Isolated Hepatic Perfusion With Melphalan for Patients With Isolated Uveal Melanoma Liver Metastases: A Multicenter, Randomized, Open-Label, Phase III Trial (the SCANDIUM Trial).

PURPOSE: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. METHODS: In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. CONCLUSION: IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

Comparative evaluation of combined efficacy of methylene blue mediated antimicrobial photodynamic therapy (a-PDT) using 660 nm diode laser versus Erbium-chromium-yttrium-scandium-gallium-garnet (Er, Cr: YSGG) laser as an adjunct to scaling and root planing on clinical parameters in supportive periodontal therapy: A randomized split-mouth trial.

AIM: The aim of this study was to evaluate combined efficacy of methylene blue mediated antimicrobial photodynamic therapy (a-PDT) using 660 nm diode laser versus Er, Cr: YSGG laser as an adjunct to scaling and root planing on improving the Probing depth (PD), Clinical attachment level (CAL), Plaque Index (PI) and Gingival Index (GI).clinical parameters in Supportive periodontal therapy. MATERIALS AND METHOD: In this split-mouth, double-blind, randomized controlled trial, we compared a-PDT versus Er,Cr:YSGG as an adjunct to scaling and root planning (SRP) with SRP alone in Supportive periodontal therapy. A total of 36 subjected were enrolled. In each patient, two quadrants constituted the control group (Group I - Scaling and root planing SRP alone), one site in other quadrant constituted the test group 1 (Group II - SRP followed by application of Er, Cr: YSGG laser), and another site in different quadrant constituted the test group 2 (Group III - SRP followed by antimicrobial Photodynamic therapy using diode laser). The diode laser was operated at a peak power of 70 mW using a 0.6 mm diameter fiber-optic tip. Each site was irradiated with a power density of 28 mW/cm2, for 10 s, thus delivering a total energy of 16.72 J/cm2 per tooth. Whereas, the Er,Cr:YSGG laser's parameters were set to 1 W of power, 10% air, and 15% water. The same procedure was repeated at 1st, 2nd and 3rd week for both the laser therapies. Plaque index (PI), Gingival index (GI), Probing depth (PD,) and Clinical attachment level (CAL) were measured by a single examiner at baseline and 3 months follow up. Inter group analysis of the parameters were done using One-way ANOVA and pairwise comparison was carried out by Tukey's post hoc test. Intra group analysis was performed using Students's paired t test. Statistical significance was set to p < 0.05. RESULTS: There were no significant differences between participants for clinical parameters at baseline. PI, GI PD, and CAL significantly improved at 3 months follow up compared to baseline in both the study groups (Group II - SRP + Er,Cr:YSGG, Group III - SRP + a-PDT) with P < 0.05. Adjunctive use of Er,Cr:YSGG laser with SRP showed better clinical outcomes than a-PDT with SRP. CONCLUSION: Nonsurgical periodontal therapy of chronic periodontitis using Er, Cr: YSGG, and a-PDT as an adjunct to SRP was significantly more effective than SRP alone in reducing PD, CAL, GI, and PI at 3 months follow up. Adjunctive use of Er,Cr:YSGG laser with SRP showed better clinical outcomes than a-PDT with SRP. However, the long-term positive benefits of the laser therapies are yet unknown and more research with longer follow-ups are required.

Antibacterial, remineralising and matrix metalloproteinase inhibiting scandium-doped phosphate glasses for treatment of dental caries.

OBJECTIVES: Antibiotic resistance is increasingly a growing global threat. This study aimed to investigate the potential use of newly developed scandium-doped phosphate-based glasses (Sc-PBGs) as an antibacterial and anticariogenic agent through controlled release of Sc3+ ions. METHODS: Sc-PBGs with various calcium and sodium oxide contents were produced and characterised using thermal and spectroscopic analysis. Degradation behaviour, ion release, antibacterial action against Streptococcus mutans, anti-matrix metalloproteinase-2 (MMP-2) activity, remineralisation potential and in vivo biocompatibility were also investigated. RESULTS: The developed glass system showed linear Sc3+ ions release over time. The released Sc3+ shows statistically significant inhibition of S. mutans biofilm (1.2 log10 CFU reduction at 6 h) and matrix metalloproteinase-2 (MMP-2) activity, compared with Sc-free glass and positive control. When Sc-PBGs were mounted alongside enamel sections, subjected to acidic challenges, alternating hyper- and hypomineralisation layers consistent with periods of re- and demineralisation were observed demonstrating their potential remineralising action. Furthermore, Sc-PBGs produced a non-toxic response when implanted subcutaneously for 2 weeks in Sprague Dawley rats. SIGNIFICANCE: Since Sc3+ ions might act on various enzymes essential to the biological mechanisms underlying caries, Sc-PBGs could be a promising therapeutic agent against cariogenic bacteria.

Evaluation of 177Lu and 47Sc Picaga-Linked, Prostate-Specific Membrane Antigen-Targeting Constructs for Their Radiotherapeutic Efficacy and Dosimetry.

Lu-177-based, targeted radiotherapeutics/endoradiotherapies are an emerging clinical tool for the management of various cancers. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) remains the workhorse for such applications but can limit apparent molar activity or efficient charge modulation, which can impact target binding and, as a consequence, target efficacy. Previously, our lab had developed the small, rare earth selective bifunctional chelator, picaga, as an efficient bifunctional chelator for scandium and lutetium isotopes. Here, we assess the performance of these constructs for therapy in prostate-specific membrane antigen (PSMA)-expressing tumor xenografts. To assess the viability of picaga conjugates in conjunction with long in vivo circulation, a picaga conjugate functionalized with a serum albumin binding moiety, 177Lu-picaga-Alb53-PSMA, was also synthesized. A directly comparative, low, single 3.7 MBq dose treatment study with Lu-PSMA-617 was conducted. Treatment with 177Lu-picaga-Alb53-PSMA resulted in tumor regression and lengthened median survival (54 days) when compared with the vehicle (16 days), 47Sc-picaga-DUPA-, 177Lu-picaga-DUPA-, and 177Lu-PSMA-617-treated cohorts (21, 23, and 21 days, respectively).

Efficacy of using erbium, chromium-doped: Yttrium scandium gallium garnet laser-treated dentine in a dentine barrier test device.

OBJECTIVES: The aim of this study was to evaluate the efficacy of using erbium, chromium-doped:yttrium scandium gallium garnet (Er,Cr:YSGG) laser-treated dentine in a dentine barrier test device. MATERIALS AND METHODS: The test materials (G-Bond™ and Vitrebond™) were applied onto laser-treated or laser-untreated dentine discs. After 24 h of exposure with perfusion of the test chamber, cell survival was evaluated based on enzyme activity and compared to a nontoxic control material. The mean of the control was set to 100% viability. Data were analyzed using the one-way analysis of variance and the Tukey's honest significant difference tests. RESULTS: The responses of bovine pulp-derived cells after exposure to G-Bond and Vitrebond on Er,Cr:YSGG laser-treated and laser-untreated dentin were statistically different from negative control group (P < 0.05). CONCLUSION: Er,Cr:YSGG laser treatment was not successful enough in decreasing the cytotoxic effects of the dental materials. Different parameters of Er,Cr:YSGG laser or different laser types could be investigated as an alternative to minimizing the cytotoxic effects of dental materials.

Development of bone seeker radiopharmaceuticals by Scandium-47 and estimation of human absorbed dose.

In this study labeling EDTMP (ethylenediamine tetra(methylene phosphonic acid)) and HEDP (Hydroxyethylidene-1, 1-Diphosphonic Acid) as the carrier ligands with Scandium-47 were investigated. The biokinetics of the bone seeking of labeled ligands with Scandium-47 were assessed by measuring the skeletal absorbed dose and then the mice data extrapolated to human absorbed dose and compared with the 186/188Rhenium-HEDP, 153Samarium-EDTMP dosimetry data estimated by other researchers. Because the availability of 47Sc was limited we performed some preliminary studies using 46Sc.

Production and purification of Scandium-47: A potential radioisotope for cancer theranostics.

In this study, production of 47Sc radionuclide by irradiating the natural titanium dioxide powder (TiO2) in the fast neutron flux (~3*1013ncm-2s-1) for 4 days in Tehran Research Reactor (TRR, Iran) and separation from titanium target was investigated. The study showed the feasibility of production 47Sc by TRR. The separation efficiency and radiochemical purity (ScCl3) of radio-scandium, 47Sc radionuclide purity were obtained 98%, 99% and 88% respectively.

Efficacy of Erbium, Chromium-doped:Yttrium, Scandium, Gallium, and Garnet Laser Irradiation Combined with Resin-based Tricalcium Silicate and Calcium Hydroxide on Direct Pulp Capping: A Randomized Clinical Trial.

INTRODUCTION: The purpose of this randomized clinical study was to evaluate the efficiency of erbium, chromium-doped:yttrium, scandium, gallium, and garnet (Er,Cr:YSGG) laser irradiation combined with a resin-based tricalcium silicate material and calcium hydroxide in direct pulp capping for a 6-month follow-up period. METHODS: A total of 60 teeth of 60 patients between the ages of 18 and 41 years were recruited for this study. Sixty permanent vital teeth without symptoms and radiographic changes were randomly assigned to the following 4 groups (n = 15): Gr CH, the exposed area was sealed with calcium hydroxide (CH) paste; Gr laser CH, the treated area was sealed with CH paste after Er,Cr:YSGG laser irradiation at an energy level of 0.5 W without water and with 45% air; Gr TheraCal, TheraCal LC (Bisco, Schaumburg, IL) was applied directly to the exposed pulp; and Gr Laser TheraCal, TheraCal LC was applied after irradiation with an Er,Cr:YSGG laser. At the 1-week and 1-, 3-, and 6-month recall examinations, the loss of vitality, spontaneous pain, reactions to thermal stimuli and percussion, and radiographic changes were considered as failure. RESULTS: The success rates in the CH and TheraCal groups were 73.3% and 66.6%, respectively. These rates did not reveal any significant difference. In both laser groups, success rates were 100%. The Er,Cr:YSGG laser-irradiated TheraCal and Er,Cr:YSGG laser-irradiated CH groups showed statistically higher success rates than the TheraCal and CH groups, respectively. CONCLUSIONS: Er,Cr:YSGG laser irradiation at 0.5 W without water combined with pulp capping agents can be recommended for direct pulp therapy.

Promising prospects for 44Sc-/47Sc-based theragnostics: application of 47Sc for radionuclide tumor therapy in mice.

UNLABELLED: In recent years, (47)Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of (47)Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. METHODS: (47)Sc was produced via the (46)Ca(n,γ)(47)Ca[Formula: see text](47)Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the (47)Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. (47)Sc-labeled cm10 was tested on folate receptor-positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor-bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either (47)Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. RESULTS: Irradiation of (46)Ca resulted in approximately 1.8 GBq of (47)Ca, which subsequently decayed to (47)Sc. Separation of (47)Sc from (47)Ca was obtained with 80% yield in only 10 min. The (47)Sc was then available in a small volume (∼500 µL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. (47)Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro (47)Sc-cm10 showed folate receptor-specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received (47)Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. CONCLUSION: With this study, we demonstrated the suitability of using (47)Sc for therapeutic purposes. On the basis of our recent results obtained with (44)Sc-folate, the present work confirms the applicability of (44)Sc/(47)Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.

Complexes of low energy beta emitters 47Sc and 177Lu with zoledronic acid for bone pain therapy.

Targeted radiopharmaceuticals have been mostly developed to visualize and/or treat oncologic diseases. In targeted radiotherapy radionuclide selection is a key issue, because the radionuclide should provide the appropriate radiation absorbed dose, matching the desirable biologic effect, but at the same time it should preclude irradiation of surrounding healthy tissues. Among the last generation of bisphosphonates with cyclic side chains, zoledronic acid is the most potent bisphosphonate, described till now, which inhibits bone resorption. In this paper, we describe the synthesis, properties and hydroxyapatite binding of zoledronic acid labeled with two low energy beta emitters, (47)Sc and (177)Lu. Radiochemicals labeled with low energy electron emitters are preferred, because they deliver both a therapeutic dose to the bone and spare the bone marrow. Hydroxyapatite adsorption experiments have shown that the binding values obtained with complexes of zoledronic acid labeled with (46)Sc and (177)Lu are much higher than those of bisphosphonates labeled with (153)Sm and (166)Ho. Hence, complexes of zoledronic acid with either (46)Sc or (177)Lu seems to be a promising radiopharmaceutical for bone pain therapy.

Radiochemical purification of no-carrier-added scandium-47 for radioimmunotherapy.

A procedure, adaptable to large-scale remote operation, was developed to purify no-carrier-added (NCA) 47Sc from irradiated Ti targets. Methods based on extraction chromatography and cation-exchange chromatography were compared. Results of this comparison led to the development of an optimized procedure based on cation-exchange with Dowex AG 50W-X4 and 47Sc elution with HCl/HF. This method gave 90-97% overall 47Sc recovery, with a Ti separation factor greater than 2.4 x 10(-5), and specific activities > or = 0.9 GBq microgram-1. Use of the 47Sc product, for labeling monoclonal antibodies, resulted in consistent labeling yields of > or = 90%.