Intraoperative Photoacoustic Imaging of Breast Cancer

Breast cancer is one of the most common cancers to affect women, presenting a lifetime risk of 1 in 8. Treatment of stage 1 and 2 cancers usually involves breast conserving surgery (BCS). The goal of BCS is to remove the entire tumour with a surrounding envelope of healthy tissue, referred to as a negative margin. Unfortunately, up to 50% of surgeries fail to remove the whole tumour. To minimize the risk of cancer recurrence, a second surgery, must therefore be performed. Currently, there is no widely accepted intraoperative tool to significantly mitigate this problem. Employed systems are usually based on imaging, such as x-ray or ultrasonography. Unfortunately, sensitivity and specificity deficits, especially related to breast density, reduce the effectiveness of these methods. Photoacoustic tomography (PAT) is a relatively new imaging modality which uses safe near-infrared laser illumination to generate 3-D images of soft tissues to a depth of up to several cm. We used a custom designed and built intraoperative PAT system, called iPAT, to perform a 100 patient study on freshly excised breast lumpectomy specimens within the surgical setting. The system enabled the evaluation of tumour extent, shape, morphology and position within lumpectomy specimens measuring up to 11 cm in diameter. Scan results were used to compare iPAT-derived tumour size to the gold-standard pathologic examination, and when available, to x-ray, ultrasonography and DCE-MRI. Imaging results were also used to classify specimen margins as close or wide, and positive predictive values (PPV), negative predictive values (NPV), sensitivity and specificity were then calculated to estimate the effectiveness of the iPAT system at predicting lumpectomy margin status. With a close margin prevalence of 35%, the PPV, NPV, sensitivity and specificity of iPAT were found to be 71%, 83%, 69%, and 84%, respectively. Information provided by the iPAT system identified 9 out of the 12 positive specimens, potentially reducing the positive margin rate by 75%. . Contrary to expected photoacoustic contrast mechanisms, iPAT images of hemoglobin distribution correlated poorly with US and X-ray tumour imaging, while hypo-intense regions in lipid-weighted iPAT images were in excellent agreement

Anniversary Paper: Evolution of ultrasound physics and the role of medical physicists and the AAPM and its journal in that evolution

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134810/1/mp2048.pd

Development and Validation of Mechatronic Systems for Image-Guided Needle Interventions and Point-of-Care Breast Cancer Screening with Ultrasound (2D and 3D) and Positron Emission Mammography

The successful intervention of breast cancer relies on effective early detection and definitive diagnosis. While conventional screening mammography has substantially reduced breast cancer-related mortalities, substantial challenges persist in women with dense breasts. Additionally, complex interrelated risk factors and healthcare disparities contribute to breast cancer-related inequities, which restrict accessibility, impose cost constraints, and reduce inclusivity to high-quality healthcare. These limitations predominantly stem from the inadequate sensitivity and clinical utility of currently available approaches in increased-risk populations, including those with dense breasts, underserved and vulnerable populations. This PhD dissertation aims to describe the development and validation of alternative, cost-effective, robust, and high-resolution systems for point-of-care (POC) breast cancer screening and image-guided needle interventions. Specifically, 2D and 3D ultrasound (US) and positron emission mammography (PEM) were employed to improve detection, independent of breast density, in conjunction with mechatronic and automated approaches for accurate image acquisition and precise interventional workflow. First, a mechatronic guidance system for US-guided biopsy under high-resolution PEM localization was developed to improve spatial sampling of early-stage breast cancers. Validation and phantom studies showed accurate needle positioning and 3D spatial sampling under simulated PEM localization. Subsequently, a whole-breast spatially-tracked 3DUS system for point-of-care screening was developed, optimized, and validated within a clinically-relevant workspace and healthy volunteer studies. To improve robust image acquisition and adaptability to diverse patient populations, an alternative, cost-effective, portable, and patient-dedicated 3D automated breast (AB) US system for point-of-care screening was developed. Validation showed accurate geometric reconstruction, feasible clinical workflow, and proof-of-concept utility across healthy volunteers and acquisition conditions. Lastly, an orthogonal acquisition and 3D complementary breast (CB) US generation approach were described and experimentally validated to improve spatial resolution uniformity by recovering poor out-of-plane resolution. These systems developed and described throughout this dissertation show promise as alternative, cost-effective, robust, and high-resolution approaches for improving early detection and definitive diagnosis. Consequently, these contributions may advance breast cancer-related equities and improve outcomes in increased-risk populations and limited-resource settings

Improving access to ultrasound imaging in northern, remote communities

Access to healthcare services—including access to medical imaging—is an important determinant of health outcomes. This thesis aims to improve understanding of and address gaps in access to ultrasound imaging for patients in northern, remote communities, and advance a novel ultrasound technology with the ultimate goal of improving patient care and health outcomes. This thesis first brings greater understanding of patients’ perceptions of access and factors which shape access to ultrasound imaging in northern, remote communities in Saskatchewan, Canada. A qualitative study was performed using interpretive description as a methodological approach and a multi-dimensional conceptualization of access to care as a theoretical framework. The study identified barriers which patients in northern, remote communities face in accessing ultrasound imaging, and demonstrated that geographic remoteness from imaging facilities was a central barrier. To determine whether disparities in access to ultrasound imaging resulted in disparities in utilization of ultrasound services, two population-based studies assessed the association between sociodemographic and geographic factors and obstetrical and non-obstetrical ultrasound utilization in Saskatchewan. In the first study investigating obstetrical ultrasound utilization, multivariate logistic regression analysis demonstrated that women living in rural areas, remote areas, and low income neighbourhoods, as well as status First Nations women, were less likely to have a second trimester ultrasound, an important aspect of prenatal care. In a second study investigating non-obstetrical ultrasound utilization across the entire provincial population, multivariate Poisson regression analysis similarly demonstrated lower rates of non-obstetrical ultrasound utilization among individuals living in rural and remote areas, individuals residing in low income neighbourhoods, and status First Nations persons. To address the barriers which patients in northern, remote communities face in accessing ultrasound imaging and to minimize disparities in ultrasound imaging utilization as identified in previous studies in this thesis, telerobotic ultrasound technology was investigated as a solution to improve access to ultrasound imaging. Using this technology, radiologists and sonographers could remotely manipulate an ultrasound probe via a robotic arm, thereby remotely performing an ultrasound exam while patients remained in their home community. A clinical trial comparing conventional and telerobotic ultrasound approaches was undertaken, validating this technology for obstetrical ultrasound imaging. To determine the feasibility of using telerobotic technology to establish an ultrasound service delivery model to remotely provide diagnostic ultrasound exams in underserved communities, pilot telerobotic ultrasound clinics were developed in three northern, remote communities. Telerobotic ultrasound exams were sufficient for diagnosis in the majority of cases, minimizing travel or reducing wait times for these patients. This technology was subsequently evaluated during a COVID-19 outbreak in northern Saskatchewan, demonstrating the potential of this technology to provide critical ultrasound services to an underserved northern population and minimize health inequities during the COVID-19 pandemic. An economic evaluation was performed to compare a service delivery model using telerobotic ultrasound technology to alternative service delivery models. Telerobotic ultrasound combined with an itinerant sonographer service was found to be the lowest cost option from both a publicly funded healthcare payer perspective and a societal perspective for many northern, remote communities. This thesis provides key insights for health system leaders seeking improved understanding and novel solutions to improve access to ultrasound imaging in northern, remote communities. Findings suggest that telerobotic ultrasound is a viable solution to improve access to ultrasound imaging and reduce costs associated with ultrasound service delivery. Evidence in this thesis may be used to help improve ultrasound services and health equity for patients in underserved northern, remote communities. Continued respectful collaboration with northern, remote, Indigenous peoples and communities will be a critical aspect to ensure that ultrasound services meet community needs

New Mechatronic Systems for the Diagnosis and Treatment of Cancer

Both two dimensional (2D) and three dimensional (3D) imaging modalities are useful tools for viewing the internal anatomy. Three dimensional imaging techniques are required for accurate targeting of needles. This improves the efficiency and control over the intervention as the high temporal resolution of medical images can be used to validate the location of needle and target in real time. Relying on imaging alone, however, means the intervention is still operator dependent because of the difficulty of controlling the location of the needle within the image. The objective of this thesis is to improve the accuracy and repeatability of needle-based interventions over conventional techniques: both manual and automated techniques. This includes increasing the accuracy and repeatability of these procedures in order to minimize the invasiveness of the procedure. In this thesis, I propose that by combining the remote center of motion concept using spherical linkage components into a passive or semi-automated device, the physician will have a useful tracking and guidance system at their disposal in a package, which is less threatening than a robot to both the patient and physician. This design concept offers both the manipulative transparency of a freehand system, and tremor reduction through scaling currently offered in automated systems. In addressing each objective of this thesis, a number of novel mechanical designs incorporating an remote center of motion architecture with varying degrees of freedom have been presented. Each of these designs can be deployed in a variety of imaging modalities and clinical applications, ranging from preclinical to human interventions, with an accuracy of control in the millimeter to sub-millimeter range

High-resolution fluorescence endomicroscopy for rapid evaluation of breast cancer margins

Breast cancer is a major public health problem world-wide and the second leading cause of cancer-related female deaths. Breast conserving surgery (BCS), in the form of wide local excision (WLE), allows complete tumour resection while maintaining acceptable cosmesis. It is the recommended treatment for a large number of patients with early stage disease or, in more advanced cases, following neoadjuvant chemotherapy. About 30% of patients undergoing BCS require one or more re-operative interventions, mainly due to the presence of positive margins. The standard of care for surgical margin assessment is post-operative examination of histopathological tissue sections. However, this process is invasive, introduces sampling errors and does not provide real-time assessment of the tumour status of radial margins. The objective of this thesis is to improve intra-operative assessment of margin status by performing optical biopsy in breast tissue. This thesis presents several technical and clinical developments related to confocal fluorescence endomicroscopy systems for real-time characterisation of different breast morphologies. The imaging systems discussed employ flexible fibre-bundle based imaging probes coupled to high-speed line-scan confocal microscope set-up. A preliminary study on 43 unfixed breast specimens describes the development and testing of line-scan confocal laser endomicroscope (LS-CLE) to image and classify different breast pathologies. LS-CLE is also demonstrated to assess the intra-operative tumour status of whole WLE specimens and surgical excisions with high diagnostic accuracy. A third study demonstrates the development and testing of a bespoke LS-CLE system with methylene blue (MB), an US Food and Drug Administration (FDA) approved fluorescent agent, and integration with robotic scanner to enable large-area in vivo imaging of breast cancer. The work also addresses three technical issues which limit existing fibre-bundle based fluorescence endomicroscopy systems: i) Restriction to use single fluorescence agent due to low-speed, single excitation and single fluorescence spectral band imaging systems; ii) Limited Field of view (FOV) of fibre-bundle endomicroscopes due to small size of the fibre tip and iii) Limited spatial resolution of fibre-bundle endomicroscopes due to the spacing between the individual fibres leading to fibre-pixelation effects. Details of design and development of a high-speed dual-wavelength LS-CLE system suitable for high-resolution multiplexed imaging are presented. Dual-wavelength imaging is achieved by sequentially switching between 488 nm and 660 nm laser sources for alternate frames, avoiding spectral bleed-through, and providing an effective frame rate of 60 Hz. A combination of hand-held or robotic scanning with real-time video mosaicking, is demonstrated to enable large-area imaging while still maintaining microscopic resolution. Finally, a miniaturised piezoelectric transducer-based fibre-shifting endomicroscope is developed to enhance the resolution over conventional fibre-bundle based imaging systems. The fibre-shifting endomicroscope provides a two-fold improvement in resolution and coupled to a high-speed LS-CLE scanning system, provides real-time imaging of biological samples at 30 fps. These investigations furthered the utility and applications of the fibre-bundle based fluorescence systems for rapid imaging and diagnosis of cancer margins.Open Acces

Patient-specific simulation environment for surgical planning and preoperative rehearsal

Surgical simulation is common practice in the fields of surgical education and training. Numerous surgical simulators are available from commercial and academic organisations for the generic modelling of surgical tasks. However, a simulation platform is still yet to be found that fulfils the key requirements expected for patient-specific surgical simulation of soft tissue, with an effective translation into clinical practice. Patient-specific modelling is possible, but to date has been time-consuming, and consequently costly, because data preparation can be technically demanding. This motivated the research developed herein, which addresses the main challenges of biomechanical modelling for patient-specific surgical simulation. A novel implementation of soft tissue deformation and estimation of the patient-specific intraoperative environment is achieved using a position-based dynamics approach. This modelling approach overcomes the limitations derived from traditional physically-based approaches, by providing a simulation for patient-specific models with visual and physical accuracy, stability and real-time interaction. As a geometrically- based method, a calibration of the simulation parameters is performed and the simulation framework is successfully validated through experimental studies. The capabilities of the simulation platform are demonstrated by the integration of different surgical planning applications that are found relevant in the context of kidney cancer surgery. The simulation of pneumoperitoneum facilitates trocar placement planning and intraoperative surgical navigation. The implementation of deformable ultrasound simulation can assist surgeons in improving their scanning technique and definition of an optimal procedural strategy. Furthermore, the simulation framework has the potential to support the development and assessment of hypotheses that cannot be tested in vivo. Specifically, the evaluation of feedback modalities, as a response to user-model interaction, demonstrates improved performance and justifies the need to integrate a feedback framework in the robot-assisted surgical setting.Open Acces