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      Combined Analysis of Phase III Trials Evaluating [ 99mTc]Tilmanocept and Vital Blue Dye for Identification of Sentinel Lymph Nodes in Clinically Node-Negative Cutaneous Melanoma

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          Abstract

          Background

          [ 99mTc]Tilmanocept is a CD206 receptor-targeted radiopharmaceutical designed for sentinel lymph node (SLN) identification. Two nearly identical nonrandomized phase III trials compared [ 99mTc]tilmanocept to vital blue dye.

          Methods

          Patients received [ 99mTc]tilmanocept and blue dye. SLNs identified intraoperatively as radioactive and/or blue were excised and histologically examined. The primary end point, concordance, was the proportion of blue nodes detected by [ 99mTc]tilmanocept; 90 % concordance was the prespecified minimum concordance level. Reverse concordance, the proportion of radioactive nodes detected by blue dye, was also calculated. The prospective statistical plan combined the data from both trials.

          Results

          Fifteen centers contributed 154 melanoma patients who were injected with both agents and were intraoperatively evaluated. Intraoperatively, 232 of 235 blue nodes were detected by [ 99mTc]tilmanocept, for 98.7 % concordance ( p < 0.001). [ 99mTc]Tilmanocept detected 364 nodes, for 63.7 % reverse concordance (232 of 364 nodes). [ 99mTc]Tilmanocept detected at least one node in more patients ( n = 150) than blue dye ( n = 138, p = 0.002). In 135 of 138 patients with at least one blue node, all blue nodes were radioactive. Melanoma was identified in the SLNs of 22.1 % of patients; all 45 melanoma-positive SLNs were detected by [ 99mTc]tilmanocept, whereas blue dye detected only 36 (80 %) of 45 ( p = 0.004). No positive SLNs were detected exclusively by blue dye. Four of 34 node-positive patients were identified only by [ 99mTc]tilmanocept, so 4 (2.6 %) of 154 patients were correctly staged only by [ 99mTc]tilmanocept. No serious adverse events were attributed to [ 99mTc]tilmanocept.

          Conclusions

          [ 99mTc]Tilmanocept met the prespecified concordance primary end point, identifying 98.7 % of blue nodes. It identified more SLNs in more patients, and identified more melanoma-containing nodes than blue dye.

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          Most cited references22

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          Technical details of intraoperative lymphatic mapping for early stage melanoma.

          The initial route of metastases in most patients with melanoma is via the lymphatics to the regional nodes. However, routine lymphadenectomy for patients with clinical stage I melanoma remains controversial because most of these patients do not have nodal metastases, are unlikely to benefit from the operation, and may suffer troublesome postoperative edema of the limbs. A new procedure was developed using vital dyes that permits intraoperative identification of the sentinel lymph node, the lymph node nearest the site of the primary melanoma, on the direct drainage pathway. The most likely site of early metastases, the sentinel node can be removed for immediate intraoperative study to identify clinically occult melanoma cells. We successfully identified the sentinel node(s) in 194 of 237 lymphatic basins and detected metastases in 40 specimens (21%) on examination of routine hematoxylin-eosin-stained slides (12%) or exclusively in immunohistochemically stained preparations (9%). Metastases were present in 47 (18%) of 259 sentinel nodes, while nonsentinel nodes were the sole site of metastasis in only two of 3079 nodes from 194 lymphadenectomy specimens that had an identifiable sentinel node, a false-negative rate of less than 1%. Thus, this technique identifies, with a high degree of accuracy, patients with early stage melanoma who have nodal metastases and are likely to benefit from radical lymphadenectomy.
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            Sentinel-node biopsy or nodal observation in melanoma.

            We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma. Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy. Among 1269 patients with an intermediate-thickness primary melanoma, the mean (+/-SE) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6% in the biopsy group and 73.1+/-2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59 to 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1+/-1.3% and 86.6+/-1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3+/-4.6% among patients with tumor-positive sentinel nodes and 90.2+/-1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3+/-4.6% vs. 52.4+/-5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P=0.004). The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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              Molecular characterization of the human macrophage mannose receptor: demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells

              The macrophage mannose receptor is an integral membrane protein expressed on the surface of tissue macrophages. After ligation of mannose-rich glycoconjugates or pathogens, the receptor mediates endocytosis and phagocytosis of the bound ligands by macrophages. The cDNA-derived primary structure of the mannose receptor predicts a cysteine-rich NH2-terminal domain, followed by a fibronectin type II region. The remainder of the ectodomain is comprised of eight carbohydrate recognition-like domains, followed by a transmembrane region, and a cytoplasmic tail. Transfection of the mannose receptor cDNA into Cos-I cells is necessary for receptor-mediated endocytosis of mannose-rich glycoconjugate as well as phagocytosis of yeasts. Deletion of the cytoplasmic tail results in a mutant receptor that is able to bind but not ingest the ligated pathogens, suggesting that the signal for phagocytosis is contained in the cytoplasmic tail.
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                Author and article information

                Contributors
                vernon.sondak@moffitt.org
                Journal
                Ann Surg Oncol
                Ann. Surg. Oncol
                Annals of Surgical Oncology
                Springer-Verlag (New York )
                1068-9265
                1534-4681
                3 October 2012
                3 October 2012
                February 2013
                : 20
                : 2
                : 680-688
                Affiliations
                [ ]H. Lee Moffitt Cancer Center, Tampa, FL USA
                [ ]STATKING Clinical Services, Fairfield, OH USA
                [ ]Sourasky Medical Center, Tel Aviv, Israel
                [ ]University Hospitals Seidman Cancer Center, Cleveland, OH USA
                [ ]California Pacific Medical Center, San Francisco, CA USA
                [ ]John Wayne Cancer Institute, Santa Monica, CA USA
                [ ]MetroHealth Medical Center/Case Western Reserve University, Cleveland, OH USA
                [ ]UC Davis Cancer Center, Sacramento, CA USA
                [ ]San Diego Moores Center Institute, University of California, La Jolla, CA USA
                Article
                2612
                10.1245/s10434-012-2612-z
                3560941
                23054107
                0ab8dc6a-d246-4374-b599-8c05c659591a
                © The Author(s) 2012
                History
                : 19 May 2012
                Categories
                Melanomas
                Custom metadata
                © Society of Surgical Oncology 2013

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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