Story of Rubidium-82 and Advantages for Myocardial Perfusion PET Imaging.

Rubidium-82 has a long story, starting in 1954. After preclinical studies in dogs showing that myocardial uptake of this radionuclide was directly proportional to myocardial blood flow (MBF), clinical studies were performed in the 80s leading to an approval in the USA in 1989. From that time, thousands of patients have been tested and their results have been reported in three meta-analyses.

A pretargeting system for tumor PET imaging and radioimmunotherapy.

Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy.

Tumor immunotargeting using innovative radionuclides.

This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical use. However, alternative radionuclides, with more appropriate physical properties, such as lutetium-177 or copper-67, as well as alpha-emitting radionuclides, including astatine-211, bismuth-213, actinium-225, and others are currently reviving hopes in cancer treatments, both in hematological diseases and solid tumors.

¹⁸F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma.

Purpose: PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial.

Methods: Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months.

Improvement of radioimmunotherapy using pretargeting.

During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled monoclonal antibodies and receptor binding agents. Conventional radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor, and potential excessive radiation to normal tissues.

Radiolabeled antibodies for cancer imaging and therapy.

Radiolabeled antibodies were studied first for tumor detection by single-photon imaging, but FDG PET stopped these developments. In the meantime, radiolabeled antibodies were shown to be effective in the treatment of lymphoma. Radiolabeling techniques are well established and radiolabeled antibodies are a clinical and commercial reality that deserves further studies to advance their application in earlier phase of the diseases and to test combination and adjuvant therapies including radiolabeled antibodies in hematological diseases.

Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement.

Unlabelled: The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome.

Methods: From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.

Pretargeted radioimmunotherapy (pRAIT) in medullary thyroid cancer (MTC).

Prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival, based on prognostic factors, such as serum calcitonin doubling time (Ct DT). Pretargeted radioimmunotherapy (pRAIT) is a novel targeted radionuclide therapy, using a bispecific monoclonal antibody (BsMAb) and a radiolabeled bivalent hapten, designed to improve the therapeutic index and to deliver increased tumor-absorbed doses to relatively radioresistant solid tumors. Pretargeting has demonstrated a more favorable therapeutic index and clinical efficacy than directly labeled anti-carcinoembryonic antigen (CEA) MAb in preclinical MTC models.

The ARRONAX project.

A new high-energy and high-intensity cyclotron, ARRONAX, has been set into operation in 2010. ARRONAX can accelerate both negative ions (H- and D-) and positive ions (He++ and HH+). Protons can be accelerated from 30 MeV up to 70 MeV with a maximum beam intensity of 2 × 375 μAe whereas He++ can be accelerated at 68 MeV with a maximum beam current of 70 μAe.

High rates of durable responses with anti-CD22 fractionated radioimmunotherapy: results of a multicenter, phase I/II study in non-Hodgkin's lymphoma.

Purpose: Fractionated radioimmunotherapy targeting CD22 may substantially improve responses and outcome in non-Hodgkin's lymphoma (NHL).

Patients And Methods: A multicenter trial evaluated two or three weekly infusions of yttrium-90 ((90)Y) epratuzumab tetraxetan (humanized anti-CD22 antibody) in 64 patients with relapsed/refractory NHL, including 17 patients who underwent prior autologous stem-cell transplantation (ASCT). Objective (OR) and complete responses (CR/complete response unconfirmed [CRu]), as well as progression-free survival (PFS), were determined.

Pretargeted radioimmunotherapy in rapidly progressing, metastatic, medullary thyroid cancer.

Medullary thyroid cancer (MTC) patients with localized residual disease and/or distant metastases may survive for several years or rapidly progress and die of their disease. Thus, highly reliable prognostic factors are needed for an early distinction between high-risk patients who need to be treated and low-risk patients who warrant a watch-and-wait approach. Calcitonin doubling time is an independent predictor of survival, with a high predictive value in a population of patients who have not normalized their calcitonin, even after repeated surgery.

[Radiolabeled antibodies for cancer treatment].

The first treatment ever by radio-immunotherapy (RIT) was performed by William H. Beierwaltes in 1951 and was a success. Fifty years later, the main question is to find ways of extending the success of radiolabelled anti-CD20 antibodies in indolent non-Hodgkin's lymphoma to other forms of cancer.

Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors.

Radioimmunotherapy (RIT) has been proven effective in the treatment of radiosensitive non-Hodgkin lymphoma but, for radioresistant solid tumors, new approaches are necessary to improve the clinical effectiveness. A real improvement has been the introduction of the pretargeting technology which appeared to be able to significantly increase tumor-to-normal organ uptake ratios.Another very promising approach consists in associating RIT with other treatment modalities.

Current status and perspectives in peptide receptor radiation therapy.

Regulatory peptide receptors are overexpressed in numerous human cancers. The specific receptor binding property of peptides can be exploited by their labelling with a radionuclide and their use as carriers to guide the radioactivity to the tissues expressing their specific receptors. During the past decade, radiolabelled receptor-binding peptides have emerged as an important class of radiopharmaceuticals for tumour diagnosis and therapy.

What can be expected from nuclear medicine tomorrow?

Imaging can take advantage of developments in "omics" approaches and go from routine individual biomarkers to multiple-scale biomarker profiles. Imaging structural, functional, metabolic, cellular, and molecular changes will be made possible by multimodality hybrid techniques, such as positron emission tomography-magnetic resonance imaging. Imaging should predict treatment response, look at stratification for specific treatment modalities, and look at the "omic" characterization of an individual patient or a specific tumor.

ARRONAX, a high-energy and high-intensity cyclotron for nuclear medicine.

Purpose: This study was aimed at establishing a list of radionuclides of interest for nuclear medicine that can be produced in a high-intensity and high-energy cyclotron.

Methods: We have considered both therapeutic and positron emission tomography radionuclides that can be produced using a high-energy and a high-intensity cyclotron such as ARRONAX, which will be operating in Nantes (France) by the end of 2008. Novel radionuclides or radionuclides of current limited availability have been selected according to the following criteria: emission of positrons, low-energy beta or alpha particles, stable or short half-life daughters, half-life between 3 h and 10 days or generator-produced, favourable dosimetry, production from stable isotopes with reasonable cross sections.