89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors: CEA-mediated tumor accumulation and role of IL-2 receptor-binding.

Cergutuzumab amunaleukin (CEA-IL2v) is an immunocytokine directed against carcinoembryonic antigen (CEA) containing an IL2v-moiety with abolished IL-2 receptor (IL-2R) α binding. We describe the biodistribution and tumor accumulation of 89Zr-labeled CEA-IL2v. Twenty-four patients with advanced solid CEA positive (CEA+) or negative (CEA-) tumors received CEA-IL2v 6 mg (4 CEA+; 3 CEA-), 20 mg (9 CEA+), or 30 mg (4 CEA+; 4 CEA-) biweekly. In cycle 1, 2 mg of the total dose comprised 89Zr-CEA-IL2v (50 MBq) and serial 89Zr-PET imaging was conducted. Four CEA+ patients with visually confirmed 89Zr-CEA-IL2v tumor accumulation at 20 mg had repeated 89Zr-PET imaging during cycle 4. 89Zr-CEA-IL2v immuno-PET demonstrated preferential drug accumulation in CEA+ tumors (%ID/mLpeak CEA- 3.6 × 10-3 vs. CEA+ 6.7 ×∙10-3). There was a non-significant trend towards dose-dependent tumor uptake, with higher uptake at doses ≥20 mg. Biodistribution was dose- and CEA-independent with major accumulation in lymphoid tissue compatible with IL-2R binding. Reduced exposure and reduced tumor accumulation (%ID/mLpeak 57% lower) on cycle 4 vs. cycle 1 was consistent with peripheral expansion of immune cells. The findings of this immune PET imaging study with 89Zr-CEA-IL2v support the therapeutic concept of CEA-IL2v, confirming selective and targeted tumor accumulation with this novel immunocytokine.

Reproducibility of hippocampal atrophy rates measured with manual, FreeSurfer, AdaBoost, FSL/FIRST and the MAPS-HBSI methods in Alzheimer's disease.

The purpose of this study is to assess the reproducibility of hippocampal atrophy rate measurements of commonly used fully-automated algorithms in Alzheimer disease (AD). The reproducibility of hippocampal atrophy rate for FSL/FIRST, AdaBoost, FreeSurfer, MAPS independently and MAPS combined with the boundary shift integral (MAPS-HBSI) were calculated. Back-to-back (BTB) 3D T1-weighted MPRAGE MRI from the Alzheimer's Disease Neuroimaging Initiative (ADNI1) study at baseline and year one were used. Analysis on 3 groups of subjects was performed - 562 subjects at 1.5T, a 75 subject group that also had manual segmentation and 111 subjects at 3T. A simple and novel statistical test based on the binomial distribution was used that handled outlying data points robustly. Median hippocampal atrophy rates were -1.1%/year for healthy controls, -3.0%/year for mildly cognitively impaired and -5.1%/year for AD subjects. The best reproducibility was observed for MAPS-HBSI (1.3%), while the other methods tested had reproducibilities at least 50% higher at 1.5T and 3T which was statistically significant. For a clinical trial, MAPS-HBSI should require less than half the subjects of the other methods tested. All methods had good accuracy versus manual segmentation. The MAPS-HBSI method has substantially better reproducibility than the other methods considered.

Early 18F-FDG PET/CT Evaluation Shows Heterogeneous Metabolic Responses to Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer.

OBJECTIVE: The aim of this pilot study was to explore intrapatient mixed metabolic response and early 18F-FDG PET response evaluation using predefined quantification strategies in patients with advanced KRAS wild-type colorectal adenocarcinoma (mCRC) treated with cetuximab. METHODS: A 18F-FDG PET was performed at baseline and after 2 cycles of cetuximab. Metabolic response was categorized using thresholds suggested in PERCIST. Quantitative analysis was done for the sum of all target lesions, ≤ 5 lesions and the metabolically most active lesion per PET. Quantitative data were correlated with clinical benefit, according to RECIST v1.1, after two months of treatment. RESULTS: In nine evaluable patients the total number of target lesions was 34 (1-8 per patient). Mixed metabolic response was observed in three out of seven patients with multiple target lesions, using TLG. Dichotomised metabolic data of the sum of all or ≤ 5 lesions had a concordance with clinical benefit of 89% using SULmax or SULpeak, and 100% using TLG. Evaluating the metabolically most active lesion, concordance was 89% for all three units. Additionally, the decrease in TLG was significantly correlated with PFS for all three quantification strategies. CONCLUSION: Mixed metabolic response was observed in nearly half of the patients with advanced KRAS wild-type mCRC treated with cetuximab. If ≤ 5 target lesions were evaluated using TLG clinical benefit was predicted correctly for all patients. Moreover, decrease in TLG is significantly correlated with the duration of PFS. Validation of these promising preliminary results in a larger cohort is currently on-going. TRIAL REGISTRATION: ClinicalTrials.gov NCT01691391.

Repeatability of Radiomic Features in Non-Small-Cell Lung Cancer [(18)F]FDG-PET/CT Studies: Impact of Reconstruction and Delineation.

PURPOSE: To assess (1) the repeatability and (2) the impact of reconstruction methods and delineation on the repeatability of 105 radiomic features in non-small-cell lung cancer (NSCLC) 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomorgraphy/computed tomography (PET/CT) studies. PROCEDURES: Eleven NSCLC patients received two baseline whole-body PET/CT scans. Each scan was reconstructed twice, once using the point spread function (PSF) and once complying with the European Association for Nuclear Medicine (EANM) guidelines for tumor PET imaging. Volumes of interest (n = 19) were delineated twice, once on PET and once on CT images. RESULTS: Sixty-three features showed an intraclass correlation coefficient ≥ 0.90 independent of delineation or reconstruction. More features were sensitive to a change in delineation than to a change in reconstruction (25 and 3 features, respectively). CONCLUSIONS: The majority of features in NSCLC [(18)F]FDG-PET/CT studies show a high level of repeatability that is similar or better compared to simple standardized uptake value measures.

89Zr-cetuximab PET imaging in patients with advanced colorectal cancer.

Monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR) are used in the treatment of advanced colorectal cancer (mCRC). Approximately 50% of patients benefit despite patient selection for RAS wild type (wt) tumors. Based on the hypothesis that tumor targeting is required for clinical benefit of anti-EGFR treatment, biodistribution and tumor uptake of (89)Zr-cetuximab by Positron Emission Tomography (PET), combining the sensitivity of PET with the specificity of cetuximab for EGFR was evaluated. Ten patients with wt K-RAS mCRC received 37 ± 1 MBq (89)Zr-cetuximab directly (<2 h) after the first therapeutic dose of cetuximab. PET-scans were performed from 1 hour to 10 days post injection (p.i.). Biodistribution was determined for blood and organs. Uptake in tumor lesions was quantified by Standardized Uptake Value (SUV) and related to response. In 6 of 10 patients (89)Zr-cetuximab uptake in tumor lesions was detected. Four of 6 patients with (89)Zr-cetuximab uptake had clinical benefit, while progressive disease was observed in 3 of 4 patients without (89)Zr-cetuximab uptake. Taken together, tumor uptake of 89Zr-cetuximab can be visualized by PET imaging. The strong relation between uptake and response warrants further clinical validation as an innovative selection method for cetuximab treatment in patients with wt RAS mCRC.

Hippocampal volume change measurement: quantitative assessment of the reproducibility of expert manual outlining and the automated methods FreeSurfer and FIRST.

BACKGROUND: To measure hippocampal volume change in Alzheimer's disease (AD) or mild cognitive impairment (MCI), expert manual delineation is often used because of its supposed accuracy. It has been suggested that expert outlining yields poorer reproducibility as compared to automated methods, but this has not been investigated. AIM: To determine the reproducibilities of expert manual outlining and two common automated methods for measuring hippocampal atrophy rates in healthy aging, MCI and AD. METHODS: From the Alzheimer's Disease Neuroimaging Initiative (ADNI), 80 subjects were selected: 20 patients with AD, 40 patients with mild cognitive impairment (MCI) and 20 healthy controls (HCs). Left and right hippocampal volume change between baseline and month-12 visit was assessed by using expert manual delineation, and by the automated software packages FreeSurfer (longitudinal processing stream) and FIRST. To assess reproducibility of the measured hippocampal volume change, both back-to-back (BTB) MPRAGE scans available for each visit were analyzed. Hippocampal volume change was expressed in µL, and as a percentage of baseline volume. Reproducibility of the 1-year hippocampal volume change was estimated from the BTB measurements by using linear mixed model to calculate the limits of agreement (LoA) of each method, reflecting its measurement uncertainty. Using the delta method, approximate p-values were calculated for the pairwise comparisons between methods. Statistical analyses were performed both with inclusion and exclusion of visibly incorrect segmentations. RESULTS: Visibly incorrect automated segmentation in either one or both scans of a longitudinal scan pair occurred in 7.5% of the hippocampi for FreeSurfer and in 6.9% of the hippocampi for FIRST. After excluding these failed cases, reproducibility analysis for 1-year percentage volume change yielded LoA of ±7.2% for FreeSurfer, ±9.7% for expert manual delineation, and ±10.0% for FIRST. Methods ranked the same for reproducibility of 1-year µL volume change, with LoA of ±218 µL for FreeSurfer, ±319 µL for expert manual delineation, and ±333 µL for FIRST. Approximate p-values indicated that reproducibility was better for FreeSurfer than for manual or FIRST, and that manual and FIRST did not differ. Inclusion of failed automated segmentations led to worsening of reproducibility of both automated methods for 1-year raw and percentage volume change. CONCLUSION: Quantitative reproducibility values of 1-year microliter and percentage hippocampal volume change were roughly similar between expert manual outlining, FIRST and FreeSurfer, but FreeSurfer reproducibility was statistically significantly superior to both manual outlining and FIRST after exclusion of failed segmentations.

How robust is the language architecture? The case of mood.

In neurocognitive research on language, the processing principles of the system at hand are usually assumed to be relatively invariant. However, research on attention, memory, decision-making, and social judgment has shown that mood can substantially modulate how the brain processes information. For example, in a bad mood, people typically have a narrower focus of attention and rely less on heuristics. In the face of such pervasive mood effects elsewhere in the brain, it seems unlikely that language processing would remain untouched. In an EEG experiment, we manipulated the mood of participants just before they read texts that confirmed or disconfirmed verb-based expectations about who would be talked about next (e.g., that "David praised Linda because … " would continue about Linda, not David), or that respected or violated a syntactic agreement rule (e.g., "The boys turns"). ERPs showed that mood had little effect on syntactic parsing, but did substantially affect referential anticipation: whereas readers anticipated information about a specific person when they were in a good mood, a bad mood completely abolished such anticipation. A behavioral follow-up experiment suggested that a bad mood did not interfere with verb-based expectations per se, but prevented readers from using that information rapidly enough to predict upcoming reference on the fly, as the sentence unfolds. In all, our results reveal that background mood, a rather unobtrusive affective state, selectively changes a crucial aspect of real-time language processing. This observation fits well with other observed interactions between language processing and affect (emotions, preferences, attitudes, mood), and more generally testifies to the importance of studying "cold" cognitive functions in relation to "hot" aspects of the brain.