How molecular imaging will enable robotic precision surgery: the role of artificial intelligence, augmented reality, and navigation

Molecular imaging is one of the pillars of precision surgery. Its applications range from early diagnostics to therapy planning, execution, and the accurate assessment of outcomes. In particular, molecular imaging solutions are in high demand in minimally invasive surgical strategies, such as the substantially increasing field of robotic surgery. This review aims at connecting the molecular imaging and nuclear medicine community to the rapidly expanding armory of surgical medical devices. Such devices entail technologies ranging from artificial intelligence and computer-aided visualization technologies (software) to innovative molecular imaging modalities and surgical navigation (hardware). We discuss technologies based on their role at different steps of the surgical workflow, i.e., from surgical decision and planning, over to target localization and excision guidance, all the way to (back table) surgical verification. This provides a glimpse of how innovations from the technology fields can realize an exciting future for the molecular imaging and surgery communities.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Goggle Augmented Imaging and Navigation System for Fluorescence-Guided Surgery

Surgery remains the only curative option for most solid tumors. The standard-of-care usually involves tumor resection and sentinel lymph node biopsy for cancer staging. Surgeons rely on their vision and touch to distinguish healthy from cancer tissue during surgery, often leading to incomplete tumor resection that necessitates repeat surgery. Sentinel lymph node biopsy by conventional radioactive tracking exposes patients and caregivers to ionizing radiation, while blue dye tracking stains the tissue highlighting only superficial lymph nodes. Improper identification of sentinel lymph nodes may misdiagnose the stage of the cancer. Therefore there is a clinical need for accurate intraoperative tumor and sentinel lymph node visualization. Conventional imaging modalities such as x-ray computed tomography, positron emission tomography, magnetic resonance imaging, and ultrasound are excellent for preoperative cancer diagnosis and surgical planning. However, they are not suitable for intraoperative use, due to bulky complicated hardware, high cost, non-real-time imaging, severe restrictions to the surgical workflow and lack of sufficient resolution for tumor boundary assessment. This has propelled interest in fluorescence-guided surgery, due to availability of simple hardware that can achieve real-time, high resolution and sensitive imaging. Near-infrared fluorescence imaging is of particular interest due to low background absorbance by photoactive biomolecules, enabling thick tissue assessment. As a result several near-infrared fluorescence-guided surgery systems have been developed. However, they are limited by bulky hardware, disruptive information display and non-matched field of view to the user. To address these limitations we have developed a compact, light-weight and wearable goggle augmented imaging and navigation system (GAINS). It detects the near-infrared fluorescence from a tumor accumulated contrast agent, along with the normal color view and displays accurately aligned, color-fluorescence images via a head-mounted display worn by the surgeon, in real-time. GAINS is a platform technology and capable of very sensitive fluorescence detection. Image display options include both video see-through and optical see-through head-mounted displays for high-contrast image guidance as well as direct visual access to the surgical bed. Image capture options from large field of view camera as well high magnification handheld microscope, ensures macroscopic as well as microscopic assessment of the tumor bed. Aided by tumor targeted near-infrared contrast agents, GAINS guided complete tumor resection in subcutaneous, metastatic and spontaneous mouse models of cancer with high sensitivity and specificity, in real-time. Using a clinically-approved near-infrared contrast agent, GAINS provided real-time image guidance for accurate visualization of lymph nodes in a porcine model and sentinel lymph nodes in human breast cancer and melanoma patients with high sensitivity. This work has addressed issues that have limited clinical adoption of fluorescence-guided surgery and paved the way for research into developing this approach towards standard-of-care practice that can potentially improve surgical outcomes in cancer

Sonde de biopsie optique afin d'améliorer la sécurité et la précision de diagnostic des biopsies neurochirurgicales

L’évolution de la médecine moderne tend de plus en plus vers une approche personnalisée, nécessitant l’échantillonnage des tumeurs par biopsie pour des analyses histologiques, moléculaires et génomiques menant à un diagnostic précis. Les limites de sensibilité des techniques d’imagerie, les erreurs de ciblage et l’hétérogénéité des lésions sont des limitations importantes à cette approche conduisant souvent à des échantillons de mauvaise qualité, et au besoin de biopsies répétées. Cette thèse vise à la conception d’une aiguille de biopsie guidée par spectroscopie Raman pour améliorer la sécurité et l’efficacité de la procédure de biopsie du cerveau. Le premier objectif consiste à valider l’utilisation de la spectroscopie Raman pour fins de caractérisation de tissus cérébraux. L’intégration d’un système de sonde Raman peropératoire au flux de travail chirurgical et son optimisation pour utilisation en salle d’opération a été effectuée. Une preuve de concept au cours de résections de tumeurs cérébrales sur 10 patients a démontré que le système peut distinguer les tissus vitaux et nécrotiques avec une sensibilité de 84% et une spécificité de 89%. Le second objectif vise à intégrer cette technique dans une aiguille de biopsie commerciale. Ceci impose des contraintes techniques importantes qui ont nécessité l’utilisation d’une différente plage spectrale, le high wavenumber. L’utilisation du high wavenumber a d’abord été validée en utilisant la sonde peropératoire. Cette étude a été effectuée sur 17 patients, démontrant une détection de régions denses en cellules cancéreuses (> 60%) avec une sensibilité de 80% et une spécificité de 90%. L’intégration a ensuite été effectuée sur un premier prototype d’aiguille Raman, et nous démontrons pour la première fois l’utilisation de ce système in vivo dans un modèle de biopsie cérébrale porcine. Finalement, un deuxième prototype utilisant plus d’information spectrale a été développé. Nous présentons une preuve de concept effectuée pour la première fois sur 3 patients humains pendant des procédures de biopsies cérébrales. L’utilisation de ce prototype est prévue dans le cadre d’une étude clinique multicentrique. Les résultats de cette thèse doctorale préparent le terrain pour la traduction clinique de cette méthode de caractérisation moléculaire optique en temps réel pour une biopsie sécuritaire et efficace.----------ABSTRACT The evolution of modern medicine is moving more and more towards a personalized approach, requiring the sampling of tumors with biopsy procedures for histological, molecular and genomic analyzes for an accurate diagnosis. Sensitivity limits of imaging techniques, targeting errors and lesion heterogeneity are important limitations to this approach often leading to poor quality samples, and the need for repeated biopsies. This thesis aims at the development of a biopsy needle guided with Raman spectroscopy to improve safety and efficiency of brain biopsy procedures. The first objective is the validation of Raman spectroscopy for the characterization of brain tissue. The integration of an intraoperative Raman probe system into the surgical workflow and optimization for use in the operating room was performed. A proof of concept was carried out during brain tumor resection in 10 patients demonstrating that the system can distinguish between vital and necrotic tissues with a sensitivity of 84% and a specificity of 89%. The second objective is to integrate the technique into a commercial biopsy needle. This imposes important technical constraints that required the use of a different spectral range, called the high wavenumber. The use of the high wavenumber was first validated using intraoperative probe. This study was carried out on 17 patients, demonstrating a detection of dense cancer (> 60% cancer cells) with a sensitivity of 80% and a specificity of 90%. The integration was then performed on a first prototype Raman needle, and we demonstrate for the first time the use of this system in vivo in a porcine brain biopsy model. Finally, a second prototype using more spectral information was developed. A proof of concept using the device to measure Raman spectra at the tip of the needle on 3 patients during cerebral biopsy procedures is presented for the first time. The use of this prototype is planned as part of a multi-center clinical study. The results of this doctoral thesis set the stage for the clinical translation of this real-time optical molecular characterization method for safe and efficient biopsy

Novel Magnetic Resonance Imaging-Compatible Mechatronic Needle Guidance System for Prostate Focal Laser Ablation Therapy

Advances in prostate cancer (PCa) screening techniques have led to diagnosis of many cases of low-grade and highly localized disease. Conventional whole-gland therapies often result in overtreatment in such cases and debate still surrounds the optimal method of oncologic control. MRI-guided prostate focal laser ablation (FLA) is a minimally invasive treatment option, which has demonstrated potential to destroy localized lesions while sparing healthy prostatic tissue, thereby reducing treatment-related side effects. Many challenges still exist in the development of FLA, including patient selection; tumour localization, visualization, and characterization; needle guidance; and evaluation of treatment efficacy. The objective of this thesis work was to advance and enhance techniques for needle guidance in MRI-guided focal laser ablation (FLA) therapy of PCa. Several steps were taken in achieving this goal. Firstly, we evaluated the overlap between identified lesions and MRI-confirmed ablation regions using conventional needle guidance. Non-rigid thin-plate spline registration of pre-operative and intra-operative images was performed to align lesions with ablation boundaries and quantify the degree of coverage. Complete coverage of the lesion with the ablation zone is a clinically important metric of success for FLA therapy and we found it was not achieved in many cases. Therefore, our next step was to develop an MRI-compatible, remotely actuated mechatronic system for transperineal FLA of prostate cancer. The system allows physicians in the MRI scanner control room to accurately target lesions through 4 degrees of freedom while the patient remains in the scanner bore. To maintain compatibility with the MRI environment, piezoelectric motors were used to actuate the needle guidance templates, the device was constructed from non-ferromagnetic materials, and all cables were shielded from electromagnetic interference. The MR compatibility and needle placement accuracy of the device were evaluated with virtual and phantom targets. The system should next be validated for accuracy and usefulness in a clinical trial where more complex tissue properties and potential patient motion will be encountered. Future advances in modeling the tissue properties and compensating for deformation of the prostate, as well as predicting needle deflection, will further bolster the potential of FLA as option for the management of PCa

Postoperative hypoparathyroidism - Current and novel preventative methods

Background Hypocalcaemia is the most common complication following thyroid surgery. It is associated with significant short and long-term patient morbidity. Many studies have assessed and reported on risks, predictive and preventative factors for post-operative hypocalcaemia. The aims of this research were to search the literature for useful preventative measures of post-thyroidectomy hypoparathyroidism and to assess two novel modalities for their potential in the early intraoperative identification and preservation of parathyroid glands to avoid postoperative hypocalcaemia. The objectives of the study were: 1- To perform a systematic review and meta-analysis of the effectiveness of preventative and other surgical measures on post-thyroidectomy hypocalcaemia. 2- To study Methylene Blue (MB) emitted fluorescence from soft tissue structures in the rabbit neck thereby examining its potential for use in human surgery to differentiate between thyroid and parathyroid glands. 3- To determine the electrical impedance patterns of the thyroid, parathyroid and other soft tissue structure in the rabbit neck thereby examining the potential of impedance spectroscopy as an intraoperative tool for parathyroid identification. Methods Systematic review and meta-analysis: A comprehensive search of PubMed, EMBASE, and Cochrane databases was performed for studies reporting on preventative and other surgical measures and their effect on reducing post-thyroidectomy hypoparathyroidism. Quality of included papers was assessed using the Cochrane risk of bias tool or a modified Newcastle-Ottawa Scale (NOS). The results of all included studies were summarized and meta-analyses were performed where appropriate. Two animal experiments were then carried out to assess the potential role of two novel modalities, near-infrared (NIR) fluorescence imaging using intravenous (IV) MB and electrical impedance spectroscopy (EIS), in the prevention of post-operative hypocalcaemia. Near-infrared (NIR) fluorescence imaging using intravenous MB: Thyroid and external parathyroid glands (PGs) were exposed in six New Zealand White (NZW) rabbits under anaesthesia. Varying doses of MB (0.025 - 3 mg/kg) were injected through the marginal ear vein. NIR fluorescence from exposed tissues was recorded at different time intervals (0 - 74 minutes) using Fluobeam®700 device. Electrical Impedance Spectroscopy (EIS): The central neck compartment was dissected in nine freshly culled NZW rabbits. In vivo and ex vivo electrical impedance (EI) were measured from thyroid lobes, external PGs, adipose tissue and strap muscle using APX100TM device. The glands identified in these experiments were resected and sent for histological assessment. Results Systematic review and meta-analysis: This included 39 randomised controlled trials (RCTs) and 37 observational studies. Interventions studied included; haemostatic techniques, extent of thyroidectomy and central neck dissection, surgical approach, supplements (calcium, vitamin D and thiazide diuretics), parathyroid gland auto-transplantation (PGAT) and intra-operative parathyroid gland (PG) identification, truncal ligation of inferior thyroid artery (ITA), pre-operative magnesium infusion, and use of magnification loupes and surgicel. Measures associated with significantly lower rates of transient hypocalcaemia in meta-analysis were: post-operative calcium and vitamin D supplementation compared to either calcium supplements alone (odds ratio (OR) 0.66; p=0.04) or no supplements (OR 0.34; p=0.007), and bilateral subtotal thyroidectomy (BST) compared to Hartley Dunhill (HD) procedure (OR 0.35; p=0.01). Meta-analyses did not demonstrate any measure to be significantly associated with a reduction in permanent hypocalcaemia. NIR fluorescence: Thyroid and external PGs were the only neck structures to demonstrate significant fluorescence in the central neck compartment. External PGs demonstrated lower fluorescence intensities and reduced washout times at all MB doses compared to the thyroid gland. A dose of 0.1 mg/kg MB was adequate to identify fluorescence; this also delineated the blood supply of the external PGs. EIS: The impedance was higher for thyroid tissue at lower frequencies and for parathyroid tissue at higher frequencies. Ex vivo electrical impedance spectra were significantly higher compared to the in vivo spectra across all frequencies for thyroid and parathyroid tissues (p < 0.001). The ratio of low to high frequency in vivo impedance of thyroid, parathyroid and muscle was significantly different (p < 0.001), allowing for differentiation between these tissues. Histology confirmed correct identification of all excised thyroid and PGs in both experiments. Conclusions The systematic review identified post-operative calcium and vitamin D supplementation and bilateral subtotal thyroidectomy (over HD) as being effective in prevention of transient hypocalcaemia. However, the majority of RCTs were of low quality, primarily due to lack of blinding. The wide variability in study design, outcome definitions and assessment methods prevented meaningful summation of results from studies on a number of preventative measures and for permanent hypocalcemia. NIR fluorescence with IV MB helps to differentiate between thyroid and PGs in the rabbit. This has the potential to improve outcomes in thyroid and parathyroid surgery by increasing the accuracy of parathyroid identification. The use of low doses of MB may also avoid the side effects associated with currently used doses in humans (3-7mg/kg). Electrical impedance spectra of rabbit thyroid and parathyroid glands are distinct and different from each other and from skeletal muscle. If these results are replicated in human tissue, they have the potential to improve patient outcomes by achieving early identification and preservation of PGs