68Ga-DOTATATE for Tumor Localization in Tumor-Induced Osteomalacia.

CONTEXT: Phosphaturic mesenchymal tumors (PMTs) are small, typically difficult to localize, and express somatostatin receptors. Recent work suggests imaging studies using 68Gallium (68Ga)-conjugated somatostatin peptide analogues, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)TATE, which enables somatostatin receptor imaging with positron emission tomography (PET), may be useful at identifying these tumors. OBJECTIVE: Our objective was to evaluate the use of 68Ga-DOTATATE PET/computed tomography (CT) for tumor localization in tumor-induced osteomalacia (TIO). DESIGN: This was a single-center prospective study of patients with TIO. SETTING: The study was conducted at the National Institutes of Health Clinical Center between February 2014 and February 2015. SUBJECTS: Eleven subjects (six females, five males) with TIO were included. INTERVENTION: Subjects underwent 68Ga-DOTATATE PET/CT in addition to 111In-pentetreotide single-photon emission CT (Octreoscan- SPECT/CT) and fluorodeoxyglucose-PET/CT (18F FDG-PET/CT) scan. MAIN OUTCOME MEASURES: Localization of PMTs on the previously described imaging modalities were determined. RESULTS: The tumor was successfully localized in 6/11 (54.5%) subjects (one was metastatic). The tumor was identified by 68Ga-DOTATATE in all six cases. Both Octreoscan-SPECT/CT and 18F FDG-PET each identified the tumor in 4/6. In no cases was 68Ga-DOTATATE the only imaging study to identify the tumor. CONCLUSIONS: In this first prospective study comparing 68Ga-DOTATATE PET/CT to Octreoscan-SPECT/CT and 18F FDG-PET in TIO localization, 68Ga-DOTATATE PET/CT demonstrated the greatest sensitivity and specificity, suggesting that it may be the best single study for localization of PMTs in TIO.

Results of (68)Gallium-DOTATATE PET/CT Scanning in Patients with Multiple Endocrine Neoplasia Type 1.

BACKGROUND: Screening for neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN1) is recommended to detect primary and metastatic tumors, which can result in significant morbidity and mortality. The utility of somatostatin receptor imaging (68)Gallium-DOTATATE PET/CT in patients with MEN1 is not known. The aim of this study was to prospectively determine the accuracy of (68)Gallium-DOTATATE PET/CT vs (111)In- pentetreotide single-photon emission CT (SPECT)/CT and anatomic imaging in patients with MEN1. STUDY DESIGN: We performed a prospective study comparing (68)Gallium-DOTATATE PET/CT, (111)In-pentetreotide SPECT/CT, and triphasic CT scan to clinical, biochemical, and pathologic data in 26 patients with MEN1. RESULTS: (68)Gallium-DOTATATE PET/CT detected 107 lesions; (111)In-pentetreotide SPECT/CT detected 33 lesions; and CT scan detected 48 lesions. Lesions detected on (68)Gallium-DOTATATE PET/CT had high standard uptake value (SUV)(max) (median SUV(max) = 72.8 [range 19 to 191]). In 7 of the 26 patients (27%), (68)Gallium-DOTATATE PET/CT was positive, with a negative (111)In-pentetreotide SPECT/CT, and in 10 patients (38.5%), additional metastases were detected (range 0.3 cm to 1.5 cm). In 8 of the 26 patients (31%), there was a change in management recommendations as a result of the findings on (68)Gallium-DOTATATE PET/CT that were not seen on (111)In-pentetreotide SPECT/CT and CT scan. CONCLUSIONS: (68)Gallium-DOTATATE PET/CT is more sensitive for detecting NETs than (111)In-pentetreotide SPECT/CT and CT scan in patients with MEN1. This imaging technique should be integrated into radiologic screening and surveillance of patients with MEN1 because it can significantly alter management recommendations.

Mutation-targeted therapy with sunitinib or everolimus in patients with advanced low-grade or intermediate-grade neuroendocrine tumours of the gastrointestinal tract and pancreas with or without cytoreductive surgery: protocol for a phase II clinical trial.

INTRODUCTION: Finding the optimal management strategy for patients with advanced, metastatic neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas is a work in progress. Sunitinib and everolimus are currently approved for the treatment of progressive, unresectable, locally advanced or metastatic low-grade or intermediate-grade pancreatic NETs. However, mutation-targeted therapy with sunitinib or everolimus has not been studied in this patient population. METHODS AND ANALYSIS: This prospective, open-label phase II clinical trial was designed to determine if mutation-targeting therapy with sunitinib or everolimus for patients with advanced low-grade or intermediate-grade NETs is more effective than historically expected results with progression-free survival (PFS) as the primary end point. Patients ≥18 years of age with progressive, low-grade or intermediate-grade locally advanced or metastatic NETs are eligible for this study. Patients will undergo tumour biopsy (if they are not a surgical candidate) for tumour genotyping. Patients will be assigned to sunitininb or everolimus based on somatic/germline mutations profile. Patients who have disease progression on either sunitinib or everolimus will crossover to the other drug. Treatment will continue until disease progression, unacceptable toxicity, or consent to withdrawal. Using the proposed criteria, 44 patients will be accrued within each treatment group during a 48-month period (a total of 88 patients for the 2 treatments), and followed for up to an additional 12 months (a total of 60 months from entry of the first patient) to achieve 80% power in order to test whether there is an improvement in PFS compared to historically expected results, with a 0.10 α level one-sided significance test. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board of the National Cancer Institute (NCI-IRB Number 15C0040; iRIS Reference Number 339636). The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION NUMBER: NCT02315625.

Phase I trial of systemic intravenous infusion of interleukin-13-Pseudomonas exotoxin in patients with metastatic adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare but lethal malignancy without effective current therapy for metastatic disease. IL-13-PE is a recombinant cytotoxin consisting of human interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin A (PE). The main objectives of this Phase I dose-escalation trial were to assess the maximum-tolerated dose (MTD), safety, and pharmacokinetics (PK) of IL-13-PE in patients with metastatic ACC. Eligible patients had confirmed IL-13 receptor alpha 2 (IL-13Rα2) expressions in their tumors. IL-13-PE at dose of 1-2 µg/kg was administered intravenously (IV) on day 1, 3, and 5 in a 4-week cycle. Six patients received 1 µg/kg and two patients received 2 µg/kg of IL-13-PE. Dose-limiting toxicity was observed at 2 µg/kg, at which patients exhibited thrombocytopenia and renal insufficiency without requiring dialysis. PK analysis demonstrated that at MTD, the mean maximum serum concentration (Cmax ) of IL-13-PE was 21.0 ng/mL, and the terminal half-life of IL-13-PE was 30-39 min. Two (25%) of the eight patients had baseline neutralizing antibodies against PE. Three (75%) of the remaining four tested patients developed neutralizing antibodies against IL-13-PE within 14-28 days of initial treatment. Of the five patients treated at MTD and assessed for response, one patient had stable disease for 5.5 months before disease progression; the others progressed within 1-2 months. In conclusion, systemic IV administration of IL-13-PE is safe at 1 µg/kg. All tested patients developed high levels of neutralizing antibodies during IL-13-PE treatment. Use of strategies for immunodepletion before IL-13-PE treatment should be considered in future trials.

Detection of insulinoma using (68)Gallium-DOTATATE PET/CT: a case report.

Insulinomas are the most common cause of endogenous hyperinsulinemic hypoglycemia in non-diabetic adults. They are most often benign, small and difficult to localize with current imaging techniques. This is of high importance, as complete surgical resection is the only curative treatment. Anatomic imaging, (111)In-pentetreotide scan and (68)Gallium-DOTATATE positron emission tomography/computed tomography (PET/CT) were compared in a patient with insulinoma. (68)Gallium-DOTATATE PET/CT and selective arterial calcium stimulation localized the insulinoma. At surgery, a tumor in the anterior aspect of the pancreatic body was found which confirmed the preoperative localization, and a 2.1 cm tumor was enucleated, World Health Organization (WHO) grade I insulinoma. The patient remains euglycemic and free of symptoms at last follow up. In conclusion, (68)Gallium-DOTATATE PET/CT imaging may be a useful adjunct localizing study for insulinomas. It is a non-invasive preoperative localization study that could guide surgical exploration for successful therapy.