Preclinical Pharmacokinetics and Dosimetry of an 89Zr Labelled Anti-PDL1 in an Orthotopic Lung Cancer Murine Model.

Anti-PDL1 is a monoclonal antibody targeting the programmed death-cell ligand (PD-L1) by blocking the programmed death-cell (PD-1)/PD-L1 axis. It restores the immune system response in several tumours, such as non-small cell lung cancer (NSCLC). Anti-PDL1 or anti-PD1 treatments rely on PD-L1 tumoural expression assessed by immunohistochemistry on biopsy tissue. However, depending on the biopsy extraction site, PD-L1 expression can vary greatly. Non-invasive imaging enables whole-body mapping of PD-L1 sites and could improve the assessment of tumoural PD-L1 expression. METHODS: Pharmacokinetics (PK), biodistribution and dosimetry of a murine anti-PDL1 radiolabelled with zirconium-89, were evaluated in both healthy mice and immunocompetent mice with lung cancer. Preclinical PET (µPET) imaging was used to analyse [89Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans. RESULTS: Organ distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoural uptake occurred within 24 h post-injection of [89Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) and image quality. An in vivo blocking study confirmed that [89Zr]DFO-anti-PDL1 specifically targeted PD-L1 in CMT167 lung tumours in mice. AUC in organs was estimated using a 1-compartment PK model and extrapolated to human (using allometric scaling) in order to estimate the radiation exposure in human. Human-estimated effective dose was 131 µSv/MBq. CONCLUSION: The predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging.

Whole-Body Characterization of Estrogen Receptor Status in Metastatic Breast Cancer with 16α-18F-Fluoro-17ß-Estradiol Positron Emission Tomography: Meta-Analysis and Recommendations for Integration into Clinical Applications.

Estrogen receptor (ER) status by immunohistochemistry (IHC) of cancer tissue is currently used to direct endocrine therapy in breast cancer. Positron emission tomography (PET) with 16α-18F-fluoro-17ß-estradiol (18 F-FES) noninvasively characterizes ER ligand-binding function of breast cancer lesions. Concordance of imaging and tissue assays should be established for 18 F-FES PET to be an alternative or complement to tissue biopsy for metastatic lesions. We conducted a meta-analysis of published results comparing 18 F-FES PET and tissue assays of ER status in patients with breast cancer. PubMed and EMBASE were searched for English-language manuscripts with at least 10 patients and low overall risk of bias. Thresholds for imaging and tissue classification could differ between studies but had to be clearly stated. We used hierarchical summary receiver-operating characteristic curve models for the meta-analysis. The primary analysis included 113 nonbreast lesions from 4 studies; an expanded analysis included 327 total lesions from 11 studies. Treating IHC results as the reference standard, sensitivity was 0.78 (95% confidence region 0.65-0.88) and specificity 0.98 (0.65-1.00) for the primary analysis of nonbreast lesions. In the expanded analysis including non-IHC tissue assays and all lesion sites, sensitivity was 0.81 (0.73-0.87) and specificity 0.86 (0.68-0.94). These results suggest that 18 F-FES PET is useful for characterization of ER status of metastatic breast cancer lesions. We also review current best practices for conducting 18 F-FES PET scans. This imaging assay has potential to improve clinically relevant outcomes for patients with (historically) ER-positive metastatic breast cancer, including those with brain metastases and/or lobular histology. IMPLICATIONS FOR PRACTICE: 16α-18F-fluoro-17ß-estradiol positron emission tomography (18 F-FES PET) imaging assesses estrogen receptor status in breast cancer in vivo. This work reviews the sensitivity and specificity of 18 F-FES PET in a meta-analysis with reference tissue assays and discusses best practices for use of the tracer as an imaging biomarker. 18 F-FES PET could enhance breast cancer diagnosis and staging as well as aid in therapy selection for patients with metastatic disease. Tissue sampling limitations, intrapatient heterogeneity, and temporal changes in molecular markers make it likely that 18 F-FES PET will complement existing assays when clinically available in the near future.

Evaluation of [18F]FNM biodistribution and dosimetry based on whole-body PET imaging of rats.

INTRODUCTION: The aim of this work was to study the biodistribution, metabolism and radiation dosimetry of rats injected with [18F]FNM using PET/CT images. This novel radiotracer targeting NMDA receptor has potential for investigation for neurological and psychiatric diseases. METHODS: Free fraction and stability in fresh human plasma were determined in vitro. PET/CT was performed on anesthetized rats. Organs were identified and 3D volumes of interest (VOIs) were manually drawn on the CT in the center of each organ. Time activity curves (TACs) were created with these VOIs, enabling the calculation of residence times. To confirm these values, ex vivo measurements of organs were performed. Plasma and urine were also collected to study in vivo metabolism. Data was extrapolated to humans, effective doses were estimated using ICRP-60 and ICRP-89 dosimetric models and absorbed doses were estimated using OLINDA/EXM V1.0 and OLINDA/EXM V2.0 (which use weighting factors from ICRP-103 to do the calculations). RESULTS: The [18F]FNM was stable in human plasma and the diffusible free fraction was 53%. As with memantine, this tracer is poorly metabolized in vivo. Ex vivo distributions validated PET/CT data as well as demonstrating a decrease of radiotracer uptake in the brain due to anesthesia. Total effective dose was around 6.11 µSv/MBq and 4.65 µSv/MBq for female and male human dosimetric models, respectively. CONCLUSIONS: This study shows that the presented compound exhibits stability in plasma and plasma protein binding very similar to memantine. Its dosimetry shows that it is suitable for use in humans due to a low total effective dose compared to other PET radiotracers.

Prospective comparison of 18F-NaF PET/CT versus 18F-FDG PET/CT imaging in mandibular extension of head and neck squamous cell carcinoma with dedicated analysis software and validation with surgical specimen. A preliminary study.

BACKGROUND: The aim of this study is to propose a new method to quantify radioactivity with PET/CT imaging in mandibular extension in head and neck squamous cell carcinoma (HNSCC), using innovative software, and to compare results with microscopic surgical specimens. PATIENTS AND METHODS: This prospective study enrolled 15 patients who underwent 18F-NaF and 18F-FDG PET/CT. We compared the delineations of bone invasions obtained with 18F-NaF PET/CT and 18F-FDG PET/CT with the results of histopathological analysis of mandibular resections (from right and left bone borders). A method for visualization and quantification of PET images was developed. RESULTS: For all patients, a significant difference (p = 0.032 for right limits and p = 0.011 for left limits) was observed between 18F-FDG PET/CT imaging and histopathology results, and no significant difference (p = 0.88 for right limits and p = 0.55 for left limits) was observed between 18F-NaF PET/CT imaging and histopathology results. The right limits were less than 10 mm in 93% of patients, and the left limits were less than 10 mm in 86% of patients. CONCLUSIONS: The dedicated software enabled the objective delineation of radioactivity within the bone. We can confirm that 18F-NaF is a precise and specific bone marker for the assessment of intraosseous mandibular extensions of head and neck cancers. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Clinical outcomes 1 year after empiric 131I therapy for hyperthyroid disorders: real life experience and predictive factors of functional response.

Radioiodine is a therapeutic option in Europe for Graves' disease (GD) and toxic multinodular goiter (MNG). PURPOSE: To compare empiric and calculated I activities using 2013 EANM recommendations. To look for predictive factors of therapeutic response to an empiric activity of I. To assess clinical situations favoring calculated treatment modalities. PATIENTS AND METHODS: Prospective monocentric study of clinical outcomes at 1 year follow-up in 86 patients with GD and MNG who received empiric I therapeutic activities (348-939 MBq). Differences between empiric and calculated activities were confronted to clinical outcomes. Physicians were not aware of the calculated activity at the time of prescription. RESULTS: One year after treatment, 9% (5/57) of GD patients and 7% (2/29) of MNG patients were still in a hyperthyroid state. Thyroid volume was reduced by 67% for GD and by 50% for MNG. In GD, empiric I activities were higher than calculated ones (564±131 vs. 316±319 MBq, P<0.001) in 93% (53/57) of patients. Pretherapeutic thyroid volume (>26 ml for GD; >40 ml for MNG) was associated with persistent hyperthyroidism. CONCLUSION: Empirically administered I for GD and MNG was associated with very high efficacy in thyroid function control and no side effects. Thyroid volume reduction did not preclude treatment efficacy. Activity calculation could be a useful method for treating patients with GD and thyroid volumes higher than 26 ml or patients with MNG and thyroid volumes higher than 40 ml. A selective approach based on pretherapeutic thyroid volume and radioiodine biokinetics might improve treatment success.

Radiosynthesis of [18F]AV1451 in pharmaceutical conditions and its biological characteristics.

In this study, we describe the radiosynthesis of [18F]AV1451 in terms of its pharmaceutical quality and characterise its physical and biological properties. We performed an in vitro serum stability study in fresh human plasma and a plasma protein binding study. The radiochemical yield was 24% (decay corrected), and the product met all regulatory quality requirements. We found that this compound is stable in fresh human plasma and binds tightly to plasma proteins, especially lipoproteins.

Genomics of Multiple Myeloma.

Multiple myeloma (MM) is characterized by wide variability in the chromosomal/genetic changes present in tumor plasma cells. Genetically, MM can be divided into two groups according to ploidy and hyperdiploidy versus nonhyperdiploidy. Several studies in gene expression profiling attempted to identify subentities in MM without convincing results. These studies mostly confirmed the cytogenetic data and subclassified patients according to 14q32 translocations and ploidy. More-recent data that are based on whole-exome sequencing have confirmed this heterogeneity and show many gene mutations but without a unifying mutation. These newer studies have shown the frequent alteration of the mitogen-activated protein kinase pathway. The most interesting data have demonstrated subclonality in all patients with MM, including subclonal mutations of supposed driver genes KRAS, NRAS, and BRAF.

Serum free light chains, not urine specimens, should be used to evaluate response in light-chain multiple myeloma.

Guidelines for monitoring multiple myeloma (MM) patients expressing light chains only (light-chain MM [LCMM]) rely on measurements of monoclonal protein in urine. Alternatively, serum free light chain (sFLC) measurements have better sensitivity over urine methods, however, demonstration that improved sensitivity provides any clinical benefit is lacking. Here, we compared performance of serum and urine measurements in 113 (72κ, 41λ) newly diagnosed LCMM patients enrolled in the Intergroupe Francophone du Myélome (IFM) 2009 trial. All diagnostic samples (100%) had an abnormal κ:λ sFLC ratio, and involved (monoclonal) FLC (iFLC) expressed at levels deemed measurable for monitoring (≥100 mg/L). By contrast, only 64% patients had measurable levels of monoclonal protein (≥200 mg per 24 hours) in urine protein electrophoresis (UPEP). After 1 and 3 treatment cycles, iFLC remained elevated in 71% and 46% of patients, respectively, whereas UPEP reported a positive result in 37% and 18%; all of the patients with positive UPEP at cycle 3 also had elevated iFLC levels. Importantly, elevated iFLC or an abnormal κ:λ sFLC ratio after 3 treatment cycles associated with poorer progression-free survival (P = .006 and P < .0001, respectively), whereas positive UPEP or urine immunofixation electrophoresis (uIFE) did not. In addition, patients with an abnormal κ:λ sFLC ratio had poorer overall survival (P = .022). Finally, early normalization of κ:λ sFLC ratio but not negative uIFE predicted achieving negative minimal residual disease, as determined by flow cytometry, after consolidation therapy (100% positive predictive value). We conclude that improved sensitivity and prognostic value of serum over urine measurements provide a strong basis for recommending the former for monitoring LCMM patients.

Radiolabeling of [18F]-fluoroethylnormemantine and initial in vivo evaluation of this innovative PET tracer for imaging the PCP sites of NMDA receptors.

INTRODUCTION: The N-methyl-D-aspartate receptor (NMDAr) is an ionotropic receptor that mediates excitatory transmission. NMDAr overexcitation is thought to be involved in neurological and neuropsychiatric disorders such as Alzheimer disease and schizophrenia. We synthesized [(18)F]-fluoroethylnormemantine ([(18)F]-FNM), a memantine derivative that binds to phencyclidine (PCP) sites within the NMDA channel pore. These sites are primarily accessible when the channel is in the active and open state. METHODS: Radiosynthesis was carried out using the Raytest® SynChrom R&D fluorination module. Affinity of this new compound was determined by competition assay. We ran a kinetic study in rats and computed a time-activity curve based on a volume-of-interest analysis, using CARIMAS® software. We performed an ex vivo autoradiography, exposing frozen rat brain sections to a phosphorscreen. Adjacent sections were used to detect NMDAr by immunohistochemistry with an anti-NR1 antibody. As a control of the specificity of our compound for NMDAr, we used a rat anesthetized with ketamine. Correlation analysis was performed with ImageJ software between signal of autoradiography and immunostaining. RESULTS: Fluorination yield was 10.5% (end of synthesis), with a mean activity of 3145 MBq and a specific activity above 355 GBq/µmol. Affinity assessment allowed us to determine [(19)F]-FNM IC50 at 6.1 10(-6)M. [(18)F]-FMN concentration gradually increased in the brain, stabilizing at 40 minutes post injection. The brain-to-blood ratio was 6, and 0.4% of the injected dose was found in the brain. Combined ex vivo autoradiography and immunohistochemical staining demonstrated colocalization of NMDAr and [(18)F]-FNM (r=0.622, p<0.0001). The highest intensity was found in the cortex and cerebellum, and the lowest in white matter. A low and homogeneous signal corresponding to unspecific binding was observed when PCP sites were blocked with ketamine. CONCLUSIONS: [(18)F]-FNM appears to be a promising tracer for imaging NMDAr activity for undertaking preclinical studies in perspective of clinical detection of neurological or neuropsychological disorders.

Radiolabelling rituximab with (99m)Tc in three steps procedure.

Lymphomas are the most frequent haematological malignancy. In non-Hodgkin's lymphomas (NHL), more than 90% of tumor cells express the cluster of differentiation (CD) 20 antigen. At the end of frontline therapy, the evaluation of remission is based on computed tomography (CT) and positron emission tomography coupled with computer tomography (PET/CT) with [(18)F]-fluorodeoxyglucose ([(18)F]FDG). Unfortunately, these techniques are not specific and cannot distinguish residual active tumor from inflammation. The aim of this study was to develop a specific radiotracer of NHL CD 20+ cells for clinical applications. The radiolabelling technique presented, based on the use of tricarbonyl compound, does not include an antibody reduction because this step could damage the protein. Actually, rituximab, an anti-CD 20 chimeric antibody used for the treatment of these NHL, was radiolabelled with Isolink® (99m)Tc-tricarbonyl compound in a three-step procedure without using a specific antibody reducer. Radiolabelling yield was greater than 97%. In vitro experiments showed a conservation of antibody integrity. In vivo experiments using Single-photon emission computed tomography/CT showed significant tumor targeting 24 h after injection of the radiotracer. It was consequently possible to develop an immunoradiolabelling method to specifically detect the residual disease. As this procedure is fast, reproducible and gentle, it will be possible to comply with Good Manufacturing Practices.