Detection of melanoma, breast cancer and head and neck squamous cell cancer sentinel lymph nodes by Tc-99m Tilmanocept (Lymphoseek®).

Technetium-99m-labeled Tilmanocept or Lymphoseek® (Cardinal Health, Dublin, Ohio) is a soluble, synthetic molecule with a small diameter (7 nm), which is comprised of technetium-99m chelated to a dextran backbone containing multiple units of mannose ligands with a high affinity for CD206, a receptor located on the surface of macrophages and dendritic cells that are found in high concentration in lymph nodes. It enables quick transit from the injection site and rapid lymph node accumulation. The binding of mannose ligand and CD206 results in the internalization of the ligand and receptor into the cell. Once the Technetium-99m-labeled Tilmanocept (Lymphoseek®) reaches the lymph node, it is readily internalized by the macrophages and dendritic cells within the draining lymph nodes. Technetium-99m-labeled Tilmanocept (Lymphoseek®) has been extensively studied as a radioisotope for detection of sentinel lymph nodes in melanoma, breast cancer and head and neck squamous cell carcinoma in clinical trials. Based on its safety and ability to detect sentinel lymph nodes satisfactorily, it has been approved by the FDA to use as a radioisotope for preoperative lymphoscintigraphy for identification of sentinel lymph nodes in these types of cancer. Further, the FDA has expanded approval of Technetium-99m-labeled for sentinel lymph node mapping of all solid tumors as well as in pediatric patients.

The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with 99mTc-Tilmanocept SPECT.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients' outcome and management. High infiltration of CD206+ M2-like macrophages in the tumor microenvironment (TME) indicates poor prognosis and survival in TNBC patients. As we previously showed that membrane expression of GRP94, an endoplasmic reticulum chaperone, was associated with the anti-inflammatory profile of human PBMC-derived M2 macrophages, we hypothesized that intra-tumoral CD206+ M2 macrophages expressing GRP94 may represent innovative targets in TNBC for theranostic purposes. We demonstrate in a preclinical model of 4T1 breast tumor-bearing BALB/c mice that (i) CD206-expressing M2-like macrophages in the TME of TNBC can be specifically detected and quantified using in vivo SPECT imaging with 99mTc-Tilmanocept, and (ii) the inhibition of GRP94 with the chemical inhibitor PU-WS13 induces a decrease in CD206-expressing M2-like macrophages in TME. This result correlated with reduced tumor growth and collagen content, as well as an increase in CD8+ cells in the TME. 99mTc-Tilmanocept SPECT imaging might represent an innovative non-invasive strategy to quantify CD206+ tumor-associated macrophages as a biomarker of anti-GRP94 therapy efficacy and TNBC tumor aggressiveness.

Does 99mTc-tilmanocept, as next generation radiotracer, meet with the requirements for improved sentinel node imaging?

INTRODUCTION AND OBJECTIVES: To evaluate the migration of 99mTc-tilmanocept from the injection site (IS) as well as the uptake in sentinel nodes (SNs) and non-SNs for lymphatic mapping in patients with breast cancer and melanoma, scheduled for SN biopsy after interstitial tracer administration. MATERIALS AND METHODS: For 29 primary tumours in 28 patients (mean age: 62y, range: 45-81y) scheduled for SN biopsy planar images were acquired 10 and 120min after administration of 74MBq 99mTc-tilmanocept, in order to evaluate lymphatic drainage as well as uptake ratios between injection site (IS), SN and non-SN. SPECT-CT was performed immediately after delayed planar images to enable anatomical lymph node localization. RESULTS: SNs were visualized in all patients (100%) with drainage to 34 basins. Uptake in non-SNs was perceived in 16 basins (47%). Number of SNs was concordant between early and delayed images in all basins excepting five (86%). In 24 patients tracer migrated to one lymph node basin (LNB), in three to 2 and in one to 4. When IS was included (N=29) on image, IS/SN ratio could be measured per LNB. The IS/SN ratio at 2h compared to 15min decreased with an average of 66% (range: 15-96%). SN/non-SN 2h ratio in LNBs with visible non-SNs averaged 6.6 (range: 2.3-15.6). In 9 patients with two SNs SN1/SN2 ratio averaged 1.9 on delayed images. At histopathology, SNs were found to be tumour positive in 7 basins (20%). CONCLUSION: 99mTc-tilmanocept appears to meet the requirements for improved SN imaging in breast cancer and melanoma on the basis of early and persistent SN visualization frequently accompanied by no or markedly less non-SN uptake. This is associated to rapid migration from the injection site together with increasing SN uptake and retention as expressed by decreasing IS/SN and persistently high SN/non-SN ratios. Further head-to-head comparison of 99mTc-tilmanocept with standard SN radiotracers in larger series of patients is necessary.

A receptor-binding radiopharmaceutical for imaging of traumatic brain injury in a rodent model: [99mTc]Tc-tilmanocept.

INTRODUCTION: Blood-brain barrier (BBB) disruption and subsequent neuro-inflammation occur following traumatic brain injury (TBI), resulting in a spectrum of human nervous system disorders. [99mTc]Tc-tilmanocept is a receptor-binding radiopharmaceutical FDA-approved for sentinel lymph node mapping. We hypothesize that after an intravenous (i.v.) injection, [99mTc]Tc-tilmanocept, will traverse a disrupted BBB and bind to CD206-bearing microglial cells. METHODS: Age-matched mice were divided into three groups: 5-days post TBI (n = 4), and 5-days post sham (n = 4), and naïve controls (n = 4). IRDye800CW-labeled [99mTc]Tc-tilmanocept (0.15 nmol per gram body weight) and FITC-labeled bovine serum albumin (FITC-BSA) were injected (i.v.) into each mouse. Mice were imaged with a high-resolution gamma camera for 45 min. Immediately after imaging, the brains were perfused with fixative, excised, imaged with a fluorescence scanner, assayed for radioactivity, and prepared for histology. RESULTS: In vivo nuclear imaging, ex vivo fluorescence imaging, ex vivo gamma well counting, and histo-microscopy demonstrated enhanced tilmanocept uptake in the TBI region. The normalized [99mTc]Tc-tilmanocept uptake value from nuclear imaging and the maximum pixel intensity from fluorescence imaging of the TBI group (1.12 ±â€¯0.12 and 2288 ±â€¯278 a.u., respectively) were significantly (P < 0.04) higher than the sham group (0.64 ±â€¯0.28 and 1708 ±â€¯101 a.u., respectively) and the naive group (0.76 ±â€¯0.24 and 1643 ±â€¯391 a.u., respectively). The mean [99mTc]Tc-tilmanocept scaled uptake in the TBI brains (0.058 ±â€¯0.013%/g) was significantly (P < 0.010) higher than the scaled brain uptake of the sham group (0.031 ±â€¯0.011%/g) and higher (P = 0.04) than the uptake of the naïve group (0.020 ±â€¯0.002%/g). Fluorescence microscopy demonstrated increased uptake of the IRDye800CW-tilmanocept and FITC-BSA in the TBI brain regions. CONCLUSION: [99mTc]Tc-tilmanocept traverses disrupted blood-brain barrier and localizes within the injured region. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [99mTc]Tc-tilmanocept could serve as an imaging biomarker for TBI-associated neuroinflammation and any disease process that involves a disruption of the blood-brain barrier.

Sentinel Lymph Node Biopsy in Breast Cancer with 99mTc-Tilmanocept: A Multicenter Study on Real-Life Use of a Novel Tracer.

99mTc-tilmanocept is a novel radiopharmaceutical for sentinel lymph node (SLN) biopsy in breast cancer. Our aim was to describe results with 99mTc-tilmanocept in a heterogeneous group of breast cancer patients scheduled for SLN biopsy. Methods: Radiotracer preparation followed the manufacturer's indications. Local protocols for SLN detection within 9 participant centers were not changed for the entire duration of the study. In total, 344 patients with T1-T4, N0-N2 breast cancer (352 lesions) were included. Superficial (intradermal or periareolar) or deep (peritumoral or intratumoral) injections were performed. The doses were adjusted depending on the scheduled time for surgery. Results: Lymphoscintigraphy was able to depict at least 1 SLN in 339 of 352 breast lesions (96.3%), and the intraoperative SLN detection rate reached 97.2%. On univariable analysis, SLN detection rates did not differ by age, clinical T or N stage, tumor location, histologic subtype, or prior neoadjuvant therapy. Lymphoscintigraphy showed higher SLN detection in patients with a normal weight (body mass index < 25) than in those who were overweight or obese (body mass index ≥ 25), at 99.2% versus 94.6%, respectively (P = 0.031). The proportion of patients with preoperative lymphoscintigraphic detection or excised SLNs was higher with superficial than deep injections. Reinjected cases were significantly lower when superficial injection was chosen first (P < 0.001). Injection site and the tumor markers human epidermal growth factor receptor 2 and estrogen receptor had an impact on preoperative SLN visualization and intraoperative localization. In 80 cases, SLN biopsy resulted in a positive lymph node. During a mean follow-up of 19 mo, no axillary recurrences were observed. Conclusion: Whatever the protocol, 99mTc-tilmanocept showed good results in a heterogeneous breast cancer population, although the best results were achieved when a superficial injection was chosen.

Cy3-tilmanocept labeling of macrophages in joints of mice with antibody-induced arthritis and synovium of human patients with rheumatoid arthritis.

γ-Tilmanocept (99m Tc-tilmanocept) is a receptor-directed, radiolabeled tracer that is FDA-approved for guiding sentinel lymph node biopsy. Tilmanocept binds the C-type lectin mannose receptor (MR, CD206) on macrophages. In this study, nonradioactive, fluorescently-labeled Cy3-tilmanocept was used to detect CD206+ mononuclear cells in the cartilage of mice with antibody-induced arthritis and in the synovial fluid and tissue of human subjects with rheumatoid arthritis (RA) for comparison with osteoarthritis (OA), and healthy volunteer (HV) controls. Murine arthritis was induced by injection of monoclonal anti-cartilage antibody followed by injection of Escherichia coli lipopolysaccharide. Post-arthritis development (7-11 days), the mice were injected intravenously with Cy3-tilmanocept followed by in vivo and ex vivo epifluorescence imaging. Two-photon imaging, immunofluorescence, and immunohistochemistry were used to identify articular and synovial macrophages (CD206, F4/80, and Cy3-tilmanocept binding) in murine tissues. Cy3-tilmanocept epifluorescence was present in arthritic knees and elbows of murine tissues; no radiographic changes were noted in the skeletons. However, inflammatory arthritic changes were apparent by histopathology and immunohistochemistry (F4/80), immunofluorescence (CD206) and Cy3-tilmanocept binding. In human RA synovial fluid, Cy3-tilmanocept staining correlated with CD206+ /CD16+ cells; negligible labeling was observed in OA samples. Cy3-tilmanocept colocalized with CD206 and staining was significantly higher in RA synovial tissue compared to OA or HV. Our results demonstrate that imaging with Cy3-tilmanocept can detect in vivo inflammatory, CD206+ macrophages in an early arthritis animal model and in human RA patients. These data establish a novel tool for preclinical research of early arthritis and have implications for early RA detection and monitoring of therapeutic efficacy in humans.

Comparison of 99mTc-Tilmanocept and Hybrid Indocyanine Green-99mTc-Albumin Nanocolloid Drainage in a Patient With Melanoma in the Scalp.

We present the planar lymphoscintigraphies and SPECT/CT images of a 60-year-old man diagnosed as having melanoma (Breslow 1.8 mm) in left parietal scalp, close to head midline. Sentinel lymph node biopsy using Tc-tilmanocept was performed, but the surgery was canceled. Two weeks later, sentinel lymph node biopsy was repeated, but using the hybrid radiotracer indocyanine green-Tc-albumin nanocolloid. The lymphatic drainage in left laterocervical region was similar with these 2 radiotracers, but on the right side, more sentinel lymph nodes were detected with nanocolloid compared with tilmanocept.

CT-based Airway Flow Model to Assess Ventilation in Chronic Obstructive Pulmonary Disease: A Pilot Study.

Background The lack of functional information in thoracic CT remains a limitation of its use in the clinical management of chronic obstructive pulmonary disease (COPD). Purpose To compare the distribution of pulmonary ventilation assessed by a CT-based full-scale airway network (FAN) flow model with hyperpolarized xenon 129 (129Xe) MRI (hereafter, 129Xe MRI) and technetium 99m-diethylenetriaminepentaacetic acid aerosol SPECT ventilation imaging (hereafter, V-SPECT) in participants with COPD. Materials and Methods In this prospective study performed between May and August 2017, pulmonary ventilation in participants with COPD was computed by using the FAN flow model. The modeled pulmonary ventilation was compared with functional imaging data from breath-hold time-series 129Xe MRI and V-SPECT. FAN-derived ventilation images on the coronal plane and volumes of interest were compared with functional lung images. Percentage lobar ventilation estimated by the FAN model was compared with that measured at 129Xe MRI and V-SPECT. The statistical significance of ventilation distribution between FAN and functional images was demonstrated with the Spearman correlation coefficient and χ2 distance. Results For this study, nine participants (seven men [mean age, 65 years ± 5 {standard deviation}] and two women [mean age, 63 years ± 7]) with COPD that was Global Initiative for Chronic Obstructive Lung Disease stage II-IV were enrolled. FAN-modeled ventilation profile showed strong positive correlation with images from 129Xe MRI (ρ = 0.67; P < .001) and V-SPECT (ρ = 0.65; P < .001). The χ2 distances of the ventilation histograms in the volumes of interest between the FAN and 129Xe MRI and FAN and V-SPECT were 0.16 ± 0.08 and 0.28 ± 0.14, respectively. The ratios of lobar ventilations in the models were linearly correlated to images from 129Xe MRI (ρ = 0.67; P < .001) and V-SPECT (ρ = 0.59; P < .001). Conclusion A CT-based full-scale airway network flow model provided regional pulmonary ventilation information for chronic obstructive pulmonary disease and correlates with hyperpolarized xenon 129 MRI and technetium 99m-diethylenetriaminepentaacetic acid aerosol SPECT ventilation imaging. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Schiebler and Parraga in this issue.

[99mTc]Tilmanocept Lymphscintigraphy after inconclusive [99mTc]Nanocolloid Scan in Breast Cancer.

Lymphatic mapping for identification and subsequent removal of the sentinel lymph node (SLN) is an established procedure in breast cancer and cutaneous melanoma to minimize the extent of surgery (and thus, associated morbidity), simplify histopathological processing and subsequently provide prognostic information and help choose the optimal patient management. Established methods for SLN mapping include visual identification of nodal staining after peritumoral injection of a (blue) dye or the use of lymphoscintigraphy with technetium-labelled nanocolloid. In experienced hands, success rates for both methods exceed 95 %, nonetheless in some patients they fail despite correct application and imaging techniques. Potential reasons for false-negative SLN detection rates -beyond poor tracer injection technique or imaging of the wrong nodal basin- include inadequate pathologic examination of the SLN or complete replacement of the SLN with neoplastic disease, causing the injected tracer to completely bypass the infiltrated node 1.Beyond colloid particles, the more specific receptor-targeting small molecule [99mTc]Tilmanocept has recently been approved for scintigraphic SLN detection. Tilmanocept, or mannosyl diethylene-triamine-pentaacetate (DTPA) dextran, has a small molecular size of approximately 7 nm and works via specific binding to the mannose receptor (CD206) 2. The mannose receptor is particularly overexpressed on macrophages and dendritic precursor cells within lymph nodes, thus uptake in lymph nodes is not dependent on particle size 2, 3. In pilot studies scintigraphic SLN detection with [99mTc]Tilmanocept was superior to dye staining 4. Given its beneficial properties, [99mTc]Tilmanocept might offer advantages over the alternatively used radiocolloids. We present four cases of [99mTc]Tilmanocept application after inconclusive or unsuccessful attempts of SLN detection using [99mTc]nanocolloid lymphoscintigraphy.

99mTc-Tilmanocept Versus 99mTc-Sulfur Colloid in Lymphoscintigraphy: Sentinel Lymph Node Identification and Patient-Reported Pain.

Lymphoscintigraphy plays a vital role in sentinel lymph node (SLN) identification in oncologic breast surgery. The effectiveness of SLN localization and the degree of patient pain were compared between filtered 99mTc-sulfur colloid (99mTc-SC) and 99mTc-tilmanocept. Methods: A retrospective review of patients undergoing lymphoscintigraphy for breast cancer using 99mTc-SC (June 1, 2010, to December 31, 2011) or 99mTc-tilmanocept (June 1, 2013, to January 31, 2014) was performed. SLN appearance time and uptake, SLN pathology, proportion of positive SLNs removed, and pain scores were compared for each radiopharmaceutical using the χ2 test, Fisher exact test, and unequal variance t test, as appropriate. Results: In total, 76 patients, with 86 evaluated axillae, underwent lymphoscintigraphy: 29 with 99mTc-SC and 47 with 99mTc-tilmanocept. The mean SLN appearance time was 11.0 min for 99mTc-SC and 19.3 min for 99mTc-tilmanocept (P = 0.003). There was no difference in the mean transit uptake percentage: 2.2% for 99mTc-SC and 1.9% for 99mTc-tilmanocept (P = 0.55). 99mTc-tilmanocept identified a greater proportion of intraoperative blue nodes than did 99mTc-SC (P = 0.03). There was no significant difference between 99mTc-SC and 99mTc-tilmanocept in the number of SLNs removed, number of patients with positive SLNs, or pain score. Conclusion: 99mTc-SC use in lymphoscintigraphy is an acceptable alternative to 99mTc-tilmanocept for SLN detection in breast cancer, on the basis of the similarity in intraoperative SLN identification and pain scores.

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.

Consecutive Case Series of Melanoma Sentinel Node Biopsy for Lymphoseek Compared to Sulfur Colloids.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an important adjunct in the staging of patients with melanoma. Preoperative lymphoscintigraphy with radiolabeled isotopes is essential to localize sentinel nodes for removal. Our study compared the effectiveness of Lymphoseek to standard sulfur colloids in patients with melanoma undergoing SLNB. METHODS: We queried our IRB-approved melanoma database to identify 370 consecutive patients who underwent SLNB from 2012 to 2016 with at least 1 y of follow-up. There were 185 patients in each group. Data points included characteristics of the primary melanoma lymphoscintigraphy and SLNB. Student's t-test and chi-square were used to analyze the data with a P value of <0.05 being considered significant. RESULTS: Patients were equally matched in regard to age, sex, and primary characteristics of their melanoma. In comparison to sulfur colloid, Lymphoseek required lower radiation dosages (P < 0.001), shorter mapping times (P = 0.008), and decreased number of sentinel nodes removed (P = 0.03). There was no difference in the number of patients with positive nodes (P = 0.5). In addition, there were no statistical differences between the two radioactive tracers in regard to the number of patients with false-negative SLNB. CONCLUSION: Lymphoseek has the potential to decrease radioactivity and mapping time in patients who need SLNB. With a decrease in the number of nodes removed without loss of sensitivity, there is a potential to avoid unnecessary node removal and thus complications such as lymphedema. Longer follow-up will help to determine if there is any increase in false-negative rates despite fewer nodes removed.

Automated Region of Interest Detection Method in Scintigraphic Glomerular Filtration Rate Estimation.

The glomerular filtration rate (GFR) is a crucial index to measure renal function. In daily clinical practice, the GFR can be estimated using the Gates method, which requires the clinicians to define the region of interest (ROI) for the kidney and the corresponding background in dynamic renal scintigraphy. The manual placement of ROIs to estimate the GFR is subjective and labor-intensive, however, making it an undesirable and unreliable process. This work presents a fully automated ROI detection method to achieve accurate and robust GFR estimations. After image preprocessing, the ROI for each kidney was delineated using a shape prior constrained level set (spLS) algorithm and then the corresponding background ROIs were obtained according to the defined kidney ROIs. In computer simulations, the spLS method had the best performance in kidney ROI detection compared with the previous threshold method (threshold) and the Chan-Vese level set (cvLS) method. In further clinical applications, 223 sets of 99mTc-diethylenetriaminepentaacetic acid renal scintigraphic images from patients with abnormal renal function were reviewed. Compared with the former ROI detection methods (threshold and cvLS), the GFR estimations based on the ROIs derived by the spLS method had the highest consistency and correlations (r = 0.98, p < 0.001) with the reference estimated by experienced physicians. The results indicate that the proposed automated ROI detection method has great potential in automated ROI detection for accurate and robust GFR estimation in dynamic renal scintigraphy.

The synthesis of a new macromolecule for the sentinel node detection: 99mTc-gly-mannosyl-dextran.

OBJECTIVE: We aimed to design and synthesize a new macromolecule for sentinel node detection to improve the imaging quality and avoid possible adverse effect. BACKGROUND: The imaging of sentinel lymph node has been an important field in the nuclear medicine. A lot of imaging agents have been developed, including Tc-sulfer colloid, Tc-labeled dextrans and the latest Tc-DTPA-mannosyl-dextran. With the technology advanced, the imaging ability of the agents has been better and better. However, there are still some drawbacks. MATERIALS AND METHODS: The new macromolecule agent was based on the dextran macromolecule backbone. Then the gly-gly-gly and mannose molecules were conjugated onto the backbone proportionally by targeting two different reaction sites. Once the new macromolecule was labelled with Tc, its imaging ability was tested by single-photon emission computed tomography scanning with Tc-sulfur colloid as the comparison. RESULTS: The average numbers of gly-gyl-gyl and mannosyl groups on the dextran backbone are determined to be ∼1: 2 per dextran. The average molecular diameter and molecular weight are measured to be 5.4±0.7 nm and 10 324 g/mol, respectively. The macromolecule is labelled by Tc with 93.2±2.4% radiochemical yield. The lymphatic imaging by single-photon emission computed tomography with the labeled compound showed no worse imaging ability but cost less time than the commercially available Tc-sulfur colloid. CONCLUSION: A new macromolecule imaging agent for sentinel node detection has been synthesized with better imaging ability and less imaging time cost.

Next generation of radiotracers for sentinel lymph node biopsy: What is still necessary to establish new imaging paradigms? / Nueva generación de radiotrazadores para la biopsia del ganglio centinela: ¿qué es necesario para establecer nuevos paradigmas de imagen?

Sentinel lymph node (SLN) biopsy is now the standard of care for regional staging in several solid tumors. The interstitial administration of a radiotracer around the primary tumor provide the possibility to sequentially obtain images with a gamma camera and visualize lymphatic mapping and the SLN. There is, however, a large geographical variability in those radiotracers and nanocolloids ranging from 15-100nm which are most widely employed in Europe, while filtered and unfiltered 99mTc-sulfur colloid (range 20-1000nm) is usually used in the USA with different drawbacks in its use. The new radiotracer 99mTc-Tilmanocept, designed specifically for the identification of SLNs and recently becoming commercially available in USA and Europe, appears to have the potency to overcome the shortcomings described for the conventional radiotracers used until now for SLN biopsy and at the same time to transform current imaging paradigms. After delineating the challenges for the next generation of radiotracers, this paper discusses the properties of 99mTc-Tilmanocept, its validation process for SLN biopsy and its emerging clinical applications in various malignancies.

Outcomes of "one-day" vs "two-day" injection protocols using Tc-99m tilmanocept for sentinel lymph node biopsy in breast cancer.

No prior studies have compared Tc-99m tilmanocept (TcTM) one-day and two-day injection protocols for sentinel lymph node (SLN) biopsy in breast cancer (BC). We retrospectively identified patients with clinically node-negative BC undergoing SLN biopsy at our institution. Patients received a single, intradermal peritumoral injection of TcTM on day of surgery or day prior to surgery in addition to an intraoperative injection of isosulfan blue dye. Univariable and multivariable Poisson regression count models were constructed to assess the effects of injection timing, radiologist, patient and surgeon characteristics on the number of removed SLNs. A total of 617 patients underwent SLN biopsy with TcTM and blue dye. Sixty-seven (10.9%) patients were injected with the two-day protocol. Patients in the one-day protocol had a mean of 3.0 (standard deviation (SD) 1.9) SLNs removed compared with 2.7 (SD 1.4) SLNs in the two-day protocol, P-value = .13. On multivariable analysis, patient age and operating surgeon significantly affected the number of removed SLNs; however, the injection timing and the nuclear radiologist did not influence the number of removed SLNs. The performance of Tc-99m tilmanocept did not differ significantly between one-day and two-day injection protocols. These results are similar to other radiotracers used for SLN biopsy in BC.

Tc-99m tilmanocept versus Tc-99m sulfur colloid in breast cancer sentinel lymph node identification: Results from a randomized, blinded clinical trial.

INTRODUCTION: No prior trials have compared sentinel lymph node (SLN) identification outcomes between Tc-99m tilmanocept (TcTM) and Tc-99m sulfur colloid (TcSC) in breast cancer (BC). METHODS: We report on the secondary outcomes from a randomized, double-blinded, single surgeon clinical trial comparing post-injection site pain between TcTM and TcSC. Patients were randomized to receive a preoperative single, peritumoral intradermal injection of TcTM or TcSC. The number of total, "hot", and blue nodes detected and removed were compared between groups. RESULTS: Fifty-two (27-TcSC and 25-TcTM) patients were enrolled and underwent definitive surgical treatment. At least one "hot" SLN was detected in all patients. Three (5.8%) patients had a disease positive-SLN. The total number of SLNs removed was 61 (mean 2.26 (standard deviation (SD) 0.90)) in the TcSC group and 54 (mean 2.16 (SD 0.90)) in the TcTM group, P = 0.69. The total number of "hot" nodes in the TcSC group was 1.96 (SD 0.76) compared to 2.04 (SD 0.73) in the TcTM group, P = 0.71. CONCLUSIONS: The number of identified SLNs did not differ significantly between TcTM and TcSC. Given that no significant technical advantages exist between the two agents, surgeons should choose a radiopharmaceutical based on cost and side effect profile.

Use of 99mTc-Tilmanocept as a Single Agent for Sentinel Lymph Node Identification in Breast Cancer: A Retrospective Pilot Study.

99mTc-tilmanocept received recent Food and Drug Administration approval for lymphatic mapping in 2013. However, to our knowledge, no prior studies have evaluated the use of 99mTc-tilmanocept as a single agent in sentinel lymph node (SLN) biopsy in breast cancer. Methods: We executed this retrospective pilot study to assess the ability of 99mTc-tilmanocept to identify sentinel nodes as a single agent in clinically node-negative breast cancer patients. Patients received a single intradermal injection overlying the tumor of either 18.5 MBq (0.5 mCi) of 99mTc-tilmanocept on the day of surgery or 74.0 MBq (2.0 mCi) on the day before surgery by a radiologist. Immediate 3-view lymphoscintigraphy was performed. Intraoperatively, SLNs were identified with a portable γ-probe. A node was classified as hot if the count (per second) of the node was more than 3 times the background count. Descriptive statistics are reported. Results: Nineteen patients underwent SLN biopsy with single-agent 99mTc-tilmanocept. Immediate lymphoscintigraphy identified at least 1 sentinel node in 13 of 17 patients (76.5%). Intraoperatively, at least 1 (mean, 1.7 ± 0.8; range, 1-3) hot node was identified in all patients. Three patients (15.8%) had 1 disease-positive SLN. Conclusion: In this small, retrospective pilot study, 99mTc-tilmanocept performed well as a single agent for intraoperative sentinel node identification in breast cancer. A larger, randomized clinical trial is warranted to compare 99mTc-tilmanocept as a single agent with other radiopharmaceuticals for sentinel node identification in breast cancer.

Application of a Novel CD206+ Macrophage-Specific Arterial Imaging Strategy in HIV-Infected Individuals.

Background: The ability to noninvasively assess arterial CD206+ macrophages may lead to improved understanding of human immunodeficiency virus (HIV)-associated cardiovascular disease. Methods: We trialed a novel macrophage-specific arterial imaging technique. Results: We demonstrated colocalization between technetium Tc 99m tilmanocept (99mTc-tilmanocept) and CD206+ macrophages ex vivo. In vivo application of 99mTc-tilmanocept single-photon emission computed tomography/computed tomography revealed high-level 99mTc-tilmanocept uptake across 20.4% of the aortic surface volume among HIV-infected subjects, compared with 4.3% among non-HIV-infected subjects (P = .009). Among all subjects, aortic high-level 99mTc-tilmanocept uptake was related to noncalcified aortic plaque volume (r = 0.87; P = .003) on computed tomographic angiography, and this relationship held when we controlled for HIV status. Conclusion: These first-in-human data introduce a novel macrophage-specific arterial imaging technique in HIV. Clinical Trials Registration: NCT02542371.

Glomerular hyperfiltration in children with cancer: prevalence and a hypothesis.

BACKGROUND: Glomerular hyperfiltration has recently been reported in children with malignancies and has been attributed to increased solute from breakdown of tumor tissues. OBJECTIVE: To evaluate the prevalence of hyperfiltration in the pediatric oncology population and explore its pathophysiological mechanism. MATERIALS AND METHODS: Tc-99 m diethylenetriaminepentaacetic acid (DTPA) glomerular filtration rate (GFR) examinations (437 studies) and medical records of 177 patients <21 years of age diagnosed with a malignancy between January 2005 and October 2013 were retrospectively reviewed. Hyperfiltration was defined as a GFR ≥ 160 ml/min/1.73 m2. RESULTS: Seventy-seven (43.5%) patients had hyperfiltration in at least one GFR exam. A significantly higher percentage of patients with central nervous system (CNS) tumors (63.6%) had hyperfiltration when compared to other tumor types (27.3%, P < 0.001). No association was found between hyperfiltration and age, gender, race or bone marrow involvement. There was a significant trend toward decreasing hyperfiltration after the second cycle of chemotherapy (P = 0.006) and a significant increase in subjects with low GFR (<100 ml/min/1.73 m2) with increasing number of cycles of chemotherapy (P = 0.005). CONCLUSION: Glomerular hyperfiltration is common in children with malignancies at diagnosis and during initial cycles of chemotherapy. It is particularly prevalent in patients with central nervous tumors, which are frequently smaller in volume. Therefore, the pathophysiological mechanism of hyperfiltration cannot be explained solely on the basis of large tumor volume and subsequent cell breakdown. We hypothesize that host hypermetabolic state plays an important role in pathophysiology of hyperfiltration.