Non-invasive, in vivo, characterization of cutaneous metastases using a novel multimodal RCM-OCT imaging device: a case-series.

BACKGROUND: Cutaneous metastases (CM) diagnosis is clinically challenging, requiring an invasive biopsy for confirmation. A novel, RCM-OCT device combines the advantage of horizontal high-resolution reflectance confocal microscopy (RCM) images and vertical deeper optical coherence tomography (OCT) images to aid in non-invasive diagnosis of CM from breast cancers. OBJECTIVE: Characterize CM from breast cancers using RCM-OCT device. METHODS: Seven patients suffering from breast cancers with suspicious CM were consented and imaged with RCM-OCT device. CM features were defined by comparing with histopathology. Tumour depths were measured on OCT and on H&E-images and correlated using statistical analysis Pearson test. 3D-OCT images were reconstructed to enhance tumour visualization. RESULTS: 6/7 lesions were CM from breast cancers, and one was vascular ectasia, on histopathology. CM appeared as greyish-darkish oval to round structures within the dermis on RCM and OCT-images. On RCM, individual tumour cells were seen, enabling identification of even small tumour foci; while, on OCT deeper tumours were detected. Inflammatory cells, dilated vessels and coarse collagen were identified in the dermis. Pearson correlation had an r2 of 0.38 and a significant P-value <0.004 for depth measurements. CM from breast cancers could be differentiated from ecstatic vessels on 3D-reconstructed OCT image. LIMITATION: Small sample size and lack of clinical mimickers. CONCLUSION: RCM-OCT can detect CM and has potential in aiding non-invasive diagnosis and management.

PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

Optical coherence tomography imaging for cancer diagnosis and therapy guidance.

Optical Coherence Tomography (OCT) is an emerging optical technology that has shown great promise for early cancer detection. Using backreflected light to visualize tissue microstructure, OCT can provide information on nuclear size and shape, nuclear-to-cytoplasmic ratio, and the organization and structure of glands. It can also provide functional information, like blood flow, tissue birefringence, etc. These capabilities could potentially be employed in three ways: as a primary diagnostic test to replace biopsy, as a screening tool to direct biopsy, and as a diagnostic tool to guide therapy and monitor therapy response. In this paper we present an application of OCT for pancreatic cancer diagnosis and therapy guidance.

Spectral-domain low coherence interferometry/optical coherence tomography system for fine needle breast biopsy guidance.

A novel technology and instrumentation for fine needle aspiration (FNA) breast biopsy guidance is presented. This technology is based on spectral-domain low coherence interferometry (SD-LCI). The method, apparatus, and preliminary in vitro/in vivo results proving the viability of the method and apparatus are presented in detail. An advanced tissue classification algorithm, preliminarily tested on breast tissue specimens and a mouse model of breast cancer is presented as well. Over 80% sensitivity and specificity in differentiating all tissue types and 93% accuracy in differentiating fatty tissue from fibrous or tumor tissue was obtained with this technology and apparatus. These results suggest that SD-LCI could help for more precise needle placement during the FNA biopsy and therefore could substantially reduce the number of the nondiagnostic aspirates and improve the sensitivity and specificity of the FNA procedures.

Three dimensional tracking for volumetric spectral-domain optical coherence tomography.

We present a three-dimensional (3D) tracker for a clinical ophthalmic spectral domain optical coherence tomography (SD-OCT) system that combines depth-tracking with lateral tracking, providing a stabilized reference frame for 3D data recording and post acquisition analysis. The depth-tracking system is implemented through a real-time dynamic feedback mechanism to compensate for motion artifact in the axial direction. Active monitoring of the retina and adapting the reference arm of the interferometer allowed the whole thickness of the retina to be stabilized to within +/-100 mum. We achieve a relatively constant SNR from image to image by stabilizing the image of the retina with respect to the depth dependent sensitivity of SD-OCT. The depth tracking range of our system is 5.2 mm in air and the depth is adjusted every frame.nhancement in the stability of the images with the depth-tracking algorithm is demonstrated on a healthy volunteer.

Ultrahigh-resolution full-field optical coherence microscopy using InGaAs camera.

Full-field optical coherence microscopy (FFOCM) is an interferometric technique for obtaining wide-field microscopic images deep within scattering biological samples. FFOCM has primarily been implemented in the 0.8 mum wavelength range with silicon-based cameras, which may limit penetration when imaging human tissue. In this paper, we demonstrate FFOCM at the wavelength range of 0.9 - 1.4 mum, where optical penetration into tissue is presumably greater owing to decreased scattering. Our FFOCM system, comprising a broadband spatially incoherent light source, a Linnik interferometer, and an InGaAs area scan camera, provided a detection sensitivity of 86 dB for a 2 sec imaging time and an axial resolution of 1.9 mum in water. Images of phantoms, tissue samples, and Xenopus Laevis embryos were obtained using InGaAs and silicon camera FFOCM systems, demonstrating enhanced imaging penetration at longer wavelengths.

Spectrally-modulated full-field optical coherence microscopy for ultrahigh-resolution endoscopic imaging.

Full-field optical coherence microscopy (FFOCM) utilizes coherence gating to obtain high-resolution optical sections in thick tissues. FFOCM is an attractive technology for endoscopic microscopy at the cellular level since it does not require a high NA objective lens or beam scanning and is therefore particularly amenable to miniaturization. In this manuscript, we present a novel scheme for conducting FFOCM that utilizes spectrally modulated, spatially incoherent illumination and a static Linnik interferometer. This approach is advantageous for endoscopic microscopy since it allows FFOCM to be conducted through a single multimode fiber optic imaging bundle and does not require moving parts in the endoscope probe. Images acquired from biological samples in free space demonstrate that this new method provides the same detailed microscopic structure as that of conventional FFOCM. High-resolution images were also obtained through a multimode fiber bundle, further supporting the potential of this method for endoscopic microscopy.

Rapid wavelength-swept spectrally encoded confocal microscopy.

Spectrally encoded confocal microscopy (SECM) is a technique that allows confocal microscopy to be performed through the confines of a narrow diameter optical fiber probe. We present a novel scheme for performing SECM in which a rapid wavelength swept source is used. The system allows large field of view images to be acquired at rates up to 30 frames/second. Images of resolution targets and tissue specimens acquired ex vivo demonstrate high lateral (1.4 mum) and axial (6 mum) resolution. Imaging of human skin was performed in vivo at depths of up to 350 mum, allowing cellular and sub-cellular details to be visualized in real time.

Adaptive ranging for optical coherence tomography.

At present, optical coherence tomography systems have a limited imaging depth or axial scan range, making diagnosis of large diameter arterial vessels and hollow organs difficult. Adaptive ranging is a feedback technique where image data is utilized to adjust the coherence gate offset and range. In this paper, we demonstrate an adaptive optical coherence tomography system with a 7.0 mm range. By matching the imaging depth to the approximately 1.5 mm penetration depth in tissue, a 3 dB sensitivity improvement over conventional imaging systems with a 3.0 mm imaging depth was realized.

OCT-based arterial elastography: robust estimation exploiting tissue biomechanics.

We present a novel multi-resolution variational framework for vascular optical coherence elastography (OCE). This method exploits prior information about arterial wall biomechanics to produce robust estimates of tissue velocity and strain, reducing the sensitivity of conventional tracking methods to both noise- and strain-induced signal decorrelation. The velocity and strain estimation performance of this new estimator is demonstrated in simulated OCT image sequences and in benchtop OCT scanning of a vascular tissue sample.

Three-dimensional spectrally encoded imaging.

A method for three-dimensional surface measurements with phase-sensitive spectrally encoded imaging is demonstrated. Both transverse and depth information is transmitted through a single-mode optical fiber, allowing this scheme to be incorporated into a miniature probe. This approach is demonstrated by measurement of the profile of a lens surface and by three-dimensional imaging of the face of a small doll.

Speckle reduction in optical coherence tomography by "path length encoded" angular compounding.

Speckle, the dominant factor reducing image quality in optical coherence tomography (OCT), limits the ability to identify cellular structures that are essential for diagnosis of a variety of diseases. We describe a new high-speed method for implementing angular compounding by path length encoding (ACPE) for reducing speckle in OCT images. By averaging images obtained at different incident angles, with each image encoded by path length, ACPE maintains high-speed image acquisition and requires minimal modifications to OCT probe optics. ACPE images obtained from tissue phantoms and human skin in vivo demonstrate a qualitative improvement over traditional OCT and an increased SNR that correlates well with theory.

High-speed optical frequency-domain imaging.

We demonstrate high-speed, high-sensitivity, high-resolution optical imaging based on optical frequency-domain interferometry using a rapidly-tuned wavelength-swept laser. We derive and show experimentally that frequency-domain ranging provides a superior signal-to-noise ratio compared with conventional time-domain ranging as used in optical coherence tomography. A high sensitivity of -110 dB was obtained with a 6 mW source at an axial resolution of 13.5 microm and an A-line rate of 15.7 kHz, representing more than an order-of-magnitude improvement compared with previous OCT and interferometric imaging methods.

Three-dimensional optical tomographic imaging of breast in a human subject.

We present for the first time a full three-dimensional (3-D) reconstruction of absorption images of breast from continuous-wave (cw) measurements performed on a premenopausal woman. Our 3-D optical images clearly reveal a large primary tumor as well as a small secondary tumor in a separate location of the breast. The multiple tumors identified by our 3-D optical imaging have been confirmed by the subsequent biopsy examination of the breast. Quantitative information of the optical images obtained is provided in terms of the location, size, and absorption coefficient of the tumors.

Imaging of in vitro and in vivo bones and joints with continuous-wave diffuse optical tomography.

WWe present what is believed to be the first absorption and scattering images of in vitro and in vivo bones and joints from continuous-wave tomographic measurements. Human finger and chicken bones embedded in cylindrical scattering media were imaged at multiple transverse planes with Clemson multi-channel diffuse optical imager. Both absorption and scattering images were obtained using our nonlinear, finite element based reconstruction algorithm. This study shows that diffuse optical tomography (DOT) has the potential to be used for detection and monitoring of bone and joint diseases such as osteoporosis and arthritis.

Quantitative optical image reconstruction of turbid media by use of direct-current measurements.

We present a detailed experimental study concerning quantitative optical property reconstruction of heterogeneous turbid media by use of absolute dc data only. We performed experiments by using tissuelike phantoms in both single-target and multitarget configurations in which variations in target size and optical contrast with the background were explored. Our results show that both scattering and absorption images can be reconstructed quantitatively by use of dc data only, whereas it was impossible to obtain such quantitative information in previously reported studies. We believe that this improvement is primarily a result of the realization of a novel data preprocessing/optimization scheme for accurately determining several critical parameters needed for reconstruction. The use of this data preprocessing/optimization scheme also eliminates the calibration reference measurement previously required for reconstruction. Experimental confirmation of this scheme is given in detail.

Experimental three-dimensional optical image reconstruction of heterogeneous turbid media from continuous-wave data.

This paper demonstrates experimental three-dimensional (3D) image reconstruction of optically heterogeneous turbid media from near-infrared continuous-wave measurements. Successful reconstruction is achieved through a full 3D finite-element based, Newton-type reconstruction algorithm. Our experimental evidence shows that both absorption and scattering images of a 10x15 mm cylindrical object embedded in a 50x50 mm cylindrical background can be reconstructed using our algorithm.