis during lung biopsy procedures: The importance of an adequate internal reference and real-time feedback

Objectives: Difficulties in obtaining a representative tissue sample are a major obstacle in timely selecting the optimal treatment for patients with lung cancer or other malignancies. Having a modality to provide needle guidance and confirm the biopsy site selection could be of great clinical benefit, especially when small masses are targeted. The objective of this study was to evaluate whether diffuse reflectance spectroscopy (DRS) at the tip of a core biopsy needle can be used for biopsy site confirmation in real time, thereby enabling optimized biopsy acquisition and improving diagnostic capability. Materials and methods: We included a total of 23 patients undergoing a routine computed tomography (CT) guided transthoracic needle biopsy of a lesion suspected for lung cancer or metastatic disease. DRS measurements were acquired during needle insertion and clinically relevant parameters were extracted from the spectral data along the needle paths. Histopathology results were compared with the DRS data at the final measurement position. Results: Analysis of the collective data acquired from all enrolled subjects showed significant differences (p < 0.01) for blood content, stO2, water content, and scattering amplitude. The identified spectral contrast matched the final pathology in 20 out of 22 clinical cases that could be used for analysis, which corresponds with an overall diagnostic performance of 91%. Three cases underlined the importance of adequate reference measurements and the need for real time diagnostic feedback. Continuous real time DRS measurements performed during a biopsy procedure in one patient provided clear information with respect to the variation in tissue and allowed identification of the tumour boundary. Conclusions: The presented technology creates a basis for the design and clinical implementation of integrated fibre-optic tools for a variety of minimal invasive applications