Comparative aspects of targeted sentinel lymph node mapping in veterinary and human medicine: opportunities for future research.

There is a significant overlap in the genetic, metabolic and epigenetic alterations between human and companion animal cancers, including those of the oral cavity, breast, bladder, skin, lungs and pancreas. In many cancer types, the identification and removal of affected lymph nodes are essential for accurate cancer management, including treatment and prognosis. Historically, lymphadenectomy and subsequent radical resection based on regional anatomy, palpation and lymph node aspirates were considered sufficient; however, modern approaches with sentinel lymph node mapping (SLN) mapping have increased the accuracy of surgical decision-making. Preoperative and intraoperative SLN mapping techniques in veterinary patients parallel those used in human medicine. While many of these techniques are highly successful, the main challenges with current methodologies are their sensitivity and specificity for the presence of cancer, which can be overcome via precision medicine and targeted SLN mapping agents. Given the large population of dogs and cats with cancer, the crossover of knowledge between species can help to deepen our understanding of many of these cancers and can be useful in evaluating new drugs and/or therapies. In this review, we discuss SLN mapping techniques in veterinary medicine and the concept of precision medicine as it relates to targeted SLN mapping imaging agents. The large number of companion animals affected by cancer is an underutilized resource to bridge the translational gap and we aim to provide a reference for the use of dogs and cats as a comparative model for human SLN mapping.

99mTc-Tilmanocept performance for sentinel node mapping in breast cancer, melanoma, and head and neck cancer: a systematic review and meta-analysis from a European expert panel.

PURPOSE: Although multiple radiopharmaceuticals are currently available for sentinel node (SN) biopsy, 99mTc-tilmanocept is of particular interest due to its low molecular weight and specific binding capability for the mannose receptors of lymphatic reticuloendothelial cells. In the current systematic review and meta-analysis, we aimed to provide an update from a European expert panel on the performance of 99mTc-tilmanocept for SN biopsy. METHODS: A systematic literature search of the PubMed/Medline and Embase databases was performed to identify studies on the use of 99mTc-tilmanocept for SN identification in oncological patients. The articles' methodological quality was assessed before inclusion. The pooled estimates of the pre-/intraoperative detection rates (DR; proportion of patients with ≥ 1 SN identified) and/or pN + sensitivity (SN + /pN + patients ratio), with 95% confidence intervals (CIs), were calculated for breast cancer, melanoma, and head and neck cancer. RESULTS: Twenty-four articles were included in the systematic review, and twenty-one provided data for the meta-analysis. According to data availability, the 99mTc-tilmanocept-estimated pooled preoperative and intraoperative DRs were 0.94 (95%CI, 0.88-1.01) and 0.99 (0.98-1.00) for breast cancer, 0.98 (0.96-0.99) and 1.00 (0.99-1.00) for melanoma, and 0.97 (0.93-1.02) and 0.99 (0.96-1.01) for head and neck carcinoma. Finally, the pooled sensitivity for nodal metastasis in melanoma was 0.97 (95% CI, 0.92-1.03). CONCLUSION: 99mTc-tilmanocept is a promising radiotracer for SN mapping in patients with breast cancer, melanoma, or head and neck cancer. We strongly believe that multicenter trials are still needed to assess if 99mTc-tilmanocept is superior to other radiotracers used in clinical routine.

Sentinel Node Identification in Melanoma: Current Clinical Impact, New Emerging SPECT Radiotracers and Technological Advancements. An Update of the Last Decade.

BACKGROUND: Melanoma is the most lethal skin cancer with a mortality rate of 262 cases per 100.000 cases. The sentinel lymph node (SLN) is the first lymph node draining the tumor. SLN biopsy is a widely accepted procedure in the clinical setting since it provides important prognostic information, which helps patient management, and avoids the side effects of complete lymph node dissection. The rationale of identifying and removing the SLN relies on the low probability of subsequent metastatic nodes in case of a negative histological exam performed in the SLN. DISCUSSION: Recently, new analytical approaches, based on the evaluation of scintigraphic images are also exploring the possibility to predict the metastatic involvement of the SLN. 99mTc-labeled colloids are still the most commonly used radiotracers but new promising radiotracers, such as 99mTc- Tilmanocept, are now on the market. In the last decades, single photon emission computed tomography- computerized tomography (SPECT/CT) has gained wider diffusion in clinical departments and there is large evidence about its superior diagnostic accuracy over planar lymphoscintigraphy (PL) in the detection of SLN in patients with melanoma. Scientists are also investigating new hybrid techniques combining functional and anatomical images for the depiction of SLN but further evidence about their value is needed. CONCLUSION: This review examined the predictive and prognostic factors of lymphoscintigraphy for metastatic involvement of SLN, the currently available and emerging radiotracers and the evidence of the additional value of SPECT/CT over PL for the identification of SLN in patients with melanoma. Finally, the review discussed the most recent technical advances in the field.

Molecular Imaging of the Glomerulus via Mesangial Cell Uptake of Radiolabeled Tilmanocept.

An unmet need for the clinical management of chronic kidney disease is a predictive tool of kidney function during the first decade of the disease, when there is silent loss of glomerular function. The objective of this study was to demonstrate receptor-mediated binding of tilmanocept to CD206 within the kidney and provide evidence of kinetic sensitivity of this binding to renal function. Methods: Rats were positioned in a PET scanner with the liver and kidneys within the field of view. After an intravenous injection of 68Ga-IRDye800-tilmanocept, using 1 of 2 scaled molar doses (0.02 nmol/g, n = 5; or 0.10 nmol/g, n = 5), or coinjection (n = 3) of 68Ga-IRDye800-tilmanocept (0.10 nmol/g) and unlabeled tilmanocept (5.0 nmol/g), or a negative control, 68Ga-IRDye800-DTPA-galactosyl-dextran (0.02 nmol/g, n = 5), each animal was imaged for 20 min followed by a whole-body scan. Frozen kidney sections were stained for podocytes and CD206 using immunofluorescence. Molecular imaging of diabetic db/db mice (4.9 wk, n = 6; 7.3 wk, n = 4; 13.3 wk, n = 6) and nondiabetic db/m mice (n = 6) was performed with fluorescence-labeled 99mTc-tilmanocept (18.5 MBq, 2.6 nmol). Thirty minutes after injection, blood, liver, kidneys, and urine were assayed for radioactivity. Renal time-activity curves were generated. Results: Rat PET whole-body images and time-activity curves of 68Ga-IRDye800-tilmanocept demonstrated receptor-mediated renal accumulation with evidence of glomerular uptake. Activity within the renal cortex persisted during the 40-min study. Histologic examination demonstrated colocalization of CD206 and IRDye800-tilmanocept within the glomerulus. The glomerular accumulation of the coinjection and the negative control studies were significantly less than the CD206-targeted agent. The db/db mice displayed a multiphasic renal time-activity curve with high urinary bladder accumulation; the nondiabetic mice exhibited renal uptake curves dominated by a single phase with low bladder accumulation. Conclusion: This study demonstrated receptor-mediated binding to the glomerular mesangial cells and kinetic sensitivity of tilmanocept to chronic renal disease. Given the role of mesangial cells during the progression of diabetic nephropathy, PET or SPECT renal imaging with radiolabeled tilmanocept may provide a noninvasive quantitative assessment of glomerular function.

99mTc-Tilmanocept: A Novel Molecular Agent for Lymphatic Mapping and Sentinel Lymph Node Localization.

Preoperative lymphatic mapping in conjunction with intraoperative γ-probe detection is widely used for sentinel node localization in melanoma, breast cancer, and other malignancies. (99m)Tc-radiocolloids have been the standard radiotracers used for sentinel node mapping. (99m)Tc-tilmanocept is a receptor-binding molecular imaging agent approved by the U.S. Food and Drug Administration for lymphatic mapping and lymph node localization in breast cancer, melanoma, clinically node-negative squamous cell carcinoma of the oral cavity, and other solid tumors. It has several advantages over conventional radiocolloids, including rapid injection site clearance, high sentinel node extraction, and low distal node accumulation, which can lead to efficient resource use.