SignificanceDespite recent advances in multimodal optical imaging, oral imaging systems often do not provide real-time actionable guidance to the clinician who is making biopsy and treatment decisions.AimWe demonstrate a low-cost, portable active biopsy guidance system (ABGS) that uses multimodal optical imaging with deep learning to directly project cancer risk and biopsy guidance maps onto oral mucosa in real time.ApproachCancer risk maps are generated based on widefield autofluorescence images and projected onto the at-risk tissue using a digital light projector. Microendoscopy images are obtained from at-risk areas, and multimodal image data are used to calculate a biopsy guidance map, which is projected onto tissue.ResultsRepresentative patient examples highlight clinically actionable visualizations provided in real time during an imaging procedure. Results show multimodal imaging with cancer risk and biopsy guidance map projection offers a versatile, quantitative, and precise tool to guide biopsy site selection and improve early detection of oral cancers.ConclusionsThe ABGS provides direct visible guidance to identify early lesions and locate appropriate sites to biopsy within those lesions. This represents an opportunity to translate multimodal imaging into real-time clinically actionable visualizations to help improve patient outcomes.
Purpose:In vivo optical imaging technologies like high-resolution microendoscopy (HRME) can image nuclei of the oral epithelium. In principle, automated algorithms can then calculate nuclear features to distinguish neoplastic from benign tissue. However, images frequently contain regions without visible nuclei, due to biological and technical factors, decreasing the data available to and accuracy of image analysis algorithms.
Approach: We developed the nuclear density-confidence interval (ND-CI) algorithm to determine if an HRME image contains sufficient nuclei for classification, or if a better image is required. The algorithm uses a convolutional neural network to exclude image regions without visible nuclei. Then the remaining regions are used to estimate a confidence interval (CI) for the number of abnormal nuclei per mm2, a feature used by a previously developed algorithm (called the ND algorithm), to classify images as benign or neoplastic. The range of the CI determines whether the ND-CI algorithm can classify an image with confidence, and if so, the predicted category. The ND and ND-CI algorithm were compared by calculating their positive predictive value (PPV) and negative predictive value (NPV) on 82 oral biopsies with histopathologically confirmed diagnoses.
Results: After excluding the images that could not be classified with confidence, the ND-CI algorithm had higher PPV (65% versus 59%) and NPV (78% versus 75%) than the ND algorithm.
Conclusions: The ND-CI algorithm could improve the real-time classification of HRME images of the oral epithelium by informing the user if an improved image is required for diagnosis.
Oral premalignant lesions (OPLs), such as leukoplakia, are at risk of malignant transformation to oral cancer. Clinicians can elect to biopsy OPLs and assess them for dysplasia, a marker of increased risk. However, it is challenging to decide which OPLs need a biopsy and to select a biopsy site. We developed a multimodal optical imaging system (MMIS) that fully integrates the acquisition, display, and analysis of macroscopic white-light (WL), autofluorescence (AF), and high-resolution microendoscopy (HRME) images to noninvasively evaluate OPLs. WL and AF images identify suspicious regions with high sensitivity, which are explored at higher resolution with the HRME to improve specificity. Key features include a heat map that delineates suspicious regions according to AF images, and real-time image analysis algorithms that predict pathologic diagnosis at imaged sites. Representative examples from ongoing studies of the MMIS demonstrate its ability to identify high-grade dysplasia in OPLs that are not clinically suspicious, and to avoid unnecessary biopsies of benign OPLs that are clinically suspicious. The MMIS successfully integrates optical imaging approaches (WL, AF, and HRME) at multiple scales for the noninvasive evaluation of OPLs.
Failure of cancer surgery to intraoperatively detect and eliminate microscopic residual disease (MRD) causes lethal recurrence and metastases, whereas removal of important normal tissues causes excessive morbidity. We report plasmonic nanobubble (PNB) surgical technology to intraoperatively detect and eliminate MRD in surgical bed. PNBs were generated in vivo in head and neck cancer cells by systemically targeting tumor with gold colloids and locally-applied near-infrared low energy short laser pulse, and were simultaneously detected with acoustic probe. In mouse models of head and neck squamous cell carcinoma, single cancer cells and MRD (undetectable with standard histological methods) were instantaneously non-invasively detected in solid tissue in surgical bed. In resectable MRD, PNB-guided surgery prevented local recurrence and delivered 100% tumor-free survival. In unresectable MRD, PNB nano-surgery improved survival by two-fold compared to standard surgery. PNB metrics correlated with the tumor recurrence rate. PNB surgical technology precisely detects and immediately eliminates MRD at macro- and micro-scale in a simple and safe intraoperative procedure.
We developed an automated frame selection algorithm for high-resolution microendoscopy video sequences. The algorithm rapidly selects a representative frame with minimal motion artifact from a short video sequence, enabling fully automated image analysis at the point-of-care. The algorithm was evaluated by quantitative comparison of diagnostically relevant image features and diagnostic classification results obtained using automated frame selection versus manual frame selection. A data set consisting of video sequences collected in vivo from 100 oral sites and 167 esophageal sites was used in the analysis. The area under the receiver operating characteristic curve was 0.78 (automated selection) versus 0.82 (manual selection) for oral sites, and 0.93 (automated selection) versus 0.92 (manual selection) for esophageal sites. The implementation of fully automated high-resolution microendoscopy at the point-of-care has the potential to reduce the number of biopsies needed for accurate diagnosis of precancer and cancer in low-resource settings where there may be limited infrastructure and personnel for standard histologic analysis.
We developed an automated frame selection algorithm for high resolution microendoscope images. The algorithm
rapidly selects a representative frame with minimal motion artifact from a short video sequence, enabling fully
automated image analysis at the point-of-care. The performance of the algorithm was evaluated by comparing
automatically selected frames to manually selected frames using quantitative image parameters. The implementation of fully automated high-resolution microendoscopy at the point-of-care has the potential to reduce the
number of biopsies needed for accurate diagnosis of precancer and cancer in low-resource settings, where there
may be limited infrastructure and personnel for standard histologic analysis.
Ekaterina Lukianova-Hleb, Xiaoyang Ren, Rupa Sawant, Ann Gillenwater, Michael Kupferman, Ehab Hanna, Joseph Zasadzinski, Xiangwei Wu, Vladimir Torchilin, Dmitri Lapotko
Chemoradiation-resistant cancer cells and unresectable micro-tumors limit treatment efficacy and lead to high nonspecific
toxicity or recurrence in head and neck cancers. We show the cancer cell-specific, on-demand enhancement of
the chemo- and chemoradiation therapy with mechanical intracellular impact of plasmonic nanobubbles, a laser pulseinduced
explosive nano-event, not a particle. We report cellular mechanisms of cancer cell-specific detection and
enhancement of the entry drug and X-ray dose and validate these mechanisms in vitro and in vivo for head and neck
squamous cell carcinoma. Plasmonic nanobubble technology showed more than 10-fold enhancement of the therapeutic
efficacy compared to standard chemoradiation in murine models of primary, microscopic residual and recurrent diseases.
At the same time our technology efficiently spared adjacent normal tissues due to the reduction of the effective
therapeutic doses of drug by 30-40 fold, X-rays by 15-fold and the treatment time to a single procedure. The developed
plasmonic nanobubble technology transforms a standard macro-therapy into a cell-level on-demand theranostic
treatment for primary, adjuvant and adjunct applications.
In this longitudinal study, a mouse model of 4-nitroquinoline 1-oxide chemically induced tongue carcinogenesis was used to assess the ability of optical imaging with exogenous and endogenous contrast to detect neoplastic lesions in a heterogeneous mucosal surface. Widefield autofluorescence and fluorescence images of intact 2-NBDG-stained and proflavine-stained tissues were acquired at multiple time points in the carcinogenesis process. Confocal fluorescence images of transverse fresh tissue slices from the same specimens were acquired to investigate how changes in tissue microarchitecture affect widefield fluorescence images of intact tissue. Widefield images were analyzed to develop and evaluate an algorithm to delineate areas of dysplasia and cancer. A classification algorithm for the presence of neoplasia based on the mean fluorescence intensity of 2-NBDG staining and the standard deviation of the fluorescence intensity of proflavine staining was found to separate moderate dysplasia, severe dysplasia, and cancer from non-neoplastic regions of interest with 91% sensitivity and specificity. Results suggest this combination of noninvasive optical imaging modalities can be used in vivo to discriminate non-neoplastic from neoplastic tissue in this model with the potential to translate this technology to the clinic.
Dysplastic and cancerous alterations in oral tissue can be detected noninvasively in vivo using optical techniques
including autofluorescence imaging, high-resolution imaging, and spectroscopy. Interim results are presented from a
longitudinal study in which optical imaging and spectroscopy were used to evaluate the progression of lesions over time
in patients at high risk for development of oral cancer. Over 100 patients with oral potentially malignant disorders have
been enrolled in the study to date. Areas of concern in the oral cavity are measured using widefield autofluorescence
imaging and depth-sensitive optical spectroscopy during successive clinical visits. Autofluorescence intensity patterns
and autofluorescence spectra are tracked over time and correlated with clinical observations. Patients whose lesions
progress and who undergo surgery are also measured in the operating room immediately prior to surgery using
autofluorescence imaging and spectroscopy, with the addition of intraoperative high-resolution imaging to characterize
nuclear size, nuclear crowding, and tissue architecture at selected sites. Optical measurements are compared to
histopathology results from biopsies and surgical specimens collected from the measured sites. Autofluorescence
imaging and spectroscopy measurements are continued during post-surgery followup visits. We examined correlations
between clinical impression and optical classification over time with an average followup period of 4 months. The data
collected to date suggest that multimodal optical techniques may aid in noninvasive monitoring of the progression of oral
premalignant lesions, biopsy site selection, and accurate delineation of lesion extent during surgery.
Early detection is a potential key to improving the survival rates of oral cancer patients and reducing the morbidity
associated with treatment. We seek to improve upon methods of detecting of early malignancies with oral brush biopsies
by using immunofluorescence-based assessment of the expression of multiple well-described markers commonly
overexpressed in oral cancers, such as Epidermal Growth Factor Receptor (EGFR) and Cytokeratin 8 (CK8).
Furthermore, since abnormal cells are often scarce in brush biopsy samples, we seek to use magnetic microparticles
targeted to these markers as a means of enriching the concentration of abnormal cells. Finally, we plan to conduct a small
pilot study using these methods with brush biopsies from patients of the M. D. Anderson Cancer Center Head and Neck
Clinic.
Optical techniques including widefield autofluorescence and reflectance imaging, depth-sensitive optical spectroscopy,
and high-resolution imaging can be used to noninvasively detect dysplastic and cancerous alterations in oral tissue. The
diagnostic performance of depth-sensitive optical spectroscopy with respect to histopathology is examined. A compact,
portable spectroscopy device for clinical use is described. Practical considerations for the comparison of optical
measurements to histopathologic diagnoses are outlined. Important considerations for comparison to histopathology
include the physical correspondence of the measured region to the biopsy or specimen; data collection and processing
procedures; and data analysis procedures. Multimodal combinations of widefield imaging, point spectroscopy, and highresolution
imaging may enhance the ability of clinicians to accurately assess the margins of neoplastic oral lesions in
vivo.
Darren Roblyer, Cristina Kurachi, Vanda Stepanek, Richard Schwarz, Michelle Williams, Adel El-Naggar, J. Jack Lee, Ann Gillenwater, Rebecca Richards-Kortum
Multispectral widefield optical imaging has the potential to improve early detection of oral cancer. The appropriate selection of illumination and collection conditions is required to maximize diagnostic ability. The goals of this study were to (i) evaluate image contrast between oral cancer/precancer and non-neoplastic mucosa for a variety of imaging modalities and illumination/collection conditions, and (ii) use classification algorithms to evaluate and compare the diagnostic utility of these modalities to discriminate cancers and precancers from normal tissue. Narrowband reflectance, autofluorescence, and polarized reflectance images were obtained from 61 patients and 11 normal volunteers. Image contrast was compared to identify modalities and conditions yielding greatest contrast. Image features were extracted and used to train and evaluate classification algorithms to discriminate tissue as non-neoplastic, dysplastic, or cancer; results were compared to histologic diagnosis. Autofluorescence imaging at 405-nm excitation provided the greatest image contrast, and the ratio of red-to-green fluorescence intensity computed from these images provided the best classification of dysplasia/cancer versus non-neoplastic tissue. A sensitivity of 100% and a specificity of 85% were achieved in the validation set. Multispectral widefield images can accurately distinguish neoplastic and non-neoplastic tissue; however, the ability to separate precancerous lesions from cancers with this technique was limited.
Current procedures for oral cancer screening typically involve visual inspection of the entire tissue surface at risk under
white light illumination. However, pre-cancerous lesions can be difficult to distinguish from many benign conditions
when viewed under these conditions. We have developed wide-field (macroscopic) imaging system which additionally
images in cross-polarized white light, narrowband reflectance, and fluorescence imaging modes to reduce specular glare,
enhance vascular contrast, and detect disease-related alterations in tissue autofluorescence.
We have also developed a portable system to enable high-resolution (microscopic) evaluation of cellular features within
the oral mucosa in situ. This system is a wide-field epi-fluorescence microscope coupled to a 1 mm diameter, flexible
fiber-optic imaging bundle. Proflavine solution was used to specifically label cell nuclei, enabling the characteristic
differences in N/C ratio and nuclear distribution between normal, dysplastic, and cancerous oral mucosa to be quantified.
This paper discusses the technical design and performance characteristics of these complementary imaging systems. We
will also present data from ongoing clinical studies aimed at evaluating diagnostic performance of these systems for
detection of oral neoplasia.
Worldwide incidence and mortality rates due to cancer continue to rise, with the burden of disease increasingly shifting
to developing countries. Several optical diagnostic methods are under development to enable earlier detection of cancer,
however, these are primarily intended for use in healthcare facilities in industrialized countries. Using knowledge
gained from early clinical studies with large-scale prototype systems, we have designed and tested low-cost, portable
versions of these instruments. We propose that these systems may be used for early diagnosis and screening in
developing countries, and that pilot clinical studies are warranted in these low-resource settings.
The clinical applicability of antibodies and plasmonic nanosensors as topically applied, molecule-specific optical diagnostic agents for noninvasive early detection of cancer and precancer is severely limited by our inability to efficiently deliver macromolecules and nanoparticles through mucosal tissues. We have developed an imidazole-functionalized conjugate of the polysaccharide chitosan (chitosan-IAA) to enhance topical delivery of contrast agents, ranging from small molecules and antibodies to gold nanoparticles up to 44 nm in average diameter. Contrast agent uptake and localization in freshly resected mucosal tissues was monitored using confocal microscopy. Chitosan-IAA was found to reversibly enhance mucosal permeability in a rapid, reproducible manner, facilitating transepithelial delivery of optical contrast agents. Permeation enhancement occurred through an active process, resulting in the delivery of contrast agents via a paracellular or a combined paracellular/transcellular route depending on size. Coadministration of epidermal growth factor receptor-targeted antibodies with chitosan-IAA facilitated specific labeling and discrimination between paired normal and malignant human oral biopsies. Together, these data suggest that chitosan-IAA is a promising topical permeation enhancer for mucosal delivery of optical contrast agents.
A hyperspectral imaging system using a liquid-crystal tunable filter (LCTF) was constructed for the purpose of in vivo
optical imaging of oral neoplasia. The system operates in fluorescence mode and has the dual capability of capturing
high quality widefield images and detecting fluorescence emission spectra from arbitrary locations within the captured
field of view (FOV). The system was calibrated and evaluated for spectral resolution and accuracy. In vivo
hyperspectral images were obtained from two normal volunteers and two patients with confirmed oral malignancy.
Normal volunteer measurements revealed differences in intensity and lineshape of spectra between different anatomic
locations, but intensity and lineshape were similar between different measurement sites from the same anatomic location.
Measurements from normal and neoplastic areas of two patients with previously confirmed oral neoplasia showed
differences in intensity, lineshape, and location of peak intensity. We have demonstrated that this system can provide
both high quality widefield images, and spectral information at chosen locations within the field of view.
A Monte Carlo model with site-specific input is used to predict depth-resolved fluorescence spectra from individual normal, inflammatory, and neoplastic oral sites. Our goal in developing this model is to provide a computational tool to study how the morphological characteristics of the tissue affect clinically measured spectra. Tissue samples from the measured sites are imaged using fluorescence confocal microscopy; autofluorescence patterns are measured as a function of depth and tissue sublayer for each individual site. These fluorescence distributions are used as input to the Monte Carlo model to generate predictions of fluorescence spectra, which are compared to clinically measured spectra on a site-by-site basis. A lower fluorescence intensity and longer peak emission wavelength observed in clinical spectra from dysplastic and cancerous sites are found to be associated with a decrease in measured fluorescence originating from the stroma or deeper fibrous regions, and an increase in the measured fraction of photons originating from the epithelium or superficial tissue layers. The simulation approach described here can be used to suggest an optical probe design that samples fluorescence at a depth that gives optimal separation in the spectral signal measured for benign, dysplastic, and cancerous oral mucosa.
We present a Monte Carlo model to predict fluorescence spectra of the oral mucosa obtained with a depth-selective fiber optic probe as a function of tissue optical properties. A model sensitivity analysis determines how variations in optical parameters associated with neoplastic development influence the intensity and shape of spectra, and elucidates the biological basis for differences in spectra from normal and premalignant oral sites. Predictions indicate that spectra of oral mucosa collected with a depth-selective probe are affected by variations in epithelial optical properties, and to a lesser extent, by changes in superficial stromal parameters, but not by changes in the optical properties of deeper stroma. The depth selective probe offers enhanced detection of epithelial fluorescence, with 90% of the detected signal originating from the epithelium and superficial stroma. Predicted depth-selective spectra are in good agreement with measured average spectra from normal and dysplastic oral sites. Changes in parameters associated with dysplastic progression lead to a decreased fluorescence intensity and a shift of the spectra to longer emission wavelengths. Decreased fluorescence is due to a drop in detected stromal photons, whereas the shift of spectral shape is attributed to an increased fraction of detected photons arising in the epithelium.
Oral cancer is an important global health problem. There is an urgent need for improved methods to detect oral cancer and its precursors, because early detection is the best way to reduce oral cancer mortality and morbidity. In this work, we describe simple modifications to a surgical headlight system that enables direct visualization and digital image acquisition from oral tissue in multiple imaging modalities including fluorescence, white-light reflectance, and orthogonal polarization reflectance. Images obtained with the system in-vivo demonstrate that it is an attractive technology to explore for oral cancer screening in low-resource environments where clinical expertise is often unavailable.
We report the results of an oral cavity pilot clinical trial to detect early precancer and cancer using a fiber optic probe with obliquely oriented collection fibers that preferentially probe local tissue morphology and heterogeneity using oblique polarized reflectance spectroscopy (OPRS). We extract epithelial cell nuclear sizes and 10 spectral features. These features are analyzed independently and in combination to assess the best metrics for separation of diagnostic classes. Without stratifying the data according to anatomical location or level of keratinization, OPRS is found to be sensitive to four diagnostic categories: normal, benign, mild dysplasia, high-grade dysplasia, and carcinoma. Using linear discriminant analysis, separation of normal from high-grade dysplasia and carcinoma yield a sensitivity and specificity of 90 and 86%, respectively. Discrimination of morphologically similar lesions such as normal from mild dysplasia is achieved with a sensitivity of 75% and specificity of 73%. Separation of visually indistinguishable benign lesions from high-grade dysplasia and carcinoma is achieved with good sensitivity (100%) and specificity (85%), while separation of benign from mild dysplasia gives a sensitivity of 92% and a specificity of 69%. These promising results suggest that OPRS has the potential to aid screening and diagnosis of oral precancer and cancer.
A multispectral digital microscope (MDM) is designed and constructed as a tool to improve detection of oral neoplasia. The MDM acquires in vivo images of oral tissue in fluorescence, narrow-band (NB) reflectance, and orthogonal polarized reflectance (OPR) modes, to enable evaluation of lesions that may not exhibit high contrast under standard white light illumination. The device rapidly captures image sequences so that the diagnostic value of each modality can be qualitatively and quantitatively evaluated alone and in combination. As part of a pilot clinical trial, images are acquired from normal volunteers and patients with precancerous and cancerous lesions. In normal subjects, the visibility of vasculature can be enhanced by tuning the reflectance illumination wavelength and polarization. In patients with histologically confirmed neoplasia, we observe decreased blue/green autofluorescence and increased red autofluorescence in lesions, and increased visibility of vasculature using NB and OPR imaging. The perceived lesion borders change with imaging modality, suggesting that multimodal imaging has the potential to provide additional diagnostic information not available using standard white light illumination or by using a single imaging mode alone.
Neoplastic progression in epithelial tissues is accompanied by structural and morphological changes in the stromal
collagen matrix. We used the Finite-Difference Time-Domain (FDTD) method, a popular computational technique for
full-vector solution of complex problems in electromagnetics, to establish a relationship between structural properties of
collagen fiber networks and light scattering, and to analyze how neoplastic changes alter stromal scattering properties.
To create realistic collagen network models, we acquired optical sections from the stroma of fresh normal and neoplastic
oral cavity biopsies using fluorescence confocal microscopy. These optical sections were then processed to construct
three-dimensional collagen networks of different sizes as FDTD model input. Image analysis revealed that volume
fraction of collagen fibers in the stroma decreases with neoplastic progression, and statistical texture features computed
suggest that fibers tend to be more disconnected in neoplastic stroma. The FDTD modeling results showed that
neoplastic fiber networks have smaller scattering cross-sections compared to normal networks of the same size, whereas
high-angle scattering probabilities tend to be higher for neoplastic networks. Characterization of stromal scattering is
expected to provide a basis to better interpret spectroscopic optical signals and to develop more reliable computational
models to describe photon propagation in epithelial tissues.
The use of high resolution, in vivo optical imaging may offer a clinically useful adjunct to standard histopathologic techniques. A pilot study was performed to investigate the diagnostic capabilities of optical coherence microscopy (OCM) to discriminate between normal and abnormal oral tissue. Our objective is to determine whether OCM, a technique combining the subcellular resolution of confocal microscopy with the coherence gating and heterodyne detection of optical coherence tomography, has the same ability as confocal microscopy to detect morphological changes present in precancers of the epithelium while providing superior penetration depths. We report our results using OCM to characterize the features of normal and neoplastic oral mucosa excised from 13 subjects. Specifically, we use optical coherence and confocal microscopic images obtained from human oral biopsy specimens at various depths from the mucosal surface to examine the optical properties that distinguish normal and neoplastic oral mucosa. An analysis of penetration depths achieved by the OCM and its associated confocal arm found that the OCM consistently imaged more deeply. Extraction of scattering coefficients from reflected nuclear intensity is successful in nonhyperkeratotic layers and shows differentiation between scattering properties of normal and dysplastic epithelium and invasive cancer.
In collaboration with the Department of Biomedical Engineering at the University of Texas at Austin and the UT MD Anderson Cancer Center, a laser scanning fiber confocal reflectance microscope (FCRM) system has been designed and tested for in vivo detection of cervical and oral pre-cancers. This system along with specially developed diagnosis algorithms and techniques can achieve an unprecedented specificity and sensitivity for the diagnosis of pre-cancers in epithelial tissue. The FCRM imaging system consists of an NdYAG laser (1064 nm), scanning mirrors/optics, precision pinhole, detector, and an endoscopic probe (the objective). The objective is connected to the rest of the imaging system via a fiber bundle. The fiber bundle allows the rest of the system to be remotely positioned in a convenient location. Only the objective comes into contact with the patient. It is our intent that inexpensive mass-produced disposable endoscopic probes would be produced for large clinical trials. This paper touches on the general design process of developing a miniature, high numerical aperture, injection-molded (IM) objective. These IM optical designs are evaluated and modified based on manufacturing and application constraints. Based on these driving criteria, one specific optical design was chosen and a detailed tolerance analysis was conducted. The tolerance analysis was custom built to create a realistic statistical analysis for integrated IM lens elements that can be stacked one on top of another using micro-spheres resting in tiny circular grooves. These configurations allow each lens element to be rotated and possibly help compensate for predicted manufacturing errors. This research was supported by a grant from the National Institutes of Health (RO1 CA82880). Special thanks go to Applied Image Group/Optics for the numerous fabrication meetings concerning the miniature IM objective.
The human eyes are not made to detect disease, however visual perception is the most common screening method for early cancer detection. With optimal illumination and observation configuration there is significant improvement of optical contrast between normal and pre-cancerous tissue in the oral cavity, both for reflected and fluorescent light.
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