Radiolabeled F(ab')2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models

Purpose: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively. Methods: We designed F(ab′)2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab′)2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab′)2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab′)2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Results: Radiolabeling procedure did not change F(ab′)2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab′)2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′)2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab′)2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab′)2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. Conclusions: 111In-DOTAGA-F(ab′)2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab′)2-cetuximab is an interesting theranostic tool allowing therapy and imaging

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Radiolabeled F(ab')2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models.

PURPOSE: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively. METHODS: We designed F(ab')2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab')2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab')2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab')2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors. RESULTS: Radiolabeling procedure did not change F(ab')2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab')2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab')2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab')2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab')2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. CONCLUSIONS: 111In-DOTAGA-F(ab')2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab')2-cetuximab is an interesting theranostic tool allowing therapy and imaging.

Initial performance evaluation of a preclinical PET scanner available as a clip-on assembly in a sequential PET/MRI system.

We evaluated the performance characteristics of a prototype preclinical PET scanner available as an easy clippable assembly that can dock to an MRI system. The single ring version of the PET system consists of eight detectors, each of which comprises a 12 × 12 silicon photomultipliers (SiPMs) array coupled with a dual layer of offset scintillation crystals to measure depth of interaction. The crystal arrays have 29 × 29 (30 × 30 for the outer layer) 4 mm long LYSO crystals (6 mm for the outer layer). The ring diameter is 119.2 mm and the axial field of view is 50.4 mm. The NEMA NU 4-2008 protocol was followed for studying the PET performance. Temperature stability of SiPMs was also investigated. The peak system absolute sensitivity was 4.70% with an energy window of 250-750 keV. The spatial resolution was 1.28/1.88/1.85 mm FWHM (radial/tangential/axial) at a distance of 5 mm from the center. Peak noise equivalent counting rate and scatter fraction for mouse phantom were 61.9 kcps at 14.9 MBq and 21.0%, respectively. The uniformity was 6.3% and the spill-over ratios in the images of the water-and air-filled chambers were 0.07 and 0.17, respectively. Recovery coefficients ranged from 0.13 to 0.96. Change in sensitivity as a function of ambient temperature was 0.3%/°C. These first results indicate excellent spatial resolution performance for use with animal studies. Moreover, the clippable assembly can be upgraded to accept a second ring of SiPMs modules, leading to improved sensitivity and axial coverage.

MANOTA: a promising bifunctional chelating agent for copper-64 immunoPET.

Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab-trastuzumab - which targets the HER2/neu receptor - and the average number of chelators attached ranged from 2.4 to 4.3 macrocycles per Fab. Labelling of the immunoconjugate with copper-64 was achieved in high radiochemical yields after 45 min at 37 °C, and the radiochemical purity of each 64Cu-BFC-Fab-trastuzumab reached 97% after purification. The affinity of each 64Cu-BFC-Fab-trastuzumab ranged between 10 and 50 nM as evaluated by in vitro saturation assays using the HCC1954 breast cancer cell line. PET-MR imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumours were clearly visualized on PET images at 4 and 24 hours post-injection. The tumour uptake of 64Cu-BFC-Fab-trastuzumab reached 8.9 to 12.8% ID g-1 24 hours post-injection and significant differences in non-specific liver uptake were observed depending on the BFC conjugated, the lowest being observed with MANOTA. These results show that MANOTA is a valuable tool for copper-64 radiolabelling.

Minor changes in the macrocyclic ligands but major consequences on the efficiency of gold nanoparticles designed for radiosensitization.

Many studies have been devoted to adapting the design of gold nanoparticles to efficiently exploit their promising capability to enhance the effects of radiotherapy. In particular, the addition of magnetic resonance imaging modality constitutes an attractive strategy for enhancing the selectivity of radiotherapy since it allows the determination of the most suited delay between the injection of nanoparticles and irradiation. This requires the functionalization of the gold core by an organic shell composed of thiolated gadolinium chelates. The risk of nephrogenic systemic fibrosis induced by the release of gadolinium ions should encourage the use of macrocyclic chelators which form highly stable and inert complexes with gadolinium ions. In this context, three types of gold nanoparticles (Au@DTDOTA, Au@TADOTA and Au@TADOTAGA) combining MRI, nuclear imaging and radiosensitization have been developed with different macrocyclic ligands anchored onto the gold cores. Despite similarities in size and organic shell composition, the distribution of gadolinium chelate-coated gold nanoparticles (Au@TADOTA-Gd and Au@TADOTAGA-Gd) in the tumor zone is clearly different. As a result, the intravenous injection of Au@TADOTAGA-Gd prior to the irradiation of 9L gliosarcoma bearing rats leads to the highest increase in lifespan whereas the radiophysical effects of Au@TADOTAGA-Gd and Au@TADOTA-Gd are very similar.

[Multimodality MRI and PET for restaging prostate cancer after biochemical failure of the treatment]. / Quelle imagerie pour la prise en charge de la rechute biochimique du cancer de la prostate : TEP ou IRM ?

Major improvements in the field of radiotherapy planning such as stereotactic radiation therapy, have recently been performed, aiming to the development of personalized therapeutic strategies in patients with biochemical failure of prostate cancer. However, this needs an early and accurate location of sites of recurrence. Development of multimodality magnetic resonance imaging (MRI) and positron emission tomography (PET) permits to consider this objective. Thus, it is worthwhile to apprehend the respective performance of these imaging techniques in order to rationalize their use. We propose a review of the recent literature organized by technique and by location, regarding the performance of multimodality MRI and PET for restaging of patients with biochemical failure of prostate cancer initially treated with curative intent.

Predictors of post-stress LVEF drop 6 months after reperfused myocardial infarction: a gated myocardial perfusion SPECT study.

OBJECTIVE: To identify the predictive factors of myocardial stunning as assessed by the drop in post-stress Left Ventricular Ejection Fraction (LVEF) in patients with a recent history of myocardial infarction (MI). METHODS: We prospectively included 215 consecutive patients admitted for acute MI who underwent percutaneous coronary intervention with a greater than or equal to grade-3 TIMI flow in the culprit vessel. Six months after discharge, a post-stress/rest 99mTc-sestamibi gated SPECT was performed. The perfusion score was evaluated visually using a 17-segment model. The LVEF drop was considered significant if the post-stress LVEF was ≥ 5% below the rest LVEF (QGS® software). RESULTS: A post-stress LVEF drop was observed in 51 (24%) patients. Patients with an LVEF drop were more likely than patients with a stable post-stress LVEF to have diabetes (22% vs. 10%, p = 0.048), significant ischemia (SDS > 2) (51% vs. 28% p = 0.003) and higher rest LVEF [62% (56-69) vs. 56% (49-63) p < 0.001]. In contrast, summed rest score, related to infarct size, did not differ between the groups. Multivariate logistic regression analysis identified SDS > 2 (OR 3.78, 95% CI 1.8-7.92, p < 0.001), diabetes (OR 3.35, 95% CI 1.33-8.49; p = 0.011) and rest LVEF (OR 1.08, 95% CI 1.04-1.12, p < 0.001) as independent explanatory variables of an LVEF drop. CONCLUSION: In patients with recent MI and post-procedural grade-3 TIMI flow, ischemia and diabetes were independent predictive factors of myocardial stunning. The higher incidence of reversible perfusion abnormalities validates the model of myocardial stunning in the post-MI period, and excludes the potential involvement of myocardial necrosis.

Changes in 18F-FDG tumor metabolism after a first course of neoadjuvant chemotherapy in breast cancer: influence of tumor subtypes.

BACKGROUND: The aim of this study is to evaluate the impact of the different breast cancer subtypes on the tumor (18)F-FDG uptake at baseline and on its changes after the first course of neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: One hundred and fifteen women with newly diagnosed, large or locally advanced breast cancer undergoing NAC were included. Estrogen receptor (ER), progesterone receptor (PR) and HER2 status were used to define three major tumor subtypes: triple negative (TN) (ER-/PR-/HER2-), luminal (ER+ and/or PR+; HER2-) and HER2 positive (HER2+). Using Fluorine-18 fluorodeoxyglucose positron emission tomography, the tumoral standard uptake value (SUV) maximal index was measured at baseline and just before the second course of NAC. RESULTS: TN tumors presented the highest baseline SUV (11.3 ± 8.5; P < 0.0001). The decrease of SUV after the first course of NAC (ΔSUV) was significantly higher in TN and HER2-positive subtypes (-45% ± 25% and -57% ± 30%, respectively) than in luminal one (-19% ± 35%; P < 0.0001). ΔSUV was a predictive factor of the pathological complete response only in HER2-positive tumors (cut-off = -75%; P < 0.03) with an accuracy of 76%. CONCLUSION: The baseline (18)F-FDG tumoral uptake but also its early response to NAC is different according to the immunohistological subtypes of breast cancer.

Compliance and pulse wave velocity assessed by MRI detect early aortic impairment in young patients with mutation of the smooth muscle myosin heavy chain.

PURPOSE: To evaluate aortic elasticity with MRI on young asymptomatic individuals with mutation of the smooth muscle myosin heavy chain in whom aortic enlargement is not present. MATERIALS AND METHODS: Aortic compliance, aortic distensibility, and pulse wave velocity (PWV) were semiautomatically measured from MRI in 8 asymptomatic subjects having a mutation of the MYH11 gene (M+) and 21 nonmutated relatives (M-) of similar age, sex, and blood pressure characteristics. RESULTS: Despite a similar aortic diameter in both groups, the aortic compliance and distensibility were significantly lower in M+ subjects compared with M- (0.84+/-0.33 versus 2.03+/-0.54 mm2/mmHg, 1.18+/-0.62 10(-3) versus 5.11+/-1.58 10(-3) mmHg(-1), respectively), and PWV was significantly higher (5.35+/-1.53 versus 3.60+/-0.64 m.s(-1)). A threshold aortic compliance value of 1.3 mm2/mmHg separated the two groups. The receiver operating characteristics curve analysis indicated an optimal threshold of 2.9 10(-3) mmHg(-1) for aortic distensibility (sensitivity: 87.5%, specificity: 90%), and of 4.4 m.s(-1) for PWV (sensitivity: 75%, specificity: 100%). CONCLUSION: Young asymptomatic adults with MYH11 mutation have an aortic compliance impairment which is not detectable by the sole measurement of the aortic size. Aortic compliance measurement might be part of routine examination in patients suspected of inherited aortic disease even with a normal aortic diameter.

Is NAA reduction in normal contralateral cerebral tissue in stroke patients dependent on underlying risk factors?

BACKGROUND AND PURPOSE: This retrospective study investigated the dependence of N-acetyl aspartate (NAA) ratios on risk factors for cerebral vasculopathy such as sex, age, hypertension, diabetes mellitus, carotid stenosis, and dyslipidaemia, which may have affected brain vessels and induced metabolic brain abnormalities prior to stroke. We hypothesise that in stroke patients metabolic alterations in the apparently normal contralateral brain are dependent on the presence or not of such risk factors. METHODS: Fifty nine patients (31 male, 28 female: 58.8+/-16.1 years old) with cortical middle cerebral artery (MCA) territory infarction were included. Long echo time chemical shift imaging spectroscopy was carried out on a Siemens 1.5 T Magnetom Vision scanner using a multi-voxel PRESS technique. Metabolite ratios (NAA/choline, NAA/creatine, lactate/choline, etc) were studied using uni- and multivariate analyses with respect to common risk factors. The influence of age, stroke lesion size, and time since stroke was studied using a linear regression approach. RESULTS: Age, sex, and hypertension all appeared to individually influence metabolite ratios, although only hypertension was significant after multivariate analysis. In both basal ganglia and periventricular white matter regions in apparently normal contralateral brain, the NAA/choline ratio was significantly lower in hypertensive (1.37+/-0.16 and 1.50+/-0.19, respectively) than in normotensive patients (1.72+/-0.19 and 1.85+/-0.15, respectively). CONCLUSIONS: Regarding MCA infarction, contralateral tissue remote from the lesion behaves abnormally in the presence of hypertension, the NAA ratios in hypertensive patients being significantly lower. These data suggest that hypertension may compromise the use of contralateral tissue data as a reference for comparison with ischaemic tissue.

[Role of visual analysis of first-pass contrast-enhanced MRI in reperfused myocardial infarction]. / Intérêt de l'IRM de perfusion avec analyse visuelle a la phase aiguë de l'infarctus du myocarde reperfusé.

The aim of this work is to evaluate the relationship between improvement of regional myocardial function and visual analysis of contrast-enhanced (CE) MRI in patients after acute myocardial infarction. MRI was performed on 19 patients 1 and 11 weeks after a reperfused acute myocardial infarction. Perfusion data (first-pass images [FPI] and delayed CE images) were acquired after an intravenous bolus of gadolinium-DTPA and visually analyzed using a 17 segment model. Each segment was then classified in 3 groups, according to the presence or absence of FPI and CE patterns at baseline study: group 0: normal-appearing segments; group 1: segments with delayed hyper-enhancement but no early hypo-enhancement; group 2: segments with early hypoenhancement. Relative Wall thickening (RWT) was analyzed in each segment and its improvement evaluated in each group. Between first MRI and follow-up study, a significant improvement of RWT occurred in group 1 (mean +/- SD) [from 43.43 +/- 26.59% to 76.71 +/- 47.38%; p = 0.001] but not in group 2 (from 32.73 +/- 25.58% to 39.57 +/- 30.57%; p = NS). In group 0, RWT despite normal value at baseline study exhibited a significant improvement at follow-up (from 65.23 +/- 46.52% to 79.73 +/- 48.46%; p = 0.0015). In conclusion, the combined analysis of early and delayed perfusion abnormalities in MRI in the week following myocardial infarction can predict myocardial viability and allows in the future an evaluation of the efficacy of perfusion therapy.

[Neuroradiologic emergencies in infectious pathology]. / Urgences neuroradiologiques en pathologie infectieuse.

The main goal of urgent imaging evaluation of patients with suspected CNS infection is to differentiate infectious from tumoral or vascular lesions in order to provide appropriate management. MR imaging, including diffusion weighted imaging and spectroscopy, is superior to CT imaging to characterize lesion location and etiology. The CT and MRI features of the more frequent bacterial, viral and parasitic CNS infections will be described.

Left ventricular ejection fraction calculation from automatically selected and processed diastolic and systolic frames in short-axis cine-MRI.

The calculation of the left ventricular ejection fraction (LVEF) is dependent upon the accurate measurement of diastolic and systolic left ventricular volumes. Although breath-hold cine magnetic resonance imaging (MRI) allows coverage of the whole cardiac cycle with an excellent time resolution, many authors rely on the visual selection of diastolic and the systolic short-axis slices in order to reduce the postprocessing time. An automatic method was developed to detect the endocardial contour on each image, allowing an automatic selection of the systolic frame. The calculated ejection fraction was compared with radionuclide ventriculography (RNV). Sixty-five patients were examined using an electrocardiogram (ECG)-gated gradient echo sequence. Among these examinations, manual and automatic processing with MRI were compared when the time of the systolic frame concorded. Good correlations have been found between the automatic MRI approach and RNV, and between manual and automatic processing on MRI alone. The results show that the automatic determination of the ejection fraction is feasible, and should constitute an important step toward a larger acceptance of MRI as a routine tool in heart disease imaging. One major benefit of using automatic postprocessing is that it may eliminate the visual choice of the systolic frame, inaccurate in more than 50% of the studied patients.

[Analysis of variation in delivered dose in diagnostic and therapeutic cerebral angiography]. / Analyse des variations de la dose délivrée au patient en angiographie cérébrale diagnostique et thérapeutique.

OBJECTIVES: Analysis of dose-area product (DAP) in cerebral angiography, according to the type of pathology and technique used. MATERIALS AND METHODS: Use of dosimetric and clinical data resulting from 84 diagnostic cerebral angiograms and 32 cerebral embolizations. RESULTS: The diagnostic angiography data were divided into three categories: A/ When a secondarily embolized aneurysm was diagnosed: n=17. B/ When the final diagnosis was an arteriovenous malformation (AVM): n=10. C/ In the case where the diagnosis was neither AVM, nor aneurysm to embolize: n=57. The cerebral embolizations were classified in two sub-groups: K/ When the embolization immediately followed the diagnostic angiogram: n=15. L/ When the embolization of the aneurysm took place 24 to 48H after the angiography: n=17. The mean DAP of group B containing the AVM is higher than mean DAP values in groups A and C, because of the increased cinegraphic time. There is a strong correlation between the duration of the fluoroscopy and the DAP (n=116; r=0.931; p<0.0001). Addition of runs in the group L contributes to the augmentation of the exposure time (significant difference in time: p=0.0054) and thus with the fact that DAP L>DAPK. CONCLUSION: Radiation dose during diagnostic cerebral angiography is increased in the presence of AVM. DAP of embolizations are higher when diagnostic and therapeutic phases are separated in time.

[Spontaneous hyperdense intracranial vessels seen on CT scan in polycythemia cases]. / Vaisseaux intracrâniens spontanément hyperdenses au scanner en cas de polyglobulie.

PURPOSE: A better understanding of the significance of diffuse hyperdensity affecting the circle of Willis and the dural sinuses on unenhanced CT. MATERIALS AND METHODS: We performed a retrospective study of 19 patients with a neurological manifestation and a CT scan without contrast injection. Among these 19 patients, six had been included because of primary or secondary polycythemia. The analysis of cerebral CT scans was made qualitatively by visual inspection and quantitatively. RESULTS: In patients with a hematocrit percentage exceeding 60%, both circle of Willis and dural sinuses were dense on unenhanced CT scans. A linear relation between the hemoglobin level and the contrast of the dural sinuses compared with the grey matter was observed with an excellent correlation (r = 0.934; n < 0.0001; p = 19). CONCLUSION: Increased density of cerebral vessels on unenhanced CT is a sign of a high hemoglobin level.

[Magnetic resonance imaging early after acute myocardial infarction. A visual analysis of myocardial perfusion based on a 17 segment model]. / Imagerie par résonance magnétique en postinfarctus immédiat. Analyse visuelle de la perfusion myocardique sur un modèle à 17 segments.

Magnetic resonance imaging allows an accurate calculation of the left ventricular ejection fraction and left ventricular volumes. Additionally, it makes possible to assess myocardial perfusion after gadolinium chelate injection. Late after the injection, the presence of a myocardial hyper-enhancement can be visualized. The present study has used the 17 segment standardized nomenclature for tomographic imaging of the heart as recommended for all cardiac imaging modalities. Sixty nine patients were studied after a revascularised myocardial infarction. All patients had Timi grade 3 flow in the infarct-related artery after therapy. Regional and global function was studied using cine MR short axis slices. The gadolinium chelate first pass was scored using a 5 level scale reflecting the transmural extent of the segmental myocardial enhancement. The delayed enhancement due to gadolinium accumulation in the myocardium 10 min post injection was scored in the same manner. Left ventricular ejection fraction was 51 +/- 13%. Segmental thickening parameters (systolic thickness, absolute thickening and relative thickening) appeared statistically related to the hypoperfusion and delayed enhancement scores. Absolute myocardial thickening varied from 4.8 +/- 2.7 mm in the myocardial segments free of any delayed enhancement to 2.4 +/- 2.1 mm in segments presenting with a transmural extent of the delayed hyper-enhancement. Scores obtained after gadolinium injection were also well correlated with the global left ventricular function (r = 0.65, p < 0.01 for late enhancement). Magnetic resonance imaging of the heart allows a precise characterisation of revascularised myocardium which makes this technique very attractive for evaluating the treatments designed to improve myocardial microperfusion.