Freddy T. Nguyen, MD, PhD

Research Fellow @ Massachusetts Institute of Technology, Transfusion Medicine Fellow @ Dartmouth-Hitchcock Medical Center

Publication

Optical coherence tomography: the intraoperative assessment of lymph nodes in breast cancer

During breast-conserving surgeries, axillary lymph nodes draining from the primary tumor site are removed for disease staging. Although a high number of lymph nodes are often resected during sentinel and lymph-node dissections, only a relatively small percentage of nodes are found to be metastatic, a fact that must be weighed against potential complications such as lymphedema. Without a real-time in vivo or in situ intraoperative imaging tool to provide a microscopic assessment of the nodes, postoperative paraffin section histopathological analysis currently remains the gold standard in assessing the status of lymph nodes. This paper investigates the use of optical coherence tomography (OCT), a high-resolution real-time microscopic optical-imaging technique, for the intraoperative ex vivo imaging and assessment of axillary lymph nodes. Normal (13), reactive (1), and metastatic (3) lymph nodes from 17 human patients with breast cancer were imaged intraoperatively with OCT. These preliminary clinical studies have identified scattering changes in the cortex, relative to the capsule, which can be used to differentiate normal from reactive and metastatic nodes. These optical scattering changes are correlated with inflammatory and immunological changes observed in the follicles and germinal centers. These results suggest that intraoperative OCT has the potential to assess the real-time node status in situ, without having to physically resect and histologically process specimens to visualize microscopic features.

Publication

Intraoperative evaluation of breast tumor margins with optical coherence tomography

As breast cancer screening rates increase, smaller and more numerous lesions are being identified earlier, leading to more breast-conserving surgical procedures. Achieving a clean surgical margin represents a technical challenge with important clinical implications. Optical coherence tomography (OCT) is introduced as an intraoperative high-resolution imaging technique that assesses surgical breast tumor margins by providing real-time microscopic images up to 2 mm beneath the tissue surface. In a study of 37 patients split between training and study groups, OCT images covering 1 cm(2) regions were acquired from surgical margins of lumpectomy specimens, registered with ink, and correlated with corresponding histologic sections. A 17-patient training set used to establish standard imaging protocols and OCT evaluation criteria showed that areas of higher scattering tissue with a heterogeneous pattern were indicative of tumor cells and tumor tissue in contrast to lower scattering adipocytes found in normal breast tissue. The remaining 20 patients were enrolled into the feasibility study. Of these lumpectomy specimens, 11 were identified with a positive or close surgical margin and 9 were identified with a negative margin under OCT. Based on histologic findings, 9 true positives, 9 true negatives, 2 false positives, and 0 false negatives were found, yielding a sensitivity of 100% and specificity of 82%. These results show the potential of OCT as a real-time method for intraoperative margin assessment in breast-conserving surgeries.

Publication

Clinical feasibility of microscopically-guided breast needle biopsy using a fiber-optic probe with computer-aided detection

Needle biopsy of small or nonpalpable breast lesions has a high nondiagnostic sampling rate even when needle position is guided by stereotaxis or ultrasound. We assess the feasibility of using a near-infrared fiber optic probe and computer-aided detection for the microscopic guidance of needle breast biopsy procedures. Specimens from nine consented patients undergoing breast-conserving surgery were assessed intraoperatively using a needle device with an integrated fiber-optic probe capable of assessing two physical tissue properties highly correlated to pathology. Immediately following surgical resection, specimens were probed by inserting the optical biopsy needle device into the tissue, simulating the procedure used to position standard biopsy needles. Needle positions were marked and correlated with histology, which verified measurements obtained from 58 needle positions, including 40 in adipose and 18 in tumor tissue. This study yielded tissue classifications based on measurement of optical refractive index and scattering. Confidence-rating schemes yielded combined sensitivity of 89% (16/18) and specificity of 78% (31/40). Refractive index tests alone identified tumor tissue with a sensitivity of 83% (15/18) and specificity of 75% (30/40). Scattering profiles independently identified tumor tissue with a sensitivity of 61% (11/18) and specificity of 60% (24/40). These results show that a biopsy needle with an integrated fiber optic probe can be used to identify breast tumor tissue for sampling. Integration of this probe into current practices offers the potential to reduce nondiagnostic sampling rates by directly evaluating in situ microscopic tissue properties in real-time, before removal.

Optical coherence tomography (OCT) as a diagnostic tool for the real-time intraoperative assessment of breast cancer surgical margins

Background: The decrease in the number of breast cancer deaths has largely been attributed to increased awareness, earlier detection, and improved treatment options. However, as the number of breast-conserving surgeries rose over the years, the need for negative margins and little or no residual disease has become critical to help reduce the chances of local recurrence. OCT is a high resolution imaging modality that has been used to image tumor margins in an NMU-carcinogen-induced rat mammary tumor model. Due to the location of breast lesions, the use of needle-based imaging probes may be used to further extend the reach of the OCT imaging beam by incorporating an optical fiber into biopsy needle tips, providing real-time information to guide biopsies or to place localization wires.
Material & Methods: A clinical spectral domain OCT system was developed with a super luminescent diode light source centered at 1310 nm with a bandwidth of 92 nm yielding an axial resolution of 8.3 µm. The beam delivery sample arm uses a 60 mm achromatic lens to focus 4.75 mW of light to a 35.0 µm spot size (transverse resolution) with a confocal parameter of 1.47 mm. The patients included in this study had primary breast tumors diagnosed by needle-biopsy and were in need of surgical resection, as determined by their physicians. At Carle Foundation Hospital, the OCT system was placed inside the operating room during breast conserving surgical procedures to image the tissue specimens. The OCT images were evaluated by a single operator allowing for consistent classification based on the level of scattering intensity and heterogeneity, scattering profile, and physical extent of the highly scattering area.
Results: An initial training data set of OCT images from 17 patients was used to establish standard imaging protocols and standard evaluation criteria of the surgical margins. Of the 20 additional tissue specimen imaged for the feasibility study, 11 were identified as having a positive or close surgical margin and nine as a negative margin under OCT. In comparing to the H&E histology, there were 9 true positives, 9 true negatives, 2 false positives, and 0 false negatives yielding a sensitivity of 82% and specificity of 100%.
Discussion: With an imaging penetration depth of 2-3 mm, equivalent to that used for histological assessment, OCT provides unique real-time cellular-level imaging to identify positive and close margins. In these studies, areas of higher scattering tissue with an irregular or heterogeneous pattern were identified, differentiating them from the abundant adipose tissue found in normal breast tissue. The small nucleus to cytoplasm (N/C) ratio is observed with low-scattering adipocytes compared with the larger N/C ratio found from highly-scattering tumor cells. These intraoperative imaging studies have demonstrated the ability for OCT to identify positive surgical margins.

Coherent optical imaging and guided interventions in breast cancer: translating technology into clinical applications

Breast cancer continues to be one of the most widely diagnosed forms of cancer in women and the second leading type of cancer deaths for women. The metastatic spread and staging of breast cancer is typically evaluated through the nodal assessment of the regional lymphatic system, and often this is performed during the surgical resection of the tumor mass. The recurrence rate of breast cancer is highly dependent on several factors including the complete removal of the primary tumor during surgery, and the presence of cancer cells in involved lymph nodes. Hence, developing means to more accurately resect tumor cells, along with the tumor mass, and ensure negative surgical margins, offers the potential to impact outcomes of breast cancer. The use of diffuse optical tomography has been applied for screening optical mammography applications as an alternative to standard x-ray mammography. The use of coherence ranging and coherent optical imaging in breast tissue has also found numerous applications, including intra-operative assessment of tumor margin status during lumpectomy procedures, assessment of lymph node changes for staging metastatic spread, and for guiding needle-biopsy procedures. The development, pre-clinical testing, and translation of techniques such as low-coherence interferometry (LCI) and optical coherence tomography (OCT) into clinical applications in breast cancer is demonstrated in these feasibility studies.

Magnetic protein microspheres as dynamic contrast agents for magnetomotive optical coherence tomography

Optical coherence tomography (OCT) is an emerging biomedical imaging modality that has been developed over the last 15 years. More recently, OCT has been used for the intraoperative imaging of tumor margins in breast cancer and axillary lymph nodes providing a real time in-vivo assessment of the tissue morphology. Traditional OCT images are limited by only being able to observe morphological structures. As diagnostic medicine continues to push for earlier detection, one must develop functional imaging modalities that would detect molecular information in-vivo allowing a real-time microscopic analysis of the tissue specimen. A novel modality of OCT called magnetomotive-OCT (MMOCT) has been developed by our group, employing an induced modulated magnetic field with a magnetic contrast agent to create the added contrast to structural OCT images. Modified protein microspheres with a BSA protein shell functionalized with RGD peptide sequences for targeting and an oil core have been designed and synthesized. Magnetic nanoparticles (Fe3O4) and Nile Red dye have been encapsulated into its oil core. These microspheres have previously been demonstrated to target cancer cells by functionalizing them with a layer of RGD peptides and could be functionalized with monoclonal antibodies. Preliminary results show that these magnetic microspheres, which are 2.0- 5.0 microns in size, are readily detectable under MM-OCT when embedded in a 5% agarose gel, in a 3-D scaffold of macrophage cells previously incubated with the microspheres, and when injected in-vivo into a tumor from an NMUcarcinogen rat animal model for breast cancer.

Publication

Optical coherence tomography: a review of clinical development from bench to bedside

Since its introduction, optical coherence tomography (OCT) technology has advanced from the laboratory bench to the clinic and back again. Arising from the fields of low coherence interferometry and optical time- and frequency-domain reflectometry, OCT was initially demonstrated for retinal imaging and followed a unique path to commercialization for clinical use. Concurrently, significant technological advances were brought about from within the research community, including improved laser sources, beam delivery instruments, and detection schemes. While many of these technologies improved retinal imaging, they also allowed for the application of OCT to many new clinical areas. As a result, OCT has been clinically demonstrated in a diverse set of medical and surgical specialties, including gastroenterology, dermatology, cardiology, and oncology, among others. The lessons learned in the clinic are currently spurring a new set of advances in the laboratory that will again expand the clinical use of OCT by adding molecular sensitivity, improving image quality, and increasing acquisition speeds. This continuous cycle of laboratory development and clinical application has allowed the OCT technology to grow at a rapid rate and represents a unique model for the translation of biomedical optics to the patient bedside. This work presents a brief history of OCT development, reviews current clinical applications, discusses some clinical translation challenges, and reviews laboratory developments poised for future clinical application.

Publication

Needle-based refractive index measurement using low-coherence interferometry

We present a novel needle-based device for the measurement of refractive index and scattering using low-coherence interferometry. Coupled to the sample arm of an optical coherence tomography system, the device detects the scattering response of, and optical path length through, a sample residing in a fixed-width channel. We report use of the device to make near-infrared measurements of tissues and materials with known optical properties. The device could be used to exploit the refractive index variations of tissue for medical and biological diagnostics accessible by needle insertion.

Portable real-time optical coherence tomography system for intraoperative imaging and staging of breast cancer

Breast cancer continues to be one of the most widely diagnosed forms of cancer amongst women and the second leading type of cancer deaths amongst women. The recurrence rate of breast cancer is highly dependent on several factors including the complete removal of the primary tumor and the presence of cancer cells in involved lymph nodes. The metastatic spread and staging of breast cancer is also evaluated through the nodal assessment of the regional lymphatic system. A portable real-time spectral domain optical coherence tomography system is being presented as a clinical diagnostic tool in the intraoperative delineation of tumor margins as well as for real time lymph node assessment. The system employs a super luminescent diode centered at 1310 nm with a bandwidth of 92 nm. Using a spectral domain detection system, the data is acquired at a rate of 5 KHz / axial scan. The sample arm is a galvanometer scanning telecentric probe with an objective lens (f = 60 mm, confocal parameter = 1.5 mm) yielding an axial resolution of 8.3 μm and a transverse resolution of 35.0 μm. Images of tumor margins are acquired in the operating room ex vivo on freshly excised human tissue specimen. This data shows the potential of the use of OCT in defining the structural tumor margins in breast cancer. Images taken from ex-vivo samples on the bench system clearly delineate the differences between clusters of tumor cells and nearby adipose cells. In addition, the data shows the potential for OCT as a diagnostic tool in the staging of cancer metastasis through locoregional lymph node assessment.

Physician-scientist with extensive experience developing and translating nanotechnologies and biomedical optical technologies from the bench to clinic in areas of genetics, oncology, and cardiovascular diseases. Extensive experience in community building in healthcare innovation, research, medical, and physician-scientist communities through various leadership roles.

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