Early Imaging and Molecular Changes with Neoadjuvant Bevacizumab in Stage II/III Breast Cancer.

This prospective, phase II study evaluated novel biomarkers as predictors of response to bevacizumab in patients with breast cancer (BC), using serial imaging methods and gene expression analysis. Patients with primary stage II/III BC received bevacizumab 15 mg/kg (cycle 1; C1), then four cycles of neoadjuvant docetaxel doxorubicin, and bevacizumab every 3 weeks (C2-C5). Tumour proliferation and hypoxic status were evaluated using 18F-fluoro-3'-deoxy-3'-L-fluorothymidine (FLT)- and 18F-fluoromisonidazole (FMISO)-positron emission tomography (PET) at baseline, and during C1 and C5. Pre- and post-bevacizumab vascular changes were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Molecular biomarkers were assessed using microarray analysis. A total of 70 patients were assessed for treatment efficacy. Significant decreases from baseline in tumour proliferation (FLT-PET), vascularity, and perfusion (DCE-MRI) were observed during C1 (p ≤ 0.001), independent of tumour subtype. Bevacizumab treatment did not affect hypoxic tumour status (FMISO-PET). Significant changes in the expression of 28 genes were observed after C1. Changes in vascular endothelial growth factor receptor (VEGFR)-2p levels were observed in 65 patients, with a > 20% decrease in VEGFR-2p observed in 13/65. Serial imaging techniques and molecular gene profiling identified several potentially predictive biomarkers that may predict response to neoadjuvant bevacizumab therapy in BC patients.

Ultra-low dose whole-body CT for attenuation correction in a dual tracer PET/CT protocol for multiple myeloma.

PURPOSE: To investigate within phantoms the minimum CT dose allowed for accurate attenuation correction of PET data and to quantify the effective dose reduction when a CT for this purpose is incorporated in the clinical setting. METHODS: The NEMA image quality phantom was scanned within a large parallelepiped container. Twenty-one different CT images were acquired to correct attenuation of PET raw data. Radiation dose and image quality were evaluated. Thirty-one patients with proven multiple myeloma who underwent a dual tracer PET/CT scan were retrospectively reviewed. 18F-fluorodeoxyglucose PET/CT included a diagnostic whole-body low dose CT (WBLDCT: 120 kV-80mAs) and 11C-Methionine PET/CT included a whole-body ultra-low dose CT (WBULDCT) for attenuation correction (100 kV-40mAs). Effective dose and image quality were analysed. RESULTS: Only the two lowest radiation dose conditions (80 kV-20mAs and 80 kV-10mAs) produced artifacts in CT images that degraded corrected PET images. For all the other conditions (CTDIvol ≥ 0.43 mGy), PET contrast recovery coefficients varied less than ± 1.2%. Patients received a median dose of 6.4 mSv from diagnostic CT and 2.1 mSv from the attenuation correction CT. Despite the worse image quality of this CT, 94.8% of bone lesions were identifiable. CONCLUSION: Phantom experiments showed that an ultra-low dose CT can be implemented in PET/CT procedures without any noticeable degradation in the attenuation corrected PET scan. The replacement of the standard CT for this ultra-low dose CT in clinical PET/CT scans involves a significant radiation dose reduction.

Significant dose reduction is feasible in FDG PET/CT protocols without compromising diagnostic quality.

PURPOSE: To reduce the radiation dose to patients by optimizing oncological FDG PET/CT protocols. METHODS: The baseline PET/CT protocol in our institution for oncological PET/CT examinations consisted of the administration of 5.18 MBq/kg of FDG and a CT acquisition with a reference current-time product of 120 mAs. In 2016, FDG activity was reduced to 4.44 and 3.70 MBq/kg and reference CT current-time-product was reduced to 100 and 80 mAs. 322 patients scanned with different protocols were retrospectively evaluated. For each patient, effective dose was calculated. The overall image quality was subjectively rated by the referring physician on a 4-point scale (IQ score: 1 excellent, 2 good, 3 poor but interpretable, 4 poor not interpretable). Image quality was quantitatively evaluated measuring noise in the liver. RESULTS: CT Results: Effective dose was progressively reduced from 9.5 ±â€¯2.8 to 8.0 ±â€¯2.3 and 6.2 ±â€¯1.5 mSv (p < 0.001). A mean dose reduction of 34.9% was achieved. There was a significant degradation of IQ score (p < 0.05) and noise (p < 0.001). Nevertheless, the number of poor quality studies (IQ score >2) did not increase. PET Results: Effective dose was gradually reduced from 6.5 ±â€¯1.4 to 5.7 ±â€¯1.3 and 5.0 ±â€¯1.0 mSv (p < 0.001). Average dose reduction was 23.4%. IQ score (p < 0.05) and noise (p < 0.001) significantly degraded for lower activity protocols. However, all images with reduced activity were scored as interpretable (IQ score ≤ 3). CONCLUSIONS: A significant radiation dose reduction of 28.7% was reached. Despite a slight reduction in image quality, the new regime was successfully implemented with readers reporting unchanged clinical confidence.

Impact of time-of-flight and point-spread-function in SUV quantification for oncological PET.

BACKGROUND: Accuracy in the quantification of the SUV is a critical point in PET because proper quantification of tumor uptake is essential for therapy monitoring and prognosis evaluation. Recent advances such as time-of-flight (TOF) and point-spread-function (PSF) reconstructions have dramatically improved detectability. However, first experiences with these techniques have shown a consistent tendency to measure markedly high SUV values, bewildering nuclear medicine physicians and referring clinicians. PURPOSE: We investigated different reconstruction and quantification procedures to determine the optimum protocol for an accurate SUV quantification in last generation PET scanners. METHODS: Both phantom and patient images were evaluated. A complete set of experiments was performed using a body phantom containing 6 spheres with different background levels and contrasts. Whole-body FDG PET/CT of 20 patients with breast and lung cancer was evaluated. One hundred five foci were identified by 2 experienced nuclear medicine physicians.Each acquisition was reconstructed both with classical and advanced (TOF, PSF) reconstruction techniques. Each sphere and each in vivo lesion was quantified with different parameters as follows: SUV(max), SUV(mean), and SUV(50) (mean within a 50% isocontour). RESULTS: This study has confirmed that quantification with SUV(max) produces important overestimation of metabolism in new generation PET scanners. This is a relevant result because, currently, SUV(max) is the standard parameter for quantification. SUV(50) has been shown as the best alternative, especially when applied to images reconstructed with PSF + TOF. CONCLUSIONS: SUV(50) provides accurate quantification and should replace SUV(max) in PET tomographs incorporating advanced reconstruction techniques. PSF + TOF reconstruction is the optimum for both detection and accurate quantification.

Voxel-based analysis of dual-time-point 18F-FDG PET images for brain tumor identification and delineation.

UNLABELLED: We have investigated dual-time-point (18)F-FDG PET for the detection and delineation of high-grade brain tumors using quantitative criteria applied on a voxel basis. METHODS: Twenty-five patients with suspected high-grade brain tumors and inconclusive MRI findings underwent (11)C-methionine PET and dual-time-point (18)F-FDG PET. Images from each subject were registered and spatially normalized. Parametric maps of standardized uptake value (SUV) and tumor-to-normal gray matter (TN) ratio for each PET image were obtained. Tumor diagnosis was evaluated according to 4 criteria comparing standard and delayed (18)F-FDG PET images: any SUV increase, SUV increase greater than 10%, any TN increase, and TN increase greater than 10%. Voxel-based analysis sensitivity was assessed using (11)C-methionine as a reference and compared with visual and volume-of-interest analysis for dual-time-point PET images. Additionally, volumetric assessment of the tumor extent that fulfills each criterion was compared with the volume defined for (11)C-methionine PET. RESULTS: The greatest sensitivity for tumor identification was obtained with any increase of TN ratio (100%), followed by a TN increase greater than 10% (96%), any SUV increase (80%), and an SUV increase greater than 10% (60%). These values were superior to visual analysis of standard (18)F-FDG (sensitivity, 40%) and delayed (18)F-FDG PET (sensitivity, 52%). Volume-of-interest analysis of dual-time-point PET reached a sensitivity of only 64% using the TN increase criterion. Regarding volumetry, voxel-based analysis with the TN ratio increase as a criterion, compared with (11)C-methionine PET, detected 55.4% of the tumor volume, with the other criteria detecting volumes lower than 20%. Nevertheless, volume detection presented great variability, being better for metastasis (78%) and glioblastomas (56%) than for anaplastic tumors (12%). A positive correlation was observed between the volume detected and the time of acquisition of the delayed PET image (r = 0.66, P < 0.001), showing volumes greater than 75% when the delayed image was obtained at least 6 h after (18)F-FDG injection. CONCLUSION: Compared with standard (18)F-FDG PET studies, quantitative dual-time-point (18)F-FDG PET can improve sensitivity for the identification and volume delineation of high-grade brain tumors.

(13)N-ammonia PET as a measurement of hindlimb perfusion in a mouse model of peripheral artery occlusive disease.

UNLABELLED: Peripheral arterial occlusive disease (PAOD) is a leading cause of mortality and morbidity in the western world. The development of noninvasive methods for assessment and comparison of the efficacy of novel therapies in animal models is of great importance. METHODS: Hindlimb ischemia was induced in nude mice by ligation and excision of the left femoral artery (n = 5) or the left iliac artery (n = 10). Assessment of limb perfusion was performed by small-animal PET analysis after intravenous injection of (13)N-ammonia between 24 h and 30 d after surgery using the ratio of perfusion between the left limb (ischemic) and the right limb (control). Activity concentration per area unit was calculated in regions of interest placed on 1-mm-thick images for numeric calculations, and the iliac and the femoral models were compared. In addition, histopathologic studies were performed to assess the degree of necrosis (hematoxylin-eosin) and fibrosis (sirius red). Immunohistochemistry analyses for identification of arterioles (alpha-smooth muscle actin) and endothelium-capillaries-(Bandeiraea simplicifolia I [BS-I] lectin) were also performed. RESULTS: Perfusion in both hindlimbs of control animals was similar (median of the left-to-right ratio = 0.99). Twenty-four hours after ischemia, perfusion of the ischemic limb (% mean +/- SD) was 33.3 +/- 10.6 and 22.1 +/- 9.9 in the femoral and iliac models, respectively. Spontaneous recovery of perfusion in the hindlimb that underwent surgery was significantly lower in the iliac model at day +15 (73.2 +/- 15.5 vs. 51.9 +/- 11.3; P < 0.01). Fibrosis increased progressively until day +30, whereas muscle necrosis was maximal at day +7 with a moderate reduction by day +30. In accordance with this positive effect, there was a statistically significant increase in the area covered with smooth muscle-coated vessels (arterioles) at day +30 in comparison with day 7 (P < 0.05). In addition, a correlation between (13)N-ammonia uptake and the amount of necrosis (r = -0.73; P = 0.06) and fibrosis (r = -0.67; P = 0.05) at day +30 was found. CONCLUSION: (13)N-Ammonia imaging allows semiquantitative evaluation of hindlimb perfusion in surgical mouse models of acute hindlimb ischemia. Although spontaneous perfusion recovery is observed in both models, the iliac model shows a substantially lower recovery and is hence better suited for assessment of new therapeutic strategies for acute hindlimb ischemic disease.

Functional neuroanatomy of sustained attention in schizophrenia: contribution of parietal cortices.

Deficits in sustained attention have been frequently described in schizophrenia. The neuroanatomical basis reported previously have included altered levels of activation in cingulate and prefrontal cortex, but the contribution of further regions remains unclear. We explored the full neuroanatomy underlying the sustained attentional deficits observed in naïve schizophrenics compared with controls. Participants included 10 controls and 11 patients. The experimental design included rest, auditory stimulation using clicks, and two counting tasks. Subjects were instructed to mentally count the clicks, and then to count forward at the same frequency they heard previously when listening to the clicks. Relative cerebral blood flow (relCBF) was measured by means of PET (15)O-water. Differences were observed between both groups at superior temporal cortex, superior parietal gyrus, and cerebellum during tasks requiring listening. During all counting conditions, additionally to supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPCF), precentral gyrus, cingulate, cerebellum, and inferior parietal (IP) gyrus, patients engaged other frontal structures including inferior, medial, and superior frontal areas. When counting with no auditory stimulation (C; requires components of working memory and time estimation), significant differences were observed in the level of activation of frontal and IP regions. Our naïve patients presented abnormal activation of auditory associative pathways. They failed to activate prefrontal and parietal regions at a similar level during tasks requiring increased cognitive effort, and they required a higher activation of inferior frontal regions to properly respond to cognitive demands.