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Photoacoustic microscopy offers functional information regarding tissue vasculature while ultrasound characterizes tissue structure. Combining these two modalities provides novel clinical applications including response assessment among rectal cancer patients undergoing therapy. We have previously demonstrated the capabilities of a co-registered photoacoustic and ultrasound device in vivo, but multiple challenges limited broad adoption. In this paper, we report significant improvements in an acoustic resolution photoacoustic microscopy and ultrasound (ARPAM/US) system characterized by simulation and phantom study, focusing on resolution, optical coupling, and signal characteristics. In turn, higher in-probe optical coupling efficiency, higher signal-to-noise ratio, higher data throughput, and better stability with minimal maintenance requirements were all accomplished. We applied the system to 19 ex vivo resected colorectal cancer samples and found significantly different signals between normal, cancer, and post-treatment tumor tissues. Finally, we report initial results of the first in vivo imaging study.

Abstract The heterogeneity in the pathological and clinical manifestations of ovarian cancer is a major hurdle impeding early and accurate diagnosis. A host of imaging modalities, including Doppler ultrasound, MRI, and CT, have been investigated to improve the assessment of ovarian lesions. We hypothesized that pathologic conditions might affect the ovarian vasculature and that these changes might be detectable by optical-resolution photoacoustic microscopy (OR-PAM). In our previous work, we developed a benchtop OR-PAM and demonstrated it on a limited set of ovarian and fallopian tube specimens. In this study, we collected data from over 50 patients, supporting a more robust statistical analysis. We then developed an efficient custom analysis pipeline for characterizing the vascular features of the samples, including the mean vessel diameter, vascular density, global vascular directionality, local vascular definition, and local vascular tortuosity/branchedness. Phantom studies using carbon fibers showed that our algorithm was accurate within an acceptable error range. Between normal ovaries and normal fallopian tubes, we observed significant differences in five of six extracted vascular features. Further, we showed that distinct subsets of vascular features could distinguish normal ovaries from cystic, fibrous, and malignant ovarian lesions. In addition, a statistically significant difference was found in the mean vascular tortuosity/branchedness values of normal and abnormal tubes. The findings support the proposition that OR-PAM can help distinguish the severity of tubal and ovarian pathologies.

Quantitative photoacoustic tomography (QPAT) is a valuable tool in characterizing ovarian lesions for accurate diagnosis. However, accurately reconstructing a lesion’s optical absorption distributions from photoacoustic signals measured with multiple wavelengths is challenging because it involves an ill-posed inverse problem with three unknowns: the Grüneisen parameter (Γ), the absorption distribution, and the optical fluence (ϕ). Here, we propose a novel ultrasound-enhanced Unet model (US-Unet) that reconstructs optical absorption distribution from PAT data. A pre-trained ResNet-18 extracts the US features typically identified as morphologies of suspicious ovarian lesions, and a Unet is implemented to reconstruct optical absorption coefficient maps, using the initial pressure and US features extracted by ResNet-18. To test this US-Unet model, we calculated the blood oxygenation saturation values and total hemoglobin concentrations from 655 regions of interest (ROIs) (421 benign, 200 malignant, and 34 borderline ROIs) obtained from clinical images of 35 patients with ovarian/adnexal lesions. A logistic regression model was used to compute the ROC, the area under the ROC curve (AUC) was 0.94, and the accuracy was 0.89. To the best of our knowledge, this is the first study to reconstruct quantitative PAT with PA signals and US-based structural features.

We have developed a novel photoacoustic microscopy/ultrasound (PAM/US) endoscope to image post-treatment rectal cancer for surgical management of residual tumor after radiation and chemotherapy. Paired with a deep-learning convolutional neural network (CNN), the PAM images accurately differentiated pathological complete responders (pCR) from incomplete responders. However, the role of CNNs compared with traditional histogram-feature based classifiers needs further exploration. In this work, we compare the performance of the CNN models to generalized linear models (GLM) across 24 ex vivo specimens and 10 in vivo patient examinations. First order statistical features were extracted from histograms of PAM and US images to train, validate and test GLM models, while PAM and US images were directly used to train, validate, and test CNN models. The PAM-CNN model performed superiorly with an AUC of 0.96 (95% CI: 0.95-0.98) compared to the best PAM-GLM model using kurtosis with an AUC of 0.82 (95% CI: 0.82-0.83). We also found that both CNN and GLMs derived from photoacoustic data outperformed those utilizing ultrasound alone. We conclude that deep-learning neural networks paired with photoacoustic images is the optimal analysis framework for determining presence of residual cancer in the treated human rectum.

Benefitting from advantages of optical and ultrasound imaging, photoacoustic imaging (PAI) has demonstrated potentials in a wide range of medical applications. In order to facilitate clinical applications of PAI and encourage its application in low-resource settings, research on low-cost photoacoustic imaging with inexpensive optical sources has gained attention. Here, we review the advances made in photoacoustic imaging with low-cost sources. Keywords: Photoacoustic imaging, Low-cost, Laser diode, Light emitting diode, Medical imaging

An optimized hand-held photoacoustic and ultrasound probe suitable for endo-cavity tumor subsurface imaging was designed and evaluated. Compared to previous designs, the prototype probe, consisting of four 1 mm multi-mode optical fibers attached with 1.5 mm diameter ball-shaped fiber tips sandwiched between a transvaginal ultrasound transducer and a custom-made sheath, demonstrated a higher light output and better beam homogeneity on tissue subsurface. The output power and fluence profile were simulated for different design parameters. A camera recorded fluence profiles through calibrated intralipid solution at various imaging depths. The light delivery efficiency was experimentally compared with and without the ball lenses, based on ex-vivo imaging of human colorectal cancer and in-vivo imaging of a palmar vein proximal to the human wrist. The simulations and experiments demonstrated that ball-shaped fiber tip design can achieve homogeneous fluence distribution on tissue subsurface with acceptable light output efficiency, suggesting its clinical potential for in-vivo endo-cavity imaging. Keywords: Photoacoustic imaging, Optimized light delivery probe, Ball-shaped fiber tip, Adenocarcinoma

Abstract Background Breast cancer pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) varies with tumor subtype. The purpose of this study was to identify an early treatment window for predicting pCR based on tumor subtype, pretreatment total hemoglobin (tHb) level, and early changes in tHb following NAC. Methods Twenty-two patients (mean age 56 years, range 34–74 years) were assessed using a near-infrared imager coupled with an Ultrasound system prior to treatment, 7 days after the first treatment, at the end of each of the first three cycles, and before their definitive surgery. Pathologic responses were dichotomized by the Miller-Payne system. Tumor vascularity was assessed from tHb; vascularity changes during NAC were assessed from a percentage tHb normalized to the pretreatment level (%tHb). After training the logistic prediction models using the previous study data, we assessed the early treatment window for predicting pathological response according to their tumor subtype (human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), triple-negative (TN)) based on tHb, and %tHb measured at different cycles and evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). Results In the new study cohort, maximum pretreatment tHb and %tHb changes after cycles 1, 2, and 3 were significantly higher in responder Miller-Payne 4–5 tumors (n = 13) than non-or partial responder Miller-Payne 1–3 tumors (n = 9). However, no significance was found at day 7. The AUC of the predictive power of pretreatment tHb in the cohort was 0.75, which was similar to the performance of the HER2 subtype as a single predictor (AUC of 0.78). A greater predictive power of pretreatment tHb was found within each subtype, with AUCs of 0.88, 0.69, and 0.72, in the HER2, ER, and TN subtypes, respectively. Using pretreatment tHb and cycle 1 %tHb, AUC reached 0.96, 0.91, and 0.90 in HER2, ER, and TN subtypes, respectively, and 0.95 regardless of subtype. Additional cycle 2 %tHb measurements moderately improved prediction for the HER2 subtype but did not improve prediction for the ER and TN subtypes. Conclusions By combining tumor subtypes with tHb, we predicted the pCR of breast cancer to NAC before treatment. Prediction accuracy can be significantly improved by incorporating cycle 1 and 2 %tHb for the HER2 subtype and cycle 1 %tHb for the ER and TN subtypes. Trial registration ClinicalTrials.gov, NCT02092636. Registered in March 2014.

The development of low-cost and fast photoacoustic microscopy systems enhances the clinical applicability of photoacoustic imaging systems. To this end, we present a laser scanning laser diode-based photoacoustic microscopy system. In this system, a 905 nm, 325 W maximum output peak power pulsed laser diode with 50 ns pulsewidth is utilized as the light source. A combination of aspheric and cylindrical lenses is used for collimation of the laser diode beam. Two galvanometer scanning mirrors steer the beam across a focusing aspheric lens. The lateral resolution of the system was measured to be ∼21 μm using edge spread function estimation. No averaging was performed during data acquisition. The imaging speed is ∼370 A-lines per second. Photoacoustic microscopy images of human hairs, ex vivo mouse ear, and ex vivo porcine ovary are presented to demonstrate the feasibility and potentials of the proposed system. Keywords: Photoacoustic imaging, Diode lasers, Medical imaging, Biological imaging, Low-cost sources

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/cm2, which is below the maximum permissible exposure (MPE) of 25 mJ/cm2 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.

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.

PURPOSE: Angiogenesis in advanced breast cancers is highly distorted and heterogeneous. Noninvasive imaging that can monitor angiogenesis may be invaluable initially for diagnosis and then for assessing tumor response to treatment. By combining ultrasound (US) and near-infrared (NIR) optical imaging, a reliable new technique has emerged for localizing and characterizing tumor angiogenesis within the breast. METHODS: This new technique employs a commercial US transducer coupled with an array of NIR optical fibers mounted on a hand-held probe. The US image is used for lesion localization and for guiding optical imaging reconstruction. Optical sensors are used for imaging tumor total hemoglobin distribution, which is directly related to tumor angiogenesis. RESULTS: Six large breast carcinomas were studied and microvessel density count was then performed on tissue samples obtained from these cancers. Two patients had locally advanced breast cancers and received neoadjuvant chemotherapy for 3 months. In one patient, before chemotherapy, the total hemoglobin distribution showed a high concentration at the cancer periphery; the distribution was later confined to the core area after 3 months of treatment. In another patient, as treatment progressed, the maximum hemoglobin concentration decreased from 255.3, to 147.5, to 76.9 wmol/I with an associated reduction in spatial extension. The other four patients had cancers of 2.0 to 3.0 cm in size and were imaged either at the time of core biopsy or definitive surgery. The histologic microvessel density counts from these tumor samples correlate to hemoglobin distributions with a correlation coefficient of 0.64 (P < .05). CONCLUSION: These initial results suggest that this new imaging technique may have great potential in imaging the heterogeneous vascular distribution of larger breast cancers in vivo and in monitoring treatment-related changes in angiogenesis during chemotherapy.

The diagnosis of solid benign and malignant tumors presents a unique challenge to all noninvasive imaging modalities. Ultrasound is used in conjunction with mammography to differentiate simple cysts from solid lesions. However, the overlapping appearances of benign and malignant lesions make ultrasound less useful in differentiating solid lesions, resulting in a large number of benign biopsies. Optical tomography using near-infrared diffused light has great potential for imaging functional parameters of 1) tumor hemoglobin concentration, 2) oxygen saturation, 3) metabolism, as well as other tumor distinguishing characteristics. These parameters can differentiate benign from malignant lesions. However, optical tomography, when used alone, suffers from low spatial resolution and target localization uncertainty due to intensive light scattering. Our aim is to combine diffused light imaging with ultrasound in a novel way for the detection and diagnosis of solid lesions. Initial findings of two earlystage invasive carcinomas, one combined fibroadenoma and fibrocystic change with scattered foci of lobular neoplasia/lobular carcinoma in situ, 16 benign lesions are reported in this paper. The invasive cancer cases reveal about two-fold greater total hemoglobin concentration (mean 119 μmol) than benign cases (mean 67 μmol), suggest that the discrimination of benign and malignant breast lesions might be enhanced by this type of achievable optical quantification with ultrasound localization. Furthermore, the small invasive cancers are well localized and have wavelength-dependent appearance in optical absorption maps, whereas the benign lesions appear diffused and relatively wavelength-independent.

Colorectal cancer is the second most common malignancy diagnosed globally. Critical gaps exist in diagnostic and surveillance imaging modalities for colorectal neoplasia. Although prior studies have demonstrated the capability of photoacoustic imaging techniques to differentiate normal from neoplastic tissue in the gastrointestinal tract, evaluation of deep tissue with a fast speed and a large field of view remains limited. To investigate the ability of photoacoustic technology to image deeper tissue, we conducted a pilot study using a real-time co-registered photoacoustic tomography (PAT) and ultrasound (US) system. A total of 23 ex vivo human colorectal tissue samples were imaged immediately after surgical resection. Co-registered photoacoustic images of malignancies showed significantly increased PAT signal compared to normal regions of the same sample. The quantitative relative total hemoglobin (rHbT) concentration computed from four optical wavelengths, the spectral features, such as the mean spectral slope, and 0.5-MHz intercept extracted from PAT and US spectral data, and image features, such as the first- and second-order statistics along with the standard deviation of the mean radon transform of PAT images, have shown statistical significance between untreated colorectal tumors and the normal tissue. Using either a logistic regression model or a support vector machine, the best set of parameters of rHbT and PAT intercept has achieved area-under-the-curve (AUC) values of 0.97 and 0.95 for both training and testing data sets, respectively, for prediction of histologically confirmed invasive carcinoma. [ABSTRACT FROM AUTHOR]

A mathematical model is proposed and compared to the experimental observations to understand the modulation mechanisms of fluorescence emission induced by ultrasonic waves in turbid media. The results indicated that the fluorescence modulation efficiency could be significantly improved by using microbubbles with a lipid shell.

Ultrasound (US) guided diffuse optical tomography has demonstrated great potential for breast cancer diagnosis, treatment monitoring, and chemotherapy response prediction. Optical measurements of four different wavelengths are used to reconstruct unknown optical absorption maps, which are then used to calculate the hemoglobin concentration distribution of the US visible lesion. Reconstructed absorption maps are prone to image artifacts from outliers in measurement data from tissue heterogeneity, bad coupling between tissue and light guides, and motion by patient or operator. We propose an automated iterative perturbation correction algorithm to reduce image artifacts based on the structural similarity index (SSIM) of absorption maps of four optical wavelengths. The initial image is estimated from the truncated pseudoinverse solution. The SSIM was calculated for each wavelength to assess its similarity with other wavelengths. An absorption map is repeatedly reconstructed and projected back into measurement space to quantify projection error. Outlier measurements with highest projection errors are iteratively removed until all wavelength images are structurally similar with SSIM values greater than a threshold. Clinical data demonstrate statistically significant improvement in image artifact reduction. [ABSTRACT FROM AUTHOR]

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 in 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 this study, we introduce our recently developed ultrasound-guided DOT system, which has been improved in system compactness, robustness, and user-friendliness by custom-designed electronics, automated data preprocessing, and implementation of a new two-step reconstruction algorithm. The system performance has been tested with several sets of solid and blood phantoms and the results show accuracy in reconstructed absorption coefficients as well as blood oxygen saturation. A clinical example of a breast cancer patient, who was undergoing neoadjuvant chemotherapy, is given to demonstrate the system performance. [ABSTRACT FROM AUTHOR]

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 thresholdbased 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 0.1 ± 0.05 cm−1, respectively. [ABSTRACT FROM AUTHOR]

We have developed the ultrasound (US)-guided diffuse optical tomography technique to assist US diagnosis of breast cancer and to predict neoadjuvant chemotherapy response of patients with breast cancer. The technique was implemented using a hand-held hybrid probe consisting of a coregistered US transducer and optical source and detector fibers which couple the light illumination from laser diodes and photon detection to the photomultiplier tube detectors. With the US guidance, diffused light measurements were made at the breast lesion site and the normal contralateral reference site which was used to estimate the background tissue optical properties for imaging reconstruction. However, background optical properties were affected by the chest wall underneath the breast tissue. We have analyzed data from 297 female patients, and results have shown statistically significant correlation between the fitted optical properties (μa and μs') and the chest wall depth. After subtracting the background μa at each wavelength, the difference of computed total hemoglobin (tHb) between malignant and benign lesion groups has improved. For early stage malignant lesions, the area-under-the- receiver operator characteristic curve (AUC) has improved from 88.5% to 91.5%. For all malignant lesions, the AUC has improved from 85.3% to 88.1%. Statistical test has revealed the significant difference of the AUC improvements after subtracting background tHb values. [ABSTRACT FROM AUTHOR]

Ultrasound-guided diffuse optical tomography (DOT) is a promising imaging technique that maps hemoglobin concentrations of breast lesions to assist ultrasound (US) for cancer diagnosis and treatment monitoring. The accurate recovery of breast lesion optical properties requires an effective image reconstruction method. We introduce a reconstruction approach in which US images are encoded as prior information for regularization of the inversion matrix. The framework of this approach is based on image reconstruction package "NIRFAST." We compare this approach to the US-guided dual-zone mesh reconstruction method, which is based on Born approximation and conjugate gradient optimization developed in our laboratory. Results were evaluated using phantoms and clinical data. This method improves classification of malignant and benign lesions by increasing malignant to benign lesion absorption contrast. The results also show improvements in reconstructed lesion shapes and the spatial distribution of absorption maps. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Support vector machine (SVM) is one of the most effective classification methods for cancer detection. The efficiency and quality of a SVM classifier depends strongly on several important features and a set of proper parameters. Here, a series of classification analyses, with one set of photoacoustic data from ovarian tissues ex vivo and a widely used breast cancer dataset- the Wisconsin Diagnostic Breast Cancer (WDBC), revealed the different accuracy of a SVM classification in terms of the number of features used and the parameters selected. A pattern recognition system is proposed by means of SVM-Recursive Feature Elimination (RFE) with the Radial Basis Function (RBF) kernel. To improve the effectiveness and robustness of the system, an optimized tuning ensemble algorithm called as SVM-RFE(C) with correlation filter was implemented to quantify feature and parameter information based on cross validation. The proposed algorithm is first demonstrated outperforming SVM-RFE on WDBC. Then the best accuracy of 94.643% and sensitivity of 94.595% were achieved when using SVM-RFE(C) to test 57 new PAT data from 19 patients. The experiment results show that the classifier constructed with SVM-RFE(C) algorithm is able to learn additional information from new data and has significant potential in ovarian cancer diagnosis. [ABSTRACT FROM AUTHOR]

A new two-step estimation and imaging method is developed for a two-layer breast tissue structure consisting of a breast tissue layer and a chest wall underneath. First, a smaller probe with shorter distance source-detector pairs was used to collect the reflected light mainly from the breast tissue layer. Then, a larger probe with 9 x 14 source-detector pairs and a centrally located ultrasound transducer was used to collect reflected light from the two-layer tissue structure. The data collected from the smaller probe were used to esti- mate breast tissue optical properties. With more accurate estimation of the average breast tissue properties, the second layer properties can be assessed from data obtained from the larger probe. Using this approach, the unknown variables have been reduced from four to two and the estimated bulk tissue optical properties are more accurate and robust. In addition, a two-step reconstruction using a genetic algorithm and conjugate gradient method is implemented to simultaneously reconstruct the absorption and reduced scattering maps of targets inside a two-layer tissue structure. Simulations and phantom experiments have been performed to validate the new reconstruction method, and a clinical example is given to demonstrate the feasibility of this approach. [ABSTRACT FROM AUTHOR]

A composite set of ovarian tissue features extracted from photoacoustic spectral data, beam envelope, and co-registered ultrasound and photoacoustic images are used to characterize malignant and normal ovaries using logistic and support vector machine (SVM) classifiers. Normalized power spectra were calculated from the Fourier transform of the photoacoustic beamformed data, from which the spectral slopes and 0-MHz intercepts were extracted. Five features were extracted from the beam envelope and another 10 features were extracted from the photoacoustic images. These 17 features were ranked by their p-values from t -tests on which a filter type of feature selection method was used to determine the optimal feature number for final classification. A total of 169 samples from 19 ex vivo ovaries were randomly distributed into training and testing groups. Both classifiers achieved a minimum value of the mean misclassification error when the seven features with lowest p-values were selected. Using these seven features, the logistic and SVM classifiers obtained sensitivities of 96.39 ± 3.35% and 97.82 ± 2.26%, and specificities of 98.92 ± 1.39% and 100%, respectively, for the training group. For the testing group, logistic and SVM classifiers achieved sensitivities of 92.71 ± 3.55%and 92.64 ± 3.27%, and specificities of 87.52 ± 8.78% and 98.49 ± 2.05%, respectively. [ABSTRACT FROM AUTHOR]

Laser diodes are widely used in diffuse optical tomography (DOT) systems but are typically expensive and fragile, while light-emitting diodes (LEDs) are cheaper and are also available in the near-infrared (NIR) range with adequate output power for imaging deeply seated targets. In this study, we introduce a new low-cost DOT system using LEDs of four wavelengths in the NIR spectrum as light sources. The LEDs were modulated at 20 kHz to avoid ambient light. The LEDs were distributed on a hand-held probe and a printed circuit board was mounted at the back of the probe to separately provide switching and driving current to each LED. Ten optical fibers were used to couple the reflected light to 10 parallel photomultiplier tube detectors. A commercial ultrasound systemprovided simultaneous images of target location and size to guide the image reconstruction. A frequency-domain (FD) laser-diode-based system with ultrasound guidance was also used to compare the results obtained from those of the LED-based system. Results of absorbers embedded in intralipid and inhomogeneous tissue phantoms have demonstrated that the LED-based system provides a comparable quantification accuracy of targets to the FD system and has the potential to image deep targets such as breast lesions. [ABSTRACT FROM AUTHOR]

Introduction The purpose of this study is to develop a prediction model utilizing tumor hemoglobin parameters measured by ultrasound-guided near-infrared optical tomography (US-NIR), in conjunction with standard pathologic tumor characteristics to predict pathologic response before neoadjuvant chemotherapy (NAC) is given. Methods Thirty-four patients' data were retrospectively analyzed using a multiple logistic regression model to predict response. These patients were split into 30 groups of training (24 tumors) and testing (12 tumors) for cross validation. Tumor vascularity was assessed using US-NIR measurements of total hemoglobin (tHb), oxygenated and deoxygenated hemoglobin concentrations (oxyHb and deoxyHb) acquired before treatment. Tumor pathologic variables of tumor type, Nottingham score, mitotic index, the estrogen and progesterone receptors, and human epidermal growth factor receptor 2 acquired before NAC in biopsy specimens were also used in the prediction model. The patients'pathologic response was graded based on the Miller-Payne system. The overall performance of the prediction models was evaluated using Receiver Operating Characteristic (ROC) curves. The quantitative measures were sensitivity, specificity, positive and negative predictive values (PPV and NPV), and the area under the ROC curve (AUC). Results Utilizing tumor pathologic variables alone, an average sensitivity of 56.8%, specificity of 88.9%, PPV and NPV of 84.8% and 70.9%, and AUC of 84.0% were obtained from the testing data. Among the hemoglobin predictors with and without tumor pathological variables, the best predictor is tHb combined with tumor pathological variables followed by oxyHb with pathological variables. When tHb was included as an additional predictor to tumor pathological variables, the corresponding measures improved to 79%, 94%, 90%, 86%, and AUC 92.4%, respectively. When oxyHb was included as an additional predictor to tumor variables, these measures improved to 77%, 85%, 83%, 83%, and AUC 90.6%, respectively. The addition of tHb or oxyHb significantly improves the prediction sensitivity, NPV and AUC as compared with using tumor pathological variables alone. Conclusions These initial findings indicate that combining widely used tumor pathologic variables with hemoglobin parameters determined by US-NIR, may provide a powerful tool for predicting patient pathologic response to NAC before the initiation of the treatment. [ABSTRACT FROM AUTHOR]

Coregistered ultrasound (US) and photoacoustic imaging are emerging techniques for mapping the echogenic anatomical structure of tissue and its corresponding optical absorption. We report a 128-channel imaging system with real-time coregistration of the two modalities, which provides up to 15 coregistered frames per second limited by the laser pulse repetition rate. In addition, the system integrates a compact transvaginal imaging probe with a custom-designed fiber optic assembly for in vivo detection and characterization of human ovarian tissue. We present the coregistered US and photoacoustic imaging system structure, the optimal design of the PC interfacing software, and the reconfigurable field programmable gate array operation and optimization. Phantom experiments of system lateral resolution and axial sensitivity evaluation, examples of the real-time scanning of a tumor-bearing mouse, and ex vivo human ovaries studies are demonstrated. [ABSTRACT FROM AUTHOR]

To develop an indocyanine green (ICG) tracer with slower clearance kinetics, we explored ICG-encapsulating liposomes (Lip) in three different formulations: untargeted (Lip/ICG), targeted to vascular endothelial growth factor (VEGF) receptors (scVEGF-Lip/ICG) by the receptor-binding moiety single-chain VEGF (scVEGF), or decorated with inactivated scVEGF (inactive-Lip/ICG) that does not bind to VEGF receptors. Experiments were conducted with tumor-bearing mice that were placed in a scattering medium with tumors located at imaging depths of either 1.5 or 2.0 cm. Near-infrared fluorescence diffuse optical tomography that provides depth-resolved spatial distributions of fluorescence in tumor was used for the detection of postinjection fluorescent signals. All liposome-based tracers, as well as free ICG, were injected intravenously into mice in the amounts corresponding to 5 nmol of ICG/mouse, and the kinetics of increase and decrease of fluorescent signals in tumors were monitored. A signal from free ICG reached maximum at 15-min postinjection and then rapidly declined with t1/2 of ~20 min. The signals from untargeted Lip/ICG and inactive-Lip/ICG also reached maximum at 15-min postinjection, however, declined somewhat slower than free ICG with t1/2 of ~30 min. By contrast, a signal from targeted scVEGF-Lip/ICG grew slower than that of all other tracers, reaching maximum at 30-min postinjection and declined much slower than that of other tracers with t1/2 of ~90 min, providing a more extended observation window. Higher scVEGF-Lip/ICG tumor accumulation was further confirmed by the analysis of fluorescence on cryosections of tumors that were harvested from animals at 400 min after injection with different tracers. [ABSTRACT FROM AUTHOR]

To overcome the intensive light scattering in biological tissue, diffuse optical tomography (DOT) in the near-infrared range for breast lesion detection is usually combined with other imaging modalities, such as ultrasound, x-ray, and magnetic resonance imaging, to provide guidance. However, these guiding imaging modalities may depend on different contrast mechanisms compared to the optical contrast in the DOT. As a result, they cannot provide reliable guidance for DOT because some lesions may not be detectable by a nonoptical modality but may have a high optical contrast. An imaging modality that relies on optical contrast to provide guidance is desirable for DOT. We present a system that combines a frequency-domain DOT and real-time photoacoustic tomography (PAT) systems to detect and characterize deeply seated targets embedded in a turbid medium. To further improve the contrast, the exogenous contrast agent, indocyanine green (ICG), is used. Our experimental results show that the combined system can detect a tumor-mimicking phantom, which is immersed in intralipid solution with the concentrations ranging from 100 to 10 µM and with the dimensions of 0.8 cm x 0.8 cm x 0.6 cm, up to 2.5 cm in depth. Mice experiments also confirmed that the combined system can detect tumors and monitor the ICG uptake and washout in the tumor region. This method can potentially improve the accuracy to detect small breast lesions as well as lesions that are sensitive to background tissue changes, such as the lesions located just above the chest wall. [ABSTRACT FROM AUTHOR]

A photoacoustic contrast agent that is based on bis-carboxylic acid derivative of indocyanine green (ICG) covalently conjugated to single-wall carbon nanotubes (ICG/SWCNT) is presented. Covalently attaching ICG to the functionalized SWCNT provides a more robust system that delivers much more ICG to the tumor site. The detection sensitivity of the new contrast agent in a mouse tumor model is demonstrated in vivo by our custom-built photo-acoustic imaging system. The summation of the photoacoustic tomography (PAT) beam envelope, referred to as the "PAT summation," is used to demonstrate the postinjection light absorption of tumor areas in ICG- and ICG/ SWCNT-injected mice. It is shown that ICG is able to provide 33% enhancement at approximately 20 min peak response time with reference to the preinjection PAT level, while ICG/SWCNT provides 128% enhancement at 80 min and even higher enhancement of 196% at the end point of experiments (120 min on average). Additionally, the ICG/SWCNT enhancement was mainly observed at the tumor periphery, which was confirmed by fluorescence images of the tumor samples. This feature is highly valuable in guiding surgeons to assess tumor boundaries and dimensions in vivo and to achieve clean tumor margins to improve surgical resection of tumors. [ABSTRACT FROM AUTHOR]

Tumor hypoxia is a major indicator of treatment resistance to chemotherapeutic drugs, and fluorescence optical tomography has tremendous potential to provide clinically useful, functional information by identifying tumor hypoxia. The synthesis of a 2-nitroimidazole-indocyanine green conjugate using a piperazine linker (piperazine-2-nitroimidazole-ICG) capable of robust fluorescent imaging of tumor hypoxia is described. In vivo mouse tumor imaging studies were completed and demonstrate an improved imaging capability of the new dye relative to an earlier version of the dye that was synthesized with an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG). Mouse tumors located at imaging depths of 1.5 and 2.0 cm in a turbid medium were imaged at various time points after intravenous injection of the dyes. On average, the reconstructed maximum fluorescence concentration of the tumors injected with piperazine-2-nitroimidazole-ICG was two-fold higher than that injected with ethanolamine-2-nitroimidazole-ICG within 3 h post-injection period and 1.6 to 1.7 times higher beyond 3 h post-injection. The untargeted bis-carboxylic acid ICG completely washed out after 3 h post-injection. Thus, the optimal window to assess tumor hypoxia is beyond 3 h postinjection. These findings were supported with fluorescence images of histological sections of tumor samples and an immunohistochemistry technique for identifying tumor hypoxia. [ABSTRACT FROM AUTHOR]

In diffuse optical tomography (DOT), a typical perturbation approach requires two sets of measurements obtained at the lesion breast (lesion or target site) and a contra-lateral location of the normal breast (reference site) for image reconstruction. For patients who have a small amount of breast tissue, the chest-wall underneath the breast tissue at both sites affects the imaging results. In this group of patients, the perturbation, which is the difference between measurements obtained at the lesion and reference sites, may include the information of background mismatch which can generate artifacts or affect the reconstructed quantitative absorption coefficient of the lesion. Also, for patients who have a single breast due to prior surgery, the contra-lateral reference is not available. To improve the DOT performance or overcome its limitation, we introduced a new method based on an exogenous contrast agent and demonstrate its performance using animal models. Co-registered ultrasound was used to guide the lesion localization. The results have shown that artifacts caused by background mismatch can be reduced significantly by using this new method. [ABSTRACT FROM AUTHOR]

We present a photoacoustic tomography-guided diffuse optical tomography approach using a hand-held probe for detection and characterization of deeply-seated targets embedded in a turbid medium. Diffuse optical tomography guided by coregistered ultrasound, MRI, and x ray has demonstrated a great clinical potential to overcome lesion location uncertainty and to improve light quantification accuracy. However, due to the different contrast mechanisms, some lesions may not be detectable by a nonoptical modality but yet have high optical contrast. Photoacoustic tomography utilizes a short-pulsed laser beam to diffusively penetrate into tissue. Upon absorption of the light by the target, photoacoustic waves are generated and used to reconstruct, at ultrasound resolution, the optical absorption distribution that reveals optical contrast. However, the robustness of optical property quantification of targets by photoacoustic tomography is complicated because of the wide range of ultrasound transducer sensitivity, the orientation and shape of the targets relative to the ultrasound array, and the uniformity of the laser beam. We show in this paper that the relative optical absorption map provided by photoacoustic tomography can potentially guide the diffuse optical tomography to accurately reconstruct target absorption maps. [ABSTRACT FROM AUTHOR]

Tumor vascular patterns of advanced breast cancers are complex and heterogeneous. Two typical light absorption patterns of periphery enhancement and posterior shadowing have been observed when imaging these advanced cancers using optical tomography guided by ultrasound. We perform a series simulation and phantom experiments to systemically evaluate the effects of target parameters, target locations, and target optical properties on imaging periphery enhancement absorption distribution using reflection geometry. Large tumors are modeled as concentric semiellipsoidal targets of different outer shell and inner core optical properties. We show that larger targets of more than 3 to 4 cm diameter with outer shell thicknesses less than 1 cm can be resolved at a depth less than 3 cm. A clinical example is given to show the complex vasculature distributions seen from an advanced cancer. [ABSTRACT FROM AUTHOR]

The chest wall underneath breast tissue distorts light reflection measurements, especially measurements obtained from distant source-detector pairs. For patients with a chest wall located at a shallower depth, the chest-wall effect needs to be considered in the image reconstruction procedure. Following our previous studies, this work systemically evaluates the performance of a two-layer model-based reconstruction using the finite element method, and compares it with the performance of the semi-infinite model. The results obtained from simulations and phantom experiments show that the two-layer model improves the light quantification of the targets. The improvements are attributed to improved background estimation and more accurate weight matrix calculation using a two-layer model compared to the semi-infinite model. Fitted two-layer background optical properties obtained from a group of ten patients with chest walls located less than 2 cmdeep are more representative of breast tissue and chest-wall optical properties. [ABSTRACT FROM AUTHOR]

Many endoscopic, intravascular, and transvaginal applications require light to be delivered through optical fibers in a reflection mode. For photoacoustic imaging in reflection geometry, the front-face reflectivity of the ultrasound transducer face imposes a boundary condition that affects the light fluence and its distribution inside a turbid medium. Understanding and characterizing this boundary condition is critical for maximizing tissue illumination and therefore the signal-to-noise ratio of the photoacoustic signal. We systematically analyze the light fluence under three typical commercial transducer faces having reflection coefficients of 1.4, 18, and 28, and compare the results to a transducer face with 60 coefficient at the laser wavelength of 750 nm. Monte Carlo simulations and experimental results show that light fluence and distribution obtained inside a turbid medium with the use of the 60 reflection coefficient transducer face has a significant improvement over the others, especially at shallower depths. [ABSTRACT FROM AUTHOR]

When a large, highly absorbing breast lesion is imaged by optical tomography in reflection geometry, most of the photons are absorbed by the top portion of the lesion. As a result, the lower portion of the lesion is not quantified correctly. This posterior light shadowing effect is similar to the sound shadowing effect frequently seen in pulse-echo ultrasound images. The presence of significant posterior shadowing of a lesion in ultrasound images suggests malignance. The light shadowing effect due to optical contrast is characterized using a simple measure and validated by the Monte Carlo photon-tracking method and phantom experiments. Clinical examples of large malignant and benign lesions are presented to demonstrate the shadowing effect and the utility of the measure. Understanding and quantifying the shadowing effect due to optical contrast is important for characterizing larger malignant cancers from benign lesions. [ABSTRACT FROM AUTHOR]

Ovarian cancer has the highest mortality of all gynecologic cancers, with a five-year survival rate of only 30 or less. Current imaging techniques are limited in sensitivity and specificity in detecting early stage ovarian cancer prior to its widespread metastasis. New imaging techniques that can provide functional and molecular contrasts are needed to reduce the high mortality of this disease. One such promising technique is photoacoustic imaging. We develop a 1280-element coregistered 3-D ultrasound and photoacoustic imaging system based on a 1.75-D acoustic array. Volumetric images over a scan range of 80 deg in azimuth and 20 deg in elevation can be achieved in minutes. The system has been used to image normal porcine ovarian tissue. This is an important step toward better understanding of ovarian cancer optical properties obtained with photoacoustic techniques. To the best of our knowledge, such data are not available in the literature. We present characterization measurements of the system and compare coregistered ultrasound and photoacoustic images of ovarian tissue to histological images. The results show excellent coregistration of ultrasound and photoacoustic images. Strong optical absorption from vasculature, especially highly vascularized corpora lutea and low absorption from follicles, is demonstrated. [ABSTRACT FROM AUTHOR]

We present the application of a curved array photoacoustic tomographic imaging system that can provide rapid, high-resolution photoacoustic imaging of small animal brains. The system is optimized to produce a B-mode, 90-degfield-of-view image at sub-200-mresolution at a frame rate of ∼1 framesecondwhen a 10-Hzpulse repetition rate laser is employed. By rotating samples, a complete 360-degscan can be achieved within 15 s. In previous work, two-dimensional (2-D) ex vivomouse brain cortex imaging has been reported. We report three-dimensional (3-D) small animal brain imaging obtained with the curved array system. The results are presented as a series of 2-D cross-sectional images. Besides structural imaging, the blood oxygen saturation of the animal brain cortex is also measured in vivo. In addition, the system can measure the time-resolved relative changes in blood oxygen saturation level in the small animal brain cortex. Last, ultrasonic gel coupling, instead of the previously adopted water coupling, is conveniently used in near-real-time 2-D imaging. [ABSTRACT FROM AUTHOR]

The chest wall underneath the breast tissue affects near-infrared (NIR) diffusive waves measured with reflection geometry. With the assistance of a co-registered ultrasound, the depth and the tilting angle of the chest wall can be determined and are used to model the breast as a two-layer medium. Finite element method (FEM) is suitable for modeling complex boundary conditions and is adapted to model the breast tissue and chest wall. Four parameters of bulk absorption and reduced scattering coefficients of these two layers are estimated and used for imaging reconstruction. Using a two-layer model, we have systematically investigated the effect of the chest wall on breast lesion reconstruction. Results have shown that chest-wall depth, titling angle, and difference between optical properties of two layers of lesion and reference sites affect the lesion reconstruction differently. Our analysis will be valuable and informative to researchers who are using reflectance geometry for breast imaging. The analysis can also provide guidelines for imaging operators to minimize image artifacts and to produce the best reconstruction results. [ABSTRACT FROM AUTHOR]

We develop a new tomographic imaging reconstruction algorithm for a two-layer tissue structure. Simulations and phantom experiments show more accurate reconstruction of target optical properties compared with those results obtained from a semi-infinite tissue model for layered structures. This improvement is mainly attributed to the more accurate estimation of background optical properties and more accurate estimation of weight matrix for imaging reconstruction by considering the light propagation effect in the second layer. Clinical results of breast lesions are also presented to demonstrate the utility of this new imaging algorithm. [ABSTRACT FROM AUTHOR]