Yamin Mao

A Novel Region Reconstruction Method for Fluorescence Molecular Tomography

Fluorescence molecular tomography (FMT) could exploit the distribution of fluorescent biomarkers that target tumors accurately and effectively, which enables noninvasive real-time 3-D visualization as well as quantitative analysis of small tumors in small animal studies in vivo. Due to the difficulties of reconstruction, continuous efforts are being made to find more practical and efficient approaches to accurately obtain the characteristics of fluorescent regions inside biological tissues. In this paper, we propose a region reconstruction method for FMT, which is defined as an L1-norm regularization piecewise constant level set approach. The proposed approach adopts a priori information including the sparsity of the fluorescent sources and the fluorescent contrast between the target and background. When the contrast of different fluorescent sources is low to a certain degree, our approach can simultaneously solve the detection and characterization problems for the reconstruction of FMT. To evaluate the performance of the region reconstruction method, numerical phantom experiments and in vivo bead-implanted mouse experiments were performed. The results suggested that the proposed region reconstruction method was able to reconstruct the features of the fluorescent regions accurately and effectively, and the proposed method was able to be feasibly adopted in in vivo application.

Comparison between the indocyanine green fluorescence and blue dye methods for sentinel lymph node biopsy using novel fluorescence image-guided resection equipment in different types of hospitals

Sentinel lymph node biopsy (SLNB) has become a standard of care to detect axillary lymph metastasis in early-stage breast cancer patients with clinically negative axillary lymph nodes. Current SLNB detection modalities comprising a blue dye, a radioactive tracer, or a combination of both have advantages as well as disadvantages. Thus, near-infrared fluorescence imaging using indocyanine green (ICG) has recently been regarded as a novel method that has generated interest for SLNB around the world. However, the lack of appropriate fluorescence imaging systems has hindered further research and wide application of this method. Therefore, we developed novel fluorescence image-guided resection equipment (FIRE) to detect sentinel lymph nodes (SLNs). Moreover, to compare the ICG fluorescence imaging method with the blue dye method and to explore the universal feasibility of the former, a different type of hospital study was conducted. Ninety-nine eligible patients participated in the study at 3 different types of hospitals. After subcutaneous ICG allergy testing, all the patients were subcutaneously injected with methylene blue and ICG into the subareolar area. Consequently, 276 SLNs (range 1-7) were identified in 98 subjects (detection rate: 99%) by using the ICG fluorescence imaging method. In contrast, the blue dye method only identified 202 SLNs (range 1-7) in 91 subjects (detection rate: 91.92%). Besides, the results of the fluorescence imaging method were similar in the 3 hospitals. Our findings indicate the universal feasibility of the ICG fluorescence imaging method for SLNB using the fluorescence image-guided resection equipment in early breast cancer detection.

Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green

Tissue necrosis commonly accompanies the development of a wide range of serious diseases. Therefore, highly sensitive detection and precise boundary delineation of necrotic tissue via effective imaging techniques are crucial for clinical treatments; however, no imaging modalities have achieved satisfactory results to date. Although fluorescence molecular imaging (FMI) shows potential in this regard, no effective necrosis-avid fluorescent probe has been developed for clinical applications. Here, we demonstrate that indocyanine green (ICG) can achieve high avidity of necrotic tissue owing to its interaction with lipoprotein (LP) and phospholipids. The mechanism was explored at the cellular and molecular levels through a series of in vitro studies. Detection of necrotic tissue and real-time image-guided surgery were successfully achieved in different organs of different animal models with the help of FMI using in house-designed imaging devices. The results indicated that necrotic tissue with a 0.6 mm diameter could be effectively detected with precise boundary definition. We believe that the new discovery and the associated imaging techniques will improve personalized and precise surgery in the near future.

Novel l 2,1-norm optimization method for fluorescence molecular tomography reconstruction.

Fluorescence molecular tomography (FMT) is a promising tomographic method in preclinical research, which enables noninvasive real-time three-dimensional (3-D) visualization for in vivo studies. The ill-posedness of the FMT reconstruction problem is one of the many challenges in the studies of FMT. In this paper, we propose a l 2,1-norm optimization method using a priori information, mainly the structured sparsity of the fluorescent regions for FMT reconstruction. Compared to standard sparsity methods, the structured sparsity methods are often superior in reconstruction accuracy since the structured sparsity utilizes correlations or structures of the reconstructed image. To solve the problem effectively, the Nesterovs method was used to accelerate the computation. To evaluate the performance of the proposed l 2,1-norm method, numerical phantom experiments and in vivo mouse experiments are conducted. The results show that the proposed method not only achieves accurate and desirable fluorescent source reconstruction, but also demonstrates enhanced robustness to noise.

Meshless reconstruction method for fluorescence molecular tomography based on compactly supported radial basis function.

Abstract. Fluorescence molecular tomography (FMT) is a promising tool in the study of cancer, drug discovery, and disease diagnosis, enabling noninvasive and quantitative imaging of the biodistribution of fluorophores in deep tissues via image reconstruction techniques. Conventional reconstruction methods based on the finite-element method (FEM) have achieved acceptable stability and efficiency. However, some inherent shortcomings in FEM meshes, such as time consumption in mesh generation and a large discretization error, limit further biomedical application. In this paper, we propose a meshless method for reconstruction of FMT (MM-FMT) using compactly supported radial basis functions (CSRBFs). With CSRBFs, the image domain can be accurately expressed by continuous CSRBFs, avoiding the discretization error to a certain degree. After direct collocation with CSRBFs, the conventional optimization techniques, including Tikhonov, L1-norm iteration shrinkage (L1-IS), and sparsity adaptive matching pursuit, were adopted to solve the meshless reconstruction. To evaluate the performance of the proposed MM-FMT, we performed numerical heterogeneous mouse experiments and in vivo bead-implanted mouse experiments. The results suggest that the proposed MM-FMT method can reduce the position error of the reconstruction result to smaller than 0.4 mm for the double-source case, which is a significant improvement for FMT.

Near-infrared Intraoperative Imaging of Thoracic Sympathetic Nerves: From Preclinical Study to Clinical Trial

The sympathetic nervous system controls and regulates the activities of the heart and other organs. Sympathetic nervous system dysfunction leads to disease. Therefore, intraoperative real-time imaging of thoracic sympathetic nerves (ITSN) would be of great clinical significance for diagnosis and therapy. The aim of this experimental study was to evaluate the feasibility and validity of intraoperative ITSN using indocyanine green (ICG). Methods: ITSN using ICG was performed on 10 rabbits to determine its feasibility. Animals were allocated to two groups. The rabbits in one group received the same dose of ICG, but were observed at different times. The rabbits in the other group were administered different doses of ICG, but were observed at the same time. Signal to background ratio (SBR) was measured in regions of interest in all rabbits. Furthermore, fifteen consecutive patients with pulmonary nodules were intravenously injected with ICG 24 h preoperatively and underwent near-infrared (NIR) fluorescence imaging (FI) thoracoscopic surgeries between July 2015 and June 2016. A novel self-developed NIR and white-light dual-channel thoracoscope system was used. SBRs of thoracic sympathetic nerves were calculated in all patients. Results: In the preclinical study, we were able to precisely recognize each rabbits second (T2) to fifth (T5) thoracic ganglia on both sides of the spine using ITSN with ICG. In addition, we explored the relationship between SBR and the injection time of ICG and that between SBR and the dose of ICG. Using the novel dual-channel thoracoscope system, we were able to locate the ganglia from the stellate ganglion (SG) to the sixth thoracic ganglion (T6), as well as the chains between these ganglia in all patients with a high SBR value of 3.26 (standard deviation: 0.57). The pathological results confirmed our findings. Conclusion: We were able to use ICG FI to distinguish thoracic sympathetic nerves during NIR thoracoscopic surgery. The technique may replace the rib-oriented method as standard practice for mapping the thoracic sympathetic nerves.

Precise integrin-targeting near-infrared imaging-guided surgical method increases surgical qualification of peritoneal carcinomatosis from gastric cancer in mice

Peritoneal carcinomatosis from gastric cancer represents a common recurrent gastric cancer that seriously affects the survival, prognosis, and quality of life of patients at its advanced stage. In recent years, complete cytoreduction surgery in combination with hyperthermic intraperitoneal chemotherapy has been demonstrated to improve the survival and prognosis of patients with malignant tumors including peritoneal carcinomatosis from gastric cancer. Establishing viable methods of accurately assessing the tumor burden in patients with peritoneal carcinoma and correctly selecting suitable patients in order to improve cytoreduction surgical outcomes and reduce the risk of postoperative complications has become a challenge in the field of peritoneal carcinoma research. Here, we investigated peritoneal carcinomatosis from gastric cancer in a mouse model by using our self-developed surgical navigation system that combines optical molecular imaging with an integrin-targeting Arg-Gly-Asp-indocyanine green (RGD-ICG) molecular probe. The results showed that our diagnostic method could achieve a sensitivity and specificity of up to 93.93% and 100%, respectively, with a diagnostic index (DI) of 193.93% and diagnostic accuracy rate of 93.93%.Furthermore, the minimum tumor diameter measured during the surgery was 1.8 mm and the operative time was shortened by 3.26-fold when compared with the conventionally-treated control group. Therefore, our surgical navigation system that combines optical molecular imaging with an RGD-ICG molecular probe, could improve the diagnostic accuracy rate for peritoneal carcinomatosis from gastric cancer, shorten the operative time, and improve the quality of the cytoreduction surgery for peritoneal carcinomatosis from gastric cancer, thus providing a solid foundation for its future clinical development and application.

Clinical application of near-infrared thoracoscope with indocyanine green in video-assisted thoracoscopic bullectomy

UNLABELLED Failure to identify all the possible bullous lesions was considered an important reason for the higher recurrence rate after the VATS bullectomy. We applied the latest near-infrared (NIR) thoracoscope with indocyanine green (ICG) to detect bullous lesions for patients with spontaneous pneumothorax. Two male patients with spontaneous pneumothorax and poorly identified bullae intraoperatively were included in this pilot study. An NIR thoracoscope with two different doses of ICG injection (0.2 and 0.6 mg/kg) was used to detect bullous lesions during VATS bullectomy. Partial lung resections of the bullous lesions were performed under syncretic mode. Data was managed with ImageJ software. No procedure-related complications were observed. The fluorescent signal was detected in normal lung tissue 10.5 seconds (mean, 10-11 seconds) after the ICG bolus, and lasted up to 525 seconds (mean, 480-570 seconds). The bullous lesions showed an obviously decreased fluorescent densities comparing to adjacent normal tissue. At the dosage of 0.6 mg/kg, ICG emits sufficient fluorescence to demonstrate the precise border of bullae, with the max SBR of 6.32. All resected specimens were confirmed as bullous lesions microscopically. NIR thoracoscope with intravenous ICG is a safe, accurate and real-time method to detect bullous lesions of lung tissue difficult to be found under normal light in human subjects. TRIAL REGISTRATION NCT02611245 (https://register.clinicaltrials.gov/).

The identification of sub-centimetre nodules by near-infrared fluorescence thoracoscopic systems in pulmonary resection surgeries

OBJECTIVES Current surgical procedures lack high-sensitivity intraoperative imaging guidance, leading to undetected micro tumours. In vivo near-infrared (NIR) fluorescence imaging provides a powerful tool for identifying small nodules. The aim of this study was to examine our experience of using 2 different NIR devices in pulmonary resection surgery. METHODS From August 2015 to October 2016, 36 patients with lung nodules underwent NIR fluorescence imaging thoracoscopic surgery. Two NIR devices: a D-Light P system and a SUPEREYE system were used. Patients were administered an injection of indocyanine green (ICG) through the peripheral vein 24 h preoperatively. During surgery, traditional white-light thoracoscopic exploration was performed first, followed by ICG-fluorescent-guided exploration. All detected nodules were resected and examined by a pathologist. RESULTS Of the 36 patients, 76 nodules were resected. ICG-fluorescent imaging identified 68 nodules during in vivo exploration. The mean signal-to-background ratio of lung nodules in NIR exploration was 3.29 ± 1.81. The application of NIR devices led to the detection of 9 additional nodules that were missed using traditional detection methods (1 mm computed tomography scan and white-light thoracoscopic exploration) in 7 patients (19.4%). Four of the 9 nodules were confirmed as malignant or atypical adenomatous hyperplasia (44.4%). The other 5 nodules were confirmed as false-positive nodules. The sensitivities and positive predictive values of the ICG-fluorescent imaging for lung tumours were 88.7% and 92.6%, respectively. CONCLUSIONS This study demonstrated the feasibility and safety of using ICG-fluorescent imaging for multiple lung nodules identification in video-assisted thoracoscopic surgery pulmonary resection. Clinicaltrial.gov number NCT02611245.

Sparse Reconstruction of Fluorescence Molecular Tomography Using Variable Splitting and Alternating Direction Scheme

PurposeFluorescence molecular tomography (FMT) is a novel imaging modality for three-dimensional preclinical research and has many potential applications for drug therapy evaluation and tumor diagnosis. However, FMT presents an ill-conditioned and ill-posed inverse problem, which is a challenge for its tomography reconstruction. Due to the importance of FMT reconstruction, it is valuable and necessary to develop further practical reconstruction methods for FMT.ProceduresIn this study, an efficient method using variable splitting strategy as well as alternating direction strategy (VSAD) was proposed for FMT reconstruction. In this method, the variable splitting strategy and the augmented Lagrangian function were first introduced to obtain an equivalent optimization formulation of the original problem. Then, the alternating direction scheme was used to solve the optimization problem and to accelerate its convergence. To examine the property of the VSAD method, three numerical simulation experiments (accuracy assessment experiment, robustness assessment experiment, and reconstruction speed assessment experiment) were performed and analyzed.ResultsThe results indicated that the reconstruction accuracy, the reconstruction robustness, and the reconstruction speed of FMT were satisfactory by using the proposed VSAD method. Two in vivo studies, which were conducted by using two nude mouse models, further confirmed the advantages of the proposed method.ConclusionsThe results indicated that the proposed VSAD algorithm is effective for FMT reconstruction. It was accurate, robust, and efficient for FMT imaging and was feasibly applied for in vivo FMT applications.