Distant metastases of differentiated thyroid cancer: diagnosis, treatment and outcome

The remarkably good prognosis and long-term survival in differentiated thyroid cancer (DTC) are significantly reduced in patients with distant metastasis (DM). Multi-site metastases are associated with a high mortality rate reaching 92% at 5 years necessitating early diagnosis and treatment. The most common site of metastases are the lungs, followed by the bone, with the former having better prognosis than the latter due to late detection. A number of factors contribute to the development of DM including large and multifocal primary tumour, extrathyroidal extension, aggressive histology and advanced age. In patients with good 131I uptake, 131I therapy appears highly effective and should be offered up to a cumulative activity of 22 GBq. Other measures such as surgery, radiotherapy, arterial embolisation and cementoplasty may be required. If there is low or no 131I uptake, FDG-PET should be obtained due to its prognostic impact. It may help in selecting patients for other modalities such as cytotoxic chemotherapy and redifferentiation therapy by 13-cis retinoic acid. The development of tyrosine kinase inhibitors has raised hopes in providing alternative therapy for bone metastasis, especially in older age groups with poorly differentiated tumours with no 131I uptake but good uptake of FDG

68Ga-Radiolabeling and Pharmacological Characterization of a Kit-Based Formulation of the Gastrin-Releasing Peptide Receptor (GRP-R) Antagonist RM2 for Convenient Preparation of [68Ga]Ga-RM2

Background: [68Ga]Ga-RM2 is a potent Gastrin-Releasing Peptide-receptor (GRP-R) antagonist for imaging prostate cancer and breast cancer, currently under clinical evaluation in several specialized centers around the world. Targeted radionuclide therapy of GRP-R-expressing tumors is also being investigated. We here report the characteristics of a kit-based formulation of RM2 that should ease the development of GRP-R imaging and make it available to more institutions and patients. Methods: Stability of the investigated kits over one year was determined using LC/MS/MS and UV-HPLC. Direct 68Ga-radiolabeling was optimized with respect to buffer (pH), temperature, reaction time and shaking time. Conventionally prepared [68Ga]Ga-RM2 using an automated synthesizer was used as a comparator. Finally, the [68Ga]Ga-RM2 product was assessed with regards to hydrophilicity, affinity, internalization, membrane bound fraction, calcium mobilization assay and efflux, which is a valuable addition to the in vivo literature. Results: The kit-based formulation, kept between 2 °C and 8 °C, was stable for over one year. Using acetate buffer pH 3.0 in 2.5–5.1 mL total volume, heating at 100 °C during 10 min and cooling down for 5 min, the [68Ga]Ga-RM2 produced by kit complies with the requirements of the European Pharmacopoeia. Compared with the module production route, the [68Ga]Ga-RM2 produced by kit was faster, displayed higher yields, higher volumetric activity and was devoid of ethanol. In in vitro evaluations, the [68Ga]Ga-RM2 displayed sub-nanomolar affinity (Kd = 0.25 ± 0.19 nM), receptor specific and time dependent membrane-bound fraction of 42.0 ± 5.1% at 60 min and GRP-R mediated internalization of 24.4 ± 4.3% at 30 min. The [natGa]Ga-RM2 was ineffective in stimulating intracellular calcium mobilization. Finally, the efflux of the internalized activity was 64.3 ± 6.5% at 5 min. Conclusion: The kit-based formulation of RM2 is suitable to disseminate GRP-R imaging and therapy to distant hospitals without complex radiochemistry equipment

ACS Omega

Neurotensin receptor 2 (NTS) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radiometalated neurotensin analogue targeting NTS. JMV 7488 (DOTA-(βAla)-Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase peptide synthesis, then purified, radiolabeled with Ga and In, and investigated on HT-29 cells and MCF-7 cells, respectively, and on HT-29 xenografts. [Ga]Ga-JMV 7488 and [In]In-JMV 7488 were quite hydrophilic (logD = -3.1 ± 0.2 and -2.7 ± 0.2, respectively, < 0.0001). Saturation binding studies showed good affinity toward NTS ( = 38 ± 17 nM for [Ga]Ga-JMV 7488 on HT-29 and 36 ± 10 nM on MCF-7 cells; = 36 ± 4 nM for [In]In-JMV 7488 on HT-29 and 46 ± 1 nM on MCF-7 cells) and good selectivity (no NTS binding up to 500 nM). On cell-based evaluation, [Ga]Ga-JMV 7488 and [In]In-JMV 7488 showed high and fast NTS-mediated internalization of 24 ± 5 and 25 ± 11% at 1 h for [In]In-JMV 7488, respectively, along with low NTS-membrane binding (<8%). Efflux was as high as 66 ± 9% at 45 min for [Ga]Ga-JMV 7488 on HT-29 and increased for [In]In-JMV 7488 up to 73 ± 16% on HT-29 and 78 ± 9% on MCF-7 cells at 2 h. Maximum intracellular calcium mobilization of JMV 7488 was 91 ± 11% to that of levocabastine, a known NTS agonist on HT-29 cells demonstrating the agonist behavior of JMV 7488. In nude mice bearing HT-29 xenograft, [Ga]Ga-JMV 7488 showed a moderate but promising significant tumor uptake in biodistribution studies that competes well with other nonmetalated radiotracers targeting NTS. Significant uptake was also depicted in lungs. Interestingly, mice prostate also demonstrated [Ga]Ga-JMV 7488 uptake although the mechanism was not NTS-mediated

Apport de la microscopie ionique en biologie: localisation intracellulaire et appreciation de la concentration locale de molecules marquees

SIGLEINIST T 74981 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Facteurs de variation de la captation hépatique de 18-FDG dans l'évaluation intermédiaire des lymphomes de haut grade en TEP-TDM

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Lymphome de Hodgkin (évaluation de l'intérêt d'une TEP de fin de traitement lorsque la TEP intermédiaire est négative, étude rétrospective bicentrique)

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Est-il utile d'effectuer des tests périodiques de stimulation par la rhTSH dans le cancer thyroïdien différencié de stade-I avec un premier bilan de contrôle négatif ?

PARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Membrane and Nuclear Absorbed Doses from 177Lu and 161Tb in Tumor Clusters: Effect of Cellular Heterogeneity and Potential Benefit of Dual Targeting—A Monte Carlo Study

Early use of targeted radionuclide therapy to eradicate tumor cell clusters and micrometastases might offer cure. However, there is a need to select appropriate radionuclides and assess the potential impact of heterogeneous targeting. The Monte Carlo code CELLDOSE was used to assess membrane and nuclear absorbed doses from Lu and Tb (β-emitter with additional conversion and Auger electrons) in a cluster of 19 cells (14-μm diameter, 10-μm nucleus). The radionuclide distributions considered were cell surface, intracytoplasmic, or intranuclear, with 1,436 MeV released per labeled cell. To model heterogeneous targeting, 4 of the 19 cells were unlabeled, their position being stochastically determined. We simulated situations of single targeting, as well as dual targeting, with the 2 radiopharmaceuticals aiming at different targets. Tb delivered 2- to 6-fold higher absorbed doses to cell membranes and 2- to 3-fold higher nuclear doses than Lu. When all 19 cells were targeted, membrane and nuclear absorbed doses were dependent mainly on radionuclide location. With cell surface location, membrane absorbed doses were substantially higher than nuclear absorbed doses, both with Lu (38-41 vs. 4.7-7.2 Gy) and with Tb (237-244 vs. 9.8-15.1 Gy). However, when 4 cells were not targeted by the cell surface radiopharmaceutical, the membranes of these cells received on average only 9.6% of the Lu absorbed dose and 2.9% of the Tb dose, compared with a cluster with uniform cell targeting, whereas the impact on nuclear absorbed doses was moderate. With an intranuclear radionuclide location, the nuclei of unlabeled cells received only 17% of the Lu absorbed dose and 10.8% of the Tb dose, compared with situations with uniform targeting. With an intracytoplasmic location, nuclear and membrane absorbed doses to unlabeled cells were one half to one quarter those obtained with uniform targeting, both for Lu and for Tb. Dual targeting was beneficial in minimizing absorbed dose heterogeneities. To eradicate tumor cell clusters, Tb may be a better candidate than Lu. Heterogeneous cell targeting can lead to substantial heterogeneities in absorbed doses. Dual targeting was helpful in reducing dose heterogeneity and should be explored in preclinical and clinical studies

Breast Cancer Res Treat

Neurotensin receptor-1 (NTS) is increasingly recognized as a potential target in diverse tumors including breast cancer, but factors associated with NTS expression have not been fully clarified. We studied NTS expression using the Tissue MicroArray (TMA) of primary breast tumors from Institut Bergonié. We also studied association between NTS expression and clinical, pathological, and biological parameters, as well as patient outcomes. Out of 1419 primary breast tumors, moderate to strong positivity for NTS (≥ 10% of tumoral cells stained) was seen in 459 samples (32.4%). NTS staining was cytoplasmic in 304 tumors and nuclear in 155 tumors, a distribution which appeared mutually exclusive. Cytoplasmic overexpression of NTS was present in 21.5% of all breast tumors. In multivariate analysis, factors associated with cytoplasmic overexpression of NTS in breast cancer samples were higher tumor grade, Ki67 ≥ 20%, and higher pT stage. Cytoplasmic NTS was more frequent in tumors other than luminal A (30% versus 17.3%; p < 0.0001). Contrastingly, the main "correlates" of a nuclear location of NTS were estrogen receptor (ER) positivity, low E&E (Elston and Ellis) grade, Ki67 < 20%, and lower pT stage. In NTS-positive samples, cytoplasmic expression of NTS was associated with shorter 10-year metastasis-free interval (p = 0.033) compared to NTS nuclear staining. Ancillary analysis showed NTS expression in 73% of invaded lymph nodes from NTS-positive primaries. NTS overexpression was found in about one-third of breast tumors from patients undergoing primary surgery with two distinct patterns of distribution, cytoplasmic distribution being more frequent in aggressive subtypes. These findings encourage the development of NTS-targeting strategy, including radiopharmaceuticals for imaging and therapy.Translational Research and Advanced Imaging Laborator