Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference.

BACKGROUND: Monoclonal antibodies are promising anti-myeloma treatments. As immunoglobulins, monoclonal antibodies have the potential to be identified by serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE). Therapeutic antibody interference with standard clinical SPE and IFE can confound the use of these tests for response assessment in clinical trials and disease monitoring. METHODS: To discriminate between endogenous myeloma protein and daratumumab, a daratumumab-specific immunofixation electrophoresis reflex assay (DIRA) was developed using a mouse anti-daratumumab antibody. To evaluate whether anti-daratumumab bound to and shifted the migration pattern of daratumumab, it was spiked into daratumumab-containing serum and resolved by IFE/SPE. The presence (DIRA positive) or absence (DIRA negative) of residual M-protein in daratumumab-treated patient samples was evaluated using predetermined assessment criteria. DIRA was evaluated for specificity, limit of sensitivity, and reproducibility. RESULTS: In all of the tested samples, DIRA distinguished between daratumumab and residual M-protein in commercial serum samples spiked with daratumumab and in daratumumab-treated patient samples. The DIRA limit of sensitivity was 0.2 g/L daratumumab, using spiking experiments. Results from DIRA were reproducible over multiple days, operators, and assays. The anti-daratumumab antibody was highly specific for daratumumab and did not shift endogenous M-protein. CONCLUSIONS: As the treatment of myeloma evolves to incorporate novel monoclonal antibodies, additional solutions will be needed for clinical monitoring of patient responses to therapeutic regimens. In the interim, assays such as DIRA can inform clinical outcomes by distinguishing daratumumab from endogenous M-protein by IFE.

Comparison between kinetic modelling and graphical analysis for the quantification of [18F]fluoromethylcholine uptake in mice.

BACKGROUND: Until now, no kinetic model was described for the oncologic tracer [18F]fluoromethylcholine ([18F]FCho), so it was aimed to validate a proper model, which is easy to implement and allows tracer quantification in tissues. METHODS: Based on the metabolic profile, two types of compartmental models were evaluated. One is a 3C2i model, which contains three tissue compartments and two input functions and corrects for possible [18F]fluorobetaine ([18F]FBet) uptake by the tissues. On the other hand, a two-tissue-compartment model (2C1i) was evaluated. Moreover, a comparison, based on intra-observer variability, was made between kinetic modelling and graphical analysis. RESULTS: Determination of the [18F]FCho-to-[18F]FBet uptake ratios in tissues and evaluation of the fitting of both kinetic models indicated that corrections for [18F]FBet uptake are not mandatory. In addition, [18F]FCho uptake is well described by the 2C1i model and by graphical analysis by means of the Patlak plot. CONCLUSIONS: The Patlak plot is a reliable, precise, and robust method to quantify [18F]FCho uptake independent of scan time or plasma clearance. In addition, it is easily implemented, even under non-equilibrium conditions and without creating additional errors.

Distribution patterns of 18F-labelled fluoromethylcholine in normal structures and tumors of the head: a PET/MRI evaluation.

PURPOSE: To evaluate the distribution of 18F-labelled fluoromethylcholine (FCho) in normal structures and tumors of the head region using positron emission tomography (PET) and magnetic resonance imaging. MATERIALS AND METHODS: We retrospectively reviewed the positron emission tomography, magnetic resonance imaging, and the coregistered images obtained in 17 patients with suspected high-grade gliomas. The accumulation of 18F-FCho in the normal structures and in brain lesions was visually and semiquantitatively assessed. A 4-point grading system was used for the visual analysis. A standardized uptake value (SUV) was used to quantify uptake. RESULTS: In the normal brain parenchyma, 18F-FCho uptake was faint (SUVmean, 0.15 ± 0.03 (SD)). Uptake was generally moderate in the choroid plexus (SUVmean, 0.82 ± 0.16), cavernous sinus (SUVmean, 0.87 ± 0.19), extraocular eye muscles (SUVmean, 1.10 ± 0.27), masticatory muscles (SUVmean, 0.99 ± 0.22), and bone marrow (SUVmean, 1.06 ± 0.26), whereas uptake was usually moderately intense in the pituitary gland (SUVmean, 1.90 ± 0.21). Uptake was variable in the lacrimal glands and the mucosa of the nasal cavity (for SUVmean of subgroups see text). Intense uptake was observed in the parotid glands (SUVmean, 3.27 ± 0.73). (Moderately) intense 18F-FCho uptake was observed in glioblastomas (range SUVmax, 2.26-6.37) and typical meningiomas (range SUVmax, 3.75-5.81). Uptake was globally faint in grade II and III gliomas (range SUVmax, 0.33-0.78). 18F-FCho uptake was also demonstrated in benign lesions, such as a tumefactive demyelinating brain lesion. CONCLUSIONS: 18F-FCho uptake was faint in the normal brain parenchyma and usually moderate in the choroid plexus, cavernous sinus, extraocular eye muscles, masticatory muscles, and bone marrow. Uptake in the pituitary gland was generally moderately intense, whereas uptake in the lacrimal glands and the mucosa of the nasal cavity was variable. Parotid glands had intense uptake. Also, uptake in glioblastomas and meningiomas was usually (moderately) intense, whereas uptake in grade II and III gliomas was globally faint. However, 18F-FCho uptake was not tumor specific.

Antiepileptic drugs modulate P-glycoproteins in the brain: a mice study with (11)C-desmethylloperamide.

P-glycoprotein transporters (P-gp) located at the blood-brain barrier (BBB) are likely to play a role in refractory epilepsy. In vitro studies already pointed out that several antiepileptic drugs (AEDs) are substrate of P-gp. This study proposes a new in vivo approach to investigate the interaction between some AEDs and P-gp located at the BBB. (11)C-desmethylloperamide ((11)C-dLop), a radiolabelled substrate of P-gp, was intravenously administrated after pretreatment with saline or AEDs (sodium valproate, levetiracetam, topiramate and phenytoin) at their human therapeutic and four times their therapeutic dose. The effect of the different pretreatment on the intracerebral concentration of (11)C-dLop was determined to indirectly investigate possible in vivo interactions between AEDs and P-gp. Pretreatment with levetiracetam, topiramate and phenytoin at therapeutic doses significantly decreased intracerebral concentration of (11)C-dLop. Pretreatment with a therapeutic dose of sodium valproate did not influence brain uptake of (11)C-dLop. In case of pretreatment with supratherapeutic doses of AED, (11)C-dLop brain uptake was not different compared to pretreatment with saline. The metabolisation rate of (11)C-dLop in plasma was unaltered, indicating that observed differences in brain uptake of the tracer were not due to pharmacokinetic changes. The following conclusion can be made: levetiracetam, topiramate and phenytoin demonstrate biphasic modulation of the BBB P-gp. At therapeutic doses they act as inducers of efflux, at supratherapeutic doses they have no effect on the efflux rate. Sodium valproate does not interact with P-gp at therapeutic nor at higher doses.

Kinetics of angiogenic changes in a new mouse model for hepatocellular carcinoma.

BACKGROUND: The increasing incidence of hepatocellular carcinoma in Western countries has led to an expanding interest of scientific research in this field. Therefore, a vast need of experimental models that mimic the natural pathogenesis of hepatocellular carcinoma (HCC) in a short time period is present. The goal of our study was (1) to develop an efficient mouse model for HCC research, in which tumours develop in a natural background of fibrosis and (2) to assess the time-dependent angiogenic changes in the pathogenesis of HCC. METHODS: Weekly intraperitoneal injections with the hepatocarcinogenic compound N-nitrosodiethylamine was applied as induction method and samples were taken at several time points to assess the angiogenic changes during the progression of HCC. RESULTS: The N-nitrosodiethylamine-induced mouse model provides well vascularised orthotopic tumours after 25 weeks. It is a representative model for human HCC and can serve as an excellent platform for the development of new therapeutic targets.

PET with (18)F-labelled choline-based tracers for tumour imaging: a review of the literature.

PURPOSE: To give an up-to-date overview of the potential clinical utility of (18)F-labelled choline derivatives for tumour imaging with positron emission tomography. METHODS: A PubMed search for (18)F-labelled choline analogues was performed. Review articles and reference lists were used to supplement the search findings. RESULTS: (18)F-labelled choline analogues have been investigated as oncological PET probes for many types of cancer on the basis of enhanced cell proliferation. To date, studies have focused on the evaluation of prostate cancer. Available studies have provided preliminary results for detecting local and metastatic disease. Experience with (18)F-fluorocholine PET in other tumour types, including brain and liver tumours, is still limited. In the brain, excellent discrimination between tumour and normal tissue can be achieved due to the low physiological uptake of (18)F-fluorocholine. In the liver, in which there is a moderate to high degree of physiological uptake in normal tissue, malignancy discrimination may be more challenging. CONCLUSION: PET/CT with (18)F-fluorocholine can be used to detect (recurrent) local prostate cancer, but seems to have limited value for T (tumour) and N (nodal) staging. In patients presenting with recurrent biochemical prostate cancer, it is a suitable single-step examination with the ability to exclude distant metastases when local salvage treatment is intended. In the brain, high-grade gliomas, metastases and benign lesions can be distinguished on the basis of (18)F-fluorocholine uptake. Moreover, PET imaging is able to differentiate between radiation-induced injury and tumour recurrence. In the liver, (18)F-fluorocholine PET/CT seems promising for the detection of hepatocellular carcinoma.

Reduced dimethylaminoethanol in [(18)F]fluoromethylcholine: an important step towards enhanced tumour visualization.

PURPOSE: [(18)F]Fluoromethylcholine ([(18)F]FCho) is a radiotracer generally used for tumour visualization in patients. Due to high levels of dimethylaminoethanol (DMAE) remaining in [(18)F]FCho solutions synthesized by currently available methods, tumour visualization might be compromised. METHODS: An improved purification method involving an optimized purification step for reducing the levels of DMAE was conceived. The physiological explanation for the interference of residual DMAE in [(18)F]FCho pharmacokinetics was further elaborated in a xenograft mouse model. RESULTS: The use of a series of polymer solid-phase extraction cartridges (Oasis HLB/WCX), instead of the commonly used combination of tC18 and Accell CM cartridges, reduced DMAE levels from 402.2±49.6 ppm to 3.0±0.5 ppm. Subsequent in vitro tests proved that (1) [(18)F]FCho uptake was reduced in the presence of DMAE at concentrations above 0.5 µM and (2) DMAE is a competitive inhibitor of [(18)F]FCho transport. In vivo experiments in xenograft mouse models corroborated reduced tumour uptake at DMAE plasma levels of about 2.5 µM as found in patients injected with contaminated [(18)F]FCho. CONCLUSION: Residual DMAE, even at levels below choline plasma concentrations found during fasting, compromises [(18)F]FCho uptake in vivo and care should be taken to avoid its interference in molecular imaging with [(18)F]FCho.