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For ill-posed and ill-conditioned DOT inverse problem, a two-step reconstruction method is proposed. This method obtains an initial solution from the Truncated Pseudoinverse method and uses it for conjugate-gradient based inverse mapping of optical properties.

A spatial frequency domain imaging (SFDI) was used to image ex vivo human colon tissues. Significant differences were observed between absorption, scattering, scatter slope, total hemoglobin and spatial heterogeneities of benign and malignant tissue groups.

This chapter presents details of the design and characterization of an improved photoacoustic system optimized for tomographic small animal imaging. The system uses a 128-element transducer array and features a higher operating frequency for resolution of fine features, such as brain vasculature, while retaining high sensitivity for deeper imaging. The chapter provides a discussion of the system architecture and design with special consideration of electronics and transducer parameters. It also presents simulations and characterization measurements of system performance, including resolution, field-of-view, and sensitivity. The chapter describes the effects of target geometry, orientation, and size on tomographic imaging quality. It demonstrates the impact of both system design and target characteristics through ex vivo imaging of mouse brain vasculature. The chapter explains a brief discussion of system design implications for photoacoustic imaging fidelity with the complex and varied features typical of in vivo tissues.

In this project, we propose to investigate the feasibility of a novel technology that will bring both PET and ultrasound imaging to the patient bedside to support point-ofcare(PoC) molecular imaging applications. The system will comprise of a panel detector placed behind the patient and a maneuverable probe that consists of a PET detector and an ultrasound transducer. The probe can be moved around a region-of-interest in the patients’ body to collect both PET coincidence events and ultrasound signals. The location of the maneuverable probe relative to the back panel detectors is tracked in real-time as coincidence events are recorded. These events are used for list-mode image reconstruction in near realtime to provide visual feedback to the operator who can interactively control the probe to collect additional counts from the most critical locations and/or angles in order to dynamically optimize the image quality. To prove the concept, we developed a prototype that consists of a single channel SiPM(SensL FB30035) coupled to a 3.0 $\times$3.0$\times$20.0 mm$^{ 3}$ LSO crystal as the back detector. The maneuverable probe consists of an ultrasound transducer and a PMT(Hamamatsu H8500) coupled to 48$\times$48 LSO crystals of 1.0$\times$1.0$\times$10.0 mm$^{ 3}$ each. A robotic arm allows us to position the probe at arbitrary locations. Coincidence timing resolution of 470 ps FWHM has been achieved. We have implemented a GPUbased fully 3D list-mode Time-Of-Flight image reconstruction algorithm that can model the dynamically changing geometry of this PoC system. In this study, we report preliminary results from both actual experiments using this prototype and simulations using GATE. Detector modules with larger sensitive volume will be fabricated and tested to perform more imaging studies in order to explore the capability of this class of system.

A hand-held transvaginal probe suitable for co-registered photoacoustic and ultrasound imaging of ovarian tissue was designed and evaluated. The imaging probe consists of an ultrasound transducer and four 1-mm-core multi-mode optical fibers both housed in a custom-made sheath. The probe was optimized for the highest light delivery output and best beam uniformity on tissue surface, by simulating the light fluence and power output for different design parameters. The laser fluence profiles were experimentally measured through chicken breast tissue and calibrated intralipid solution at various imaging depths. Polyethylene tubing filled with rat blood mimicking a blood vessel was successfully imaged up to ∼30 mm depth through porcine vaginal tissue at 750 nm. This imaging depth was achieved with a laser fluence on the tissue surface of 20 mJ/cm(2), which is below the maximum permissible exposure (MPE) of 25 mJ/cm(2) recommended by the American National Standards Institute (ANSI). Furthermore, the probe imaging capability was verified with ex vivo imaging of benign and malignant human ovaries. The co-registered images clearly showed different vasculature distributions on the surface of the benign cyst and the malignant ovary. These results suggest that our imaging system has the clinical potential for in vivo imaging and characterization of ovarian tissues.

Tumor hypoxia is associated with the rapid proliferation and growth of malignant tumors, and the ability to detect tumor hypoxia is important for predicting tumor response to anti-cancer treatments. We have developed a class of dye-conjugates that are related to indocyanine green (ICG, 1) to target tumor hypoxia, based on in vivo infrared fluorescence imaging using nitroimidazole moieties linked to indocyanine fluorescent dyes. We previously reported that linking 2-nitroimidazole to an indocyanine dicarboxylic acid dye derivative (2) using an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG, 3), led to a dye-conjugate that gave promising results for targeting cancer hypoxia in vivo. Structural modification of the dye conjugate replaced the ethanolamine unit with a piperazineacetyl unit and led a second generation dye conjugate, piperzine-2-nitroimidazole-ICG (4). This second generation dye-conjugate showed improved targeting of tumor hypoxia when compared with 3. Based on the hypothesis that molecules with more planar and rigid structures have a higher fluorescence yield, as they could release less absorbed energy through molecular vibration or collision, we have developed a new 2-nitroimidazole ICG conjugate, 12, with two carbon atoms less in the polyene linker. Dye-conjugate 12 was prepared from our new dye (8), and coupled to 2-nitroimidazole using a piperazine linker to produce this third-generation dye-conjugate. Spectral measurements showed that the absorption/emission wavelengths of 657/670 were shifted ∼100 nm from the second-generation hypoxia dye of 755/780 nm. Its fluorescence quantum yield was measured to be 0.467, which is about 5 times higher than that of 4 (0.083). In vivo experiments were conducted with balb/c mice and 12 showed more than twice the average in vivo fluorescence intensity in the tumor beyond two hours post retro-orbital injection as compared with 4. These initial results suggest that 12 may significantly improve in vivo tumor hypoxia targeting.

Ovarian cancer has the lowest survival rate among all the gynecologic cancers because it is predominantly diagnosed at late stages due to the lack of reliable symptoms and efficacious screening techniques. Optical coherence tomography (OCT) is an emerging technique that provides high-resolution images of biological tissue in real time, and demonstrates great potential for imaging of ovarian tissue. In this article, we review OCT studies for visualization and diagnosis of human ovaries as well as quantitative extraction of ovarian tissue optical properties for classifying normal and malignant ovaries. OCT combined with other imaging modalities to further improve ovarian tissue diagnosis is also reviewed.

Male breast cancer, although rare, is on the rise. Prospective clinical trials are unlikely and current management mirrors that of post-menopausal women. Neoadjuvant chemotherapy is widely used and pathologic complete response (pCR) predicts long-term survival. The addition of dual HER2 (human epidermal growth factor receptor 2) blockade has shown the highest pCR rates; however, there is no published data of this approach in men. Also, newer monitoring tools are necessary during a neoadjuvant therapy to help personalize treatment. Here, we describe the case of a 64-year-old man with Stage IIB (tumor size 2 to 5 cm with involvement of axillary lymph nodes), high-grade estrogen receptor, progesterone receptor, and HER2-positive invasive ductal carcinoma with a germline breast cancer susceptibility gene 1 (BRCA1) mutation who was treated in a neoadjuvant fashion with dual HER2 blockade and platinum-based chemotherapy regimen. A novel predictive tool, ultrasound-localized diffuse optical tomography, was used to monitor his progress during treatment.

Initial feasibility of a spatial frequency domain imaging system was studied consisting of a hand held miniaturized projector and a rigid endoscope. Three wavelengths and two spatial frequencies were used for imaging. The system was calibrated using tissue mimicking phantoms. In vivo imaging was performed on five live mouse tumor models, and the absorption, scattering, hemoglobin oxygen saturation was measured. The initial promising results indicate that the spatial frequency domain imaging can a very useful tool for quantitative wide field tissue evaluation during minimally invasive image guided surgery.

We present a low-cost laser scanning photoacoustic microscopy system with a pulsed laser diode as the excitation source. The system utilizes a 905 nm pulsed laser diode with 120 ns pulse width and 1 KHz repetition rate. No averaging is performed in data acquisition, resulting in a short image acquisition time. The maximum field of view is 4.6 mm × 3.7 mm and the lateral resolution is 71 μm. Images of human hairs and mouse ear are presented to demonstrate the feasibility of the system in imaging biological tissue.

A PEGylated quinoline-annulated porphyrin derivative was synthesized as in vivo photoacoustic tomography contrast agent. It possesses high solubility and stability in water and phosphate-buffered saline. No toxicity sign was observed in BALB/c mice. The dye demonstrates a 4-fold higher photoacoustic signal generation efficiency compared to fresh rat blood. Injection of the dye results in a significant enhancement of in vivo PAT images of murine tumors. Analysis of the mouse urine after injection revealed an unaltered renal filtration of the contrast agent.

Imaging of tissue with Ultrasound-guided diffuse optical tomography (DOT) is a rising imaging technique to map hemoglobin concentrations within tissue for breast cancer detection and diagnosis. Near-infrared optical imaging received a lot of attention in research as a possible technique to be used for such purpose especially for breast tumors. Since DOT images contrast is closely related to oxygenation and deoxygenating of the hemoglobin, which is an important factor in differentiating malignant and benign tumors. One of the optical imaging modalities used is the diffused optical tomography (DOT); which probes deep scattering tissue (1-5cm) by NIR optical source-detector probe and detects NIR photons in the diffusive regime. The photons in the diffusive regime usually reach the detector without significant information about their source direction and the propagation path. Because of that, the optical reconstruction problem of the medium characteristics is ill-posed even with the tomography and Back-projection techniques. The accurate recovery of images requires an effective image reconstruction method. Here, we illustrate a method in which ultrasound images are encoded as prior for regularization of the inversion matrix. Results were evaluated using phantom experiments of low and high absorption contrasts. This method improves differentiation between the low and the high contrasts targets. Ultimately, this method could improve malignant and benign cases by increasing reconstructed absorption ratio of malignant to benign. Besides that, the phantom results show improvements in target shape as well as the spatial resolution of the DOT reconstructed images.

The feasibility of a full-field optical coherence tomography (FFOCT) system for rapid wide field optical analysis of normal and malignant human ovarian tissue pathologies was demonstrated. Five features were extracted from the normalized image histogram from 56 FFOCT images, based on the differences in the morphology of the normal and malignant tissue samples.

According to the World Health Organization, breast cancer is the most common cancer among women worldwide, claiming the lives of hundreds of thousands of women each year. Near infrared diffuse optical tomography (DOT) has demonstrated a great potential as an adjunct modality for differentiation of malignant and benign breast lesions and for monitoring treatment response of patients with locally advanced breast cancers. The path toward commercialization of DOT techniques depends upon the improvement of robustness and user-friendliness of this technique in hardware and software. In the past, our group have developed three frequency domain prototype systems which were used in several clinical studies. In this study, we introduce our newly under development US-guided DOT system which is being improved in terms of size, robustness and user friendliness by several custom electronic and mechanical design. A new and robust probe designed to reduce preparation time in clinical process. The processing procedure, data selection and user interface software also updated. With all these improvements, our new system is more robust and accurate which is one step closer to commercialization and wide use of this technology in clinical settings. This system is aimed to be used by minimally trained user in the clinical settings with robust performance. The system performance has been tested in the phantom experiment and initial results are demonstrated in this study. We are currently working on finalizing this system and do further testing to validate the performance of this system. We are aiming toward use of this system in clinical setting for patients with breast cancer.

Ultrasound (US)-guided diffuse optical tomography (DOT) is a promising low-cost imaging technique for diagnosis and assessment of breast cancer. US-guided DOT is best implemented in reflection geometry, which can be co-registered with US pulse-echo imaging and also minimizes the tissue depth for adequate light penetration. However, due to intense light scattering, the DOT reconstruction problem is ill-posed. In this communication, we describe a new non-linear Born iterative reconstruction method with US-guided depth-dependent [Formula: see text] sparse regularization for improving DOT reconstruction by incorporating a priori lesion depth and shape information from the co-registered US image. Our method iteratively solves the inverse problem by updating the photon-density wave using the finite difference method, computing the weight matrix based on Born approximation, and reconstructing the absorption map using the fast iterative shrinkage-thresholding optimization algorithm (FISTA). We validate our method using both phantom and patient data and compare the results with those using the first order linear Born method. Phantom experiments demonstrate that the non-linear Born method provides more accurate target absorption reconstruction and better resolution than the linear Born method. Clinical studies on 20 patients show that non-linear Born reconstructs more realistic tumor shapes than linear Born, and improves the malignant-to-benign lesion contrast ratio from [Formula: see text] to [Formula: see text] , which is a [Formula: see text] improvement. For lesions approximately more than [Formula: see text] cm in diameter, the average malignant-to-benign lesion contrast ratio is increased from [Formula: see text] to [Formula: see text] , which is a [Formula: see text] improvement.

We report in this pilot study the diagnostic results of in vivo imaging of patients with ovarian lesions, using a co-registered photoacoustic and ultrasound (PAT/US) system. A total of 39 ovaries from 24 patients were imaged in vivo. PAT functional features, i.e., blood oxygen saturation (sO2) and relative total hemoglobin (rHbT), PAT image features, and PAT spectral features within a region of interest (ROI) in each ovarian tissue were extracted. To select the significant features, a t-test on each feature was performed, and the independent predictors were determined by evaluating correlation between each pair of predictors. To classify the ovarian lesions, we employed a generalized linear model (GLM) and a support vector machine (SVM). We used these classifiers first to distinguish benign/normal lesions from ovaries with invasive epithelial tumors and then to separate normal/benign lesions from all types of ovarian tumors. We developed classifiers once by inclusion of PAT functional features to assess the best diagnostic performance of the classifiers when multiple wavelengths data are available. Second time, we excluded the PAT functional features from the features set to evaluate the best diagnostic performance if only a single wavelength is available. Our results show that using functional features improves the classification performance, especially for distinguishing normal/benign ovarian lesions from all types of tumors. In this case, an area under ROC curve (AUC) of 0.92, 0.93 of testing data was achieved using a GLM and SVM classifier when functional features were included in the feature set while excluding these features resulted in an AUC of 0.89, 0.92, respectively.

Purpose: In previous studies, the utilization of ultrasound guided near infrared diffused light imaging (US-NIR) has shown great potential in predicting and monitoring the pathologic tumor response to neoadjuvant chemotherapy (NAC). The purpose of the current study is to develop a prediction model utilizing pretreatment tumor hemoglobin content measured by US-NIR in conjunction with standard pathologic tumor characteristics to predict pathologic response even before NAC is given. Utilizing a multiple logistic regression model, the sensitivity, specificity, positive and negative predictive values (PPV and NPV), and the area under the receiver operating characteristic curve (AUC) are determined for the models. Materials and Methods: 34 patients’ data were retrospectively analyzed using a multiple logistic regression model to predict response. These patients were split into a training group (23 patients of 24 tumors) and testing group (11 patients of 12 tumors). Tumor vascularity was assessed pre-NAC using US-NIR and measurements of total hemoglobin (tHb), oxygenated (oxyHb), and deoxygenated hemoglobin concentrations (deoxyHb) as well as tumor reduced scatter coefficients acquired before treatment. Tumor pathologic variables including the estrogen (ER) and progesterone (PR) receptors, human epidermal growth factor receptor 2 (HER2) and Nottingham score (mitotic index and grade) were acquired before NAC in biopsy specimens and were also used in the prediction model. The patients’ pathologic response was graded based on the Miller-Payne system as non- and partial-responders (grades 1-3) and near-complete and complete responders (grades 4-5). Results: Utilizing initial tumor pathologic characteristics (grade and receptor status) a sensitivity of 100%, specificity of 73.3%, PPV and NPV of 69.5% and 100%, and AUC of 0.83(95% CI: 0.637-963) were obtained from training data. When pretreatment hemoglobin parameters and reduced scatter coefficients were included as additional predictors in training data, sensitivity, specificity, PPV and NPV improved to 100% and AUC of 1.0 (95% CI: 1.0-1.0). The performance of the predictive models were validated on testing data and corresponding values were 100%, 66.7%, 75.0% and 100%, and AUC of 0.83 (CI: 0.56-1.0) when tumor pathologic parameters alone were used as predictors. While the corresponding values were 100% and AUC of 1.0 (CI: 1.0-1.0) when hemoglobin and reduced scatter parameters were added as predictors. Discussion: These initial findings indicate that combining widely used tumor pathologic variables with hemoglobin and optical scatter functional parameters determined by NIR provides a powerful tool for predicting patient response to preoperative chemotherapy before the initiation of the treatment. With the current trend to treat in the neoadjuvant setting, such a tool will be invaluable for response assessment. Plans are underway to validate this model in larger patient settings and its applicability to non-chemotherapeutic regimens. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-41.

We have prepared a series of indocyanine green dicarboxylic acid derivatives ( 9a,b, 4, 10, 13 ) with modified polyene linkers in an attempt to increase the structural rigidity of the polyene linker and thereby the fluorescent yield. Incorporation of five- and six-membered rings into the polyene system led to lower florescent yield for 9a,b, 4 and 10 , but shortening the chain by two carbon atoms led to an increase in fluorescent yield for 13 .

Most ovarian cancers are diagnosed at advanced stages due to the lack of efficacious screening techniques. Photoacoustic tomography (PAT) has a potential to image tumor angiogenesis and detect early neovascular changes of the ovary. We have developed a coregistered PAT and ultrasound (US) prototype system for real-time assessment of ovarian masses. Features extracted from PAT and US angular beams, envelopes, and images were input to a logistic classifier and a support vector machine (SVM) classifier to diagnose ovaries as benign or malignant. A total of 25 excised ovaries of 15 patients were studied and the logistic and SVM classifiers achieved sensitivities of 70.4 and 87.7%, and specificities of 95.6 and 97.9%, respectively. Furthermore, the ovaries of two patients were noninvasively imaged using the PAT/US system before surgical excision. By using five significant features and the logistic classifier, 12 out of 14 images (86% sensitivity) from a malignant ovarian mass and all 17 images (100% specificity) from a benign mass were accurately classified; the SVM correctly classified 10 out of 14 malignant images (71% sensitivity) and all 17 benign images (100% specificity). These initial results demonstrate the clinical potential of the PAT/US technique for ovarian cancer diagnosis.

We present a laser diode-based photoacoustic microscopy (PAM) system with a minimized light intensity loss for ovarian tissue imaging. A 905 nm, 650 W output peak power pulsed laser diode (PLD) is utilized as the light source. The intrinsic properties and the construction of this PLD typically make it challenging to focus its beam to a small spot size with a lowloss optical system. An optical system comprising a combination of aspheric and cylindrical lenses is presented that allows a low-loss collimation and tight focusing of the light beam. The lateral resolution of this PAM system is measured to be 40 μm using edge spread function estimation. Images of black human hairs, polyethylene tubes filled with rat blood, ex vivo mouse ear and ex vivo porcine ovary are presented.

This paper reports a method of estimating an approximate closed-form solution to the light diffusion equation for any type of geometry involving Dirichlet's boundary condition with known source location. It is based on estimating the optimum locations of multiple imaginary point sources to cancel the fluence at the extrapolated boundary by constrained optimization using a genetic algorithm. The mathematical derivation of the problem to approach the optimum solution for the direct-current type of diffuse optical systems is described in detail. Our method is first applied to slab geometry and compared with a truncated series solution. After that, it is applied to hemispherical geometry and compared with Monte Carlo simulation results. The method provides a fast and sufficiently accurate fluence distribution for optical reconstruction.

In this paper, a method of outlier removal and data selection for ultrasound-guided diffuse optical tomography is introduced. The algorithm uses multiple datasets to compose a single robust dataset based on statistical analysis.

We compared in vivo hypoxia targeting of 4-nitroimidazole-piperazine-indocyanine derivative (6) with imidazole- (5) and 2-nitroimidazole-indocyanine dye-conjugate (4). Results showed 1.5-fold and 2.5-fold intensity ratio between each pair. This is also supported by cell and immunohistochemistry results.

A spatial frequency domain imaging was used to characterize tissue absorption, scattering and spatial heterogeneity. Six features were extracted from SFDI absorption and scattering images. A sensitivity of 95% and specificity of 100% was obtained.

Diffuse Optical Tomography reconstruction is divided into coarse mesh for background region and finer mesh for target region using NIRFAST. The results show the spatial resolution of the reconstructed images and target shape are improved.

The total and oxygenated-hemoglobin concentrations measured by Ultrasound-guided diffuse optical tomography can be used as an adjunct to Ultrasound to improve sensitivity to 96.5-100% and negative predictive value to 100% in breast cancer diagnosis.

An advanced ultrasound segmentation algorithm is presented here that extracts breast lesion information for co-registered diffused optical tomography and inputs these parameters to improve reconstruction of lesion absorption maps.

Background Neoadjuvant chemotherapy has been increasingly used in treating breast cancers. Because breast cancer is a heterogeneous disease, it is important to effectively monitor the tumor response to assist in tailoring treatments to response. In our early study, we have introduced a novel ultrasound (US)-guided diffused light imaging in the near infrared (NIR) spectrum to monitor tumor vascular changes which correlated to tumor response. The objectives of this study are: (a) to validate the initial findings with a larger patient pool, and (b) to assess vascular changes at every treatment cycle and to correlate early vascular changes with the tumor pathological response. Methods: 33 patients who underwent neoadjuvant treatment were recruited from Dec. 2007 to May 2011 and their tumor vascular content was assessed with a combined imager consisting of a commercial US system coupled to a NIR imager. Patients were imaged before their treatment, at the end of each treatment cycle and before their surgery. The co-registered US was used to localize the tumor and the NIR imager was used to map the tumor vascular distribution which was assessed based on a percentage total hemoglobin (%tHb) concentration normalized to the pre-treatment level. 18 patients were treated with AC followed by Taxol. This group of patients was monitored every two weeks at the end of each treatment. The remaining patients were on 3-week cycles of chemotherapy and monitored every 3 weeks. 6 patients were treated with TC without Adriamycin (TC), or with Adriamycin (TAC), 6 HER2 positive patients were treated with TC and Herceptin (TCH); and 3 patients were treated with AC/Bevacizumab. Pathologic response was graded based on Miller and Payne system as grade 1: non-responders (A); grades 2 and 3: partial responders (B); 4: near-complete and 5: complete responders (C). Results: In the AC/Taxol group (n=18), there were 5 responders (C), 9 partial (B) and 4 non-responders (A). The statistical significance based on %tHb between groups A and C was achieved at the end of cycle 5 and the rest of the treatment cycles (p Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-10-02.

We present an ultrasound (US)-guided diffuse optical tomography for mapping tumor deoxyhemoglobin (deoxyHb) and oxyhemoglobin (oxyHb) concentrations in blood phantoms and in in-vivo patients. Because oxyHb and deoxyHb respond differently at different wavelengths, four laser diodes of wavelengths 740 nm, 780 nm, 808 nm and 830 nm were used in the study. Tumor model experiments were performed using phantoms of different hemoglobin oxygen saturations (14%–89%) representing hemoglobin oxygenation in tissue. Targets of different sizes and located at different depths were used to validate the accuracy of oxygen saturation estimation. The absolute deviations between the estimated hemoglobin oxygen saturations obtained from reconstructed absorption maps and oxygen measurements obtained using a pO2 electrode were less than 8% over the measured range of oxygen saturation. An inhomogeneous concentric blood phantom of deoxygenated center core and oxygenated outer shell was imaged and deoxyHb and oxyHb maps revealed corresponding distributions which correlated well with inhomogeneous deoxy- and oxydistributions frequently seen in breast cancers. Clinical examples are given to demonstrate the utility of US-guided optical tomography in mapping heterogeneous deoxyHb and oxyHb distributions in breast cancers.

Ovarian cancer has the lowest survival rate of the gynecologic cancers because it is predominantly diagnosed in the late stages due to the lack of reliable symptoms and efficacious screening techniques. A novel hybrid intraoperative probe has been developed and evaluated for its potential role in detecting and characterizing ovarian tissue. The hybrid intraoperative dual-modality device consists of multiple scintillating fibers and an optical coherence tomography imaging probe for simultaneously mapping the local activities of (18)F-FDG uptake and imaging of local morphological changes of the ovary. Ten patients were recruited to the study and a total of 18 normal, abnormal and malignant ovaries were evaluated ex vivo using this device. Positron count rates of 7.5/8.8-fold higher were found between malignant and abnormal/normal ovaries. OCT imaging of malignant and abnormal ovaries revealed many detailed morphologic features that could be potentially valuable for evaluating local regions with high metabolic activities and detecting early malignant changes in the ovary. These initial results have demonstrated that our novel hybrid imager has great potential for ovarian cancer detection and characterization during minimally invasive endoscopic procedures.

We have successfully synthesized imidazole-dye conjugates by linking imidazole and nitroimidazoleacetic acids to an indocyanine green (ICG) carboxylic acid derivative, using an ethanolamine linker. These dye-conjugates show absorbance peaks at 754–756 nm and fluorescence peaks at 780 nm. The dye-conjugates show a blue shift of 25 nm and 30 nm in the absorption and fluorescence spectra respectively when compared to that of standard cardiogreen. There is no change in absorption and fluorescence spectral profiles between the ICG derivative and imidazole conjugates. The extinction coefficients of new ICG derivative and imidazole conjugates are 1.8 times higher than that of standard ICG. The relative quantum yields of the new compounds are 4.5–5.5 times higher than that of the Sigma–Aldrich’s ICG. The dyes are tested for hypoxia in-vitro with 4T1 luc cell lines and it is found that the cells treated with 2-nitroimidazole ICG show a contrast of fluorescence signal of 2.5–3.0 for the cells under hypoxic to that of cells under normoxic. However pure ICG shows no significant difference between hypoxic and normoxic cells.

Purpose: A new frequency-domain estimation algorithm has been developed that uses a priori information to simultaneously improve imaging quality and time resolution in photoacoustic tomography with incomplete data sets. Methods: The method involves application of a single-stage Wiener optimal filter to augment data sets by interpolation between measurement locations using relationships determined in a reference scan. The filter can be applied in real-time using FFT methods using either fixed or dynamic references and used with any imaging algorithm. The performance of the method is compared to a modified version of constrained backprojection algorithms using simulations and experimental investigations. Results: Simulations demonstrate the effectiveness of the approach for tracking dynamic photoacoustic activity for data sets with limited views (90°) or tomographic views with a reduced number of acquisition angles at any given time (≤32). Experimental data of contrast uptake and washout using a 512-element curved transducer with 8:1 electronic multiplexing with the algorithm demonstrate full two-dimensional tomographic imaging with a temporal resolution better than 130 ms. Conclusions: The estimation algorithm enables high spatial resolution, real-time imaging of dynamic physiological events or volumetric regions for photoacoustic systems employing multiplexing or scanning.

Currently, there is no adequate technology to detect early stage ovarian cancers. Most of the cancers in the ovary are detected when the cancer has already metastasized to other parts of the body. As a result, ovarian cancer has the highest mortality of all gynecologic cancers with a 5-year survival rate of 30% or less. Thus, there is an urgent need to improve the current diagnostic techniques. Photoacoustic imaging (PAI) is an emerging modality with a great potential to assist ultrasound for detecting ovarian cancer noninvasively. In this article, we report the first study of coregistered ultrasound and PAI of 33 ex vivo human ovaries. An assessment of the photoacoustic images has revealed light absorption distribution in the ovary, which is directly related to the vasculature distribution and amount. Quantification of the light absorption levels in the ovary has indicated that, in the postmenopausal group, malignant ovaries showed significantly higher light absorption than normal ones (P = .0237). For these two groups, we have obtained a sensitivity of 83% and a specificity of 83%. This result suggests that PAI is a promising modality for improving ultrasound diagnosis of ovarian cancer.

We showed that intrinsic angiogenesis (total hemoglobin concentration) contrast holds promise as an adjunct to diagnostic mammography and US for distinguishing early-stage invasive breast cancers from benign lesions.

About 85-90% of all ovarian cancers are carcinomas; these manifest clinically as mass-forming epithelial proliferations involving the ovary. In this study, a visible light spatial frequency domain imaging (SFDI) system was used for multispectral ex vivo imaging and quantitative evaluation of freshly excised benign and malignant human ovarian tissues. A total of 14 ovaries from 11 patients undergoing oophorectomy were investigated. Using a logistic regression model with seven significant spectral and spatial features extracted from SFDI images, a sensitivity of 94.06% and specificity of 93.53% were achieved for prediction of histologically confirmed invasive carcinoma.

The ultrasound-guided diffuse optical tomography is a noninvasive imaging technique for breast cancer diagnosis and treatment monitoring. The technique uses a handheld probe capable of providing measurements of multiple wavelengths in a few seconds. These measurements are used to estimate optical absorptions of lesions and calculate the total hemoglobin concentration. Any measurement errors caused by low signal to noise ratio data and/or movements during data acquisition would reduce the accuracy of reconstructed total hemoglobin concentration. In this article, we introduce an automated preprocessing method that combines data collected from multiple sets of lesion measurements of 4 optical wavelengths to detect and correct outliers in the perturbation. Two new measures of correlation between each pair of wavelength measurements and a wavelength consistency index of all reconstructed absorption maps are introduced. For phantom and patients’ data without evidence of measurement errors, the correlation coefficient between each pair of wavelength measurements was above 0.6. However, for patients with measurement errors, the correlation coefficient was much lower. After applying the correction method to 18 patients’ data with measurement errors, the correlation has improved and the wavelength consistency index is in the same range as the cases without wavelength-dependent measurement errors. The results show an improvement in classification of malignant and benign lesions.

Diffuse optical tomography (DOT) has demonstrated huge potential in breast cancer diagnosis and treatment monitoring. DOT image reconstruction guided by ultrasound (US) improves the diffused light localization and lesion reconstruction accuracy. However, DOT reconstruction depends on tumor geometry provided by coregistered US. Experienced operators can manually measure these lesion parameters; however, training and measurement time are needed. The wide clinical use of this technique depends on its robustness and faster imaging reconstruction capability. This article introduces a semiautomated procedure that automatically extracts lesion information from US images and incorporates it into the optical reconstruction. An adaptive threshold-based image segmentation is used to obtain tumor boundaries. For some US images, posterior shadow can extend to the chest wall and make the detection of deeper lesion boundary difficult. This problem can be solved using a Hough transform. The proposed procedure was validated from data of 20 patients. Optical reconstruction results using the proposed procedure were compared with those reconstructed using extracted tumor information from an experienced user. Mean optical absorption obtained from manual measurement was 0.21±0.06 cm−1 for malignant and 0.12±0.06 cm−1 for benign cases, whereas for the proposed method it was 0.24±0.08 cm−1 and 0.12±0.05 cm−1, respectively.

Due to the correlated nature of diffused light, the problem of reconstructing optical properties using diffuse optical tomography (DOT) is ill-posed. US-, MRI- or x-ray-guided DOT approaches can reduce the total number of parameters to be estimated and improve optical reconstruction accuracy. However, when the target volume is large, the number of parameters to estimate can exceed the number of measurements, resulting in an underdetermined imaging model. In such cases, accurate image reconstruction is difficult and regularization methods should be employed to obtain a useful solution. In this manuscript, a simple two-step reconstruction method that can produce useful image estimates in DOT is proposed and investigated. In the first step, a truncated Moore-Penrose Pseudoinverse solution is computed to obtain a preliminary estimate of the image that can be reliably determined from the measured data; subsequently, this preliminary estimate is incorporated into the design of a penalized least squares estimator that is employed to compute the final image estimate. By use of phantom data, the proposed method was demonstrated to yield more accurate images than those produced by conventional reconstruction methods. The method was also evaluated with clinical data that included 10 benign and 10 malignant cases. The capability of reconstructing high contrast malignant lesions was demonstrated to be improved by use of the proposed method.

The purposes of this study were 1) to investigate the feasibility of using optical tomography in the near-infrared (NIR) spectrum combined with ultrasound (US) localization (NIR/US) in monitoring tumor vascular changes and assessing tumor pathological response during chemotherapy and 2) to compare the accuracy of NIR/US with magnetic resonance imaging (MRI) in predicting residual cancer after neoadjuvant chemotherapy. Eleven female patients were studied during treatments with a combined imager consisting of a commercially available US system coupled to an NIR imager. Contrast-enhanced MRI was performed before treatment and surgery. Tumor vascular content was assessed based on total hemoglobin concentration and volume obtained from NIR data. A percentage blood volume index (%BVI) was calculated as the percentage ratio of the product of total hemoglobin concentration and volume normalized to pretreatment values. At treatment completion, pathologic assessment revealed three response groups: complete or near-complete responders (A), partial responders (B), and nonresponders (C). The mean %BVIs of groups A, B, and C at the treatment completion were 29.1 ± 6.9%, 46.3 ± 3.7%, and 86.8 ± 30.1%, respectively (differences statistically significant, P < .04). At the end of cycle 2, the %BVI of group A was noticeably lower than that of the partial (P = .091) and nonresponder groups (P = .075). Both NIR/US and MRI were equally effective in distinguishing different response groups in this pilot study. Our initial findings indicate that NIR/US using %BVI can be used during chemotherapy to repeatedly monitor tumor vascular changes. NIR/US also may evaluate pathologic response during treatment allowing for tailoring therapies to response.

Optical tomography with ultrasound (US) localization uses coregistered ultrasound images to guide optical imaging reconstruction. To simultaneously acquire US images and optical measurements, the authors used a hand-held probe consisting of a commercial US transducer and near-infrared optical imaging sensors of multiple wavelengths. A novel image scheme was used to map the ultrasound-visible lesions for optical imaging reconstruction. As a result, the problem of intense light scattering caused by breast tissue was overcome and reliable tumor hemoglobin concentration and blood oxygen saturation distributions from a group of patients were obtained. These functional parameters are valuable for aiding US diagnosis and for assessing chemotherapy response.

A spatial frequency domain imaging (SFDI) system was developed for characterizing ex vivo human ovarian tissue using wide-field absorption and scattering properties and their spatial heterogeneities. Based on the observed differences between absorption and scattering images of different ovarian tissue groups, six parameters were quantitatively extracted. These are the mean absorption and scattering, spatial heterogeneities of both absorption and scattering maps measured by a standard deviation, and a fitting error of a Gaussian model fitted to normalized mean Radon transform of the absorption and scattering maps. A logistic regression model was used for classification of malignant and normal ovarian tissues. A sensitivity of 95%, specificity of 100%, and area under the curve of 0.98 were obtained using six parameters extracted from the SFDI images. The preliminary results demonstrate the diagnostic potential of the SFDI method for quantitative characterization of wide-field optical properties and the spatial distribution heterogeneity of human ovarian tissue. SFDI could be an extremely robust and valuable tool for evaluation of the ovary and detection of neoplastic changes of ovarian cancer.