Repeatability of quantitative18F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis

INTRODUCTION: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative18F-FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of18F-FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. METHODS: A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five18F-FLT repeatability cohorts in solid tumors.18F-FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUVmax, SUVmean, SUVpeak, proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test-retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. RESULTS: Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test-retest data for all18F-FLT uptake metrics (R2 ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUVpeak(RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUVmax ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26-28%), but did not affect the repeatability of SUV metrics. CONCLUSIONS: In multi-center studies, differences ≥ 25% in18F-FLT SUV metrics likely represent a true change in tumor uptake. Larger differences are required for FLT metrics comprising volume estimates when no lesion selection criteria are applied

Improved detection of diffuse glioma infiltration with imaging combinations: a diagnostic accuracy study

Background Surgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/FLAIR-weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration. Methods We included 20 consecutive adults with newly-diagnosed non-enhancing (seven diffuse astrocytomas, IDH-mutant; one oligodendroglioma, IDH-mutant and1p/19q-codeleted; one glioblastoma IDH-wildtype) or enhancing glioma (glioblastoma, nine IDH-wildtype and two IDH-mutant). Standardized pre-operative imaging (T1-, T2-, FLAIR-weighted and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multi-region stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by two neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis. Results A total of 174 biopsies were obtained (63 from nine non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of Apparent Diffusion Coefficient (ADC) with [18F]FET PET (AUC, 95%CI: 0.89,0.79-0.99) detected tumor better than T1G MRI (0.56,0.39-0.72;P<.001) and [18F]FET PET (0.76,0.66-0.86;P=0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65-0.98) compared to 0.69 (0.56-0.81;P=0.019) for [18F]FET PET. Conclusion and relevance Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy

Baseline and longitudinal variability of normal tissue uptake values of [F-18]-fluorothymidine-PET images

Purpose [18F]-fluorothymidine ([18F]-FLT) is a PET-tracer enabling in-vivo visualization and quantification of tumor cell proliferation. For qualitative and quantitative analysis, adequate knowledge of normal tissue uptake is indispensable. This study aimed to quantitatively investigate baseline tracer uptake of blood pool, lung, liver and bone marrow and their precision, and to assess the longitudinal effect of systemic treatment on biodistribution. Methods 18F–FLT-PET(/CT) scans (dynamic or static) of 90 treatment-naïve oncological patients were retrospectively evaluated. Twenty-three patients received double baseline scans, and another 39 patients were also scanned early and late during systemic treatment with a tyrosine kinase inhibitor. Reproducible volume of interest were placed in blood pool, lung, liver, and bone marrow. For semi-quantitative analysis, SUVmean, SUVmax, and SUVpeak with several normalizations were derived. Results SUVs of basal lung, liver, and bone marrow were not significantly different between averaged dynamic and static images, in contrast with blood pool and apical lung. Highest repeatability was seen for liver and bone marrow, with repeatability coefficients of 18.6% and 20.4% when using SUVpeak. Systemic treatment with TKIs both increased and decreased normal tissue tracer uptake at early and late time points during treatment. Conclusion Simultaneous evaluation of liver and bone marrow uptake in longitudinal response studies may be used to assess image quality, where changes in uptake outside repeatability limits should trigger investigators to perform additional quality control on individual PET images. Advances in knowledge For [18F]-FLT PET images, liver and bone marrow have low intra-patient variability when quantified with SUVpeak, but may be affected by systemic treatment. Implications for patient care In [18F]-FLT-PET response monitoring trials, liver and bone marrow uptake may be used for quality control of [18F]-FLT PET images

Spatial concordance of DNA methylation classification in diffuse glioma

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. RESULTS: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. CONCLUSION: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists

Progression of hearing loss after LINAC-based stereotactic radiotherapy for vestibular schwannoma is associated with cochlear dose, not with pre-treatment hearing level

BACKGROUND: Although stereotactic radiotherapy (SRT) for vestibular schwannoma has demonstrated excellent local control rates, hearing deterioration is often reported after treatment. We therefore wished to assess the change in hearing loss after SRT and to determine which patient, tumor and treatment-related factors influence deterioration. METHODS: We retrospectively analyzed progression of hearing loss in patients with vestibular schwannoma who had received stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) as a primary treatment between 2000 and 2014. SRS had been delivered as a single fraction of 12 Gy, and patients treated with FSRT had received 30 fractions of 1.8 Gy. To compare the effects of SRS and FSRT, we converted cochlear doses into EQD2. Primary outcomes were loss of functional hearing, Gardner Robertson (GR) classes I and II, and loss of baseline hearing class. These events were used in Kaplan Meier plots and Cox regression. We also calculated the rate of change in Pure Tone Average (PTA) in dB per month elapsed after radiation-a measure we use in linear regression-to assess the associations between the rate of change in PTA and age, pre-treatment hearing level, tumor size, dose scheme, cochlear dose, and time elapsed after treatment (time-to-first-audiogram). RESULTS: The median follow-up was 36 months for 67 SRS patients and 63 months for 27 FSRT patients. Multivariate Cox regression and in linear regression both showed that the cochlear V90 was significantly associated with the progression of hearing loss. But although pre-treatment PTA correlated with rate of change in Cox regression, it did not correlate in linear regression. The time-to-first-audiogram was also significantly associated, indicating time dependency of the rate of change. None of the analysis showed a significant difference between dose schemes. CONCLUSIONS: We found no significant difference between SRS and FSRT. As the deterioration in hearing after radiotherapy for vestibular schwannoma was associated with the cochlea V90, restricting the V90 may reduce progression of hearing loss. The association between loss of functional hearing and baseline PTA seems to be biased by the use of a categorized variable for hearing loss

Autistic and Schizotypal Traits and Global Functioning in Bipolar I Disorder

Objective: To determine the expression of autistic and positive schizotypal traits in a large sample of adults with bipolar I disorder (BD-I), and the effect of co-occurring autistic and positive schizotypal traits on global functioning in BD-I. Method: Autistic and positive schizotypal traits were self-assessed in 797 individuals with BD-I recruited by the Bipolar Disorder Research Network. Differences in global functioning (rated using the Global Assessment Scale) during lifetime worst depressive and manic episodes (GASD and GASM respectively) were calculated in groups with high/low autistic and positive schizotypal traits. Regression analyses assessed the interactive effect of autistic and positive schizotypal traits on global functioning. Results: 47.2% (CI=43.7-50.7%) showed clinically significant levels of autistic traits, and 23.22% (95% CI=20.29-26.14) showed clinically significant levels of positive schizotypal traits. In the worst episode of mania, the high autistic, high positive schizotypal group had better global functioning compared to the other groups. Individual differences analyses showed that high levels of co-occurring traits were associated with better global functioning in both mood states. Limitations: Autistic and schizotypal traits were assessed using self-rated questionnaires. Conclusions: Expression of autistic and schizotypal traits in adults with BD-I is prevalent, and may be important to predict illness aetiology, prognosis, and diagnostic practices in this population. Future work should focus on replicating these findings in independent samples, and on the biological and/or psychosocial mechanisms underlying better global functioning in those who have high levels of both autistic and positive schizotypal traits

Direct comparison of [11C] choline and [18F] FET PET to detect glioma infiltration: a diagnostic accuracy study in eight patients

Background Positron emission tomography (PET) is increasingly used to guide local treatment in glioma. The purpose of this study was a direct comparison of two potential tracers for detecting glioma infiltration, O-(2-[18F]-fluoroethyl)-l-tyrosine ([18F] FET) and [11C] choline. Methods Eight consecutive patients with newly diagnosed diffuse glioma underwent dynamic [11C] choline and [18F] FET PET scans. Preceding craniotomy, multiple stereotactic biopsies were obtained from regions inside and outside PET abnormalities. Biopsies were assessed independently for tumour presence by two neuropathologists. Imaging measurements were derived at the biopsy locations from 10 to 40 min [11C] choline and 20–40, 40–60 and 60–90 min [18F] FET intervals, as standardized uptake value (SUV) and tumour-to-brain ratio (TBR). Diagnostic accuracies of both tracers were compared using receiver operating characteristic analysis and generalized linear mixed modelling with consensus histopathological assessment as reference. Results Of the 74 biopsies, 54 (73%) contained tumour. [11C] choline SUV and [18F] FET SUV and TBR at all intervals were higher in tumour than in normal samples. For [18F] FET, the diagnostic accuracy of TBR was higher than that of SUV for intervals 40–60 min (area under the curve: 0.88 versus 0.81, p = 0.026) and 60–90 min (0.90 versus 0.81, p = 0.047). The diagnostic accuracy of [18F] FET TBR 60–90 min was higher than that of [11C] choline SUV 20–40 min (0.87 versus 0.67, p = 0.005). Conclusions [18F] FET was more accurate than [11C] choline for detecting glioma infiltration. Highest accuracy was found for [18F] FET TBR for the interval 60–90 min post-injection

Whole-body diffusion-weighted imaging for staging malignant lymphoma in children

CT is currently the mainstay in staging malignant lymphoma in children, but the risk of second neoplasms due to ionizing radiation associated with CT is not negligible. Whole-body MRI techniques and whole-body diffusion-weighted imaging (DWI) in particular, may be a good radiation-free alternative to CT. DWI is characterized by high sensitivity for the detection of lesions and allows quantitative assessment of diffusion that may aid in the evaluation of malignant lymphomas. This article will review whole-body MRI techniques for staging malignant lymphoma with emphasis on whole-body DWI. Furthermore, future considerations and challenges in whole-body DWI will be discussed

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe