Spatial Auto-Regressive Analysis of Correlation in 3-D PET With Application to Model-Based Simulation of Data.

When a scanner is installed and begins to be used operationally, its actual performance may deviate somewhat from the predictions made at the design stage. Thus it is recommended that routine quality assurance (QA) measurements be used to provide an operational understanding of scanning properties. While QA data are primarily used to evaluate sensitivity and bias patterns, there is a possibility to also make use of such data sets for a more refined understanding of the 3-D scanning properties. Building on some recent work on analysis of the distributional characteristics of iteratively reconstructed PET data, we construct an auto-regression model for analysis of the 3-D spatial auto-covariance structure of iteratively reconstructed data, after normalization. Appropriate likelihood-based statistical techniques for estimation of the auto-regression model coefficients are described. The fitted model leads to a simple process for approximate simulation of scanner performance-one that is readily implemented in an R script. The analysis provides a practical mechanism for evaluating the operational error characteristics of iteratively reconstructed PET images. Simulation studies are used for validation. The approach is illustrated on QA data from an operational clinical scanner and numerical phantom data. We also demonstrate the potential for use of these techniques, as a form of model-based bootstrapping, to provide assessments of measurement uncertainties in variables derived from clinical FDG-PET scans. This is illustrated using data from a clinical scan in a lung cancer patient, after a 3-minute acquisition has been re-binned into three consecutive 1-minute time-frames. An uncertainty measure for the tumor SUVmax value is obtained. The methodology is seen to be practical and could be a useful support for quantitative decision making based on PET data.

Development of body knowledge as measured by arm differentiation in infants: From global to local?

The ability to sense and use the body parts in an organized and differentiated manner is a precursor of body knowledge in infancy. To acquire this ability, the infant's brain might explore the perceptual consequences of its bodily actions. Undifferentiated body movements would gradually be replaced by more precise actions. Only a very few studies have tested this 'global-to-local' hypothesis, and none of them have so far been replicated. In this study, we assessed arm differentiation in 4-, 6-, and 8-month-old infants using a new contingency detection task in which infants have to detect a contingency between one of their arms' activity and an audiovisual stimulus on a screen. We found that 4- to 8-month-old infants seem to be able to use their arms in a differentiated manner. However, surprisingly, we were not able to show a developmental trend in arm differentiation between 4 and 8 months of age. Statement of contribution What is already known on this subject? Foetuses and infants possess coarse control of their body and may be sensitive to sensory feedback caused by their own movements. Body knowledge might develop during the first year of life in what can be called a 'global-to-local' manner. Nevertheless, the precise age at which infants come to possess well-differentiated local body knowledge requires further investigation. What the present study adds? 4- to 8-month-old infants seem able to use their arms in a differentiated manner when exposed to an audiovisual stimulation contingent on movements of one of their arms. However, we found no developmental trend in arm differentiation between 4 and 8 months of age. We hypothesize that infants' sensitivity to sensorimotor contingencies and their ability to narrow down contingencies to a specific limb might evolve with age as a function of the infant's current sensorimotor interests.

Immune-Mediated Control of a Dormant Neurotropic RNA Virus Infection.

Genomic material from many neurotropic RNA viruses (e.g., measles virus [MV], West Nile virus [WNV], Sindbis virus [SV], rabies virus [RV], and influenza A virus [IAV]) remains detectable in the mouse brain parenchyma long after resolution of the acute infection. The presence of these RNAs in the absence of overt central nervous system (CNS) disease has led to the suggestion that they are viral remnants, with little or no potential to reactivate. Here we show that MV RNA remains detectable in permissive mouse neurons long after challenge with MV and, moreover, that immunosuppression can cause RNA and protein synthesis to rebound, triggering neuropathogenesis months after acute viral control. Robust recrudescence of viral transcription and protein synthesis occurs after experimental depletion of cells of the adaptive immune response and is associated with a loss of T resident memory (Trm) lymphocytes within the brain. The disease associated with loss of immune control is distinct from that seen during the acute infection: immune cell-depleted, long-term-infected mice display severe gait and motor problems, in contrast to the wasting and lethal disease that occur during acute infection of immunodeficient hosts. These results illuminate the potential consequences of noncytolytic, immune-mediated viral control in the CNS and demonstrate that what were once considered "resolved" RNA viral infections may, in fact, induce diseases later in life that are distinct from those caused by acute infection.IMPORTANCE Viral infections of neurons are often not cytopathic; thus, once-infected neurons survive, and viral RNAs can be detected long after apparent viral control. These RNAs are generally considered viral fossils, unlikely to contribute to central nervous system (CNS) disease. Using a mouse model of measles virus (MV) neuronal infection, we show that MV RNA is maintained in the CNS of infected mice long after acute control and in the absence of overt disease. Viral replication is suppressed by the adaptive immune response; when these immune cells are depleted, viral protein synthesis recurs, inducing a CNS disease that is distinct from that observed during acute infection. The studies presented here provide the basis for understanding how persistent RNA infections in the CNS are controlled by the host immune response, as well as the pathogenic consequences of noncytolytic viral control.

Combining structural and textural assessments of volumetric FDG-PET uptake in NSCLC.

Numerous studies have reported the prognostic utility of texture analyses and the effectiveness of radiomics in PET and PET/CT assessment of non-small cell lung cancer (NSCLC). Here we explore the potential, relative to this methodology, of an alternative model-based approach to tumour characterization, which was successfully applied to sarcoma in previous works. The spatial distribution of 3D FDG-PET uptake is evaluated in the spatial referential determined by the best-fitting ellipsoidal pattern, which provides a univariate uptake profile function of the radial position of intratumoral voxels. A group of structural features is extracted from this fit that include two heterogeneity variables and statistical summaries of local metabolic gradients. We demonstrate that these variables capture aspects of tumour metabolism that are separate to those described by conventional texture features. Prognostic model selection is performed in terms of a number of classifiers, including stepwise selection of logistic models, LASSO, random forests and neural networks with respect to two-year survival status. Our results for a cohort of 93 NSCLC patients show that structural variables have significant prognostic potential, and that they may be used in conjunction with texture features in a traditional radiomics sense, towards improved baseline multivariate models of patient overall survival. The statistical significance of these models also demonstrates the relevance of these machine learning classifiers for prognostic variable selection.

Tissue and Bronchoalveolar Lavage Biomarkers in Idiopathic Pulmonary Fibrosis Patients on Pirfenidone.

BACKGROUND: Pirfenidone is a novel anti-fibrotic agent in idiopathic pulmonary fibrosis with proven clinical benefit. Better human tissue models to demonstrate the immunomodulatory and anti-fibrotic effect of pirfenidone are required. OBJECTIVES: The purpose of the study was to use transbronchial lung cryobiopsy (TBLC), a novel technique which provides substantial tissue samples, and a large panel of biomarkers to temporally assess disease activity and response to pirfenidone therapy. METHODS: Thirteen patients with confirmed idiopathic pulmonary fibrosis (IPF) underwent full physiological and radiological assessment at diagnosis and after 6-month pirfenidone therapy. They underwent assessment for a wide range of potential serum and bronchoalveolar lavage biomarkers of disease activity. Finally, they underwent TBLC before and after treatment. Tissue samples were assessed for numbers of fibroblast foci, for Ki-67, a marker of tissue proliferation and caspase-3, a marker of tissue apoptosis. RESULTS: All patients completed treatment and investigations without significant incident. There was no significant fall in number of fibroblast foci per unit tissue volume after treatment (pre-treatment: 0.14/mm2 vs. post-treatment 0.08/mm2, p = 0.1). Likewise, there was no significant change in other markers of tissue proliferation, Ki-67 or Caspase-3 with pirfenidone treatment. We found an increase in three bronchoalveolar lavage angiogenesis cytokines, Placental Growth Factor, Vascular Endothelial Growth Factor-A, and basic Fibroblast Growth Factor, two anti-inflammatory cytokines Interleukin-10 and Interleukin-4 and Surfactant Protein-D. CONCLUSIONS: TBLC offers a unique opportunity to potentially assess the course of disease activity and response to novel anti-fibrotic activity in IPF.

Know Your Body Through Intrinsic Goals.

The first "object" that newborn children play with is their own body. This activity allows them to autonomously form a sensorimotor map of their own body and a repertoire of actions supporting future cognitive and motor development. Here we propose the theoretical hypothesis, operationalized as a computational model, that this acquisition of body knowledge is not guided by random motor-babbling, but rather by autonomously generated goals formed on the basis of intrinsic motivations. Motor exploration leads the agent to discover and form representations of the possible sensory events it can cause with its own actions. When the agent realizes the possibility of improving the competence to re-activate those representations, it is intrinsically motivated to select and pursue them as goals. The model is based on four components: (1) a self-organizing neural network, modulated by competence-based intrinsic motivations, that acquires abstract representations of experienced sensory (touch) changes; (2) a selector that selects the goal to pursue, and the motor resources to train to pursue it, on the basis of competence improvement; (3) an echo-state neural network that controls and learns, through goal-accomplishment and competence, the agent's motor skills; (4) a predictor of the accomplishment of the selected goals generating the competence-based intrinsic motivation signals. The model is tested as the controller of a simulated simple planar robot composed of a torso and two kinematic 3-DoF 2D arms. The robot explores its body covered by touch sensors by moving its arms. The results, which might be used to guide future empirical experiments, show how the system converges to goals and motor skills allowing it to touch the different parts of own body and how the morphology of the body affects the formed goals. The convergence is strongly dependent on competence-based intrinsic motivations affecting not only skill learning and the selection of formed goals, but also the formation of the goal representations themselves.

Fetal Origin of Sensorimotor Behavior.

The aim of this article is to track the fetal origin of infants' sensorimotor behavior. We consider development as the self-organizing emergence of complex forms from spontaneously generated activity, governed by the innate capacity to detect and memorize the consequences of spontaneous activity (contingencies), and constrained by the sensory and motor maturation of the body. In support of this view, we show how observations on fetuses and also several fetal experiments suggest that the fetus's first motor activity allows it to feel the space around it and to feel its body and the consequences of its movements on its body. This primitive motor babbling gives way progressively to sensorimotor behavior which already possesses most of the characteristics of infants' later behavior: repetition of actions leading to sensations, intentionality, some motor control and oriented reactions to sensory stimulation. In this way the fetus can start developing a body map and acquiring knowledge of its limited physical and social environment.

CD4+ T cells require either B cells or CD8+ T cells to control spread and pathogenesis of a neurotropic infection.

Immunity within the brain, specifically to virus-infected neurons, must be controlled to prevent neuron loss and impairment, though the process by which this occurs remains unclear. Here, we use a mouse model of neuron-restricted measles virus infection, in which immunocompetent adults survive challenge, whereas T and B cell-deficient mice succumb. This model allowed us to more precisely define the contributions of CD4+ T cells, CD8+ T cells, and B cells in neuroprotection. Both B cell knockout mice and mice depleted of CD8+ T cells survive challenge and show no signs of illness, though are less able to control viral replication than immunocompetent mice. In contrast, depletion of CD4+ T cells results in disease and death in all infected mice, though the kinetics of illness are delayed compared to RAG knockout mice. Our data suggest a coordinated interplay of adaptive immune components, which collectively controls viral spread and limits neuropathogenesis.

Feasibility of low-dose CT with model-based iterative image reconstruction in follow-up of patients with testicular cancer.

PURPOSE: We examine the performance of pure model-based iterative reconstruction with reduced-dose CT in follow-up of patients with early-stage testicular cancer. METHODS: Sixteen patients (mean age 35.6 ± 7.4 years) with stage I or II testicular cancer underwent conventional dose (CD) and low-dose (LD) CT acquisition during CT surveillance. LD data was reconstructed with model-based iterative reconstruction (LD-MBIR). Datasets were objectively and subjectively analysed at 8 anatomical levels. Two blinded clinical reads were compared to gold-standard assessment for diagnostic accuracy. RESULTS: Mean radiation dose reduction of 67.1% was recorded. Mean dose measurements for LD-MBIR were: thorax - 66 ± 11 mGy cm (DLP), 1.0 ± 0.2 mSv (ED), 2.0 ± 0.4 mGy (SSDE); abdominopelvic - 128 ± 38 mGy cm (DLP), 1.9 ± 0.6 mSv (ED), 3.0 ± 0.6 mGy (SSDE). Objective noise and signal-to-noise ratio values were comparable between the CD and LD-MBIR images. LD-MBIR images were superior (p < 0.001) with regard to subjective noise, streak artefact, 2-plane contrast resolution, 2-plane spatial resolution and diagnostic acceptability. All patients were correctly categorised as positive, indeterminate or negative for metastatic disease by 2 readers on LD-MBIR and CD datasets. CONCLUSIONS: MBIR facilitated a 67% reduction in radiation dose whilst producing images that were comparable or superior to conventional dose studies without loss of diagnostic utility.

Humour production may enhance observational learning of a new tool-use action in 18-month-old infants.

Many studies have shown that making children laugh enhances certain cognitive capacities such as attention, motivation, perception and/or memory, which in turn enhance learning. However, no study thus far has investigated whether laughing has an effect on learning earlier in infancy. The goal of this study was to see whether using humour with young infants in a demonstration of a complex tool-use task can enhance their learning. Fifty-three 18-month-old infants participated in this study and were included either in a humorous or a control demonstration group. In both groups infants observed an adult using a tool to retrieve an out-of-reach toy. What differed between groups was that in the humorous demonstration group, instead of playing with the toy, the adult threw it on the floor immediately after retrieval. The results show that infants who laughed at the demonstration in the humorous demonstration group reproduced significantly more frequent target actions than infants who did not laugh and those in the control group. This effect is discussed with regard to individual differences in terms of temperament and social capacities as well as positive emotion and dopamine release.

Biomarkers to identify ILD and predict lung function decline in scleroderma lung disease or idiopathic pulmonary fibrosis.

BACKGROUND: SSc-ILD and IPF demonstrate significant morbidity and mortality. Predicting disease progression is challenging in both diseases. OBJECTIVES: We sought a serum biomarker that could identify patients with SSc-ILD or IPF and prospectively predict short-term decline in lung function in these patients. METHODS: 10 healthy controls, 5 SSc w/o ILD, 6 SSc-ILD and 13 IPF patients underwent venesection. An array of cytokines including KL-6, SP-D and MMP7 were measured. PFTs were obtained at baseline and six months. Cytokine measurements were correlated with PFTs. RESULTS: KL-6 in IPF patients (633 ng/ml, IQR 492-1675) was significantly elevated compared to controls (198 ng/ml, IQR 52-360, p<0.01) and SSc w/o ILD patients (192 ng/ml, IQR 0-524, p<0.05); KL-6 in SSc-ILD patients (836 ng/ml, IQR 431-1303) was significantly higher than in controls (p<0.05). SP-D was significantly higher in IPF patients (542 ng/ml, IQR 305-577) compared to controls (137 ng/ml, IQR 97-284, p<0.01) or to SSc w/o ILD patients (169 ng/ml, IQR 137-219, p<0.05). In comparison with controls (0.0 ng/ml, IQR 0.0-0.6), MMP7 was significantly higher in both IPF patients (2.85 ng/ml, IQR 1.5-3.6, p<0.05) and SSc-ILD patients (5.41 ng/ml, IQR 2.6-7.2, p<0.001). Using a cut-off level of 459ng/ml for KL-6 and of 1.28 ng/ml for MMP7, 18 out of 19 patients with ILD had a serum value of either KL-6 or MMP7 above these thresholds. For all ILD patients, baseline serum SP-D correlated with ΔFVC %pred over six months (r=-0.63, p=0.005, 95% CI -0.85 to -0.24). CONCLUSIONS: Combining KL-6 with MMP7 may be a useful screening tool for patients at risk of ILD. SP-D may predict short-term decline in lung function.

Reduction of guide needle streak artifact in CT-guided biopsy.

PURPOSE: Computed tomography (CT)-guided core needle biopsy (CNB) can be affected by streak artifact obscuring the needle tip. This study investigates factors that influence the occurrence and severity of streak artifact during CNB. MATERIALS AND METHODS: Eight coaxial guide needles of two sizes from two manufacturers with and without stylets were imaged in a CT phantom, with CT reconstructed with adaptive statistical iterative reconstruction and filtered back projection. CNB-related streak artifact was quantified with profile analysis in an image-processing program. Differences between maximum attenuation at the needle tip and minimum attenuation in the streak artifact were compared for each variable. Diagnostic acceptability and streak artifact were subjectively assessed on each phantom image and on 40 clinical CNB procedures by three independent blinded reviewers following training case review. RESULTS: Artifact was significantly less with the central stylet removed versus in situ (median, 1,145 HU vs 3,390 HU; P < .001) for all needles, and less for 19-gauge needles versus 17-gauge needles (median, 1,334 HU vs 2,780 HU, respectively; P = .006). There were no differences based on manufacturer (P = .906) or reconstruction algorithm (P = .524). Independent reviews found that streak artifact was significantly reduced when the central stylet was removed (κ = 0.875-1.0; P < .001), and needle tip position was better in cases in which the stylet was removed (κ = 0.231-0.711; P < .001). CONCLUSIONS: Streak artifact can be reduced and needle tip visualization improved by confirming final biopsy needle position with the central stylet removed on CT and using smaller-gauge guide needles.

New-onset mediastinal and central nervous system sarcoidosis in a patient with metastatic melanoma undergoing CTLA4 monoclonal antibody treatment.

BACKGROUND: Ipilimumab, a cytotoxic monoclonal antibody that inhibits cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), has been established as an effective therapy in the management of advanced melanoma. Immune-mediated adverse events are a common side effect. CASE REPORT: A 37-year-old male patient was diagnosed with nodal and osseous metastatic melanoma 15 months after the initial surgical treatment for lower limb melanoma. Therapy with the anti-CTLA-4 antibody, ipilimumab, was started. Follow-up staging imaging after treatment initiation showed symmetrical bihilar adenopathy. Transbronchial biopsy showed sarcoidosis. The patient had associated systemic symptoms of fatigue, joint pains, anorexia and weight loss. Brain magnetic resonance imaging (MRI), which was performed for the investigation of headaches, showed abnormal enhancing tissue in the sella turcica and adjacent to the pituitary infundibulum, consistent with neurosarcoidosis. The condition was successfully treated with corticosteroids. CONCLUSIONS: We report a case of immunotherapy-induced mediastinal/hilar sarcoidosis, with pituitary involvement, mimicking tumour progression. This highlights the need for awareness amongst radiologists and oncologists of the mechanism of action and potential side effects of new immunotherapies.

New targeted molecular therapies for cancer: radiological response in intrathoracic malignancies and cardiopulmonary toxicity: what the radiologist needs to know.

The emergence of new novel therapeutic agents which directly target molecules that are uniquely or abnormally expressed in cancer cells (molecular targeted therapy, MTT) has changed dramatically the treatment of cancer in recent years. The clinical benefit associated with these agents is typically limited to a subset of treated patients, who in many cases are defined by a specific genomic mutations and expression lesion within their tumor cells. All these new therapy modalities represent new challenges to radiologists as their mechanism of action and side effect profiles differ from conventional chemotherapy agents. In this article we will discuss radiological patterns of response to molecular targeted therapies MTT in lung cancer, typical and atypical radiological responses of targeted molecular therapy for other intra thoracic malignancies, cardiopulmonary toxicity and other side effects of molecular targeted therapy MTT in the thorax.

Acute idiopathic scrotal edema.

We report a case of acute idiopathic scrotal edema (AISE) in a 4-year-old boy who presented with acute scrotal pain and erythema. The clinical features, ultrasound appearance, and natural history of this rare diagnosis are reviewed. In this report, we highlight the importance of good ultrasound technique in differentiating the etiology of the acute scrotum and demonstrate the color Doppler "Fountain Sign" that is highly suggestive of AISE.

Gastrointestinal stromal tumors (GIST): lesser known facts.

In an era of molecular targeted therapy, patients with advanced gastrointestinal stromal tumor (GIST) are living longer and are often followed with imaging. Therefore, it is important for the radiologists to be aware of the atypical subtypes of GIST, implications of molecular makeup, its behavior, and the uncommon metastatic sites. The aim of this pictorial review is to illustrate the lesser-known aspects of GIST including histological and molecular classifications, syndromes associated with GIST, and uncommon metastatic sites.

Molecular targeted therapies in non-GIST soft tissue sarcomas: what the radiologist needs to know.

Non-gastrointestinal stromal soft tissue sarcomas are uncommon neoplasms that have a dismal prognosis due to a high incidence of metastases and a poor response to conventional chemotherapy. The identification of characteristic genetic alterations in several of these tumors has opened the window for molecular targeted therapies in patients who have failed conventional chemotherapy. Imaging plays a critical role in assessing the response to these novel therapeutic agents. Just like the response of gastrointestinal stromal tumors to imatinib, the response of non-gastrointestinal stromal soft tissue sarcomas to molecular targeted drugs is better evaluated on imaging by alternate tumor response criteria such as the Choi criteria. In addition, these drugs are associated with distinct class-specific drug toxicities that can come to attention for the first time on imaging. The purpose of this article is to provide a primer for the radiologist on the various molecular targeted therapies in advanced/metastatic non-gastrointestinal stromal soft tissue sarcomas with emphasis on the role of imaging in assessing treatment response and complications.

Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: a study of 270 scans in 97 patients at the Dana-Farber/Brigham and Women's Cancer Center.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and lethal cutaneous neuroendocrine carcinoma. Imaging is crucial for accurate staging, which remains a strong predictor of survival, as well as earlier detection of recurrence and progression, which are common despite aggressive management. There is no consensus on the role of initial and subsequent imaging for MCC. OBJECTIVE: We sought to evaluate the use of 2-fluoro-[(18)F]-deoxy-2-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in the management of MCC. METHODS: In all, 270 FDG-PET/CT studies were performed in 97 patients with pathology-proven MCC at the Dana-Farber/Brigham and Women's Cancer Center, Boston, Mass, from August 2003 to December 2010. RESULTS: FDG-PET/CT scans were obtained as part of the initial (61 scans in 61 patients) and subsequent (209 scans in 79 patients) treatment strategies. MCCs were FDG-avid with a mean maximum standardized uptake value of primary lesions of 6.5 (range 1.3-12.9) and a mean maximum standardized uptake value of regional and distant metastases of 7.2 (range 1.5-9.9). FDG-PET/CT upstaged 16% of patients who underwent baseline scans. FDG-PET/CT studies showed that bone and bone-marrow metastases were more common than previously reported, and were often undetected by CT. LIMITATIONS: Our study is limited by its retrospective design, and potential referral bias associated with a tertiary care center. CONCLUSIONS: FDG-PET/CT performed as part of the initial management strategy tended to upstage patients with more advanced disease. FDG-PET/CT performed as part of the subsequent treatment strategy identified metastatic disease, particularly in bone/bone marrow, which was not seen on CT. FDG-PET/CT imaging is a valuable staging and restaging tool in MCC management.