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.

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.

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.

[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.

[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.

[Magnetic resonance imaging of dilatation of the ascending aorta after repair of coarctation of the aorta]. / Etude de la dilatation de l'aorte ascendante par résonance magnétique nucléaire après réparation de la coarctation de l'aorte.

The authors studied the risk factors for dilatation of the ascending aorta in patients operated for coarctation of the aorta. A prospective study of the diameters of the ascending aorta by magnetic resonance imaging was undertaken in 46 patients with an average age of 30 months (range 6 days to 11 years) at surgery, and 10 years of age (6 months to 31 years) at the time of the investigation. The diameters were measured at the level of the sinus of Valsalva, at the sino-tubular junction, and compared with reference tables with respect to body surface area. Twenty six per cent of patients had dilatation of the ascending aorta. The predisposing factors were investigated. Age, type of surgery, postoperative hypertension. Doppler gradient in the isthmic region, anatomical appearances of the repair observed by MRI were not predictive of this complication. On the other hand, age of patients at MRI and bicuspid aortic valves (present in 66% of cases) (p < 0.05) were significant risk factors. These results indicate that regular follow-up by echocardiography or MRI of the diameter of the ascending aorta is necessary in patients operated for coarctation of the aorta and with bicuspid aortic valves.

[Dermoid cyst of the ovary. False positive diagnosis in iodine 131 scintigraphy of differentiated thyroid cancers]. / Kyste dermoïde de l'ovaire. Faux positif à reconnaître lors de la surveillance scintigraphique à l'iode 131 des cancers différenciés thyroïdiens.

BACKGROUND: Total body 131-iodine labeled scintiscan is used to screen for residual tumoral tissue after ablation of differentiated thyroid carcinoma. At therapeutic doses, radioactive iodine can also be used for treatment. Thyroglobulin level, usually undetectable a few months after total thyroidectomy and metabolic irradiation with 131-iodine in patients without initial metastases, is absolutely necessary for interpreting the scintiscans. Iodine uptake occur in dermoid cysts which usually contain thyroid tissue. CASE REPORT: A 44-year old woman underwent total thyroidectomy with node dissection for papillary carcinoma of the thyroid with a vesicular architecture. Four months later, the total body 131-iodine scintiscan demonstrated a round zone of uptake in the pelvic area. The lesion was found to be a typical dermoid cyst. No thyroid or tumoral tissue could be demonstrated. DISCUSSION: Dermoid cysts can be the cause of false positive 131-scintiscans in patients followed after resection of differentiated thyroid carcinoma. Unlike previously reported cases, the dermoid cyst in this patient was totally devoid of thyroid tissue.

Comparison of epirubicin and doxorubicin cardiotoxicity induced by low doses: evolution of the diastolic and systolic parameters studied by radionuclide angiography.

BACKGROUND: Previous studies have demonstrated that epirubicin (EPI) has a lower propensity to produce cardiotoxic effects than doxorubicin (DXR) at high doses. HYPOTHESIS: The aim of the study was to compare the cardiotoxicity induced by low doses of EPI and DXR in patients before and 1 month after the end of chemotherapy. METHOD: In a prospective study, 99 patients with a mean age of 51 +/- 12 years and without cardiac disease were studied before and 1 month after the end of chemotherapy. Group 1 included 38 patients receiving 246 +/- 96 mg/m2 of DXR and Group 2 included 61 patients receiving EPI with and equivalent dose of 219 +/- 92 mg/m2 of DXR. Ejection fraction (EF) of the left ventricle (LV), peak ejection rate (PER), and peak filling rate (PFR) [expressed in end-diastolic volume/s (EDV/s)] were evaluated by gated radionuclide angiography; PFR/PER were also calculated. RESULTS: Moderate and similar alterations of left ventricular ejection fraction were shown for low doses of anthracyclines. The EF of the LV decreased from 57 +/- 6% to 54 +/- 6% for DXR group (Group 1) (p = 0.005), and from 58 +/- 5% to 55 +/- 5% for the EPI group (Group 2)(p = 0.001). The PER of the left ventricle fell from 3.08 +/- 0.46 EDV/s to 2.79 +/- 0.49 in Group 1 (p = 0.004) and from 2.98 +/- 0.50 to 2.73 +/- 0.34 EDV/s in Group 2 (p = 0.001). In contrast, no significant alteration of PFR appeared in Group 2 (from 2.72 +/- 0.51 to 2.62 +/- 0.41 EDV/s) for the equivalent dose of anthracycline, while PFR of the LV dropped from 2.82 +/- 0.76 (EDV/s) to 2.41 +/- 0.55 after doxorubicin (p = 0.004). No difference was found between 1 and 12 months after the end of the treatment in 25 patients in Group 1 and 28 patients in Group 2. These results confirm the advantage of EPI over DXR in terms of cardiotoxicity and help explain the relationship of cellular damage mechanisms with the functional parameters of nuclear investigation. CONCLUSION: A possible explanation for specific alteration after DXR could be the increased production of semiquinone free radicals, which are known to induce membrane damage and, consequently, myocardial edema and diastolic alteration.

[False positive scintigraphic images in the surveillance of differentiated thyroid cancers]. / Faux positifs scintigraphiques à l'iode 131 dans la surveillance des cancers thyroïdiens différenciés.

Iodine-131 whole body imaging and serum thyroglobulin are used in the follow-up evaluation of differentiated thyroid carcinomas. Iodine 131 is used to detect and treat functioning lesions. Iodine 131 activity detected outside the normal thyroid bed is usually attributed to metastatic disease. False-positive localization of radioiodine has been described, and may be a potential pitfall. We report here six personal cases of false-positive localisations of radioiodine du to body secretions, pathologic exudate, activity in nonlactating breast, salivary gland inflammation, ovarian teratoma. Some of these false-positive can be ruled out easily by removing of clothes, removing of nozzle in patients with tracheostomy, or by ingestion of water in subjects with abnormal mediastinal hyperfixation. Recognition of false-positive radioiodine images is very important to prevent costly additional investigation and possibly inappropriate therapy.

Abnormalities in exercising skeletal muscle in congestive heart failure can be explained in terms of decreased mitochondrial ATP synthesis, reduced metabolic efficiency, and increased glycogenolysis.

OBJECTIVE: To distinguish between the effects of reduced oxidative capacity and reduced metabolic efficiency on skeletal muscle bioenergetics during exercise in patients with congestive heart failure. DESIGN AND PATIENTS: Patients were studied by 31P magnetic resonance spectroscopy during aerobic exercise and recovery, and results compared with controls. RESULTS: In flexor digitorum superficialis muscle (26 patients) there was a 30% decrease in oxidative capacity compared with control (mean (SE) 36 (2) v 51 (4) mM/min) and also a 40% decrease in "effective muscle mass" (5 (1) v 9 (1) arbitrary units), probably at least partly the result of reduced metabolic efficiency. Both contribute to increased phosphocreatine depletion and intracellular acidosis during exercise. However, an increased concentration of ADP (an important mitochondrial regulator) during exercise permitted near-normal rates of oxidative ATP synthesis. Results were similar in gastrocnemius muscle (20 patients), with a 30% decrease in maximum oxidative capacity (29 (4) v 39 (3) mM/min) and a 65% decrease in effective muscle mass (5 (1) v 13 (2) arbitrary units). Exercise training improved maximum oxidative capacity in both muscles, and in gastrocnemius effective muscle mass also. CONCLUSIONS: Skeletal muscle exercise abnormalities in patients with congestive heart failure results more from decreased metabolic efficiency than from the abnormalities in mitochondrial oxidation. Both decreased efficiency and defective mitochondrial oxidation result in an increased activation of glycogen phosphorylase, and may be improved by exercise training.

Diastolic or systolic left and right ventricular impairment at moderate doses of anthracycline? A 1-year follow-up study of women.

A prospective study was carried out to assess the early and later alterations in left and right ventricular diastolic and systolic function after the termination of anthracycline therapy. In 33 women without cardiac disease who were treated by anthracycline therapy, cardiac function was evaluated by radionuclide angiography before the treatment (T0) and 1 month (T1) and 12 months (T12) after the end of the treatment. Cardiac function was assessed by radionuclide measurement throughout treatment. Analysis of ejection fraction (EF), peak ejection rate (PER), time to PER (TPER), peak filling rate (PFR) and time to PFR (TPFR) was performed before and after treatment. To normalise radionuclide measurements of the ventricular diastolic function, the ratio of the PFR and the EF and the ratio of the PFR and the PER were calculated. No patient developed symptomatic congestive cardiac failure. One-way analysis of variance showed a significant decrease in the three parameters (EF, PER, PFR) over time only for the left ventricle (LV); no significant alterations appeared for the right ventricle (RV). The EF of the LV decreased from 59%+/-5% at T0 to 57%+/-6% at T1 and 56%+/-5% at T12. The PER of the LV fell from 3.03+/-0.40 end-diastolic volume per second (EDV/s) at T0 to 2.79+/-0.47 at T1 and 2.78+/-0.43 at T12. The PFR of the LV dropped from 2.99+/-0.43 EDV/s at T0 to 2.62+/-0.44 at T1 and 2.56+/-0.42 at T12. For the normalised ratios, no differences were observed. Significant differences were found for EF, PER and PFR between T0 and T1, and between T0 and T12, but no difference was found between T1 and T12. This report shows simultaneous impairment of the systolic and diastolic LV radionuclide parameters at 1 and 12 months after anthracycline therapy without alteration in the RV function.

Myocardial effects of experimental acute brain death: evaluation by hemodynamic and biological studies.

BACKGROUND: Because of problems concerning the functional quality of heart transplants, more and more interest has been focused on the physiologic changes occurring during brain death, one of the major possible contributing factors to the myocardial alterations. METHODS: The aim of this study was to describe the link between acute experimental brain death and myocardial metabolism. This was achieved by in vivo 3-hour hemodynamic and biological (myocardial lactate production) studies and then in vitro 6-hour phosphorus-31 nuclear magnetic resonance spectroscopy. Two groups of pigs were involved in the study: group I (n = 10) as control and group II (n = 10) as brain-dead animals. RESULTS: Within the first hour, we observed a strong increase in myocardial activity associated with the onset of myocardial lactate production, lasting 2 hours and corresponding to a myocardial anaerobic metabolism period. Despite the apparent normalization before excision of the hearts, phosphorus-31 nuclear magnetic resonance spectroscopy revealed a significant decrease in adenosine triphosphate levels in group II when compared with group I. CONCLUSIONS: We conclude that, in our study, acute experimental brain death is associated with an early and transient period of myocardial anaerobic metabolism and adenosine triphosphate consumption. These myocardial consequences of brain death could partially explain some observations of heart graft dysfunction.

Left ventricular contractility after hypothermic preservation: predictive value of phosphorus 31-nuclear magnetic resonance spectroscopy.

Early graft failure accounts for a substantial portion of the mortality after heart transplantation. This factor underscores the need for the development of reliable methods for predicting graft performance and thus ensuring optimal clinical outcome. The aim of this study was to describe the link between myocardial metabolism evaluated throughout preservation with the use of phosphorus 31-nuclear magnetic resonance spectroscopy and ventricular contractility after reperfusion. Thirteen pig hearts were excised and preserved from 3 to 12 hours with clinical techniques. During preservation the hearts underwent phosphorus 31-nuclear magnetic resonance spectroscopy. After reperfusion, left ventricular contractility was evaluated with an isolated heart model undergoing isovolumetric contraction. Throughout storage, beta-adenosine triphosphate remained stable and intracellular pH and phosphocreatine decreased exponentially, whereas inorganic phosphate increased exponentially. Intracellular pH, phosphocreatine, inorganic phosphates measured at the onset of preservation, and intracellular pH and phosphocreatine measured at the end of preservation correlated significantly with the left ventricular contractility after reperfusion. We conclude that the metabolic state of myocardium at excision is especially important and that phosphorus 31-nuclear magnetic resonance evaluation of the heart during preservation appears to provide reliable indexes for predicting subsequent ventricular contractility after reperfusion.