Quantitative evaluation of lesion response heterogeneity for superior prognostication of clinical outcome.

PURPOSE: Standardized reporting of treatment response in oncology patients has traditionally relied on methods like RECIST, PERCIST and Deauville score. These endpoints assess only a few lesions, potentially overlooking the response heterogeneity of all disease. This study hypothesizes that comprehensive spatial-temporal evaluation of all individual lesions is necessary for superior prognostication of clinical outcome. METHODS: [18F]FDG PET/CT scans from 241 patients (127 diffuse large B-cell lymphoma (DLBCL) and 114 non-small cell lung cancer (NSCLC)) were retrospectively obtained at baseline and either during chemotherapy or post-chemoradiotherapy. An automated TRAQinform IQ software (AIQ Solutions) analyzed the images, performing quantification of change in regions of interest suspicious of cancer (lesion-ROI). Multivariable Cox proportional hazards (CoxPH) models were trained to predict overall survival (OS) with varied sets of quantitative features and lesion-ROI, compared by bootstrapping with C-index and t-tests. The best-fit model was compared to automated versions of previously established methods like RECIST, PERCIST and Deauville score. RESULTS: Multivariable CoxPH models demonstrated superior prognostic power when trained with features quantifying response heterogeneity in all individual lesion-ROI in DLBCL (C-index = 0.84, p < 0.001) and NSCLC (C-index = 0.71, p < 0.001). Prognostic power significantly deteriorated (p < 0.001) when using subsets of lesion-ROI (C-index = 0.78 and 0.67 for DLBCL and NSCLC, respectively) or excluding response heterogeneity (C-index = 0.67 and 0.70). RECIST, PERCIST, and Deauville score could not significantly associate with OS (C-index < 0.65 and p > 0.1), performing significantly worse than the multivariable models (p < 0.001). CONCLUSIONS: Quantitative evaluation of response heterogeneity of all individual lesions is necessary for the superior prognostication of clinical outcome.

Multi-organ segmentation of CT via convolutional neural network: impact of training setting and scanner manufacturer.

Objective. Automated organ segmentation on CT images can enable the clinical use of advanced quantitative software devices, but model performance sensitivities must be understood before widespread adoption can occur. The goal of this study was to investigate performance differences between Convolutional Neural Networks (CNNs) trained to segment one (single-class) versus multiple (multi-class) organs, and between CNNs trained on scans from a single manufacturer versus multiple manufacturers.Methods. The multi-class CNN was trained on CT images obtained from 455 whole-body PET/CT scans (413 for training, 42 for testing) taken with Siemens, GE, and Phillips PET/CT scanners where 16 organs were segmented. The multi-class CNN was compared to 16 smaller single-class CNNs trained using the same data, but with segmentations of only one organ per model. In addition, CNNs trained on Siemens-only (N = 186) and GE-only (N = 219) scans (manufacturer-specific) were compared with CNNs trained on data from both Siemens and GE scanners (manufacturer-mixed). Segmentation performance was quantified using five performance metrics, including the Dice Similarity Coefficient (DSC).Results. The multi-class CNN performed well compared to previous studies, even in organs usually considered difficult auto-segmentation targets (e.g., pancreas, bowel). Segmentations from the multi-class CNN were significantly superior to those from smaller single-class CNNs in most organs, and the 16 single-class models took, on average, six times longer to segment all 16 organs compared to the single multi-class model. The manufacturer-mixed approach achieved minimally higher performance over the manufacturer-specific approach.Significance. A CNN trained on contours of multiple organs and CT data from multiple manufacturers yielded high-quality segmentations. Such a model is an essential enabler of image processing in a software device that quantifies and analyzes such data to determine a patient's treatment response. To date, this activity of whole organ segmentation has not been adopted due to the intense manual workload and time required.

A Proteomics Investigation of Cigarette Smoke Exposed Wistar Rats Revealed Improved Anti-Inflammatory Effects of the Cysteamine Nanoemulsions Delivered via Inhalation.

Cigarette smoking is the major cause of chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD). It is paramount to develop pharmacological interventions and delivery strategies against the cigarette smoke (CS) associated oxidative stress in COPD. This study in Wistar rats examined cysteamine in nanoemulsions to counteract the CS distressed microenvironment. In vivo, 28 days of CS and 15 days of cysteamine nanoemulsions treatment starting on 29th day consisting of oral and inhalation routes were established in Wistar rats. In addition, we conducted inflammatory and epithelial-to-mesenchymal transition (EMT) studies in vitro in human bronchial epithelial cell lines (BEAS2B) using 5% CS extract. Inflammatory and anti-inflammatory markers, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1ß, IL-8, IL-10, and IL-13, have been quantified in bronchoalveolar lavage fluid (BALF) to evaluate the effects of the cysteamine nanoemulsions in normalizing the diseased condition. Histopathological analysis of the alveoli and the trachea showed the distorted, lung parenchyma and ciliated epithelial barrier, respectively. To obtain mechanistic insights into the CS COPD rat model, "shotgun" proteomics of the lung tissues have been carried out using high-resolution mass spectrometry wherein genes such as ABI1, PPP3CA, PSMA2, FBLN5, ACTG1, CSNK2A1, and ECM1 exhibited significant differences across all the groups. Pathway analysis showed autophagy, signaling by receptor tyrosine kinase, cytokine signaling in immune system, extracellular matrix organization, and hemostasis, as the major contributing pathways across all the studied groups. This work offers new preclinical findings on how cysteamine taken orally or inhaled can combat CS-induced oxidative stress.

Structural and optical properties of a new Milarite type Na3 Mg4 LiSi12 O30 :Eu3+ phosphor.

A new red-emitting Eu3+ (1-17 mol%)-doped Na3 Mg4 LiSi12 O30 (NMLS) phosphor was prepared using a conventional solid-state reaction method at low temperature. The prepared samples belong to a hexagonal structure with a good match to JCPDS card no. 73-0934. The photoluminescence (PL) emission spectrum showed an intense peak at 612 nm when excited at 393 nm. The variation of electric dipole transition (5 D0 -7 F2 ) emission intensity with increasing Eu3+ ion concentration was investigated. The concentration quenching at 11 mol% is due to the dipole-dipole interaction mechanism in the NMLS host. The optimized NMLS:Eu3+ phosphor shows 2.18 times higher luminescence intensity than the (Y,Gd)BO3 (YGB) commercial phosphor. The NMLS:Eu3+ showed an intense red emission, having Commission Internationale de l'éclairage (CIE) coordinates (0.6280, 0.3691) and colour purity of 99.2%. The resulting phosphor exhibits good thermal stability of 80% at 423 K. The magnified images of fingerprint showed various minute features such as bridges, sweat pores, ridge end, bifurcation, island and core with better visualization under 393 nm excitation. Furthermore, the optimized NMLS:Eu3+ was used for pc-LED, latent fingerprints, and anticounterfeit applications as a promising red phosphor.

Structural and Neuronal Integrity Measures of Fatigue Severity in Multiple Sclerosis.

Fatigue is a common and disabling symptom in Multiple Sclerosis (MS). However, consistent neuroimaging correlates of its severity are not fully elucidated. In this article, we study the neuronal correlates of fatigue severity in MS. Forty-three Relapsing Remitting MS (RRMS) patients with MS-related fatigue (Fatigue Severity Scale (FSS) range: 1-7) and Expanded Disability Status Scale (EDSS) ≤ 4, were divided into high fatigue (HF, FSS ≥ 5.1) and low fatigue groups (LF, FSS ≤ 3). We measured T2 lesion load using a semi-automated technique. Cortical thickness, volume of sub-cortical nuclei, and brainstem structures were measured using Freesurfer. Cortical Diffusion Tensor Imaging (DTI) parameters were extracted using a cross modality technique. A correlation analysis was performed between FSS, volumetric, and DTI indices across all patients. HF patients showed significantly lower volume of thalamus, (p = 0.02), pallidum (p = 0.01), and superior cerebellar peduncle ((SCP), p = 0.002). The inverse correlation between the FSS score and the above volumes was significant in the total study population. In the right temporal cortex (RTC), the Radial Diffusivity ((RD), p = 0.01) and Fractional Anisotropy ((FA), p = 0.01) was significantly higher and lower, respectively, in the HF group. After Bonferroni correction, thalamic volume, FA-RTC, and RD-RTC remained statistically significant. Multivariate regression analysis identified FA-RTC as the best predictor of fatigue severity. Our data suggest an association between fatigue severity and volumetric changes of thalamus, pallidum, and SCP. Early neuronal injury in the RTC is implicated in the pathogenesis of MS-related fatigue.

α-[11C]-Methyl-L-tryptophan--PET in 191 patients with tuberous sclerosis complex.

OBJECTIVES: This was an observational study done on a large cohort of patients with tuberous sclerosis complex (TSC) to determine whether i) the presence of α-[(11)C]-methyl-l-tryptophan (AMT) hotspots is related to the duration of seizure intractability, ii) the presence of AMT hotspots is related to specific TSC gene mutations, and iii) there is concordance between areas with an AMT hotspot and seizure lateralization/localization on scalp EEG. METHODS: One hundred ninety-one patients (mean age: 6.7 years; median: 5 years; range: 3 months to 37 years) with TSC and intractable epilepsy were included. All patients underwent AMT-PET scan. AMT uptake in each tuber and normal-appearing cortex was measured and correlated with clinical, scalp EEG, and, if available, electrocorticographic data. RESULTS: The longer the duration of seizure intractability, the greater the number of AMT hotspots (r = 0.2; p = 0.03). AMT hotspots were seen in both TSC1 and TSC2. There was excellent agreement in seizure focus lateralization between ictal scalp EEG and AMT-PET (Cohen κ 0.94) in 68 of 95 patients in whom both ictal video-EEG and AMT-PET showed lateralizing findings; in 28 of 68 patients (41%), AMT was more localizing. Furthermore, AMT-PET was localizing in 10 of 17 patients (58%) with nonlateralized ictal EEG. CONCLUSION: AMT-PET, when used together with video-EEG, provides additional lateralization/localization data, regardless of TSC mutation. The duration of seizure intractability may predict the multiplicity of areas with AMT hotspots.

Surface-based laminar analysis of diffusion abnormalities in cortical and white matter layers in neocortical epilepsy.

PURPOSE: Microstructural alterations seen in the epileptic cortex have been implicated as a cause and also result of multiple seizure activity. In the present study, we evaluated water diffusion changes at different cortical thickness fractions and in the underlying white matter of the epileptic cortex and compared them with electrographically normal cortex and also with corresponding cortical regions of healthy controls. METHODS: We selected 18 children with normal magnetic resonance imaging (MRI) who underwent two-stage epilepsy surgery to control seizures of neocortical origin, and compared their MR images with those of 18 age-matched healthy controls. First, delineation of the gray-white and gray-pial intersection surfaces was performed on high-resolution volumetric T1 MR images. Using the delineated surfaces as reference, diffusion values were measured at different cortical thickness fractions and in the underlying white matter at various depths, using diffusion tensor imaging (DTI). Cortical regions representing seizure onset and electrographically normal cortex were differentiated by electrocorticography in the epilepsy patients. KEY FINDINGS: We observed different patterns of diffusion abnormalities in both the seizure onset and electrographically normal cortical regions when compared to healthy controls. In the seizure-onset regions, a marked increase in diffusivity was noted in the cortical gray matter, and this increase was most pronounced in the outer fraction of the gray matter. Similarly, increased diffusivity was noted in the white matter underlying the epileptic cortex. The electrographically normal cortex, in contrast, showed decreased diffusivity in inner and middle cortical fractions compared to the controls. The white matter underlying the electrographically normal cortex did not show any difference in diffusivity between the children with epilepsy and controls. Finally, both the cortical gray matter and the underlying white matter regions showed decreased anisotropy in epileptic as well as electrographically normal regions when compared to controls. SIGNIFICANCE: Our results suggest specific patterns of diffusion changes in the cortical fractions and the underlying white matter of the epileptic region compared to electrographically normal and normal control regions. The abnormal increase in diffusivity of the superficial cortex might be associated with microstructural abnormalities commonly seen in layers II through IV of epileptic cortex. Such combined use of a high-resolution structural image to extract the laminar diffusion values, which are highly sensitive to microstructural alterations, could be of clinical value in localizing epileptogenic cortex.

Cerebellar pathway changes following cerebral hemispherectomy.

Following unilateral cerebral injury, several patterns of cerebellar metabolism have been noted on positron emission tomography (PET); these changes have been attributed both to the distant diaschisis as well as to reorganizational changes within the cerebellum. We used diffusion tensor magnetic resonance imaging (MRI) to study 14 children who had undergone cerebral hemispherectomy because of intractable epilepsy and compared them with those from 17 controls. In 10 children who had preoperative and postoperative scans, a paired comparison was performed. Our findings showed significantly higher fractional anisotropy values in corticopontocerebellar pathways postoperatively compared to preoperatively. When compared to controls, we found a higher rate of age-related fractional anisotropy changes of corticopontocerebellar pathways in the postoperative scans. Our results indicate reorganizational changes in the contralateral (intact) corticopontocerebellar pathway and the cerebellar white matter. These changes likely contribute to the far better motor outcomes seen in children compared to adults sustaining such cortical injuries.

Reorganization of the right arcuate fasciculus following left arcuate fasciculus resection in children with intractable epilepsy.

The authors evaluated postsurgical reorganization of the arcuate fasciculus longitudinally using diffusion tensor imaging in 10 children with intractable epilepsy, whose resections included the left arcuate fasciculus. Evaluation of fractional anisotropy before and after surgery (mean follow-up: 7.5 months) showed a significant increase (P = .002) in the right arcuate fasciculus during follow-up. There was marked enlargement of the right arcuate fasciculus postsurgically in 8 patients. The change in right arcuate fasciculus fractional anisotropy values showed a positive correlation with interval between resection and postsurgical magnetic resonance imaging (MRI) (P = .044). Comparison of 10 age-matched controls to patients pre- and postsurgery showed significantly reduced presurgery fractional anisotropy in the left (P = .018) and right (P = .036) arcuate fasciculus and no difference in postsurgery fractional anisotropy in the right arcuate fasciculus (P = .399) in patients. These findings suggest a compensatory reorganization in the right arcuate fasciculus in children with intractable epilepsy following left arcuate fasciculus resection.

Arcuate fasciculus and speech in congenital bilateral perisylvian syndrome.

Standard magnetic resonance imaging can diagnose congenital bilateral perisylvian polymicrogyria, but is limited in explaining the heterogeneous clinical spectrum of the related congenital bilateral perisylvian syndrome, characterized by pseudobulbar dysfunction, developmental delay, and epilepsy. We analyzed arcuate fasciculi using diffusion tensor imaging, a major language tract in the perisylvian region interconnecting the Broca and Wernicke areas, and at high risk of becoming developmentally affected in this condition. Six patients with congenital bilateral perisylvian syndrome underwent diffusion tensor imaging and were evaluated. The arcuate fasciculus was manually isolated, using tractography. The tract was identified in three patients who had developed speech, and whose values for various diffusion parameters were similar to those in age-matched controls (patients/controls means: fractional anisotropy, 0.50/0.52; apparent diffusion coefficient, 0.0022/0.0022 mm(2)/second; P = ns for both). However, in three patients with severe impairment and no speech development, the arcuate fasciculus could not be identified by fiber-tracking. In this small series, the absence of arcuate fasciculi on diffusion tensor imaging correlated with a more severe phenotype, which cannot be appreciated via structural magnetic resonance imaging alone.

Focal white matter abnormalities related to neurocognitive dysfunction: an objective diffusion tensor imaging study of children with Sturge-Weber syndrome.

White matter (WM) loss is associated with cognitive impairment in Sturge-Weber syndrome (SWS). In this study, we evaluated if cognitive and fine motor abnormalities are associated with impaired microstructural integrity in specific WM regions in SWS. Fifteen children with unilateral SWS (age: 3-12.4 y) and 11 controls (age: 6-12.8 y) underwent diffusion tensor imaging. Tract-based spatial statistics was used for objective comparisons of WM fractional anisotropy (FA) and mean diffusivity (MD) between the two groups. In the SWS group, WM FA and MD values were correlated with intelligence quotient (IQ) and fine motor scores, with age as a co-variate. Bilateral, multilobar WM areas showed decreased FA, whereas significant MD increases were confined to small ipsilateral posterior regions in SWS children. IQ in the SWS group (range: 47-128) was positively correlated with FA in the ipsilateral prefrontal WM and inversely associated with MD in the ipsilateral posterior parietal WM. A negative correlation between fine motor function and MD was found in ipsilateral frontal WM encompassing motor pathways. Microstructural WM abnormalities occur not only ipsilateral but also contralateral to the angioma in unilateral SWS. Nevertheless, cognitive and fine motor functions are related to diffusion abnormalities in specific ipsilateral, mostly frontal, WM regions.

Presurgical prediction of motor functional loss using tractography.

The usefulness of magnetic resonance imaging tractography is demonstrated in the presurgical planning of an 8-year-old girl with intractable epilepsy. Imaging and intracranial electrode monitoring suggested a left hemispherectomy for complete control of her seizures. Although this child was hemiplegic, she retained considerable motor function in her right hand, and her parents and the epilepsy team voiced significant concern that she would lose right-hand function after a hemispherectomy. Tractography indicated near-complete absence of her left corticospinal tract and a more robust than normal corticospinal tract in the right hemisphere. This finding suggested that her right motor function had reorganized to the right hemisphere and the ipsilateral corticospinal tract. After surgery, her seizures were completely controlled, and no change in right motor activity was evident compared with her presurgical status. Tractography helped determine the extent of cortical resection and predict the extent of motor functional loss.

Abnormal water diffusivity in corticostriatal projections in children with Tourette syndrome.

The fronto-striato-thalamic circuit has been implicated in the pathomechanism of Tourette Syndrome (TS). To study white and gray matter comprehensively, we used a novel technique called Tract-Based Spatial Statistics (TBSS) combined with voxel-based analysis (VBA) of diffusion tensor MR images in children with TS as compared to typically developing controls. These automated and unbiased methods allow analysis of cerebral white matter and gray matter regions. We compared 15 right-handed children with TS (mean age: 11.6 ± 2.5 years, 12 males) to 14 age-matched right-handed healthy controls (NC; mean age: 12.29 ± 3.2 years, 6 males). Tic severity and neurobehavioral scores were correlated with FA and ADC values in regions found abnormal by these methods. For white matter, TBSS analysis showed regions of increased ADC in the corticostriatal projection pathways including left external capsule and left and right subcallosal fasciculus pathway in TS group compared to NC group. Within the TS group, ADC for the left external capsule was negatively associated with tic severity (r= -0.586, P = 0.02). For gray matter, VBA revealed increased ADC for bilateral orbitofrontal cortex, left putamen, and left insular cortex. ADC for the right and left orbitofrontal cortex was highly correlated with internalizing problems (r = 0.665; P = 0.009, r = 0.545; P = 0.04, respectively). Altogether, this analysis revealed focal diffusion abnormalities in the corticostriatal pathway and in gray matter structures involved in the fronto-striatal circuit in TS. These diffusion abnormalities could serve as a neuroimaging marker related to tic severity and neurobehavioral abnormalities in TS subjects.

Altered water diffusivity in cortical association tracts in children with early deprivation identified with Tract-Based Spatial Statistics (TBSS).

Institutional rearing is associated with neurocognitive and behavioral difficulties. Although such difficulties are thought to reflect abnormal neurologic development resulting from early social deprivation (ED) and there is evidence for functional abnormality in children with histories of ED, the impact of early deprivation on brain anatomy has received little study in humans. The present study utilized an objective and sensitive neuroimaging analysis technique (Tract-Based Spatial Statistics) to evaluate white matter fractional anisotropy (FA) and diffusivity in a group of right-handed children with histories of ED (n = 17; mean age = 10.9 + 2.6 years) as compared with age-matched healthy controls (n = 15; mean age = 11.7 + or - 2.8 years). Participants underwent magnetic resonance imaging diffusion tensor imaging sequences and comprehensive neuropsychological evaluations. Results revealed reduced FA in frontal, temporal, and parietal white matter including components of uncinate and superior longitudinal fasciculi, in children with histories of ED, providing further support for limbic and paralimbic abnormalities in children with such histories. Furthermore, white matter abnormalities were associated with duration of time in the orphanage and with inattention and hyperactivity scores. It is suspected that the observed white matter abnormalities are associated with multiple depriving factors (e.g., poor prenatal care, postnatal stress) associated with institutional caregiving.

Altered fronto-striato-thalamic connectivity in children with Tourette syndrome assessed with diffusion tensor MRI and probabilistic fiber tracking.

The aim of the study was to determine whether abnormal connectivity of the fronto-striato-thalamic circuit underlies the morphological changes in subcortical structures of patients with Tourette syndrome and to correlate these changes with neurobehavioral measures. A total of 18 children with Tourette syndrome and 12 age-matched healthy controls underwent diffusion tensor magnetic resonance imaging. Tractography of the fronto-striato-thalamic circuit was achieved using probability distribution function of individual voxels. The Tourette syndrome group had significantly lower probability of connection between caudate nucleus and anterior-dorsolateral-frontal cortex on the left (P = .038). Obsessive-compulsive behavior was negatively associated with connectivity score of the left caudate and anterior dorsolateral frontal cortex (P = .01) and was positively associated with connectivity score for the subcallosal gyrus (P = .009) and for the lentiform nucleus (P = .008). The abnormal connectivity among components of the fronto-striato-thalamic circuit bilaterally (ie, seeds on the caudate and thalamus) in patients with Tourette syndrome provides direct evidence for the involvement of these circuits in the pathophysiology.

Diffusion tensor analysis of temporal and extra-temporal lobe tracts in temporal lobe epilepsy.

OBJECTIVE: To determine whether the major temporal lobe white matter tracts in patients with temporal lobe epilepsy manifest abnormal water diffusion properties. METHODS: Diffusion tensor MRI measurements were obtained from tractography for uncinate, arcuate, inferior longitudinal fasciculi and corticospinal tract in 13 children with left temporal lobe epilepsy and normal conventional MRI, and the data were compared to measurements in 12 age-matched normal volunteers. The relationship between tensor parameters and duration of epilepsy was also determined. RESULTS: All four tracts in the affected left hemisphere showed lower mean anisotropy, planar and linear indices, but higher spherical index in patients versus controls. Diffusion changes in the left uncinate and arcuate fasciculus correlated significantly with duration of epilepsy. Arcuate fasciculus showed a reversal of the normal left-right asymmetry. Various diffusion abnormalities were also seen in the four tracts studied in the right hemisphere. CONCLUSION: Our findings indicate abnormal water diffusion in temporal lobe and extra-temporal lobe tracts with robust changes in the direction perpendicular to the axons. Diffusion abnormalities associated with duration of epilepsy suggest progressive changes in ipsilateral uncinate and arcuate fasciculus due to chronic seizure activity. Finally, our results in arcuate fasciculus are consistent with language reorganization to the contralateral right hemisphere.

Diffusion tensor imaging of brain plasticity after occipital lobectomy.

Reorganization involving residual visual pathways with unilateral damage to the primary visual cortex was previously described. Using diffusion tensor imaging, we measured water diffusion-related changes in the optic radiation contralateral to occipital lobe ablation in children with intractable epilepsy. We studied 10 children who had undergone a resection of the unilateral occipital cortex and 13 control subjects. Diffusion tensor imaging was acquired using a 1.5 Tesla magnetic resonance scanner. Fiber bundles representing optic radiation were tracked. Diffusion parameters included mean fractional anisotropy, apparent diffusion coefficient, and diffusion parallel and perpendicular to the fiber tract. In the surgical group, fractional anisotropy values of optic radiation contralateral to the side of resection exhibited a significant positive partial correlation (r = 0.752, P = 0.019) with duration of time between surgery and diffusion tensor imaging acquisition, after controlling for age. The apparent diffusion coefficient and parallel diffusivity were higher in the surgical versus the control group, but did not differ among patients. After unilateral resection of the occipital lobe, the contralateral optic radiation undergoes significant changes in anisotropy. Such structural white-matter changes may represent an adaptive response because of unilateral occipital ablation, and may account for plasticity changes observed in functional magnetic resonance imaging.