Preclinical evaluation of sentinel node localization in the stomach via mannose-labelled magnetic nanoparticles and indocyanine green.

BACKGROUND: Gastrectomy with extended (D2) lymphadenectomy is considered standard of care for gastric cancer to provide the best possible outcomes and pathologic staging. However, D2 gastrectomy is a technically demanding operation and reported to be associated with increased complications and mortality. Application of sentinel lymph node (SLN) concept in gastric cancer has the potential to reduce patient morbidity; however, SLN techniques are not established for gastrectomy, in part due to lack of practical tracers. An effective and convenient tracer with enhanced SLN accumulation is critically needed. METHODS: Mannose-labelled magnetic tracer 'FerroTrace' and fluorescent dye indocyanine green (ICG) were injected laparoscopically into the stomach submucosa of 8 healthy swine under general anaesthesia. Intraoperative fluorescence imaging was used to highlight draining lymphatic pathways containing ICG, while preoperative T2-weighted MRI and ex vivo magnetometer probe measurements were used to identify nodes containing FerroTrace. Lymphadenectomy was performed either robotically (n = 2) or via laparotomy (n = 6). RESULTS: Mixing ICG and FerroTrace ensured concurrence of fluorescent and magnetic signals in SLNs. An initial trial with robotic dissection removed all magnetic LNs (n = 4). In the subsequent laparotomy study that targeted all ICG-LNs based on intraoperative fluorescence imaging, dissection removed an average of 4.7 ± 1.2 fluorescent, and 2.0 ± 1.3 magnetic LNs per animal. Both MRI and magnetometer detected 100% of SLNs (n = 7). FerroTrace demonstrated high specificity to SLNs, which contained 76 ± 30% of total lymphotropic iron, and 88 ± 20 % of the overall magnetometer signal. CONCLUSIONS: Through utilisation of this dual tracer approach, SLNs were identified via preoperative MRI, visualised intraoperatively with fluorescence imaging, and confirmed with a magnetometer. This combination pairs the sensitivity of ICG with SLN-specific FerroTrace and can be used for reliable SLN detection in gastric cancer, with potential applications in neoadjuvant therapy.

A neural network approach to optimising treatments for depression using data from specialist and community psychiatric services in Australia, New Zealand and Japan.

This study investigated the application of a recurrent neural network for optimising pharmacological treatment for depression. A clinical dataset of 458 participants from specialist and community psychiatric services in Australia, New Zealand and Japan were extracted from an existing custom-built, web-based tool called Psynary . This data, which included baseline and self-completed reviews, was used to train and refine a novel algorithm which was a fully connected network feature extractor and long short-term memory algorithm was firstly trained in isolation and then integrated and annealed using slow learning rates due to the low dimensionality of the data. The accuracy of predicting depression remission before processing patient review data was 49.8%. After processing only 2 reviews, the accuracy was 76.5%. When considering a change in medication, the precision of changing medications was 97.4% and the recall was 71.4% . The medications with predicted best results were antipsychotics (88%) and selective serotonin reuptake inhibitors (87.9%). This is the first study that has created an all-in-one algorithm for optimising treatments for all subtypes of depression. Reducing treatment optimisation time for patients suffering with depression may lead to earlier remission and hence reduce the high levels of disability associated with the condition. Furthermore, in a setting where mental health conditions are increasing strain on mental health services, the utilisation of web-based tools for remote monitoring and machine/deep learning algorithms may assist clinicians in both specialist and primary care in extending specialist mental healthcare to a larger patient community.

Preclinical feasibility of robot-assisted sentinel lymph node biopsy using multi-modality magnetic and fluorescence guidance in the head and neck.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a staging procedure dependent on accurate mapping of draining lymphatics via tracers. Robot-assisted SLNB enables access to multiple neck levels with a single incision and intraoperative fluorescence guidance to the SLN. METHODS: Lymphatic mapping in swine was done using a magnetic tracer and fluorescent dye, injected into the tongue. MRI preoperatively mapped lymphatic spread of the magnetic tracer. Dissection was performed using a da Vinci Xi robot guided by fluorescence-imaging of the dye. RESULTS: Robot-assisted SLNB was successfully performed in all animals (n = 5). A novel MRI protocol differentiated SLNs (n = 6) from lower echelon nodes (n = 11) based on flow progression. Fluorescence imaging provided valuable intraoperative guidance and correlated with magnetic-positive nodes. CONCLUSIONS: This study demonstrates preclinical feasibility of a robot-assisted approach to SLNB using magnetic and fluorescent tracers in the head and neck, enabling both preoperative mapping and intraoperative guidance.

Preclinical evaluation of a mannose-labeled magnetic tracer for enhanced sentinel lymph node retention in the head and neck.

Sentinel lymph node biopsy in cancers of the head and neck offers demonstrated clinical and diagnostic value, but adoption is limited by concerns about the detrimental consequence to survival of false negative results in a highly curable setting. The aim of this study was to demonstrate potential to overcome this via application of a novel mannose-labeled magnetic iron oxide tracer. In a large animal model, preoperative imaging and intraoperative magnetometer detection were used to identify magnetic lymph nodes. Iron quantification mapped the distribution of tracer within lymphatic levels. Over a 4-week test period, uptake of magnetic tracer in lymph nodes increased in a linear-like fashion, with a substantial percentage of accumulated iron (83%) being retained in the sentinel node. This result indicates a high affinity of mannose-labeled particles to the sentinel node, while providing a means for the magnetometer probe to indicate node status based on intraoperative signal.

Hybrid 99mTc-magnetite tracer for dual modality sentinel lymph node mapping.

Accuracy of sentinel lymph node identification using radioactive tracers in non-superficial cancers can be limited by radiation shine through and low spatial resolution of detection systems such as intraoperative gamma probes. By utilising a dual radioactive/magnetic tracer, sensitive lymphoscintigraphy can be paired with high spatial resolution intraoperative magnetometer probes to improve the accuracy of sentinel node detection in cancers with complex multidirectional lymphatic drainage. Dextran-coated magnetite nanoparticles (33 nm mean hydrodynamic diameter) were labelled with 99mTc and applied as a lymphotropic tracer in small and large animal models. The dual tracer could be radiolabelled with 98 ± 2% efficiency after 10 min of incubation at room temperature. Biodistribution studies of the tracer were conducted in normal rats (subdermal and intravenous tail delivery, n = 3) and swine (subdermal hind limb delivery, n = 5). In rats the dual tracer migrated through four tiers of lymph node, 20 min after subdermal injection. Results from intravenous biodistribution test for radiocolloids demonstrated no aggregation in vivo, however indicated the presence of some lower-molecular weight radioactive impurities (99mTc-dextran). In swine, the dual tracer could be effectively used to map lymphatic drainage from hind hoof to popliteal and inguinal basins using intraoperative gamma and magnetometer probes. Of the eight primary nodes excised, eight were positively identified by gamma probe and seven by magnetometer probe. The high-purity dual tracer shows early promise for sentinel node identification in complex lymphatic environments by combining sensitive preoperative lymphoscintigraphy with a high-resolution intraoperative magnetometer probe.

Clinical relevance of novel imaging technologies for sentinel lymph node identification and staging.

The sentinel lymph node (SLN) concept has become a standard of care for patients with breast cancer and melanoma, yet its clinical application to other cancer types has been somewhat limited. This is mainly due to the reduced accuracy of conventional SLN mapping techniques (using blue dye and/or radiocolloids as lymphatic tracers) in cancer types where lymphatic drainage is more complex, and SLNs are within close proximity to other nodes or the tumour site. In recent years, many novel techniques for SLN mapping have been developed including fluorescence, x-ray, and magnetic resonant detection. Whilst each technique has its own advantages/disadvantages, the role of targeted contrast agents (for enhanced retention in the SLN, or for immunostaging) is increasing, and may represent the new standard for mapping the SLN in many solid organ tumours. This review article discusses current limitations of conventional techniques, limiting factors of nanoparticulate based contrast agents, and efforts to circumvent these limitations with modern tracer architecture.

Immunospecific targeting of CD45 expressing lymphoid cells: towards improved detection agents of the sentinel lymph node.

This study was designed to demonstrate the potential of small nanoparticulate lymphotropic contrast agents designed to bind with high affinity to lymphoid cells overexpressing the CD45 antigen. To this end, small gold nanoparticles used as model were conjugated to anti-CD45 antibodies and injected in mice in the dorsal toe of the fore/hind paw. Chemical analysis demonstrated rapid uptake and transport of the nanoparticles in the lymphatic as well as significant retention of the nanoparticles with high binding affinity to lymphoid cells in the popliteal and axillary lymph nodes in comparison to non-targeted nanoparticles.