Synthesis of 225Ac-PSMA-617 for Preclinical Use.

BACKGROUND: The recent approval of radiopharmaceuticals for diagnosis and treatment of cancer is ushering nuclear medicine into a new era of theranostics and alpha therapy using radiopharmaceuticals labeled with 225Ac shows remarkable results in clinical trials. As such, reliable methods for the synthesis and quality control of 225Ac-radiopharmaceuticals are needed. OBJECTIVE: 225Ac-PSMA-617 is being used for targeted alpha therapy in patients with prostate cancer, and we had cause to synthesize the agent for preclinical use. However, technology transfer proved cumbersome owing to the paucity of information available on synthesizing and analyzing 225Ac-radiotherapeutics. To address this need, we describe a straightforward synthesis of 225Ac-PSMA- 617 as well as suitable approaches for quality control analysis using standard equipment in a modern PET Center. METHODS: PSMA-617 precursor was dissolved in 25 µL metal-free water (0.67 mg/mL) and combined with 500 µL 0.05M Tris buffer, pH 9. Actinium stock solution (~65 µCi in 15 µL) was added and the reaction was heated at 120°C for 40-50 min. The reaction was cooled and 0.6 mL gentisic acid solution (4 mg/mL in 0.2 M NH4OAc) was added. To formulate the dose for injection, sterile saline, USP (8 mL) was added and the pH was adjusted by the addition of 100 µL 0.05 M Tris buffer (pH 9) to give a final pH of ~7.2. The final solution was filtered using a 0.22 µm GV sterile filter into a sterile dose vial. Radiochemical purity was determined by radio-TLC (eluent: 50mM Sodium Citrate, pH 5), and plates were analyzed using an AR2000 scanner. RESULTS: The method provided 225Ac-PSMA-617 in high radiochemical yield (57 ± 3 µCi, >99%) and radiochemical purity (98 ± 1%), formulated for preclinical studies (9 mL, pH = 7.2), n=3. CONCLUSION: A straightforward synthesis of 225Ac-PSMA-617 is described that will facilitate production for (pre)clinical studies. The approach could also be applicable to the synthesis of other alpha radiotherapeutics incorporating 225Ac.

Musculoskeletal injury outcomes: 2-year retrospective service evaluation of a UK defence primary care rehabilitation facility (PCRF).

INTRODUCTION: Musculoskeletal injury represents the leading cause of medical discharge from the UK Armed Forces. This study evaluates effectiveness of care provision within a large primary care rehabilitation facility (PCRF) against directed defence best practice guidelines (BPGs) METHODS: All new patient electronic records from January to July 16 were interrogated to identify demographics, causation, injury pathology, timelines and outcomes. RESULTS: 393 eligible records (81.9% male) were identified. 17.6% were officers, 32.8% were seniors and 49.6% were juniors. The average age was 35.1 years (mode 30). The average wait to treatment was 8.3 days with 75.6% key performance indicator compliance. 47.3% were repeat injuries. The average care timeline was 117.1 days with 8.7 average treatment sessions needed. 30 remained under care at 2 years. 17.8% accessed hydrotherapy and 44% underwent exercise remedial instructors care. 14.2% of individuals required concurrent DCMH care (15.9% male and 26.8% female). 28.5% required multidisciplinary injury assessment clinic intervention with 74.1% compliance against BPGs. 2.9% used the Defence Medical Rehabilitation Centre. Common pathologies were low back pain (LBP) (n=67), upper limb (UL) soft tissue (n=40) and knee trauma (n=38). LBP had the highest recurrence rates (71.6%). Anterior knee pain took the longest (173.1 days) but had the best outcome on discharge. Ankles and lower limb muscle injuries had the best outcomes. Patella tendinopathy and knee trauma had the poorest outcome on discharge. LBP and patellar tendinopathy had the lowest fully fit rates at 2 years (56.7% and 53.8%, respectively). At 2 years, 58.2% of individuals achieved full fitness (60.7% men and 46.4% women), rising to 64% and 55%, respectively, when including those retained with limitations. CONCLUSIONS: The PCRF was generally compliant with BPGs, achieving good functional outcomes on discharge. Women were disproportionally represented, had higher concurrent DCMH attendance and poorer overall long-term outcomes. Repeat injury rates were significantly high.