Lymphoscintigraphy Using Tilmanocept Detects Multiple Sentinel Lymph Nodes in Melanoma Patients.

BACKGROUND: Technetium-99m-labeled Tilmanocept, a multivalent mannose, is readily internalized by the CD206 surface receptor on macrophages and dendritic cells which are abundantly present in lymph nodes. We want to examine the drainage patterns of Technetium-99m-labeled Tilmanocept to sentinel lymph nodes (SLNs) in melanoma patients following the 10% rule. METHODS: Multi-center retrospective review of patients with cutaneous melanoma undergoing SLN biopsy using Technetium-99m-labeled Tilmanocept between 2008 and 2014 was conducted. Statistical methods were used for data analyses. RESULTS: Of the 564 patients (mean age of 60.3 and 62% male) with preoperative lymphoscintigraphy showing at least one SLN, several primary tumor sites were included: 27% head/neck, 33% trunk, 21% upper extremity and 19% lower extremity. For the head/neck primary site, 36.5% of patients had multiple draining basins; for the trunk site, 36.4% of patients; for the upper extremity site, 13% of patients; and for the lower extremity, 27.4% of patients. A median of 3 (range 1-18) SLNs were identified and resected. Overall, 78% of patients had >1 SLN identified by Technetium-99m-labeled Tilmanocept. In a multivariate model, patients with >1 SLN were significantly associated with age, Breslow depth, tumor location and higher AJCC tumor stage. A total of 17.7% of patients (100/564) had a positive SLN identified. A total of 145 positive SLNs were identified out of 1,812 SLNs with a positive SLN rate of 8%. Positive SLN status was significantly associated with younger age, greater Breslow depth, mitosis rate, higher AJCC tumor stage, presence of ulceration and angiolymphatic invasion. CONCLUSIONS: Using the 10% rule, Technetium-99m-labeled Tilmanocept detects multiple SLNs in most melanoma patients.

A Pilot Study of Hepatic Irradiation with Yttrium-90 Microspheres Followed by Immunotherapy with Ipilimumab and Nivolumab for Metastatic Uveal Melanoma.

Background: Liver metastases from uveal melanoma carry a very poor prognosis. Hepatic artery infusions with Yttrium-90 (90Y) resin microspheres have some activity in this disease, and radiation and immunotherapy may be synergistic. The primary objective of this study was to determine the safety and tolerability of sequential 90Y resin microspheres and immunotherapy with ipilimumab and nivolumab in metastatic uveal melanoma. Materials and Methods: Twenty-six patients with uveal melanoma with hepatic metastases were entered into a pilot study. Treatment consisted of two infusions of 90Y resin microspheres, one to each lobe of the liver, followed in 2-4 weeks by immunotherapy with ipilimumab and nivolumab every 3 weeks for four doses, then maintenance immunotherapy with nivolumab alone. Results: Initial dosing of both 90Y and immunotherapy resulted in excessive toxicity. With decreasing the dosage of 90Y to limit the normal liver dose to 35Gy and lowering the ipilimumab dose to 1 mg/kg, the toxicity was tolerable, with no apparent change in efficacy. There was one complete and four confirmed partial responses, for an objective response rate of 20% and a disease control rate of 68%. The median progression-free survival was 5.5 months (95% confidence interval [CI]: 1.3-9.7 months), with a median overall survival of 15 months (95% CI: 9.7-20.1 months). Conclusions: With dose reductions, sequential therapy with 90Y and immunotherapy with ipilimumab and nivolumab is safe and tolerable, and has activity in metastatic uveal melanoma. These results justify a controlled trial to demonstrate whether 90Y resin microspheres add to the utility of combination immunotherapy in this disease. Clinical Trial Registration number: NCT02913417.

Pinhole single-photon emission computed tomography for myocardial perfusion imaging of mice.

OBJECTIVES: Although transgenic mice have emerged as powerful experimental models of cardiovascular disease, methods for in vivo phenotypic assessment and characterization remain limited, motivating the development of new instruments for biologic measurement. BACKGROUND: We have developed a single-photon emission computed tomography system with a pinhole collimator (pinhole SPECT) for high-resolution cardiovascular imaging of mice. In this study, we describe a protocol for myocardial perfusion imaging of mice using technetium-99m ((99m)Tc)-sestamibi and demonstrate the feasibility for measurement of perfusion defect size from pinhole SPECT images. METHODS: Mice were anesthetized and injected with 370 MBq (10 mCi) of (99m)Tc-sestamibi. Tomographic projection images were acquired by rotating each mouse in a vertical axis in front of a stationary clinical scintillation camera equipped with a pinhole collimator. BALB/c mice (n = 15) were imaged after the permanent ligation of the left anterior descending coronary artery. The resulting defect size was measured from circumferential profiles of short-axis images. After imaging, the hearts were excised and sectioned to obtain ultra-high resolution digital autoradiographs of (99m)Tc-sestamibi, from which the actual infarct size was determined. RESULTS: Reconstructed image quality was equivalent to that obtained for clinical myocardial perfusion imaging. Linear regression analysis produced a correlation coefficient of 0.83 (p < 0.001) between the measured and actual values of the defect size. CONCLUSIONS: These results demonstrate that myocardial perfusion can be characterized qualitatively and quantitatively in mice using pinhole SPECT.

Dual-modality imaging of function and physiology.

Dual-modality imaging is a technique in which computed tomography (CT) or magnetic resonance imaging is combined with positron emission tomography or single-photon emission CT to acquire structural and functional images with an integated system. The data are acquired in a single procedure; the patient remains on the scanner table while undergoing both x-ray and radionuclide studies to facilitate correlation between the structural and functional images. The resulting data can aid in localization, enabling more specific diagnosis than can be obtained with a conventional imaging study. In addition, the anatomic information can be used to compensate the correlated radionuclide data for physical perturbations such as photon attenuation, scatter radiation, and partial volume errors. Thus, dual-modality imaging provides a priori information that can improve both the visual quality and the quantitative accuracy of the radionuclide images. Dual-modality imaging systems are also being developed for biologic research involving small animals. Small-animal dual-modality systems offer advantages for measurements that currently are performed invasively with autoradiography and tissue sampling. By acquiring data noninvasively, dual-modality imaging permits serial studies in a single animal, enables measurements to be performed with fewer animals, and improves the statistical quality of the data.

Performance evaluation of a pinhole SPECT system for myocardial perfusion imaging of mice.

The increasing use of transgenic mice as models of human physiology and disease has motivated the development of dedicated in vivo imaging systems for anatomic and functional characterization of mice as an adjunct to or a replacement for established ex vivo techniques. We have developed a pinhole single photon emission computed tomography (SPECT) system for high resolution imaging of mice with cardiovascular imaging as the primary application. In this work, we characterize the system performance through phantom studies. The spatial resolution and sensitivity were measured from images of a line source and point source, respectively, and were reported for a range of object-to-pinhole distances and pinhole diameters. Tomographic images of a uniform cylindrical phantom, Defrise phantom, and grid phantom were used to characterize the image uniformity and spatial linearity. The uniform phantom image did not contain any ring or reconstruction artifacts, but blurring in the axial direction was evident in the Defrise phantom images. The grid phantom images demonstrated excellent spatial linearity. A novel phantom modeling perfusion of the left ventricle of a mouse was designed and built with perfusion defects of varying sizes to evaluate the system performance for myocardial perfusion imaging of mice. The defect volumes were measured from the pinhole SPECT images and correlated to the actual defect volumes calculated according to geometric formulas. Linear regression analysis produced a correlation coefficient of r = 0.995 (p < 0.001), demonstrating the feasibility for measurement of perfusion defect size in mice using pinhole SPECT. We have performed phantom studies to characterize the spatial resolution, sensitivity, image uniformity, and spatial linearity of the pinhole SPECT system. Measurement of the perfusion defect size is a valuable phenotypic assessment and will be useful for hypothesis testing in murine models of cardiovascular disease.