Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Learning auditory space: generalization and long-term effects

Background: Previous findings have shown that humans can learn to localize with altered auditory space cues. Here we analyze such learning processes and their effects up to one month on both localization accuracy and sound externalization. Subjects were trained and retested, focusing on the effects of stimulus type in learning, stimulus type in localization, stimulus position, previous experience, externalization levels, and time. Method: We trained listeners in azimuth and elevation discrimination in two experiments. Half participated in the azimuth experiment first and half in the elevation first. In each experiment, half were trained in speech sounds and half in white noise. Retests were performed at several time intervals: just after training and one hour, one day, one week and one month later. In a control condition, we tested the effect of systematic retesting over time with post-tests only after training and either one day, one week, or one month later. Results: With training all participants lowered their localization errors. This benefit was still present one month after training. Participants were more accurate in the second training phase, revealing an effect of previous experience on a different task. Training with white noise led to better results than training with speech sounds. Moreover, the training benefit generalized to untrained stimulus-position pairs. Throughout the post-tests externalization levels increased. In the control condition the long-term localization improvement was not lower without additional contact with the trained sounds, but externalization levels were lower. Conclusion: Our findings suggest that humans adapt easily to altered auditory space cues and that such adaptation spreads to untrained positions and sound types. We propose that such learning depends on all available cues, but each cue type might be learned and retrieved differently. The process of localization learning is global, not limited to stimulus-position pairs, and it differs from externalization processes.Foundation for Science and TechnologyFEDE

A meta-analytic review of stand-alone interventions to improve body image

Objective Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. Methods The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. Results The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. Conclusions The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions

Genetic and Epigenetic Alterations of the NF2 Gene in Sporadic Vestibular Schwannomas

BACKGROUND: Mutations in the neurofibromatosis type 2 (NF2) tumor-suppressor gene have been identified in not only NF2-related tumors but also sporadic vestibular schwannomas (VS). This study investigated the genetic and epigenetic alterations in tumors and blood from 30 Korean patients with sporadic VS and correlated these alterations with tumor behavior. METHODOLOGY/PRINCIPAL FINDINGS: NF2 gene mutations were detected using PCR and direct DNA sequencing and three highly polymorphic microsatellite DNA markers were used to assess the loss of heterozygosity (LOH) from chromosome 22. Aberrant hypermethylation of the CpG island of the NF2 gene was also analyzed. The tumor size, the clinical growth index, and the proliferative activity assessed using the Ki-67 labeling index were evaluated. We found 18 mutations in 16 cases of 30 schwannomas (53%). The mutations included eight frameshift mutations, seven nonsense mutations, one in-frame deletion, one splicing donor site, and one missense mutation. Nine patients (30%) showed allelic loss. No patient had aberrant hypermethylation of the NF2 gene and correlation between NF2 genetic alterations and tumor behavior was not observed in this study. CONCLUSIONS/SIGNIFICANCE: The molecular genetic changes in sporadic VS identified here included mutations and allelic loss, but no aberrant hypermethylation of the NF2 gene was detected. In addition, no clear genotype/phenotype correlation was identified. Therefore, it is likely that other factors contribute to tumor formation and growth

Prevalence of a history of prior varicella/herpes zoster infection in multiple sclerosis

Varicella zoster virus (VZV) infection has been implicated in multiple sclerosis (MS), but direct causal involvement has been disputed. Nevertheless, knowledge of VZV exposure is important, given the risk of serious complications of first exposure while undergoing immunosuppressive treatment, in particular with fingolimod. We distributed questionnaires to MS clinic patients, requesting information about history of chickenpox, sibling/household/occupational exposure, history of zoster (shingles), and disease-modifying treatment. A random, proportionally representative sample of 51 patients that included patients with positive, negative, and unknown chickenpox history were selected for determination of VZV IgG by ELISA. Of 1206 distributed questionnaires, 605 were returned (50% response rate). Of these, 86% reported history of chickenpox, 5.6% gave negative history, and 8.5% did not know. Of 594 who answered the zoster question, 78% gave a negative response, 4% did not know, and 104 (17%) answered yes. Of these, 83 reported 1 episode; 12 had 2; 5 had 3; and 1 each reported 5, 6, and 15 episodes. Of 51 patients tested for VZV IgG (44 “yes,” 4 “no,” and 3 “I don’t know” answers to the question of whether they had chickenpox), 48 were seropositive; the 3 seronegative all had reported having had chickenpox. The high rate of MS patients reporting prior chickenpox infection is comparable with previous reports. A substantial proportion of MS patients, estimated to be higher than an age-matched general population, report single or multiple episodes of zoster. These data are useful for consideration of immunosuppressive treatments and/or VZV and zoster vaccination

Saccadic latency in hepatic encephalopathy: a pilot study

Hepatic encephalopathy is a common complication of cirrhosis. The degree of neuro-psychiatric impairment is highly variable and its clinical staging subjective. We investigated whether eye movement response times—saccadic latencies—could serve as an indicator of encephalopathy. We studied the association between saccadic latency, liver function and paper- and pencil tests in 70 patients with cirrhosis and 31 patients after liver transplantation. The tests included the porto-systemic encephalopathy (PSE-) test, critical flicker frequency, MELD score and ammonia concentration. A normal range for saccades was established in 31 control subjects. Clinical and biochemical parameters of liver, blood, and kidney function were also determined. Median saccadic latencies were significantly longer in patients with liver cirrhosis when compared to patients after liver transplantation (244 ms vs. 278 ms p < 0.001). Both patient groups had prolonged saccadic latency when compared to an age matched control group (175 ms). The reciprocal of median saccadic latency (μ) correlated with PSE tests, MELD score and critical flicker frequency. A significant correlation between the saccadic latency parameter early slope (σE) that represents the prevalence of early saccades and partial pressure of ammonia was also noted. Psychometric test performance, but not saccadic latency, correlated with blood urea and sodium concentrations. Saccadic latency represents an objective and quantitative parameter of hepatic encephalopathy. Unlike psychometric test performance, these ocular responses were unaffected by renal function and can be obtained clinically within a matter of minutes by non-trained personnel

Tolerability of NGX-4010, a capsaicin 8% dermal patch, following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with post-herpetic neuralgia

<p>Abstract</p> <p>Background</p> <p>Post-herpetic neuralgia (PHN) is a common type of neuropathic pain that can severely affect quality of life. NGX-4010, a capsaicin 8% dermal patch, is a localized treatment that can provide patients with significant pain relief for up to 3 months following a single 60-minute application. The NGX-4010 application can be associated with application-site pain and in previous clinical trials pretreatment with a topical 4% lidocaine anesthetic was used to enhance tolerability. The aim of the current investigation was to evaluate tolerability of NGX-4010 after pretreatment with lidocaine 2.5%/prilocaine 2.5% anesthetic cream.</p> <p>Methods</p> <p>Twenty-four patients with PHN were pretreated with lidocaine 2.5%/prilocaine 2.5% cream for 60 minutes before receiving a single 60-minute application of NGX-4010. Tolerability was assessed by measuring patch application duration, the proportion of patients completing over 90% of the intended treatment duration, application site-related pain using the Numeric Pain Rating Scale (NPRS), and analgesic medication use to relieve such pain. Safety was assessed by monitoring adverse events (AEs) and dermal irritation using dermal assessment scores.</p> <p>Results</p> <p>The mean treatment duration of NGX-4010 was 60.2 minutes and all patients completed over 90% of the intended patch application duration. Pain during application was transient. A maximum mean change in NPRS score of +3.0 was observed at 55 minutes post-patch application; pain scores gradually declined to near pre-anesthetic levels (+0.71) within 85 minutes of patch removal. Half of the patients received analgesic medication on the day of treatment; by Day 7, no patients required medication. The most common AEs were application site-related pain, erythema, edema, and pruritus. All patients experienced mild dermal irritation 5 minutes after patch removal, which subsequently decreased; at Day 7, no irritation was evident. The maximum recorded dermal assessment score was 2.</p> <p>Conclusion</p> <p>NGX-4010 was well tolerated following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with PHN. The tolerability of the patch application appeared comparable with that seen in other studies that used 4% lidocaine cream as the pretreatment anesthetic. This study is registered at <url>http://www.clinicaltrials.gov</url> as number <a href="http://www.clinicaltrials.gov/ct2/show/NCT00916942">NCT00916942</a>.</p

Medio-Frontal and Anterior Temporal abnormalities in children with attention deficit hyperactivity disorder (ADHD) during an acoustic antisaccade task as revealed by electro-cortical source reconstruction

<p>Abstract</p> <p>Background</p> <p>Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent disorders in children and adolescence. Impulsivity is one of three core symptoms and likely associated with inhibition difficulties. To date the neural correlate of the antisaccade task, a test of response inhibition, has not been studied in children with (or without) ADHD.</p> <p>Methods</p> <p>Antisaccade responses to visual and acoustic cues were examined in nine unmedicated boys with ADHD (mean age 122.44 ± 20.81 months) and 14 healthy control children (mean age 115.64 ± 22.87 months, three girls) while an electroencephalogram (EEG) was recorded. Brain activity before saccade onset was reconstructed using a 23-source-montage.</p> <p>Results</p> <p>When cues were acoustic, children with ADHD had a higher source activity than control children in Medio-Frontal Cortex (MFC) between -230 and -120 ms and in the left-hemispheric Temporal Anterior Cortex (TAC) between -112 and 0 ms before saccade onset, despite both groups performing similarly behaviourally (antisaccades errors and saccade latency). When visual cues were used EEG-activity preceding antisaccades did not differ between groups.</p> <p>Conclusion</p> <p>Children with ADHD exhibit altered functioning of the TAC and MFC during an antisaccade task elicited by acoustic cues. Children with ADHD need more source activation to reach the same behavioural level as control children.</p