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Journal of Immunology Research 2017Pseudophenomena, that is, imaging alterations due to therapy rather than tumor evolution, have an important impact on the management of glioma patients and the results... (Review)
Review
Pseudophenomena, that is, imaging alterations due to therapy rather than tumor evolution, have an important impact on the management of glioma patients and the results of clinical trials. RANO (response assessment in neurooncology) criteria, including conventional MRI (cMRI), addressed the issues of pseudoprogression after radiotherapy and concomitant chemotherapy and pseudoresponse during antiangiogenic therapy of glioblastomas (GBM) and other gliomas. The development of cancer immunotherapy forced the identification of further relevant response criteria, summarized by the iRANO working group in 2015. In spite of this, the unequivocal definition of glioma progression by cMRI remains difficult particularly in the setting of immunotherapy approaches provided by checkpoint inhibitors and dendritic cells. Advanced MRI (aMRI) may in principle address this unmet clinical need. Here, we discuss the potential contribution of different aMRI techniques and their indications and pitfalls in relation to biological and imaging features of glioma and immune system interactions.
Topics: Disease Progression; Glioblastoma; Glioma; Humans; Immunotherapy; Magnetic Resonance Imaging
PubMed: 28512646
DOI: 10.1155/2017/5813951 -
Neurosurgery Sep 2017Neuroimaging plays an ever evolving role in the diagnosis, treatment planning, and post-therapy assessment of brain tumors. This review provides an overview of current... (Review)
Review
Neuroimaging plays an ever evolving role in the diagnosis, treatment planning, and post-therapy assessment of brain tumors. This review provides an overview of current magnetic resonance imaging (MRI) methods routinely employed in the care of the brain tumor patient. Specifically, we focus on advanced techniques including diffusion, perfusion, spectroscopy, tractography, and functional MRI as they pertain to noninvasive characterization of brain tumors and pretreatment evaluation. The utility of both structural and physiological MRI in the post-therapeutic brain evaluation is also reviewed with special attention to the challenges presented by pseudoprogression and pseudoresponse.
Topics: Brain; Brain Neoplasms; Humans; Magnetic Resonance Imaging; Neuroimaging
PubMed: 28486641
DOI: 10.1093/neuros/nyx103 -
BMB Reports May 2017The circadian clock is an internal system that is synchronized by external stimuli, such as light and temperature, and influences various physiological and developmental...
The circadian clock is an internal system that is synchronized by external stimuli, such as light and temperature, and influences various physiological and developmental processes in living organisms. In the model plant Arabidopsis, transcriptional, translational and post-translational processes are interlocked by feedback loops among morning- and eveningphased genes. In a post-translational loop, plant-specific singlegene encoded GIGANTEA (GI) stabilize the F-box protein ZEITLUPE (ZTL), driving the targeted-proteasomal degradation of TIMING OF CAB EXPRESSION 1 (TOC1) and PSEUDORESPONSE REGULATOR 5 (PRR5). Inherent to this, we demonstrate the novel biochemical function of GI as a chaperone and/or co-chaperone of Heat-Shock Protein 90 (HSP90). GI prevents ZTL degradation as a chaperone and facilitates ZTL maturation together with HSP90/HSP70, enhancing ZTL activity in vitro and in planta. GI is known to be involved in a wide range of physiology and development as well as abiotic stress responses in plants, but it could also interact with diverse client proteins to increase protein maturation. Our results provide evidence that GI helps proteostasis of ZTL by acting as a chaperone and a co-chaperone of HSP90 for proper functioning of the Arabidopsis circadian clock. [BMB Reports 2017; 50(5): 235-236].
PubMed: 28454605
DOI: 10.5483/bmbrep.2017.50.5.064 -
Neuro-oncology Jun 2017The current method for assessing progressive disease (PD) in glioblastoma is according to the Response Assessment in Neuro-Oncology (RANO) criteria. Bevacizumab-treated... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The current method for assessing progressive disease (PD) in glioblastoma is according to the Response Assessment in Neuro-Oncology (RANO) criteria. Bevacizumab-treated patients may show pseudo-response on postcontrast T1-weighted (T1w) MRI, and a more infiltrative non-enhancing growth pattern on T2w/fluid attenuated inversion recovery (FLAIR) images. We investigated whether the RANO criteria remain the method of choice for assessing bevacizumab-treated recurrent glioblastoma when compared with various volumetric methods.
METHODS
Patients with assessable MRI data from the BELOB trial (n = 148) were included. Patients were treated with bevacizumab, lomustine, or both. At first and second radiological follow-up (6 and 12 wk), PD was determined using the 2D RANO criteria and various volumetric methods based on enhancing tumor only and enhancing plus non-enhancing tumor. Differences in overall survival (OS) between PD and non-PD patients were assessed with the log-rank test and a Cox model. Hazard ratios (HRs) and their 95% CIs were determined.
RESULTS
For all patients together, all methods (except subtraction of non-enhancing from enhancing volume at first follow-up) showed significant differences in OS between PD and non-PD patients (P < .001). The largest risk increase for death in case of PD at both first and second follow-up was found with the RANO criteria: HR = 2.81 (95% CI, 1.92-4.10) and HR = 2.80 (95% CI, 1.75-4.49), respectively. In the bevacizumab-treated patients, all methods assessed showed significant differences in OS between PD and non-PD patients. There were no significant differences between methods.
CONCLUSIONS
In the first 12 weeks, volumetric methods did not provide significant improvement over the RANO criteria as a posttreatment prognostic marker.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Contrast Media; Glioblastoma; Humans; Lomustine; Magnetic Resonance Imaging; Neoplasm Recurrence, Local; Survival Rate; Treatment Outcome
PubMed: 28204639
DOI: 10.1093/neuonc/now311 -
Journal of Nuclear Medicine : Official... May 2017Restoration of the blood-brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite...
Restoration of the blood-brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite tumor progression. This so-called pseudoresponse is difficult to differentiate from a true tumor response with conventional MRI. Initial patient studies have indicated that PET using -(2-F-fluoroethyl)-l-tyrosine (F-FET) may be helpful for solving this diagnostic problem. This study was performed to investigate the effects of bevacizumab on BBB permeability and F-FET uptake in a human xenograft model. Human U87 glioblastoma cells were implanted into the striatum of immunodeficient RNU rats. F-FET PET scans and ex vivo autoradiography were performed in animals receiving a single high dose of bevacizumab (45 mg/kg 2 d before PET; = 9) or in animals receiving 2 lower doses (10 mg/kg 9 and 2 d before PET; = 10) to evaluate short-term and long-term effects on the BBB, respectively, and in control animals without bevacizumab treatment ( = 8). Time-activity curves, slope, and tumor-to-brain ratios of F-FET uptake (18-61 min after injection) were evaluated using a volume-of-interest analysis. After PET scanning, Evans blue dye (EBD) was injected into animals, and cryosections of the brains were evaluated by autoradiography, by histology, and for EBD fluorescence to assess BBB permeability. Compared with the control, short-term bevacizumab therapy resulted in a trend toward BBB restoration ( = 0.055) and long-term therapy resulted in a significant decrease ( = 0.004) in BBB permeability, as assessed by EBD fluorescence. In contrast, no significant differences in tumor-to-brain ratios or slope of F-FET uptake were observed in PET and autoradiography ( > 0.05). F-FET uptake in glioblastomas seems to be largely independent of BBB permeability and reflects the viability of tumor tissue during antiangiogenic therapy more reliably than contrast-enhanced MRI.
Topics: Animals; Bevacizumab; Blood-Brain Barrier; Brain Neoplasms; Capillary Permeability; Glioma; Male; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Reproducibility of Results; Sensitivity and Specificity; Tyrosine
PubMed: 28153956
DOI: 10.2967/jnumed.116.187047 -
NeuroImage. Clinical 2017Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor... (Review)
Review
Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor tissue from posttherapeutic effects following neurosurgical resection, chemoradiation, alkylating chemotherapy, radiosurgery, and/or immunotherapy may be limited. Metabolic imaging using PET can provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. This review article focuses predominantly on the amino acid PET tracers C-methyl-l-methionine (MET), -(2-[F]fluoroethyl)-l-tyrosine (FET) and 3,4-dihydroxy-6-[F]-fluoro-l-phenylalanine (FDOPA) and summarizes investigations regarding monitoring of brain tumor therapy.
Topics: Amino Acids; Brain Neoplasms; Dihydroxyphenylalanine; Humans; Methionine; Positron-Emission Tomography; Radiopharmaceuticals; Tyrosine
PubMed: 28116231
DOI: 10.1016/j.nicl.2016.12.020 -
Neurotherapeutics : the Journal of the... Apr 2017Radiographic endpoints including response and progression are important for the evaluation of new glioblastoma therapies. The current RANO criteria was developed to... (Review)
Review
Radiographic endpoints including response and progression are important for the evaluation of new glioblastoma therapies. The current RANO criteria was developed to overcome many of the challenges identified with previous guidelines for response assessment, however, significant challenges and limitations remain. The current recommendations build on the strengths of the current RANO criteria, while addressing many of these limitations. Modifications to the current RANO criteria include suggestions for volumetric response evaluation, use contrast enhanced T1 subtraction maps to increase lesion conspicuity, removal of qualitative non-enhancing tumor assessment requirements, use of the post-radiation time point as the baseline for newly diagnosed glioblastoma response assessment, and "treatment-agnostic" response assessment rubrics for identifying pseudoprogression, pseudoresponse, and a confirmed durable response in newly diagnosed and recurrent glioblastoma trials.
Topics: Brain; Brain Neoplasms; Clinical Trials as Topic; Disease Progression; Glioblastoma; Humans; Image Enhancement; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Treatment Outcome
PubMed: 28108885
DOI: 10.1007/s13311-016-0507-6 -
Journal of Neuro-oncology Oct 2016Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with...
Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with anti-angiogenic agents is complicated by pseudoprogression and pseudoresponse. The hypothesis being tested in this study was that 3D H-1 magnetic resonance spectroscopic imaging (MRSI) provides estimates of levels of choline, creatine, N-acetylaspartate (NAA), lactate and lipid that change in response to treatment and that metrics describing these characteristics are associated with survival. Thirty-one patients with newly diagnosed GBM and being treated with radiation therapy (RT), temozolomide, erlotinib and bevacizumab were recruited to receive serial MR scans that included 3-D lactate edited MRSI at baseline, mid-RT, post-RT and at specific follow-up time points. The data were processed to provide estimates of metrics representing changes in metabolite levels relative to normal appearing brain. Cox proportional hazards analysis was applied to examine the relationship of these parameters with progression free survival (PFS) and overall survival (OS). There were significant reductions in parameters that describe relative levels of choline to NAA and creatine, indicating that the treatment caused a decrease in tumor cellularity. Changes in the levels of lactate and lipid relative to the NAA from contralateral brain were consistent with vascular normalization. Metabolic parameters from the first serial follow-up scan were associated with PFS and OS, when accounting for age and extent of resection. Integrating metabolic parameters into the assessment of patients with newly diagnosed GBM receiving therapies that include anti-angiogenic agents may be helpful for tracking changes in tumor burden, resolving ambiguities in anatomic images caused by non-specific treatment effects and for predicting outcome.
Topics: Adult; Aged; Antineoplastic Agents, Immunological; Aspartic Acid; Bevacizumab; Brain Neoplasms; Choline; Creatine; Dacarbazine; Female; Glioblastoma; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Proton Therapy; Statistics, Nonparametric; Temozolomide; Young Adult
PubMed: 27535746
DOI: 10.1007/s11060-016-2229-3 -
Nature Communications Oct 2016A double-negative feedback loop formed by the morning genes CIRCADIAN CLOCK ASSOCIATED1 (CCA1)/LATE ELONGATED HYPOCOTYL (LHY) and the evening gene TIMING OF CAB...
A double-negative feedback loop formed by the morning genes CIRCADIAN CLOCK ASSOCIATED1 (CCA1)/LATE ELONGATED HYPOCOTYL (LHY) and the evening gene TIMING OF CAB EXPRESSION1 (TOC1) contributes to regulation of the circadian clock in Arabidopsis. A 24-h circadian cycle starts with the peak expression of CCA1 at dawn. Although CCA1 is targeted by multiple transcriptional repressors, including PSEUDO-RESPONSE REGULATOR9 (PRR9), PRR7, PRR5 and CCA1 HIKING EXPEDITION (CHE), activators of CCA1 remain elusive. Here we use mathematical modelling to infer a co-activator role for LIGHT-REGULATED WD1 (LWD1) in CCA1 expression. We show that the TEOSINTE BRANCHED 1-CYCLOIDEA-PCF20 (TCP20) and TCP22 proteins act as LWD-interacting transcriptional activators. The concomitant binding of LWD1 and TCP20/TCP22 to the TCP-binding site in the CCA1 promoter activates CCA1. Our study reveals activators of the morning gene CCA1 and provides an action mechanism that ensures elevated expression of CCA1 at dawn to sustain a robust clock.
Topics: Anthocyanins; Arabidopsis; Arabidopsis Proteins; Binding Sites; Gene Expression Regulation, Plant; Models, Genetic; Period Circadian Proteins; Promoter Regions, Genetic; Protein Binding; Transcription Factors
PubMed: 27734958
DOI: 10.1038/ncomms13181 -
The Plant Cell Oct 2016The circadian clock allows plants to anticipate and respond to daily changes in ambient temperature. Mechanisms establishing the timing of circadian rhythms in...
The circadian clock allows plants to anticipate and respond to daily changes in ambient temperature. Mechanisms establishing the timing of circadian rhythms in Arabidopsis thaliana through temperature entrainment remain unclear. Also incompletely understood is the temperature compensation mechanism that maintains consistent period length within a range of ambient temperatures. A genetic screen for Arabidopsis mutants affecting temperature regulation of the PSEUDO-RESPONSE REGULATOR7 promoter yielded a novel allele of the SICKLE (SIC) gene. This mutant, sic-3, and the existing sic-1 mutant both exhibit low-amplitude or arrhythmic expression of core circadian clock genes under cool ambient temperature cycles, but not under light-dark entrainment. sic mutants also lengthen free running period in a manner consistent with impaired temperature compensation. sic mutant alleles accumulate LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED1 (CCA1) splice variants, among other alternatively spliced transcripts, which is exacerbated by cool temperatures. The cca1-1 lhy-20 double mutant is epistatic to sic-3, indicating the LHY and CCA1 splice variants are needed for sic-3 circadian clock phenotypes. It is not expected that SIC is directly involved in the circadian clock mechanism; instead, SIC likely contributes to pre-mRNA metabolism, and the splice variants that accumulate in sic mutants likely affect the circadian clock response to cool ambient temperature.
Topics: Alternative Splicing; Arabidopsis; Arabidopsis Proteins; Circadian Clocks; Cold Temperature; DNA-Binding Proteins; Gene Expression Regulation, Plant; Promoter Regions, Genetic; Transcription Factors
PubMed: 27624757
DOI: 10.1105/tpc.16.00223