[(99m)Tc]Tilmanocept Accurately Detects Sentinel Lymph Nodes and Predicts Node Pathology Status in Patients with Oral Squamous Cell Carcinoma of the Head and Neck: Results of a Phase III Multi-institutional Trial.

BACKGROUND: [(99m)Tc]Tilmanocept, a novel CD206 receptor-targeted radiopharmaceutical, was evaluated in an open-label, phase III trial to determine the false negative rate (FNR) of sentinel lymph node biopsy (SLNB) relative to the pathologic nodal status in patients with intraoral or cutaneous head and neck squamous cell carcinoma (HNSCC) undergoing tumor resection, SLNB, and planned elective neck dissection (END). Negative predictive value (NPV), overall accuracy of SLNB, and the impact of radiopharmaceutical injection timing relative to surgery were assessed. METHODS AND FINDINGS: This multicenter, non-randomized, single-arm trial (ClinicalTrials.gov identifier NCT00911326) enrolled 101 patients with T1-T4, N0, and M0 HNSCC. Patients received 50 µg [(99m)Tc]tilmanocept radiolabeled with either 0.5 mCi (same day) or 2.0 mCi (next day), followed by lymphoscintigraphy, SLNB, and END. All excised tissues were evaluated for tissue type and tumor presence. [(99m)Tc]Tilmanocept identified one or more SLNs in 81 of 83 patients (97.6 %). Of 39 patients identified with any tumor-positive nodes (SLN or non-SLN), one patient had a single tumor-positive non-SLN in whom all SLNs were tumor-negative, yielding an FNR of 2.56 %; NPV was 97.8 % and overall accuracy was 98.8 %. No significant differences were observed between same-day and next-day procedures. CONCLUSIONS: Use of receptor-targeted [(99m)Tc]tilmanocept for lymphatic mapping allows for a high rate of SLN identification in patients with intraoral and cutaneous HNSCC. SLNB employing [(99m)Tc]tilmanocept accurately predicts the pathologic nodal status of intraoral HNSCC patients with low FNR, high NPV, and high overall accuracy. The use of [(99m)Tc]tilmanocept for SLNB in select patients may be appropriate and may obviate the need to perform more extensive procedures such as END.

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.

BACKGROUND: [(99m)Tc]Tilmanocept is a CD206 receptor-targeted radiopharmaceutical designed for sentinel lymph node (SLN) identification. Two nearly identical nonrandomized phase III trials compared [(99m)Tc]tilmanocept to vital blue dye. METHODS: Patients received [(99m)Tc]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 [(99m)Tc]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 [(99m)Tc]tilmanocept, for 98.7 % concordance (p < 0.001). [(99m)Tc]Tilmanocept detected 364 nodes, for 63.7 % reverse concordance (232 of 364 nodes). [(99m)Tc]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 [(99m)Tc]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 [(99m)Tc]tilmanocept, so 4 (2.6 %) of 154 patients were correctly staged only by [(99m)Tc]tilmanocept. No serious adverse events were attributed to [(99m)Tc]tilmanocept. CONCLUSIONS: [(99m)Tc]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.

Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials.

BACKGROUND: Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance. METHODS: A total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept. RESULTS: A total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept. CONCLUSION: [(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.

Increasing the sample size at interim for a two-sample experiment without Type I error inflation.

For the case of a one-sample experiment with known variance σ² =1, it has been shown that at interim analysis the sample size (SS) may be increased by any arbitrary amount provided: (1) The conditional power (CP) at interim is ≥ 50% and (2) there can be no decision to decrease the SS (stop the trial early). In this paper we verify this result for the case of a two-sample experiment with proportional SS in the treatment groups and an arbitrary common variance. Numerous authors have presented the formula for the CP at interim for a two-sample test with equal SS in the treatment groups and an arbitrary common variance, for both the one- and two-sided hypothesis tests. In this paper we derive the corresponding formula for the case of unequal, but proportional SS in the treatment groups for both one-sided superiority and two-sided hypothesis tests. Finally, we present an SAS macro for doing this calculation and provide a worked out hypothetical example. In discussion we note that this type of trial design trades the ability to stop early (for lack of efficacy) for the elimination of the Type I error penalty. The loss of early stopping requires that such a design employs a data monitoring committee, blinding of the sponsor to the interim calculations, and pre-planning of how much and under what conditions to increase the SS and that this all be formally written into an interim analysis plan before the start of the study.

A clinical study of plaque removal with an advanced rechargeable power toothbrush and a battery-operated device.

PURPOSE: To compare the safety and efficacy of two recently introduced modern power toothbrushes with different characteristics. MATERIALS AND METHODS: This was a single-blind, randomized, crossover study which compared the ability of two power toothbrushes to remove plaque during a 2-minute brushing period. The two brushes were the Braun Oral-B 3D Excel (D17), a rechargeable toothbrush with an oscillating/rotating/pulsating action and the Colgate Actibrush, a battery-operated device with an oscillating/rotating action. Seventy-four healthy subjects from a general population who met the inclusion/exclusion criteria used the two brushes on alternate days for a period of familiarization before returning to the test facility. At this visit, subjects with a whole mouth mean Proximal/Marginal Plaque Index of > or = 2.20 after 23-25 hours of no oral hygiene were randomly assigned to one of two treatment sequences, D17/Actibrush and Actibrush/D17, balanced for age and gender. Subjects brushed with their assigned toothbrush after which post-brushing plaque scores were recorded. After a 2-week washout phase subjects returned to the test facility and brushed with the alternate toothbrush as described. Data from the two visits were pooled, after which plaque removal efficacies were compared. Change from prebrushing treatment means were compared using ANOVA with models appropriate for the crossover design. RESULTS: Both toothbrushes were found to be safe and both significantly reduced plaque levels (P < or = 0.0001), but the D17 was significantly more effective than the Actibrush for the whole mouth and for approximal sites. Plaque reductions for the D17 were 46.5%, 55.2% and 42.9% for whole mouth, marginal and approximal sites, respectively while reductions for the Actibrush for the whole mouth, marginal, and approximal sites, were 41.5%, 52.5% and 36.8% respectively. It is concluded that the Braun Oral-B D17 may offer advantages in terms of plaque removal over the battery-powered Actibrush, particularly at hard to reach approximal sites.

A clinical investigation into the effect of toothbrush wear on efficacy.

It is generally recommended that toothbrushes should be replaced after three-months' use in order to maintain efficacy. This clinical investigation employed a single-use, cross-over study and a three-month parallel-group study to investigate the effect of toothbrush wear on plaque and gingival health. Toothbrushes were artificially worn using a laboratory wear machine to simulate three months of clinical toothbrush use. Results from the single-use study showed that both the new and the worn toothbrushes significantly reduced whole mouth, marginal and approximal plaque scores from pre- to post-brushing (p < 0.0001). The new brush was, however, significantly more effective than the worn brush, demonstrating 13.4%, 11.0%, and 17.0% greater plaque reduction for whole mouth, marginal and approximal sites, respectively (p < 0.0001). Results from the three-month study confirmed this finding, with significant differences in plaque reduction (p < 0.0001) between the new and worn toothbrushes at 6 and 12 weeks for all sites. A significant difference (p < 0.0001) between the groups was also found for mean whole mouth gingivitis scores; this difference favoring the new brush at both 6 and 12 weeks. Examination of hard and soft oral tissues revealed no significant difference between the new and the worn brushes with respect to safety. It is concluded that a worn toothbrush is less effective than a new toothbrush for plaque removal and control of gingivitis.

The efficacy of Tilmanocept in sentinel lymph mode mapping and identification in breast cancer patients: a comparative review and meta-analysis of the 99mTc-labeled nanocolloid human serum albumin standard of care.

Sentinel lymph node (SLN) mapping is common, however question remains as to what the ideal imaging agent is and how such an agent might provide reliable and stable localization of SLNs. (99m)Tc-labeled nanocolloid human serum albumin (Nanocoll) is the most commonly used radio-labeled colloid in Europe and remains the standard of care (SOC). It is used in conjunction with vital blue dyes (VBDs) which relies on simple lymphatic drainage for localization. Although the exact mechanism of Nanocoll SLN localization is unknown, there is general agreement that Nanocoll exhibits the optimal size distribution and radiolabeling properties of the commercially available radiolabel colloids. [(99m)Tc]Tilmanocept is a novel radiopharmaceutical designed to address these deficiencies. Our aim was to compare [(99m)Tc]Tilmanocept to Nanocoll for SLN mapping in breast cancer. Data from the Phase III clinical trials of [(99m)Tc]Tilmanocept's concordance with VBD was compared to a meta-analysis of a review of the literature to identify a (99m)Tc albumin colloid SOC. The primary endpoints were SLN localization rate and degree of localization. Six studies were used for a meta-analysis to identify the colloid-based SOC. Five studies (6,134 patients) were used to calculate the SOC localization rate of 95.91 % (CI 0.9428-0.9754) and three studies (1,380 patients) were used for the SOC SLN degree of localization of 1.6683 (CI 1.5136-1.8230). The lower bound of the confidence interval was used for comparison to Tilmanocept. Tilmanocept data included 148 patients, and pooled analysis revealed a 99.99 % (CI 0.9977-1.0000) localization rate and degree of localization of 2.16 (CI 1.964-2.3600). Tilmanocept was superior to the Nanocoll SOC for both endpoints (P < 0.0001).

Laboratory evaluation of oil spill bioremediation products in salt and freshwater systems.

Ten oil spill bioremediation products were tested in the laboratory for their ability to enhance biodegradation of weathered Alaskan North Slope crude oil in both freshwater and saltwater media. The products included nutrients to stimulate inoculated microorganisms, nutrients plus an oil-degrading inoculum, nutrients plus compounds intended to stimulate oil-degrading activity, or other compounds intended to enhance microbial activity. The product tests were undertaken to evaluate significant modifications in the existing official United States Environmental Protection Agency (EPA) protocol used for qualifying commercial bioremediation agents for use in oil spills. The EPA protocol was modified to include defined formulas for the exposure waters (freshwater, saltwater), a positive control using a known inoculum and nutrients, two negative controls (one sterile, the other inoculated but nutrient-limited), and simplified oil chemical analysis. Three analysts conducted the product test independently in each type of exposure water in round-robin fashion. Statistical tests were performed on analyst variability, reproducibility, and repeatability, and the performance of the various products was quantified in both exposure media. Analysis of variance showed that the analyst error at each time-point was highly significant (P values ranged from 0.0001 to 0.008, depending on water type and oil fraction). In the saltwater tests, six products demonstrated various degrees of biodegradative activity against the alkane fraction of the crude oil and three degraded the aromatic hydrocarbons by >10%. In the freshwater tests, eight products caused >20% loss of alkane hydrocarbons, of which five degraded the alkanes by >50%. Only four products were able to degrade polycyclic aromatic hydrocarbons (PAHs) by >20%, one of which caused 88% removal. However, when the variability of the analysts was taken into consideration, only one of the ten products was found to yield significant percent removals of the PAH fraction and only in freshwater. Viable microorganism population analysis (most-probable-number method) was also performed on every sample by each operator to measure the changes in aromatic and alkane hydrocarbon-degrading organism numbers. In general, little evidence of significant growth of either alkane- or PAH-degraders occurred among any of the ten products in either the saltwater or freshwater testing.