Michael Winterdahl

Erlotinib Accumulation in Brain Metastases from Non-small Cell Lung Cancer: Visualization by Positron Emission Tomography in a Patient Harboring a Mutation in the Epidermal Growth Factor Receptor

Introduction: Drugs directed toward the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva®) and gefitinib (Iressa®), are used for the treatment of patients with advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. However, whether erlotinib actually enters into brain metastases has not been adequately elucidated. In this study, we investigated the accumulation of [11C]-erlotinib by positron emission tomography (PET) combined with computed tomography (CT) and magnetic resonance imaging (MRI). Methods: A 32-year-old patient with NSCLC and multiple brain metastases was treated with first-line erlotinib. EGFR mutations were determined by analyzing a fine-needle lung tumor biopsy taken before the treatment. A PET/CT of the brain with [11C]-erlotinib was performed during treatment, and a MRI of the head and a CT of the chest were performed pre- and posttreatment. Results: The primary lung tumor displayed an erlotinib-sensitizing exon 19 deletion in the EGFR gene, and [11C]-erlotinib PET/CT showed accumulation in the brain metastases. Posttreatment MRI and CT demonstrated regression of both brain metastases and primary lung tumor. Conclusion: Our data demonstrated that erlotinib accumulated in brain metastases in a NSCLC patient who responded to the treatment.

PET imaging of patients with non-small cell lung cancer employing an EGF receptor targeting drug as tracer

Background:We have previously developed 11C-erlotinib as a new positron emission tomography (PET) tracer and shown that it accumulates in epidermal growth factor receptor (EGFR)-positive lung cancer xenografts in mice. Here, we present a study in patients with non-small cell lung cancer (NSCLC) investigating the feasibility of 11C-erlotinib PET as a potential method for the identification of lung tumours accumulating erlotinib.Methods:Thirteen patients with NSCLC destined for erlotinib treatment were examined by contrast-enhanced computed tomography (CT), 11C-erlotinib PET/low-dose CT and 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET/low-dose CT before start of the erlotinib treatment. After 12 weeks treatment, they were examined by 18F-FDG PET/contrast-enhanced CT for the assessment of clinical response.Results:Of the 13 patients included, 4 accumulated 11C-erlotinib in one or more of their lung tumours or lymph-node metastases. Moreover, 11C-erlotinib PET/CT identified lesions that were not visible on 18F-FDG PET/CT. Of the four patients with accumulation of 11C-erlotinib, one died before follow-up, whereas the other three showed a positive response to erlotinib treatment. Three of the nine patients with no accumulation died before follow-up, four showed progressive disease while two had stable disease after 12 weeks of treatment.Conclusion:Our data show a potential for 11C-erlotinib PET/CT for visualizing NSCLC lung tumours, including lymph nodes not identified by 18F-FDG PET/CT. Large clinical studies are now needed to explore to which extent pre-treatment 11C-erlotinib PET/CT can predict erlotinib treatment response.

Hepatic Blood Perfusion Estimated by Dynamic Contrast- Enhanced Computed Tomography in Pigs Limitations of the Slope Method

ObjectiveThe aim of this study was to determine whether dynamic contrast-enhanced computed tomography (DCE-CT) and the slope method can provide absolute measures of hepatic blood perfusion from the hepatic artery (HA) and portal vein (PV) at experimentally varied blood flow rates. Materials and MethodsTen anesthetized 40-kg pigs underwent DCE-CT of the liver during periods of normocapnia (normal flow), hypocapnia (decreased flow), and hypercapnia (increased flow), which were induced by adjusting the ventilation. Reference blood flows in the HA and PV were measured continuously by surgically placed ultrasound transit-time flowmeters. For each capnic condition, the DCE-CT–estimated absolute hepatic blood perfusion from the HA and PV were calculated using the slope method and compared with flowmeter-based absolute measurements of hepatic perfusions and relative errors were analyzed. ResultsThe relative errors (mean ± SEM) of the DCE-CT based perfusion estimates were −21% ± 23% for HA and 81% ± 31% for PV during normocapnia, 9% ± 23% for HA and 92% ± 42% for PV during hypocapnia, and 64% ± 28% for HA and −2% ± 20% for PV during hypercapnia. The mean relative errors for HA were not significantly different from 0 during hypocapnia and normocapnia, and the DCE-CT slope method could detect relative changes in HA perfusion between scans. Infusion of contrast agent led to significantly increased hepatic blood perfusion, which biased the PV perfusion estimates. ConclusionsUsing the DCE-CT slope method, HA perfusion estimates were accurate at low and normal flow rates, whereas PV perfusion estimates were inaccurate and imprecise. At high flow rate, both HA perfusion estimates were significantly biased.

Hepatic blood perfusion measured by 3-minute dynamic 18F-FDG PET in pigs.

There is an unmet clinical need for an imaging method for quantification of hepatic blood perfusion. The purpose of the present study was to develop and validate a PET method using blood-to-cell clearance (K1) of 18F-FDG, 3-O-11C-methylglucose (11C-MG), or 2-18F-fluoro-2-deoxy-D-galactose (18F-FDGal) as a measure of hepatic blood perfusion without the need for portal venous blood samples. We aimed to make the method as simple as possible with the prospect of future application to clinical studies. For this purpose, we examined the possibility of using a 3-min data acquisition and a model-derived dual input calculated from measurements of radioactivity concentrations in a peripheral artery. Methods: Pigs (40 kg) underwent dynamic PET of the liver with 18F-FDG, 11C-MG, or 18F-FDGal with simultaneous measurements of time–activity curves in blood sampled from a femoral artery and the portal vein (PV); blood flow rates were measured in the hepatic artery (HA) and PV by transit-time flow meters. Two input functions were compared: A measured dual input and a model-derived dual input, the latter with the PV time–activity curve estimated from the measured arterial time–activity curve and a previously validated 1-parametric PV model. K1 was estimated for each tracer by fitting compartmental models to the data, comparing 3-min and 60-min data acquisitions and the 2 dual-input time–activity curves. Results: Agreement between K1 estimated using the measured and the model-derived dual input was good for all 3 tracers. For 18F-FDG and 11C-MG, K1 (3-min data acquisition, model-derived dual input, and 1-tissue compartmental model) correlated to the measured blood perfusion (P = 0.01 and P = 0.07, respectively). For 18F-FDGal, the correlation was not significant. Conclusion: A simplified method for quantification of hepatic blood perfusion using 3-min dynamic 18F-FDG PET or 11C-MG PET with blood sampling from only a peripheral artery was developed. Parametric K1 images were constructed and showed homogeneous blood perfusion in these normal livers.

Suppressed play behaviour and decreased oxytocin receptor binding in the amygdala after prenatal exposure to low-dose valproic acid

To better understand the role of the neuropeptide oxytocin in autism spectrum disorder (ASD), we investigated potential deficits in social play behaviour and oxytocin receptor (OXTR) density alterations in the amygdala in a rodent model of ASD. Pregnant rats were injected daily with 20 or 100 mg/kg valproic acid (VPA) or saline from day 12 until the end of pregnancy. The number of pinning and pouncing events was assessed at postnatal days 29–34. Brains from male offspring (n=7/group) were removed at postnatal day 50. We performed quantitative autoradiography with an OXTR radioligand, the [125I]-ornithine vasotocin analogue, in brain slices from the amygdala and other limbic brain regions involved in rat social behaviour. The results demonstrated a significant reduction in pinning behaviour and decreased OXTR density in the central nucleus of the amygdala in the 20 mg/kg VPA group. However, the 100 mg/kg VPA group had no significant changes in the number of play behaviour-related events or OXTR binding in the central nucleus of the amygdala. The reduction in OXTR density in the amygdala may be a critical disrupting mechanism affecting social behaviour in pervasive disorders such as ASD.

Replication attempt to estimate depression severity by fuzzy logic analysis of emotion‐focused fMRI

Recently, Dr. Lu and coworkers (1) reported the use of a fuzzy logic analysis of emotion-focused functional MRI (fMRI) recordings to derive numeric estimates of depression severity. The potential importance of such findings for the use of MRI in neuropsychiatry induced us to see whether we could replicate them at our site. The regional ethical committee authorized the project. Neuroscientists from the original site came to our site to ensure that identical procedures were used in both studies. The original Chinese version of the 24-item Hamilton Depression Rating Scale was translated and was used for the standardized psychiatric interview of the replication attempt. We tested 33 women, as in the original study. They had responded to newspaper advertisements for participants in a research project on brain imaging and depression. Initial screening by email and by phone indicated that many of the women were clinically depressed. They all satisfied criteria to undergo an MRI scan, had not used a prescribed psychoactive medication for at least 2 months, and provided informed consent to participate in the study after being fully informed on the procedures. fMRI recording took place within 30 min of the psychiatric interview. The fMRI session consisted of a sequence of the emotion-focused images that was identical to that used in the original study. Data analyses were carried out by neuroscientists from the original site. Initially, they were blinded to depression ratings from the psychiatric interview. Under these conditions, the original Sugeno-type fuzzy logic algorithm failed to produce a statistically significant relationship between measures of depression severity provided by psychiatric interview compared with scores derived by fuzzy logic analysis of fMRI recordings (r 1⁄4 0.02; P 1⁄4 0.91; N 1⁄4 33). The failure of the original model parameters motivated efforts to revise the model, and 20 nonblinded datasets were randomly selected for that purpose. A new generic fuzzy logic algorithm was derived to optimize the model with the nonblinded dataset; it produced a statistically significant correlation between Hamilton scores and fMRI-based estimates of depression severity (r 1⁄4 0.59; P 1⁄4 0.006; N 1⁄4 20). However, the newly derived model failed to provide a statistically significant correlation between measures of depression severity when applied to the dataset of the remaining thirteen women (r 1⁄4 0.34; P 1⁄4 0.88; N 1⁄4 13). Then, nonblinded exploratory analyses were carried out in Nanjing, China, in efforts towards further optimization of the model. Under those conditions, inspection of the data led to exclusion of subjects in three categories: (a) healthy subjects with highly dispersed, large activations throughout the brain (two subjects), (b) severely depressed subjects with relatively few brain activations (three subjects), and (c) subjects older than 60 years (four subjects). As a result, a statistically significant correlation (r 1⁄4 0.68; r 1⁄4 0.46; P < 0.005; N 1⁄4 24) was obtained between depression severity as measured by the 24-item Hamilton rating scale and fMRI data assessed by a fuzzy logic algorithm. The authors of this letter are particularly skeptical of findings obtained by nonblind, data-dredging procedures including post hoc exclusion of subjects. Disagreements with colleagues in Nanjing, mainly concerning that topic, have caused us to discontinue the collaboration and to submit the findings here without including them as coauthors. Negative results in replication attempts are, we believe, of particular value in scientific research because they provide an empirical basis by which to evaluate the reliability of findings (2). Here, we report mainly negative results obtained in our attempt to replicate findings reported previously on the use of a fuzzy logic algorithm to estimate the severity of depression, based solely on emotion-focused fMRIrecordings. According to the original report (1), the procedure provides reliable numeric and objective estimates of depression severity that can be applied to classify subjects into depression categories and to track the recovery process. The present findings clearly challenge that viewpoint. First, blinded data analysis by the original procedures failed to provide a reliable relationship between measures of depression severity obtained by the Hamilton depression rating scale and by fuzzy logic analysis. Second, the nonblinded cross-validation procedure also failed to provide a reliable relationship between the two measures of depression severity. Third, even nonblinded, post hoc data analysis with exclusion of subjects, which we view as a questionable procedure, accounted for less than 50% of the variance between the two measures of depression severity, which we view as being insufficient for guiding day-to-day, medical decisions regarding treatment regimens. While the potential of fuzzy logic for analysis of fMRI data in depressive DOI 10.1002/jmri.23833 View this article online at wileyonlinelibrary.com. JOURNAL OF MAGNETIC RESONANCE IMAGING 37:498–499 (2013)

Vulnerability to psychogenic non-epileptic seizures is linked to low neuropeptide Y levels

Abstract Psychogenic non-epileptic seizures (PNES) is a conversion disorder that reflects underlying psychological distress. Female patients with PNES often present with a history of prolonged stressors, especially sexual abuse. In the current study, we studied the relationship between neuropeptide Y (NPY) and PNES symptoms in women with a history of sexual abuse. NPY has been associated with resilience to stress and we hypothesized that low levels would increase the extent and severity of PNES symptoms in this patient population. Serum levels of NPY, and related hormones were measured in fifteen female PNES patients and sixty female controls. PNES patients reported more severe abuse histories, feeling of abandonment, and decreased perception of quality of life than controls. Importantly, they also had lower NPY levels. Our analysis indicates that low levels of NPY in PNES may confer greater vulnerability to exhibit seizure-like symptoms and lower quality of life.

Effects of single-dose intranasal oxytocin on recognition of basic emotions and complex mental states in facial expressions: A systematic review and meta-analysis

The Development and Feasablity of an Internet-Based Cognitive Behavioral Intervention to reduce Depression and/or Anxiety after a Myocardial Infarction - The U-CARE Heart study

NPY/Y2 gene therapeutic overexpression in hippocampus of experimental Beagle dogs

people worldwide. Current treatment is only symptomatic and fails to control seizures in about 40% of patients. Gene therapy with NPY overexpression has emerged as an alternative treatment strategy for epilepsy, showing inhibitory effect on seizures in animal models. This effect seems to be mediated mostly via Y2 receptors, while Y1 receptor activation has an opposite outcome. To enhance NPY gene transfer effect on seizures, we additionally overexposed Y2 receipts using AAV vectors in the hippocampus of epileptic rats. We demonstrate that transgene Y2 receptors are functional and even potentiate transgene NPY effect on seizures. These data suggest that combinatorial NPY/Y2 gene therapy could be an alternative strategy to single NPY gene overexertion.