Fluency test generation and errors in focal frontal and posterior lesions.

The number produced on fluency tasks is widely used to measure voluntary response generation. To further evaluate the relationship between generation, errors, and the area of anatomical damage we administered eight fluency tasks (word, design, gesture, ideational) to a large group of focal frontal (n = 69) and posterior (n = 43) patients and controls (n = 150). Lesions were analysed by a finer-grained frontal localisation method, and traditional subdivisions (anterior/posterior, left/right frontal). Thus, we compared patients with Lateral lesions to patients with Medial lesions. Our results show that all fluency tasks are sensitive to frontal lobe damage for the number of correct responses and, for the first time, we provide evidence that seven fluency tasks show frontal sensitivity in terms of errors (perseverations, rule-breaks). Lateral (not Medial) patients produced the highest error rates, indicative of task-setting or monitoring difficulties. There was a right frontal effect for perseverative errors when retrieving known or stored items and rule-break errors when creating novel responses. Left lateral effects were specific to phonemic word fluency rule-breaks and perseverations for meaningless gesture fluency. In addition, our generation output and error findings support a frontal role in novelty processes. Finally, we confirm our previous generation findings suggesting critical roles of the superior medial region in energization and the left inferior frontal region in selection (Robinson et al., 2012). Overall, these results support the notion that frontal functions comprise a set of highly specialised cognitive processes, supported by distinct frontal regions.

Phase 1 Safety, Pharmacokinetics, and Fluorescence Imaging Study of Tozuleristide (BLZ-100) in Adults With Newly Diagnosed or Recurrent Gliomas.

BACKGROUND: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types. OBJECTIVE: To perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma. METHODS: Patients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures. RESULTS: A total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery. CONCLUSION: These results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas.

Impact of pre-therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV-specific T-cell therapy.

OBJECTIVES: Clinical response to antibody-based immunotherapies targeting checkpoint inhibitors is critically dependent on the tumor immune microenvironment (TIME). However, the precise impact of the TIME on adoptive cellular immunotherapy remains unexplored. Here we have conducted a long-term follow-up analysis of patients with recurrent glioblastoma multiforme (GBM) who were treated with autologous CMV-specific T-cell therapy to delineate the potential impact of the TIME on their clinical response. METHODS: Multiplexed immunohistochemical analysis of CD3, PD-L1 and Sox-2 in GBM tissue biopsies obtained before autologous T-cell therapy was carried out and correlated with long-term survival of GBM patients adoptively treated with T-cell therapy. RESULTS: Tumor microenvironment analyses revealed that the pre-treatment cellular composition of the tumor tissue may influence the subsequent response to adoptive T-cell therapy. GBM patients who showed prolonged overall survival following T-cell therapy had a significantly lower number of tumor-infiltrating CD3+ T cells in recurrent tumors than that in patients with short-term survival. Furthermore, long-term surviving patients showed low or undetectable PD-L1 expression in tumor cells in recurrent GBM biopsies. CONCLUSION: We hypothesise that lack of PD-L1-mediated immunosuppression in the TIME may allow efficient immune control following adoptive T-cell therapy. Future studies combining anti-PD-L1 or genetically modified T cells with PD-1 receptor knockdown could be considered to improve clinical responses in patients who have high PD-L1 expression in their tumors.

When does a strategy intervention overcome a failure of inhibition? Evidence from two left frontal brain tumour cases.

INTRODUCTION: Initiation and inhibition of responses are crucial for appropriate behaviour across different settings. Initiation and inhibition difficulties are well documented following frontal damage, although task differences have limited our understanding. The Hayling Sentence Completion Test was designed to assess verbal initiation and inhibition within the same task. This study investigates the ability of two patients with left frontal tumours (KI: high grade glioma; PM: meningioma) to use a strategy to overcome profound suppression failures on the Hayling Test. METHOD: KI and PM completed the Hayling Test and two experimental tasks. The Selection Investigation assessed verbal initiation on a sentence completion task that varied selection demands (high/low). The Suppression and Strategy Investigation assessed ability to implement four strategies aimed to override a suppression failure and facilitate production of an unconnected word. RESULTS: On the Hayling Test, KI and PM initiated responses to complete high constraint sentences, in contrast to impaired suppression. KI benefitted minimally from strategies to overcome suppression failure although one strategy (object naming) was partially successful. KI's errors revealed fast suppression errors, in contrast to slow no responses, and selection ability was also impaired for verbal initiation. PM, however, implemented each strategy 100% to overcome a suppression failure and had no difficulty completing sentences meaningfully, regardless of selection demands. CONCLUSION: This first investigation of strategy implementation to overcome profound suppression impairments provides insights into verbal initiation, inhibition, selection and strategy mechanisms, which has implications for neurorehabilitation. Specifically, both patients had profound inhibition deficits but KI also presented with a selection deficit and was unable to implement a strategy. By contrast, PM's selection ability was intact but she was unable to generate, rather than implement, a strategy. We suggest that KI has both fast, uncontrolled semantic output and response inhibition difficulty, whereas PM's difficulty is underpinned by motivational factors.

Neuropsychological assessment of individuals with brain tumor: comparison of approaches used in the classification of impairment.

Approaches to classifying neuropsychological impairment after brain tumor vary according to testing level (individual tests, domains, or global index) and source of reference (i.e., norms, controls, and pre-morbid functioning). This study aimed to compare rates of impairment according to different classification approaches. Participants were 44 individuals (57% female) with a primary brain tumor diagnosis (mean age = 45.6 years) and 44 matched control participants (59% female, mean age = 44.5 years). All participants completed a test battery that assesses pre-morbid IQ (Wechsler adult reading test), attention/processing speed (digit span, trail making test A), memory (Hopkins verbal learning test-revised, Rey-Osterrieth complex figure-recall), and executive function (trail making test B, Rey-Osterrieth complex figure copy, controlled oral word association test). Results indicated that across the different sources of reference, 86-93% of participants were classified as impaired at a test-specific level, 61-73% were classified as impaired at a domain-specific level, and 32-50% were classified as impaired at a global level. Rates of impairment did not significantly differ according to source of reference (p > 0.05); however, at the individual participant level, classification based on estimated pre-morbid IQ was often inconsistent with classification based on the norms or controls. Participants with brain tumor performed significantly poorer than matched controls on tests of neuropsychological functioning, including executive function (p = 0.001) and memory (p < 0.001), but not attention/processing speed (p > 0.05). These results highlight the need to examine individuals' performance across a multi-faceted neuropsychological test battery to avoid over- or under-estimation of impairment.

Cognitive screening in brain tumors: short but sensitive enough?

Cognitive deficits in brain tumors are generally thought to be relatively mild and non-specific, although recent evidence challenges this notion. One possibility is that cognitive screening tools are being used to assess cognitive functions but their sensitivity to detect cognitive impairment may be limited. For improved sensitivity to recognize mild and/or focal cognitive deficits in brain tumors, neuropsychological evaluation tailored to detect specific impairments has been thought crucial. This study investigates the sensitivity of a cognitive screening tool, the Montreal Cognitive Assessment (MoCA), compared to a brief but tailored cognitive assessment (CA) for identifying cognitive deficits in an unselected primary brain tumor sample (i.e., low/high-grade gliomas, meningiomas). Performance is compared on broad measures of impairment: (a) number of patients impaired on the global screening measure or in any cognitive domain; and (b) number of cognitive domains impaired and specific analyses of MoCA-Intact and MoCA-Impaired patients on specific cognitive tests. The MoCA-Impaired group obtained lower naming and word fluency scores than the MoCA-Intact group, but otherwise performed comparably on cognitive tests. Overall, based on our results from patients with brain tumor, the MoCA has extremely poor sensitivity for detecting cognitive impairments and a brief but tailored CA is necessary. These findings will be discussed in relation to broader issues for clinical management and planning, as well as specific considerations for neuropsychological assessment of brain tumor patients.

Verbal suppression and strategy use: a role for the right lateral prefrontal cortex?

Verbal initiation, suppression and strategy generation/use are cognitive processes widely held to be supported by the frontal cortex. The Hayling Test was designed to tap these cognitive processes within the same sentence completion task. There are few studies specifically investigating the neural correlates of the Hayling Test but it has been primarily used to detect frontal lobe damage. This study investigates the components of the Hayling Test in a large sample of patients with unselected focal frontal (n = 60) and posterior (n = 30) lesions. Patients and controls (n = 40) matched for education, age and sex were administered the Hayling Test as well as background cognitive tests. The standard Hayling Test clinical measures (initiation response time, suppression response time, suppression errors and overall score), composite errors scores and strategy-based responses were calculated. Lesions were analysed by classical frontal/posterior subdivisions as well as a finer-grained frontal localization method and a specific contrast method that is somewhat analogous to voxel-based lesion mapping methods. Thus, patients with right lateral, left lateral and superior medial lesions were compared to controls and patients with right lateral lesions were compared to all other patients. The results show that all four standard Hayling Test clinical measures are sensitive to frontal lobe damage although only the suppression error and overall scores were specific to the frontal region. Although all frontal patients produced blatant suppression errors, a specific right lateral frontal effect was revealed for producing errors that were subtly wrong. In addition, frontal patients overall produced fewer correct responses indicative of developing an appropriate strategy but only the right lateral group showed a significant deficit. This problem in strategy attainment and implementation could explain, at least in part, the suppression error impairment. Contrary to previous studies there was no specific frontal effect for verbal initiation. Overall, our results support a role for the right lateral frontal region in verbal suppression and, for the first time, in strategy generation/use.

Progressive dysembryoplastic neuroepithelial tumour.

Dysembryoplastic neuroepithelial tumour (DNET) is a benign tumour characterised by cortical location and presentation with drug resistant partial seizures in children. Recently the potential for malignant transformation has been reported, however progression without malignant transformation remains rare. We report a case of clinical and radiologic progression of a DNET in a girl 10 years after initial biopsy.

Evaluation of the making sense of brain tumor program: a randomized controlled trial of a home-based psychosocial intervention.

OBJECTIVE: Despite significant psychosocial morbidity, there are few controlled trials of psychological support for people with brain tumor. This study evaluated the efficacy of the Making Sense of Brain Tumor (MSoBT) program, a home-based psychosocial intervention. DESIGN: A randomized controlled trial with a wait list condition METHODS: Fifty participants aged 17-82 years with brain tumor (54% benign) were randomly allocated to immediate treatment (n = 27) or a waitlist (n = 23). Measures included Montgomery-Asberg Depression Rating Scale (MADRS), McGill Quality of Life (MQOL) Questionnaire, Depression Anxiety Stress Scales (DASS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). The immediate treatment group received the 10-session MSoBT program, while the waitlist group received usual care for 10 weeks and were then re-assessed before receiving the MSoBT program. A 6-month post-intervention follow-up was conducted. RESULTS: Analysis of covariance adjusting for baseline functioning identified that the immediate treatment group reported significantly lower levels of depression on the MADRS (η(p)(2) = .19) and higher levels of existential well-being on the MQOL (η(p)(2) = .13) and functional well-being (η(p)(2) = .21) and global quality of life on the FACT-Br (η(p)(2) = .12) at post-assessment than the waitlist group. At 6-month follow-up participants reported significantly lower levels of depression and stress and higher existential well-being and quality of life relative to pre-intervention. CONCLUSIONS: The MSoBT program appears to have efficacy for enhancing psychological well-being and quality of life after brain tumor.

Cytomegalovirus as a novel target for immunotherapy of glioblastoma multiforme.

Progress in the treatment of glioblastoma multiforme (GBM) over the last few decades has remained marginal and GBM is still universally fatal with short survival times after initial diagnosis. Much research is focused on finding new therapeutics for GBM and immune-based approaches have shown great promise. The detection of cytomegalovirus (CMV) antigens in malignant cells has suggested that treatment strategies based on immunological intervention, such as adoptive transfer of antiviral T cells or vaccination with viral epitopes, could be exploited as cancer therapy. Here, we review the rationale for using CMV as a therapeutic target and discuss the first clinical evidence for safety and efficacy of CMV-specific cellular immunotherapy for GBM.

Cellular immunotherapy directed against human cytomegalovirus as a novel approach for glioblastoma treatment.

Glioblastoma multiforme (GBM) has a very poor prognosis, despite multimodal therapy including surgery, radiation and chemotherapy. A novel adoptive immunotherapy that exploits the presence of cytomegalovirus antigens in malignant brain cancer cells has been shown to be safe and elicit potential clinical benefit for the treatment of recurrent GBM.

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells.

Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival.

Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma.

Glioblastoma multiforme (GBM) is one of the most aggressive human brain malignancies. Even with optimal treatment, median survival is less than 6 months for patients with recurrent GBM. Immune-based therapies have the potential to improve patient outcome by supplementing standard treatment. Expression of human cytomegalovirus (CMV) antigens in GBM tissues provides the unique opportunity to target viral antigens for GBM therapy. Here, we report findings of a formal clinical assessment of safety and potential clinical efficacy of autologous CMV-specific T-cell therapy as a consolidative treatment for recurrent GBM. From a total of 19 patients with recurrent GBM, CMV-specific T cells were successfully expanded from 13 patients (68.4%), 11 of whom received up to four T-cell infusions. Combination therapy based on T-cell infusion and chemotherapy was well tolerated, and we detected only minor adverse events. The overall survival of these patients since first recurrence ranged from 133 to 2,428 days, with a median overall survival of 403 days. Most importantly, 4 of 10 patients that completed the treatment remained progression free during the study period. Furthermore, molecular profiling of CMV-specific T-cell therapy from these patients revealed distinct gene expression signatures, which correlated with their clinical response. Our study suggests that a combination therapy with autologous CMV-specific T cells and chemotherapy is a safe novel treatment option and may offer clinical benefit for patients with recurrent GBM.

Selective preservation of the beat in apperceptive music agnosia: a case study.

INTRODUCTION: Music perception involves processing of melodic, temporal and emotional dimensions that have been found to dissociate in healthy individuals and after brain injury. Two components of the temporal dimension have been distinguished, namely rhythm and metre. We describe an 18 year old male musician 'JM' who showed apperceptive music agnosia with selectively preserved metre perception, and impaired recognition of sad and peaceful music relative to age and music experience matched controls after resection of a right temporoparietal tumour. METHOD: Two months post-surgery JM underwent a comprehensive neuropsychological evaluation including assessment of his music perception abilities using the Montreal Battery for Evaluation of Amusia (MBEA, Peretz, Champod, & Hyde, 2003). He also completed several experimental tasks to explore his ability to recognise famous songs and melodies, emotions portrayed by music and a broader range of environmental sounds. Five age-, gender-, education- and musical experienced-matched controls were administered the same experimental tasks. RESULTS: JM showed selective preservation of metre perception, with impaired performances compared to controls and scoring below the 5% cut-off on all MBEA subtests, except for the metric condition. He could identify his favourite songs and environmental sounds. He showed impaired recognition of sad and peaceful emotions portrayed in music relative to controls but intact ability to identify happy and scary music. CONCLUSION: This case study contributes to the scarce literature documenting a dissociation between rhythmic and metric processing, and the rare observation of selectively preserved metric interpretation in the context of apperceptive music agnosia. It supports the notion that the anterior portion of the superior temporal gyrus (STG) plays a role in metric processing and provides the novel observation that selectively preserved metre is sufficient to identify happy and scary, but not sad or peaceful emotions portrayed in music.

The moderating effect of estimated pre-morbid IQ on the relationship between neuropsychological status and subjective well-being after brain tumour.

OBJECTIVE: People with brain tumour experience complex and distressing symptoms. Neuropsychological impairment is proposed to have a negative impact on subjective well-being; however, research is yet to examine the influence of estimated premorbid IQ on this relationship. This preliminary study investigated the moderating effect of estimated premorbid IQ on the relationship between global neuropsychological status (GNF) and depression and quality of life. METHODS: 73 adults (51% male) aged 21-65 years with primary brain tumour (52% benign) were administered a test battery assessing estimated premorbid IQ, GNF, depression (Depression Anxiety Stress Scales) and quality of life (Functional Assessment of Cancer Therapy, FACT). RESULTS: A series of two-way analysis of covariance (ANCOVA) controlling for education found a significant interaction between estimated premorbid IQ (low average to average vs high average) and GNF (low vs high) on levels of depression (p < .05) and FACT emotional well-being (p < .05). For these outcomes, individuals with high average estimated premorbid IQ and low GNF reported better well-being than those with low-average to average estimated premorbid IQ and low GNF. Higher GNF was related to greater functional well-being (p < .01) irrespective of estimated premorbid IQ. CONCLUSION: The finding that higher premorbid cognitive ability buffers the effect of neuropsychological impairment on emotional well-being after brain tumour advances understanding of the role of cognitive reserve in adjustment to neurological disorders.

Ethnicity differences in genetic susceptibility to ulcerative colitis: a comparison of Indian asians and white northern Europeans.

BACKGROUND: Studies in Caucasian populations have identified a number of genetic associations with ulcerative colitis (UC), but reports from other ethnic groups have been limited. Recent studies from India have reported an association with UC and a single polymorphism (SNP) in CARD15/NOD2 (SNP5, rs2066842), which has not been reported in Caucasian UC cohorts. In addition, strong genetic associations with SNPs in the HLA region have been reported in Indian UC populations. However, there have been no reports on the frequency of HLA class II alleles in Indian populations with inflammatory bowel disease to examine whether the associations differ from other ethnic populations. METHODS: Genotyping was performed for 137 Indian UC patients for HLA class II alleles (HLA-DRB1*1502 & HLA-DRB1*0103), IL23R (rs11209026), and CARD15/NOD2 (rs2066842). The genetic data were compared with 204 healthy Indian controls and 50 white European UC patients. RESULTS: The HLA-DRB1*0103 allele was absent in all Indian UC patients and controls in contrast to white European UC patients (9/50: 18%). The HLA-DRB1*1502 allele was significantly more frequent in the Indian UC cohort (29.2%) than controls (17.6%) (P = 0.04) and the allele was absent in the white European cohort. There were no significant differences in the frequency of the CARD15/NOD2 (rs2066842) variant or IL23R (rs11209026) between the different ethnic groups. CONCLUSIONS: The HLA-DRB1*0103 allele is rare or absent in the Indian Asian population but HLA-DRB1*1502 is positively associated with UC. Further genetic studies in this population could provide valuable information and may help distinguish the degree of influence of genetic and environmental pathogenic factors.

EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme.

Significant endeavor has been applied to identify functional therapeutic targets in glioblastoma (GBM) to halt the growth of this aggressive cancer. We show that the receptor tyrosine kinase EphA3 is frequently overexpressed in GBM and, in particular, in the most aggressive mesenchymal subtype. Importantly, EphA3 is highly expressed on the tumor-initiating cell population in glioma and appears critically involved in maintaining tumor cells in a less differentiated state by modulating mitogen-activated protein kinase signaling. EphA3 knockdown or depletion of EphA3-positive tumor cells reduced tumorigenic potential to a degree comparable to treatment with a therapeutic radiolabelled EphA3-specific monoclonal antibody. These results identify EphA3 as a functional, targetable receptor in GBM.

A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells.

Glioblastoma multiforme (GBM) is the most common form of brain tumor with a poor prognosis and resistance to radiotherapy. Recent evidence suggests that glioma-initiating cells play a central role in radioresistance through DNA damage checkpoint activation and enhanced DNA repair. To investigate this in more detail, we compared the DNA damage response in nontumor forming neural progenitor cells (NPC) and glioma-initiating cells isolated from GBM patient specimens. As observed for GBM tumors, initial characterization showed that glioma-initiating cells have long-term self-renewal capacity. They express markers identical to NPCs and have the ability to form tumors in an animal model. In addition, these cells are radioresistant to varying degrees, which could not be explained by enhanced nonhomologous end joining (NHEJ). Indeed, NHEJ in glioma-initiating cells was equivalent, or in some cases reduced, as compared with NPCs. However, there was evidence for more efficient homologous recombination repair in glioma-initiating cells. We did not observe a prolonged cell cycle nor enhanced basal activation of checkpoint proteins as reported previously. Rather, cell-cycle defects in the G(1)-S and S-phase checkpoints were observed by determining entry into S-phase and radioresistant DNA synthesis following irradiation. These data suggest that homologous recombination and cell-cycle checkpoint abnormalities may contribute to the radioresistance of glioma-initiating cells and that both processes may be suitable targets for therapy.

Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme.

The frequent detection of human cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) has raised the possibility of exploiting CMV-specific T-cell immunotherapy to control this disease in CMV--seropositive patients. Here, we have conducted a comprehensive ex vivo profiling of CMV-specific CD8(+) T-cell responses in a cohort of GBM patients. Of the patients analyzed, approximately half exhibited serological evidence of past infection with CMV. Although no CMV-specific CD8(+) T-cell responses could be detected in the serologically negative GBM patients, virus-specific CD8(+) T-cell responses were detected in all seropositive GBM patients. Using major histocompatibility complex-peptide multimers, the frequency of CMV-specific T-cells in the patients detected ranged from 0.1 to 22% of CD8(+) T-cells and a high proportion of these cells were positive for the human natural killer-1 glycoprotein CD57. Furthermore, ex vivo polychromatic functional analysis of the CMV-specific T-cells from GBM patients revealed that large proportions of these cells were unable to produce multiple cytokines (macrophage inflammatory protein (MIP)-1ß, tumor necrosis factor (TNF)α and interferon (IFN)γ) and displayed limited cytolytic function (CD107a mobilization) following stimulation with CMV peptide epitopes. However, in vitro stimulation with CMV peptide epitopes in the presence of γC cytokine dramatically reversed the polyfunctional profile of these antigen-specific T-cells with high levels of MIP-1ß, TNFα, IFNγ and CD107a mobilization. Most importantly, adoptive transfer of these in vitro-expanded T-cells in combination with temozolomide (TMZ) therapy into a patient with recurrent GBM was coincident with a long-term disease-free survival. These studies provide an important platform for a formal assessment of combination therapies based on CMV-specific T-cells and TMZ for recurrent GBM.

Serum metabolic profiling in inflammatory bowel disease.

BACKGROUND: The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract whose pathogenesis is not completely understood. (1)H nuclear magnetic resonance (NMR) spectroscopy of serum generates comprehensive metabolic profiles, reflecting systemic metabolism, which may be altered in disease states. AIM: The aim of this study was to use (1)H NMR-based serum metabolic profiling in the investigation of CD patients, UC patients, and controls, potentially to provide insights into disordered metabolism in IBD, and into underlying mechanisms of disease. METHODS: Serum metabolic profiles were acquired from 67 individuals (24 CD patients, 20 UC patients, and 23 healthy controls). The multivariate pattern-recognition techniques of principal components analysis (PCA) and partial least squares discriminant analysis with orthogonal signal correction (OSC-PLS-DA) were used to investigate differences between cohorts. RESULTS: OSC-PLS-DA distinguished CD and UC cohorts with significant predictive accuracy, highlighting differences in lipid and choline metabolism. Metabolic profiles of both CD and UC cohorts, and the combined IBD cohort, differed significantly from controls: metabolites of importance in the OSC-PLS-DA models included lipoproteins (especially HDL cholesterol), choline, N-acetylglycoprotein, and amino acids. CONCLUSIONS: (1)H NMR-based metabolic profiling has identified distinct differences in serum metabolic phenotype between CD and UC patients, as well as between IBD patients and controls.