Auger radiation targeted into DNA: a therapy perspective

Background: Auger electron emitters that can be targeted into DNA of tumour cells represent an attractive systemic radiation therapy goal. In the situation of DNA-associated decay, the high linear energy transfer (LET) of Auger electrons gives a high relative biological efficacy similar to that of α particles. In contrast to α radiation, however, Auger radiation is of low toxicity when decaying outside the cell nucleus, as in cytoplasm or outside cells during blood transport. The challenge for such therapies is the requirement to target a high percentage of all cancer cells. An overview of Auger radiation therapy approaches of the past decade shows several research directions and various targeting vehicles. The latter include hormones, peptides, halogenated nucleotides, oligonucleotides and internalising antibodies. Discussion: Here, we will discuss the basic principles of Auger electron therapy as compared with vector-guided α and β radiation. We also review some radioprotection issues and briefly present the main advantages and disadvantages of the different targeting modalities that are under investigatio

Endorsement of International Consensus Radiochemistry Nomenclature Guidelines

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Prevalence of symptomatic and silent stress-induced perfusion defects in diabetic patients with suspected coronary artery disease referred for myocardial perfusion scintigraphy

Purpose: Silent myocardial ischaemia—as evaluated by stress-induced perfusion defects on myocardial perfusion scintigraphy (MPS) in patients without a history of chest pain—is frequent in diabetes and is associated with increased rates of cardiovascular events. Its prevalence has been determined in asymptomatic diabetic patients, but remains largely unknown in diabetic patients with suspected coronary artery disease (CAD) in the clinical setting. In this study we therefore sought (a) to determine the prevalence of symptomatic and silent perfusion defects in diabetic patients with suspected CAD and (b) to characterise the eventual predictors of abnormal perfusion. Methods: The patient population comprised 133 consecutive diabetic patients with suspected CAD who had been referred for MPS. Studies were performed with exercise (41%) or pharmacological stress testing (1-day protocol, 99mTc-sestamibi, 201Tl or both). We used semi-quantitative analysis (20-segment polar maps) to derive the summed stress score (SSS) and the summed difference score (SDS). Results: Abnormal MPS (SSS≥4) was observed in 49 (37%) patients (SSS=4.9±8.4, SDS=2.4±4.7), reversible perfusion defects (SDS≥2) in 40 (30%) patients [SSS=13.3±10.9; SDS=8.0±5.6; 20% moderate to severe (SDS>4), 7% multivessel] and fixed defects in 21 (16%) patients. Results were comparable between patients with and patients without a history of chest pain. Of 75 patients without a history of chest pain, 23 (31%, 95% CI=21-42%) presented reversible defects (SSS=13.9±11.3; SDS=7.4±1.2), indicative of silent ischaemia. Reversible defects were associated with inducible ST segment depression during MPS stress [odds ratio (OR)=3.2, p<0.01). Fixed defects were associated with erectile dysfunction in males (OR=3.7, p=0.02) and lower aspirin use (OR=0.25, p=0.02). Conclusion: Silent stress-induced perfusion defects occurred in 31% of the patients, a rate similar to that in patients with a history of chest pain. MPS could identify these patients with a potentially increased risk of cardiovascular event

Short fluorodeoxyuridine exposure of different human glioblastoma lines induces high-level accumulation of S-phase cells that avidly incorporate 125I-iododeoxyuridine

Purpose: Radio-iododeoxyuridine (IdUrd) is a potential Auger radiation therapy agent incorporated into DNA during the synthesis phase. In this study we sought to optimise S-phase targeting by modulating cellular cycling and radio-IdUrd DNA incorporation using short non-toxic fluorodeoxyuridine (FdUrd) incubations. Methods: Three human glioblastoma cell lines with different p53 expression were pre-treated with various FdUrd conditions. After different intervals, 125I-IdUrd DNA incorporation was measured. Fluorescence-activated cell sorter cell cycle analysis was performed after identical intervals post FdUrd pre-treatment. Results: The highest increase in 125I-IdUrd DNA incorporation was induced by 1-h incubation with 1μM FdUrd. Increase in radio-IdUrd DNA incorporation was greatest 16-24h after FdUrd, reaching factors of ≥7.5 over baseline incorporation in the three cell lines. Furthermore, cell synchronisation in S phase was observed with a peak of ≥69.5% in the three cell lines at 16 and 24h post FdUrd, corresponding to an increase of 2.5-4.1 over baseline. Conclusion: FdUrd-induced thymidine synthesis inhibition led to S-phase accumulation that was maximal after an interval of 16-24h and time-correlated with the highest radio-IdUrd DNA incorporation. These observations might allow the rational design of an Auger radiation therapy targeting a maximal number of S-phase cells in single treatment cycle

Quantification of myocardial blood flow with 82Rb positron emission tomography: clinical validation with 15O-water

Purpose: Quantification of myocardial blood flow (MBF) with generator-produced 82Rb is an attractive alternative for centres without an on-site cyclotron. Our aim was to validate 82Rb-measured MBF in relation to that measured using 15O-water, as a tracer 100% of which can be extracted from the circulation even at high flow rates, in healthy control subject and patients with mild coronary artery disease (CAD). Methods: MBF was measured at rest and during adenosine-induced hyperaemia with 82Rb and 15O-water PET in 33 participants (22 control subjects, aged 30 ± 13years; 11 CAD patients without transmural infarction, aged 60 ± 13years). A one-tissue compartment 82Rb model with ventricular spillover correction was used. The 82Rb flow-dependent extraction rate was derived from 15O-water measurements in a subset of 11 control subjects. Myocardial flow reserve (MFR) was defined as the hyperaemic/rest MBF. Pearson's correlation r, Bland-Altman 95% limits of agreement (LoA), and Lin's concordance correlation ρ c (measuring both precision and accuracy) were used. Results: Over the entire MBF range (0.66-4.7ml/min/g), concordance was excellent for MBF (r = 0.90, [82Rb-15O-water] mean difference ± SD = 0.04 ± 0.66ml/min/g, LoA = −1.26 to 1.33ml/min/g, ρ c = 0.88) and MFR (range 1.79-5.81, r = 0.83, mean difference = 0.14 ± 0.58, LoA = −0.99 to 1.28, ρ c = 0.82). Hyperaemic MBF was reduced in CAD patients compared with the subset of 11 control subjects (2.53 ± 0.74 vs. 3.62 ± 0.68ml/min/g, p = 0.002, for 15O-water; 2.53 ± 1.01 vs. 3.82 ± 1.21ml/min/g, p = 0.013, for 82Rb) and this was paralleled by a lower MFR (2.65 ± 0.62 vs. 3.79 ± 0.98, p = 0.004, for 15O-water; 2.85 ± 0.91 vs. 3.88 ± 0.91, p = 0.012, for 82Rb). Myocardial perfusion was homogeneous in 1,114 of 1,122 segments (99.3%) and there were no differences in MBF among the coronary artery territories (p > 0.31). Conclusion: Quantification of MBF with 82Rb with a newly derived correction for the nonlinear extraction function was validated against MBF measured using 15O-water in control subjects and patients with mild CAD, where it was found to be accurate at high flow rates. 82Rb-derived MBF estimates seem robust for clinical research, advancing a step further towards its implementation in clinical routin

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics

Purpose: It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated 131I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkin's lymphoma (NHL). Methods: Patients received standard weekly therapy with rituximab (375mg/m2) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185MBq 131I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post 131I-rituximab injection prior to the second and third injections, respectively. Results: A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T1/2β, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T1/2 of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05mSv/MBq (range 0.48-0.59mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver. Conclusion: These results show that the biodistribution and tissue kinetics of 131I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry stud

11C-acetate PET in the early evaluation of prostate cancer recurrence

Purpose: The first aim of the study was to investigate the diagnostic potential of 11C-acetate PET in the early detection of prostate cancer recurrence. A second aim was the evaluation of early and late PET in this context. Methods: The study population comprised 32 prostate cancer patients with early evidence of relapse after initial radiotherapy (group A) or radical surgery (group B). The median PSA of group A (n=17) patients was 6ng/ml (range 2.6-30.2) while that of group B (n=15) was 0.4ng/ml (range 0.08-4.8). Pelvic-abdominal-thoracic PET was started 2min after injection of 11C-acetate and evaluated after fusion with CT. Results: Group A: Taking a SUVmax≥2 as the cut-off, PET showed local recurrences in 14/17 patients and two equivocal results. Distant disease was observed in six patients and an equivocal result was obtained in one. Endorectal MRI was positive in 12/12 patients. Biopsy confirmed local recurrence in six of six (100%) patients. PET was positive in five of the six patients with biopsy-proven recurrences, the result in the remaining patient being equivocal. Group B: Among the 15 patients, visual interpretation was positive for local recurrences in five patients and equivocal in four. One obturator lymph node was positive. Endorectal MRI was positive in 11/15 patients and equivocal in two. Positional correlation of positive/equivocal results on PET and endorectal MRI was observed in seven of nine patients. PSA decreased significantly after salvage radiotherapy in 8/14 patients, providing strong evidence for local recurrence. PET of the eight patients responding to RT was positive in three and equivocal in two. Conclusion: 11C-acetate PET was found to be valuable in the early evaluation of prostate cancer relapse. Optimising scanning time and use of modern PET-CT equipment might allow further improvemen

Biokinetics and dosimetry of 111In-DOTA-NOC-ATE compared with 111In-DTPA-octreotide

Purpose: The biokinetics and dosimetry of 111In-DOTA-NOC-ATE (NOCATE), a high-affinity ligand of SSTR-2 and SSTR-5, and 111In-DTPA-octreotide (Octreoscan™, OCTREO) were compared in the same patients. Methods: Seventeen patients (10 men, 7 women; mean age 60years), referred for an OCTREO scan for imaging of a neuroendocrine tumour (15), thymoma (1) or medullary thyroid carcinoma (1), agreed to undergo a second study with NOCATE. Whole-body anterior-posterior scans were recorded 0.5 (100% reference scan), 4, 24 and 48h (17 patients) and 120h (5 patients) after injection. In 16 patients the OCTREO scan (178 ± 15MBq) was performed 16 ± 5days before the NOCATE scan (108 ± 14MBq) with identical timing; 1 patient had the NOCATE scan before the OCTREO scan. Blood samples were obtained from 14 patients 5min to 48h after injection. Activities expressed as percent of the initial (reference) activity in the whole body, lung, kidney, liver, spleen and blood were fitted to biexponential or single exponential functions. Dosimetry was performed using OLINDA/EXM. Results: Initial whole-body, lung and kidney activities were similar, but retention of NOCATE was higher than that of OCTREO. Liver and spleen uptakes of NOCATE were higher from the start (p < 0.001) and remained so over time. Whole-body activity showed similar α and β half-lives, but the β fraction of NOCATE was double that of OCTREO. Blood T 1/2β for NOCATE was longer (19 vs. 6h). As a result, the effective dose of NOCATE (105μSv/MBq) exceeded that of OCTREO (52μSv/MBq), and the latter result was similar to the ICRP 106 value of 54μSv/MBq. Differential activity measurement in blood cells and plasma showed an average of <5% of NOCATE and OCTREO attached to globular blood components. Conclusion: NOCATE showed a slower clearance from normal tissues and its effective dose was roughly double that of OCTRE