Theranostic 64Cu-DOTHA2-PSMA allows low toxicity radioligand therapy in mice prostate cancer model.

Introduction: We have previously shown that copper-64 (64Cu)-DOTHA2-PSMA can be used for positron emission tomography (PET) imaging of prostate cancer. Owing to the long-lasting, high tumoral uptake of 64Cu-DOTHA2-PSMA, the objective of the current study was to evaluate the therapeutic potential of 64Cu-DOTHA2-PSMA in vivo. Methods: LNCaP tumor-bearing NOD-Rag1nullIL2rgnull (NRG) mice were treated with an intraveinous single-dose of 64Cu-DOTHA2-PSMA at maximal tolerated injected activity, natCu-DOTHA2-PSMA at equimolar amount (control) or lutetium-177 (177Lu)-PSMA-617 at 120 MBq to assess their impact on survival. Weight, well-being and tumor size were followed until mice reached 62 days post-injection or ethical limits. Toxicity was assessed through weight, red blood cells (RBCs) counts, pathology and dosimetry calculations. Results: Survival was longer with 64Cu-DOTHA2-PSMA than with natCu-DOTHA2-PSMA (p < 0.001). Likewise, survival was also longer when compared to 177Lu-PSMA-617, although it did not reach statistical significance (p = 0.09). RBCs counts remained within normal range for the 64Cu-DOTHA2-PSMA group. 64Cu-DOTHA2-PSMA treated mice showed non-pathological fibrosis and no other signs of radiation injury. Human extrapolation of dosimetry yielded an effective dose of 3.14 × 10-2 mSv/MBq, with highest organs doses to gastrointestinal tract and liver. Discussion: Collectively, our data showed that 64Cu-DOTHA2-PSMA-directed radioligand therapy was effective for the treatment of LNCaP tumor-bearing NRG mice with acceptable toxicity and dosimetry. The main potential challenge is the hepatic and gastrointestinal irradiation.

68Ga-DOTATATE Prepared from Cyclotron-Produced 68Ga: An Integrated Solution from Cyclotron Vault to Safety Assessment and Diagnostic Efficacy in Neuroendocrine Cancer Patients.

Cyclotron production of 68Ga is a promising approach to supply 68Ga radiopharmaceuticals. To validate this capability, an integrated solution for a robust synthesis of 68Ga-DOTATATE prepared from cyclotron-produced 68Ga was achieved. A retrospective comparison analysis was performed on patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68Ga produced by a cyclotron or eluted from a generator to demonstrate the clinical safety and diagnostic efficacy of the radiopharmaceutical as a routine standard-of-care diagnostic tool in the clinic. Methods: An enriched pressed 68Zn target was irradiated by a cyclotron with a proton beam set at 12.7 MeV for 100 min. The fully automated process uses an in-vault dissolution system in which a liquid distribution system transfers the dissolved target to a dedicated hot cell for the purification of 68GaCl3 and radiolabeling of DOTATATE using a cassette-based automated module. Quality control tests were performed on the resulting tracer solution. The internal radiation dose for 68Ga-DOTATATE was based on extrapolation from rat biodistribution experiments. A retrospective comparison analysis was performed on patients who underwent PET/CT imaging after injection of DOTATATE labeled with cyclotron- or generator-produced 68Ga. Results: The synthesis of 68Ga-DOTATATE (20.7 ± 1.3 GBq) with high apparent molar activity (518 ± 32 GBq/µmol at the end of synthesis) was completed in 65 min, and the radiopharmaceutical met the requirements specified in the European Pharmacopoeia monograph on 68Ga-chloride (accelerator-produced) solution for radiolabeling. 68Ga-DOTATATE was stable for at least 5 h after formulation. The dosimetry calculated with OLINDA for cyclotron- and generator-produced 68Ga-DOTATATE was roughly equivalent. The SUVmean or SUVmax of tumoral lesions with cyclotron-produced 68Ga-DOTATATE was equivalent to that with generator-produced 68Ga. Among physiologic uptake levels, a significant difference was found in kidneys, spleen, and stomach wall, with lower values in cyclotron-produced 68Ga-DOTATATE in all cases. Conclusion: Integrated cyclotron production achieves reliable high yields of clinical-grade 68Ga-DOTATATE. The clinical safety and imaging efficacy of cyclotron-produced 68Ga-DOTATATE in humans provide supporting evidence for its use in routine clinical practice.

68Ga-DOTATOC PET/CT in detecting neuroendocrine tumours responsible for initial or recurrent paraneoplastic Cushing's syndrome.

PURPOSE: Paraneoplastic Cushing's syndrome (PCS) is frequently caused by neuroendocrine tumours (NETs). Approximately 20% of tumours are still occult years later. Gallium-68 somatostatin receptor-PET/CT is promising for the detection of the causal primary NET, but its role in case of recurrent PCS is rarely reported. We report our experience with DOTATOC PET/CT in localising the causal NET in cases of initial but also recurrent PCS, and its clinical impact. METHODS: A retrospective review of all DOTATOC PET/CTs performed in consecutive patients referred for PCS to our centre, between January 2011 and June 2017, was done. Nineteen patients underwent 26 PET/CTs, 13 for detection of a primary NET, seven for persistent or recurrent PCS after resection, and six for surveillance after resection of NETs previously detected on a DOTATOC PET/CT in our centre. RESULTS: Among the 13 PET/CTs performed to search for primary NET, five were positive: four carcinoid lung tumours were confirmed after resection and one lung focus was not confirmed since surgery would have carried a high risk. Clinical impact was 23% (3/13). Among the seven PET/CTs performed for persistent or recurrent PCS, six were true-positive, with confirmation of metastatic lymph nodes after resection. Clinical impact was 57% (4/7). All PET/CTs performed for surveillance were true-negative. CONCLUSIONS: DOTATOC PET/CT seems to be a valuable tool for detection of the NET responsible for persistent or recurrent PCS after surgery. In this context, DOTATOC PET/CT was more effective than for the detection of the causal tumour in initial PCS.

Tumor Heterogeneity Detected by 68Ga DOTATOC and 18F-FDG PET/CTs in One Malignant Insulinoma With Involvement of the Portal Splenic Confluence and Ovarian Metastases.

A 67-year-old woman was referred for staging of an insulinoma. CT has shown a pancreatic tumor, a portal thrombus, and an ovarian mass presumed not to be related with the insulinoma. These three lesions were highly positive on Ga DOTATOC PET/CT, leading to the hypothesis of a malignant insulinoma with neoplastic vein thrombus and ovarian metastasis, which was subsequently confirmed histologically. Despite severe hypoglycemia preventing fasting, F-FDG PET/CT was informative, showing significant uptake by the thrombus, which corresponded to the most aggressive lesion (Ki67 of 3.5% for the primary pancreatic tumor and 19.6% for the thrombus).