Pouyan Mohajerani

Multimodal Molecular Imaging of Integrin αvβ3 for In Vivo Detection of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Late detection of then nonresectable or metastasized tumors emphasizes the need for novel imaging approaches. Here, we report on so far nonexploited potentials of αvβ3 integrin–targeted molecular imaging technologies for detection of PDAC using genetically engineered mouse models. Methods: Immunohistochemistry and Western blot were used for characterization of αvβ3 expression in murine and human PDAC. We applied IntegriSense 680 fluorescence molecular tomography, intraoperative fluorescence imaging, and 68Ga-NODAGA-RGD PET for αvβ3 integrin molecular in vivo imaging of spontaneous PDAC occurring in Ptf1a+/Cre;Kras+/LSL-G12D;p53LoxP/LoxP mice. (NODAGA is 1,4,7-triazacyclononane-1,4-bis[acetic acid]-7-[2-glutaric acid] and RGD is arginine-glycine-aspartic acid.) Results: αvβ3 integrin is expressed in tumor cells of human and murine PDAC. IntegriSense fluorescence molecular tomography and 68Ga-NODAGA-RGD PET enabled faithful visualization of PDAC. Furthermore, intraoperative optical imaging with IntegriSense 680 allowed good delineation of tumor borders. Conclusion: Imaging approaches targeting αvβ3 integrin expand the potential of molecular imaging for identification of αvβ3-positive PDAC with potential implications in early detection, fluorescence-guided surgery, and therapy monitoring.

FMT-PCCT: Hybrid Fluorescence Molecular Tomography—X-Ray Phase-Contrast CT Imaging of Mouse Models

The implementation of hybrid fluorescence molecular tomography (FMT) and X-ray computed tomography (CT) has been shown to be a necessary development, not only for combining anatomical with functional and molecular contrast, but also for generating optical images of high accuracy. FMT affords highly sensitive 3-D imaging of fluorescence bio-distribution, but in stand-alone form it offers images of low resolution. It was shown that FMT accuracy significantly improves by considering anatomical priors from CT. Conversely, CT generally suffers from low soft tissue contrast. Therefore utilization of CT data as prior information in FMT inversion is challenging when different internal organs are not clearly differentiated. Instead, we combined herein FMT with emerging X-ray phase-contrast CT (PCCT). PCCT relies on phase shift differences in tissue to achieve soft tissue contrast superior to conventional CT. We demonstrate for the first time FMT-PCCT imaging of different animal models, where FMT and PCCT scans were performed in vivo and ex vivo, respectively. The results show that FMT-PCCT expands the potential of FMT in imaging lesions with otherwise low or no CT contrast, while retaining the cost benefits of CT and simplicity of hybrid device realizations. The results point to the most accurate FMT performance to date.

Optical and Optoacoustic Model-Based Tomography: Theory and current challenges for deep tissue imaging of optical contrast

Light offers a range of interactions with tissue that give rise to an extensive list of methods to sense physical, chemical, or biological processes. Combined with using safe and nonionizing radiation, optical imaging is considered as a fundamental tool in the biomedical sciences [1].

Compression of Born ratio for fluorescence molecular tomography/x-ray computed tomography hybrid imaging: methodology and in vivo validation.

The 360° rotation geometry of the hybrid fluorescence molecular tomography/x-ray computed tomography modality allows for acquisition of very large datasets, which pose numerical limitations on the reconstruction. We propose a compression method that takes advantage of the correlation of the Born-normalized signal among sources in spatially formed clusters to reduce the size of system model. The proposed method has been validated using an ex vivo study and an in vivo study of a nude mouse with a subcutaneous 4T1 tumor, with and without inclusion of a priori anatomical information. Compression rates of up to two orders of magnitude with minimum distortion of reconstruction have been demonstrated, resulting in large reduction in weight matrix size and reconstruction time.

Frequency domain optoacoustic tomography using amplitude and phase.

We introduce optoacoustic tomographic imaging using intensity modulated light sources and collecting amplitude and phase information in the frequency domain. Imaging is performed at multiple modulation frequencies. The forward modeling uses the Greens function solution to the pressure wave equation in frequency domain and the resulting inverse problem is solved using regularized least squares minimization. We study the effect of the number of frequencies and of the bandwidth employed on the image quality achieved. The possibility of employing an all-frequency domain optoacoustic imaging for experimental measurements is studied as a function of noise. We conclude that frequency domain optoacoustic tomography may evolve to a practical experimental method using light intensity modulated sources, with advantages over time-domain optoacoustics.

Fluorescence-aided Tomographic Imaging of Synovitis in the Human Finger

PURPOSE To propose and evaluate indocyanine green (ICG)-enhanced tomographic optical imaging for detection and characterization of synovitis in affected finger joints of patients with rheumatoid arthritis and differentiation from healthy joints in comparison to 3-T magnetic resonance (MR) imaging. MATERIALS AND METHODS This prospective pilot study was approved by the institutional ethics committee. Six arthritic proximal interphalangeal (PIP) joints in six patients (five women and one man; mean age ± standard deviation, 62.6 years ± 13.3) with clinically determined rheumatoid arthritis and six healthy PIP joints from six volunteers (four women and two men; mean age, 41.5 years ± 20.2) were examined with an ICG-enhanced fluorescence molecular tomography (FMT) system and 3-T MR imaging as the standard of reference. The degree of inflammation was graded semiquantitatively on a four-point ordinate scale according to the Outcome Measures in Rheumatology Clinical Trials Rheumatoid Arthritis MR Imaging Score, or OMERACT RAMRIS. FMT reconstructions were coregistered with the MR images. Groups were compared by using a two-sided t test, and a weighted κ coefficient was used for comparing FMT and MR imaging semiquantitative scores, as well as assessing intrareader agreement. RESULTS FMT was used to detect synovitis in all arthritic joints. The reconstructed FMT signal correlated with MR imaging findings in intensity and spatial, transverse profile. Semiquantitative scoring of FMT correlated well with MR imaging findings (weighted κ coefficient = 0.90). The reconstructed quantitative FMT signal, denoting synovial hyperperfusion, was used to differentiate between synovitis and healthy joints (healthy joints, 1.25 ± 0.59; arthritic joints, 3.13 ± 1.03; P < .001). CONCLUSION FMT enhanced with ICG provided depth-resolved imaging of synovitis in PIP joints. FMT may help detect synovitis in patients with rheumatoid arthritis.

Spatiotemporal analysis for indocyanine green-aided imaging of rheumatoid arthritis in hand joints

Abstract. Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease, with a prevalence of 0.5 to 1% in the general population. Imaging can possibly aid in early diagnosis, crucial to effective personalized therapeutic strategies and treatment follow-up. The intravenous administration of indocyanine green (ICG) has been considered for identifying synovial hyperperfusion as an RA physiological biomarker. However, while the distribution of ICG in the human hand is a time-dependent process, the particular biodistribution dynamic patterns established following intravenous administration have not yet been studied. For this reason, the dynamic relationships of ICG distribution in the human hand in RA patients using a method based on principal component analysis are analyzed. In vivo analyses were corroborated by simulations of clinical scenarios using a finite element method. Observations of spatiotemporal characteristics are contrasted to fluorescence intensity images and magnetic resonance images of the hand joints, employed as the anatomical and diagnostic reference. Processing results for 450 joints from 5 healthy volunteers and 10 patients show that image features obtained from the spatiotemporal analysis offer good congruence with synovitis and reveal better detection performance compared to observations of raw fluorescence intensity images.

An Inversion Scheme for Hybrid Fluorescence Molecular Tomography Using a Fuzzy Inference System

The imaging performance of fluorescence molecular tomography (FMT) improves when information from the underlying anatomy is incorporated into the inversion scheme, in the form of priors. The requirement for incorporation of priors has recently driven the development of hybrid FMT systems coupled to other modalities, such as X-ray CT and MRI. A critical methodological aspect in this modality relates to the particular method selected to incorporate prior information obtained from the anatomical imaging modality into the FMT inversion. We propose herein a new approach for utilizing prior information, which preferentially minimizes residual errors associated with measurements that better describe the anatomical segments considered. This preferential minimization was realized using a weighted least square (WLS) approach, where the weights were optimized using a Mamdani-type fuzzy inference system. The method of priors introduced herein was deployed as a two-step structured regularization approach and was verified with experimental measurements from phantoms as well as ex vivo and in vivo animal studies. The results demonstrate accurate performance and minimization of reconstruction bias, without requiring user input for setting the regularization parameters. As such, the proposed method offers significant progress in incorporation of anatomical priors in FMT and, as a result, in realization of the full potential of hybrid FMT.

Early recognition of lung cancer by integrin targeted imaging in K-ras mouse model.

Non‐small cell lung cancer is characterized by slow progression and high heterogeneity of tumors. Integrins play an important role in lung cancer development and metastasis and were suggested as a tumor marker; however their role in anticancer therapy remains controversial. In this work, we demonstrate the potential of integrin‐targeted imaging to recognize early lesions in transgenic mouse model of lung cancer based on spontaneous introduction of mutated human gene bearing K‐ras mutation. We conducted ex vivo and fluorescence molecular tomography‐X‐ray computed tomography (FMT‐XCT) in vivo imaging and analysis for specific targeting of early lung lesions and tumors in rodent preclinical model for lung cancer. The lesions and tumors were characterized by histology, immunofluorescence and immunohistochemistry using a panel of cancer markers. Ex vivo, the integrin‐targeted fluorescent signal significantly differed between wild type lung tissue and K‐ras pulmonary lesions (PL) at all ages studied. The panel of immunofluorescence experiments demonstrated that PL, which only partially show cancer cell features were detected by αvβ3‐integrin targeted imaging. Human patient material analysis confirmed the specificity of target localization in different lung cancer types. Most importantly, small tumors in the lungs of 4‐week‐old animals could be noninvasively detected in vivo on the fluorescence channel of FMT‐XCT. Our findings demonstrated αvβ3‐integrin targeted fluorescent imaging to specifically detect premalignant pleural lesions in K‐ras mice. Integrin targeted imaging may find application areas in preclinical research and clinical practice, such as early lung cancer diagnostics, intraoperative assistance or therapy monitoring.

Fast Fourier backprojection for frequency-domain optoacoustic tomography

We present a time-efficient backprojection image reconstruction approach applied to frequency-domain (FD) optoacoustic tomography based on tissue illumination at multiple, discrete frequencies. The presented method estimates the Fourier transform of a spatial, circular profile of the underlying image using the amplitude and phase data. These data are collected over multiple frequencies using an acoustic transducer positioned at several locations around the sample. Fourier-transform values for absent frequencies are estimated using interpolation based on low-pass filtering in the image domain. Reconstruction results are presented for synthetic measurements using numerical phantoms, and the results are compared with FD model-based reconstructions.