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Purpose: Tumor Treating Fields (TTFields) are alternating electric fields at 150 to 200 kHz that exert their anticancer effect by destroying tumor cells when they undergo mitosis. TTFields are currently being tested in patients with non-small cell lung cancer with advanced disease (NCT02973789) and those with brain metastasis (NCT02831959). However, the distribution of these fields within the thoracic compartment remains poorly understood. Methods and Materials: Using positron emission tomography-computed tomography image data sets obtained from a series of 4 patients with poorly differentiated adenocarcinoma, the positron emission tomography-positive gross tumor volume (GTV), clinical target volume (CTV), and structures from the chest surface to the intrathoracic compartment were manually segmented, followed by 3-dimensional physics simulation and computational modeling using finite element analysis. Electric field-volume histograms, specific absorption rate-volume histograms, and current density-volume histograms were generated to produce plan quality metrics (95%, 50%, and 5% volumes) for quantitative comparisons between models. Results: Unlike other organs in the body, the lungs have a large volume of air, which has a very low electric conductivity value. Our comprehensive and individualized models demonstrated heterogeneity in electric field penetration to the GTVs with differences upwards of 200% and yielded a diverse range of TTFields distributions. Target contact with the conductive pleura intensified TTFields at the GTV and CTV. Furthermore, in a sensitivity analysis, varying electric conductivity and mass density of the CTV altered TTFields coverage to both the CTV and GTV. Conclusions: Personalized modeling is important to accurately estimate target coverage at the tumor volumes and surrounding normal tissue structures in the thorax.

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Purpose: Cerebral edema is an important component of brain metastasis, and its presence may alter the distribution of tumor-treating fields (TTFields). We therefore performed a computational study to model the extent of this alteration according to various edema conditions associated with the metastasis. Methods and Materials: Postacquisition magnetic resonance imaging data sets were obtained from 2 patients with solitary brain metastases from non-small cell lung cancer. After delineation of various anatomies, a 3-dimensional finite element mesh model was generated and then solved for the distribution of applied electric fields, rate of energy deposition, and current density at the gross tumor volume (GTV), edema, and other cranial structures. Electric field-volume histograms, specific absorption rate-volume histograms, and current density-volume histograms were generated, by which plan quality metrics were derived from and used to evaluate relative differences in field coverage between models under various conditions. Results: Changes in the conductivity of cerebral edema altered the electric fields, rate of energy deposition, and current density at the GTV region. At the cerebral edema region, increasing electric conductivity of the edema only decreased the electric fields and rate of energy deposition while the current density increased. The ratio of edema-to-tumor is also important because the plan quality metrics increased linearly when the edema-to-GTV ratio decreased, and increased vice versa. Furthermore, a conductive necrotic core additionally altered the distribution of TTFields according to the plan quality metrics. Conclusions: Our modeling study demonstrated that cerebral edema alters the distribution of applied TTFields in patients. Personalized treatment planning will need to take into account the modulating effects of cerebral edema on TTFields as well as additional effects from a necrotic core inside the GTV.

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PURPOSE: Since the inception of tumor treating fields (TTFields) therapy as a Food and Drug Administration-approved treatment with known clinical efficacy against recurrent and newly diagnosed glioblastoma, various in silico modeling studies have been performed in an effort to better understand the distribution of applied electric fields throughout the human body for various malignancies or metastases. METHODS AND MATERIALS: Postacquisition attenuation-corrected positron emission tomography-computed tomography image data sets from 2 patients with ovarian carcinoma were used to fully segment various intrapelvic and intra-abdominal gross anatomic structures. A 3-dimensional finite element mesh model was generated and then solved for the distribution of applied electric fields, rate of energy deposition, and current density at the clinical target volumes (CTVs) and other intrapelvic and intra-abdominal structures. Electric field-volume histograms, specific absorption rate-volume histograms, and current density-volume histograms were generated, by which plan quality metrics were derived from and used to evaluate relative differences in field coverage between models under various conditions. RESULTS: TTFields therapy distribution throughout the pelvis and abdomen was largely heterogeneous, where specifically the field intensity at the CTV was heavily influenced by surrounding anatomic structures as well as its shape and location. The electric conductivity of the CTV had a direct effect on the field strength within itself, as did the position of the arrays on the surface of the pelvis and/or abdomen. CONCLUSION: The combined use of electric field-volume histograms, specific absorption rate-volume histograms, current density-volume histograms, and plan quality metrics enables a personalized method to dosimetrically evaluate patients receiving TTFields therapy for ovarian carcinoma when certain patient- and tumor-specific factors are integrated with the treatment plan.

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INTRODUCTION: Tumor Treating Fields (TTFields) are alternating electric fields at 200 kHz that disrupt tumor cells as they undergo mitosis. Patient survival benefit has been demonstrated in randomized clinical trials but much of the data are available only for supratentorial glioblastomas. We investigated a series of alternative array configurations for the posterior fossa to determine the electric field coverage of a cerebellar glioblastoma. METHODS: Semi-automated segmentation of neuro-anatomical structures was performed while the gross tumor volume (GTV) was manually delineated. A three-dimensional finite-element mesh was generated and then solved for field distribution. RESULTS: Compared to the supratentorial array configuration, the alternative array configurations consist of posterior displacement the 2 lateral opposing arrays and inferior displacement of the posteroanterior array, resulting in an average increase of 46.6% electric field coverage of the GTV as measured by the area under the curve of the electric field-volume histogram (EAUC). Hotspots, or regions of interest with the highest 5% of TTFields intensity (E5%), had an average increase of 95.6%. Of the 6 posterior fossa configurations modeled, the PAHorizontal arrangement provided the greatest field coverage at the GTV when the posteroanterior array was placed centrally along the patient's posterior neck and horizontally parallel, along the longer axis, to the coronal plane of the patient's head. Varying the arrays also produced hotspots proportional to TTFields coverage. CONCLUSIONS: Our finite element modeling showed that the alternative array configurations offer an improved TTFields coverage to the cerebellar tumor compared to the conventional supratentorial configuration.

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OBJECTIVE: To use functional magnetic resonance imaging (fMRI) in craniopharyngioma (CP) patients to examine the hypothesis that hypothalamic damage due to CP and its treatment results in enhanced perception of food reward and/or impaired central satiety processing. METHODS: Pre- and post-meal responses to visual food cues in brain regions of interest (ROI; bilateral nucleus accumbens, bilateral insula, and medial orbitofrontal cortex) were assessed in 4 CP patients versus 4 age- and weight-matched controls. Stimuli consisted of images of high- ('fattening') and low-calorie ('non-fattening') foods in blocks, alternating with non-food object blocks. After the first fMRI scan, subjects drank a high-calorie test meal to suppress appetite, then completed a second fMRI scan. Within each ROI, we calculated mean z-scores for activation by fattening as compared to non-fattening food images. RESULTS: Following the test meal, controls showed suppression of activation by food cues while CP patients showed trends towards higher activation. CONCLUSION: These data, albeit in a small group of patients, support our hypothesis that perception of food cues may be altered in hypothalamic obesity (HO), especially after eating, i.e. in the satiated state. The fMRI approach is encouraging for performing future mechanistic studies of the brain response to food cues and satiety in patients with hypothalamic or other forms of childhood obesity.

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This study examines whether midlife change in episodic memory predicts hippocampal volume in old age. From the Seattle Longitudinal Study we retrospectively identified 84 healthy, cognitively normal individuals, age 52 to 87, whose episodic memory had reliably declined (n = 33), improved (n = 28) or remained stable (n = 23) over a 14-year period in midlife (age 43-63). Midlife memory improvement was associated with 13% larger hippocampal volume (p < 0.01) in old age (age 66-87), compared with old age individuals whose midlife episodic memory had either declined or remained stable during midlife. Midlife memory change did not predict total hippocampal volume for those currently in late middle age (age 52-65). The pattern of findings was not modified by gender, apolipoprotein ε4 status, education or current memory performance. Change in midlife memory scores over 14 years, but not any single assessment, predicted hippocampal volumes in old age, emphasizing the importance of longitudinal data in examining brain-cognition relationships. These findings suggest that improvement in memory in midlife is associated with sparing of hippocampal volume in later life.

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Serial diffusion tensor imaging scans were collected at baseline and 1 year follow-up to investigate the neurodegenerative profile of white matter (WM) in seven individuals with the Huntington's Disease (HD) gene mutation and seven control subjects matched on age and gender. In the HD subjects, but not controls, a significant reduction of fractional anisotropy (FA), a measure of WM integrity, between baseline and followup was evident throughout the brain. In addition, a DTI scalar associated with the stability of axons, axial diffusivity, showed significant longitudinal decreases from year 1 to year 2 in HD subjects, declines that overlapped to greater degree with FA discrepancies than longitudinal increases in radial diffusivity, a DTI variable sensitive to demylinization. These preliminary results provide the first longitudinal DTI evidence of WM degeneration in HD and support the notion that FA abnormalities in HD may be a result of axonal injury or withdrawal. These results suggest that longitudinal FA changes may serve as a neuropathological biomarker in HD.

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Opposing theories of striatal hyper- and hypodopaminergic functioning have been suggested in the pathophysiology of externalizing behavior disorders. To test these competing theories, the authors used functional MRI to evaluate neural activity during a simple reward task in 12- to 16-year-old boys with attention-deficit/hyperactivity disorder and/or conduct disorder (n = 19) and in controls with no psychiatric condition (n = 11). The task proceeded in blocks during which participants received either (a) monetary incentives for correct responses or (b) no rewards for correct responses. Controls exhibited striatal activation only during reward, shifting to anterior cingulate activation during nonreward. In contrast, externalizing adolescents exhibited striatal activation during both reward and nonreward. Externalizing psychopathology appears to be characterized by deficits in processing the omission of predicted reward, which may render behaviors that are acquired through environmental contingencies difficult to extinguish when those contingencies change.

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Amygdala dysfunction has been proposed as a critical contributor to social impairment in autism spectrum disorders (ASD). The current study investigated biochemical abnormalities in the amygdala in 20 high functioning adults with autistic disorder or Asperger's disorder and 19 typically developing adults matched on age and IQ. Magnetic resonance spectroscopy was used to measure N-acetyl aspartate (NAA), creatine/phosphocreatine (Cre), choline/choline containing compounds (Cho), and Myoinositol (mI) in the right and left amygdala. There were no significant between-group differences in any of the metabolites. However, NAA and Cre levels were significantly correlated to clinical ratings on the Autism Diagnostic Interview-Revised. This suggests that altered metabolite levels in the amygdala may be associated with a more severe early developmental course in ASD.

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