Early Assessment Window for Predicting Breast Cancer Neoadjuvant Therapy using Biomarkers, Ultrasound, and Diffuse Optical Tomography.

PURPOSE: The purpose of the study was to assess the utility of tumor biomarkers, ultrasound (US) and US-guided diffuse optical tomography (DOT) in early prediction of breast cancer response to neoadjuvant therapy (NAT). METHODS: This prospective HIPAA compliant study was approved by the institutional review board. Forty one patients were imaged with US and US-guided DOT prior to NAT, at completion of the first three treatment cycles, and prior to definitive surgery from February 2017 to January 2020. Miller-Payne grading was used to assess pathologic response. Receiver operating characteristic curves (ROCs) were derived from logistic regression using independent variables, including: tumor biomarkers, US maximum diameter, percentage reduction of the diameter (%US), pretreatment maximum total hemoglobin concentration (HbT) and percentage reduction in HbT (%HbT) at different treatment time points. Resulting ROCs were compared using area under the curve (AUC). Statistical significance was tested using two-sided two-sample student t-test with P < 0.05 considered statistically significant. Logistic regression was used for ROC analysis. RESULTS: Thirty-eight patients (mean age = 47, range 24-71 years) successfully completed the study, including 15 HER2 + of which 11 were ER + ; 12 ER + or PR + /HER2-, and 11 triple negative. The combination of HER2 and ER biomarkers, %HbT at the end of cycle 1 (EOC1) and %US (EOC1) provided the best early prediction, AUC = 0.941 (95% CI 0.869-1.0). Similarly an AUC of 0.910 (95% CI 0.810-1.0) with %US (EOC1) and %HbT (EOC1) can be achieved independent of HER2 and ER status. The most accurate prediction, AUC = 0.974 (95% CI 0.933-1.0), was achieved with %US at EOC1 and %HbT (EOC3) independent of biomarker status. CONCLUSION: The combined use of tumor HER2 and ER status, US, and US-guided DOT may provide accurate prediction of NAT response as early as the completion of the first treatment cycle. CLINICAL TRIAL REGISTRATION NUMBER: NCT02891681. https://clinicaltrials.gov/ct2/show/NCT02891681 , Registration time: September 7, 2016.

Assessing Rectal Cancer Treatment Response Using Coregistered Endorectal Photoacoustic and US Imaging Paired with Deep Learning.

Background Conventional radiologic modalities perform poorly in the radiated rectum and are often unable to differentiate residual cancer from treatment scarring. Purpose To report the development and initial patient study of an imaging system comprising an endorectal coregistered photoacoustic (PA) microscopy (PAM) and US system paired with a convolution neural network (CNN) to assess the rectal cancer treatment response. Materials and Methods In this prospective study (ClinicalTrials.gov identifier NCT04339374), participants completed radiation and chemotherapy from September 2019 to September 2020 and images were obtained with the PAM/US system prior to surgery. Another group's colorectal specimens were studied ex vivo. The PAM/US system consisted of an endorectal imaging probe, a 1064-nm laser, and one US ring transducer. The PAM CNN and US CNN models were trained and validated to distinguish normal from malignant colorectal tissue using ex vivo and in vivo patient data. The PAM CNN and US CNN were then tested using additional in vivo patient data that had not been seen by the CNNs during training and validation. Results Twenty-two patients' ex vivo specimens and five patients' in vivo images (a total of 2693 US regions of interest [ROIs] and 2208 PA ROIs) were used for CNN training and validation. Data from five additional patients were used for testing. A total of 32 participants (mean age, 60 years; range, 35-89 years) were evaluated. Unique PAM imaging markers of the complete tumor response were found, specifically including recovery of normal submucosal vascular architecture within the treated tumor bed. The PAM CNN model captured this recovery process and correctly differentiated these changes from the residual tumor. The imaging system remained highly capable of differentiating tumor from normal tissue, achieving an area under the receiver operating characteristic curve of 0.98 (95% CI: 0.98, 0.99) for data from five participants. By comparison, the US CNN had an area under the receiver operating characteristic curve of 0.71 (95% CI: 0.70, 0.73). Conclusion An endorectal coregistered photoacoustic microscopy/US system paired with a convolutional neural network model showed high diagnostic performance in assessing the rectal cancer treatment response and demonstrated potential for optimizing posttreatment management. © RSNA, 2021 Supplemental material is available for this article. See also the editorial by Klibanov in this issue.

Effect and correction of optode coupling errors in breast imaging using diffuse optical tomography.

In diffuse optical tomography (DOT) and spectroscopy (DOS) using handheld probes, tissue curvature can cause bad fiber-to-tissue contact. Understanding and minimizing image artifacts caused by these coupling errors would significantly improve DOT and DOS image quality. In this work, we utilized Monte Carlo simulations and experiments with gelatin-Intralipid phantoms to systematically study the influence of source or detector (optode) coupling errors. Optode coupling errors can increase the amplitude and decrease the phase of the measured diffuse reflectance, creating artifacts in the reconstructed absorption maps, such as hot spots on the edges. We propose an outlier removal algorithm that can correct these image artifacts, and we demonstrate its performance using simulations, phantom experiments, and breast patient data acquired with bad probe contact due to a dense or small breast. Further, we designed and implemented a new resistance-type thin-film force sensor array that provides real-time optode coupling feedback and guides the outlier removal to minimize optode coupling errors. Our approaches and study results have significant implications for reducing image artifacts arising from handheld probes, which are commonly used with mobile and wearable DOT and DOS devices.

Role of blood oxygenation saturation in ovarian cancer diagnosis using multi-spectral photoacoustic tomography.

In photoacoustic tomography (PAT), a tunable laser typically illuminates the tissue at multiple wavelengths, and the received photoacoustic waves are used to form functional images of relative total haemoglobin (rHbT) and blood oxygenation saturation (%sO2 ). Due to measurement errors, the estimation of these parameters can be challenging, especially in clinical studies. In this study, we use a multi-pixel method to smooth the measurements before calculating rHbT and %sO2 . We first perform phantom studies using blood tubes of calibrated %sO2 to evaluate the accuracy of our %sO2 estimation. We conclude by presenting diagnostic results from PAT of 33 patients with 51 ovarian masses imaged by our co-registered PAT and ultrasound system. The ovarian masses were divided into malignant and benign/normal groups. Functional maps of rHbT and %sO2 and their histograms as well as spectral features were calculated using the PAT data from all ovaries in these two groups. Support vector machine models were trained on different combinations of the significant features. The area under ROC (AUC) of 0.93 (0.95%CI: 0.90-0.96) on the testing data set was achieved by combining mean %sO2 , a spectral feature, and the score of the study radiologist.

Target depth-regularized reconstruction in diffuse optical tomography using ultrasound segmentation as prior information.

Ultrasound (US)-guided diffuse optical tomography (DOT) is a promising non-invasive functional imaging technique for diagnosing breast cancer and monitoring breast cancer treatment response. However, because larger lesions are highly absorbing, reconstructions of these lesions using reflection geometry may exhibit light shadowing, which leads to inaccurate quantification of their deeper portions. Here we propose a depth-regularized reconstruction algorithm combined with a semi-automated interactive neural network (CNN) for depth-dependent reconstruction of absorption distribution. CNN segments co-registered US to extract both spatial and depth priors, and the depth-regularized algorithm incorporates these parameters into the reconstruction. Through simulation and phantom data, the proposed algorithm is shown to significantly improve the depth distribution of reconstructed absorption maps of large targets. Evaluated with 26 patients with larger breast lesions, the algorithm shows 2.4 to 3 times improvement in the top-to-bottom reconstructed homogeneity of the absorption maps for these lesions.

Optimal breast cancer diagnostic strategy using combined ultrasound and diffuse optical tomography.

Ultrasound (US)-guided near-infrared diffuse optical tomography (DOT) has demonstrated great potential as an adjunct breast cancer diagnosis tool to US imaging alone, especially in reducing unnecessary benign biopsies. However, DOT data processing and image reconstruction speeds remain slow compared to the real-time speed of US. Real-time or near real-time diagnosis with DOT is an important step toward the clinical translation of US-guided DOT. Here, to address this important need, we present a two-stage diagnostic strategy that is both computationally efficient and accurate. In the first stage, benign lesions are identified in near real-time by use of a random forest classifier acting on the DOT measurements and the radiologists' US diagnostic scores. Any lesions that cannot be reliably classified by the random forest classifier will be passed on to the second stage which begins with image reconstruction. Functional information from the reconstructed hemoglobin concentrations is employed by a Support Vector Machine (SVM) classifier for diagnosis at the end of the second stage. This two-step classification approach which combines both perturbation data and functional features, results in improved classification, as denoted by the receiver operating characteristic (ROC) curve. Using this two-step approach, the area under the ROC curve (AUC) is 0.937 ± 0.009, with a sensitivity of 91.4% and specificity of 85.7%. In comparison, using functional features and US score yields an AUC of 0.892 ± 0.027, with a sensitivity of 90.2% and specificity of 74.5%. Most notably, the specificity is increased by more than 10% due to the implementation of the random forest classifier.

Reducing image artifact in diffuse optical tomography by iterative perturbation correction based on multiwavelength measurements.

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.

Compact ultrasound-guided diffuse optical tomography system for breast cancer imaging.

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.

Two step imaging reconstruction using truncated pseudoinverse as a preliminary estimate in ultrasound guided diffuse optical tomography.

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.

Diffuse optical tomography using semiautomated coregistered ultrasound measurements.

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.