No abstract

Purpose To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177 Lu-Dotatate. Methods In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results Significantly prolonged median PFS occurred with 177 Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177 Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions 177 Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11 This article is part of the Topical Collection on Endocrinology.

Introduction: Gastrin Releasing peptide receptors (GRPRs) are potential molecular imaging targets in a variety of tumors. Recently, a 68 Ga-labelled antagonist to GRPRs, NeoBOMB1, was developed for PET. We report on the outcome of a Phase I/IIa clinical trial (EudraCT 2016-002053-38) within the EU-FP7 project Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with Metastatic Gastrointestinal Stromal Tumours ('MITIGATE') (grant agreement number 602306) in patients with oligometastatic gastrointestinal stromal tumors (GIST). Materials and methods:The main objectives were evaluation of safety, biodistribution, dosimetry and preliminary tumor targeting of 68 Ga-NeoBOMB1 in patients with advanced TKI-treated GIST using PET/CT. Six patients with histologically confirmed GIST and unresectable primary or metastases undergoing an extended protocol for detailed pharmacokinetic analysis were included. 68 Ga-NeoBOMB1 was prepared using a kit procedure with a licensed 68 Ge/ 68 Ga generator. 3 MBq/kg body-weight were injected intravenously and safety parameters were assessed. PET/CT included dynamic imaging at 5 min, 11 min and 19 min as well as static imaging at 1, 2 and 3-4 h p.i. for dosimetry calculations. Venous blood samples and urine were collected for pharmacokinetics. Tumor targeting was assessed on a per-lesion and perpatient basis.Results: 68 Ga-NeoBOMB1 (50 µg) was prepared with high radiochemical purity (yield >97%). Patients received 174 ± 28 MBq of the radiotracer, which was well tolerated in all patients over a follow-up period of 4 weeks. Dosimetry calculations revealed a mean adsorbed effective dose of 0.029 ± 0.06 mSv/MBq with highest organ dose to the pancreas (0.274 ± 0.099 mSv/MBq). Mean plasma half-life was 27.3 min with primarily renal clearance (mean 25.7 ± 5.4% of injected dose 4h p.i.). Plasma metabolite analyses revealed high stability, metabolites were only detected in the urine. In three patients a significant uptake with increasing maximum standard uptake values (SUVmax at 2h p.i.: 4.3 to 25.9) over time was found in tumor lesions. Conclusion:This Phase I/IIa study provides safety data for 68 Ga-NeoBOMB1, a promising radiopharmaceutical for targeting GRPR-expressing tumors. Safety profiles and pharmacokinetics are suitable for PET imaging and absorbed dose estimates are comparable to other 68 Ga-labelled radiopharmaceuticals used in clinical routine.

The efficacy of levothyroxine suppressive therapy in the treatment of benign solitary thyroid nodules is controversial. In order to investigate this issue further we studied 122 patients with a solitary, solid or predominantly solid, thyroid nodule. The benign (colloid) nature of all nodules was proved by fine-needle aspiration biopsy. At the pertechnetate-99m thyroid scanning 91% of the nodules were "cold" and 9% "warm". All the patients received suppressive oral doses of levothyroxine (0.1 to 0.2 mg/day). Fifty-three patients were treated with levothyroxine for 6 months, 31 for 9 months and 38 for 12 months. The size of each nodule before and after treatment was evaluated by high-resolution ultrasonography. The actual suppression of TSH secretion was monitored at 3-month intervals using an ultrasensitive immunometric assay. At the end of levothyroxine treatment, patients were classified as responders (decrease in nodule volume \m=ge\50%,68/122 = 55.7%; mean percent change in nodule volume = \m=-\77.1\ m=+-\ 15.7%), partially responders (decrease in nodule volume <50%, 24/122 = 19.7%; mean percent change in nodule volume = \m=-\27.5\m=+-\10.1%),and nonresponders, when either no change in nodule volume (16/122 = 13.1%) or an increase in nodule volume (14/122 = 11.5%) was observed. In each group serum free T4 rose significantly in response to levothyroxine therapy, whereas serum free T3 remained unchanged. TSH levels were undetectable in all patients. Both the proportion of responders, partially responders and nonresponders, and the mean percent decrease in nodule volume in the responder group were not significantly different in patients treated with levothyroxine for 6, 9 or 12 months, respectively. Therefore, it appears that levothyroxine therapy is effective within 6 months in reducing the size of colloid solitary, solid or predominantly solid, thyroid nodules or in preventing their further growth in about 90% of our patients.Although thyroid suppression is recommended for the medical treatment of benign thyroid nodules (1-3), its efficacy in reducing nodule volume is con¬ troversial. Response rates as high as 61% (4) and as low as 9% (5) have in fact been reported. More recently, Gharib et al. (6) showed that levothyro¬ xine (L-T4) therapy given over a 6-month period did not reduce the size of colloid thyroid nodules despite effective suppression of TSH secretion.In order further to investigate the usefulness of thyroid hormone suppression in the treatment of nodular goitre, we studied the effects on nodule volume of suppressive doses of L-T4 in 122 patients with a colloid solitary, solid or predominantly solid, thyroid nodule. Patients and MethodsThe investigation, which started in November 1988, was conducted in accordance with the principles of the Hel¬ sinki II Declaration. Since the aim of the present study was to investigate the effects of L-T4 therapy on benign (colloid) solitary, solid or predominantly solid (with small cystic spaces =£0.5 cm) thyroid nodules, exclusion criteria included the following:...

The analysis of the JNK-dependent apoptosis pathway can provide biomarkers for activated lymphocytes in the active phase of RRMS and a gene expression signature for disease status. The reported results might be useful to stratify patients, thereby supporting the development of novel therapies.