A Common Cell of Origin for Inflammatory Myofibroblastic Tumor and Lung Adenocarcinoma with ALK rearrangement.

This case signifies the importance of obtaining tumor comprehensive genomic profiling (CGP) as it has utility in cancer type classification and helping in diagnosing recurrence/metastasis or separately occurring primary tumors. CGP can also help guiding treatment as in this case separately occurring Inflammatory Myofibroblastic Tumor had ALK fusion and responded to crizotinib. As treatment progresses, new biopsies should be obtained and CGP used to evaluate for appearance of any new genomic alterations, in order to guide further therapy.

Safety of image guided research biopsies in patients with thoracic malignancies.

OBJECTIVE: A common opportunity to collect research samples is during image-guided percutaneous core needle biopsies (CNBs) performed when clinically indicated or for assessing clinical trial eligibility. The relative safety of extra CNBs collected for research is undefined. MATERIALS AND METHODS: Patients who underwent CNB for research purposes only [RO], as clinically indicated [CI], or as part of a clinical trial [CT] were identified. 30-day post-procedure adverse events (AEs) among the cohorts were examined and compared to the 2020 Society of Interventional Radiology QI guidelines. RESULTS: 236 patients with thoracic cancers (90 % NSCLC, 5 % SCLC, 4 % mesothelioma, and 1 % thymic) had 292 CNBs (63 RO, 229 CI + CT). AEs occurred in 13 % of both the RO and CI + CT groups. Compared to the CI + CT group, the RO group did not have a higher pneumothorax incidence (RO: 5/29 [17 %], CI + CT: 18/114 [16 %], p = 0.79); both were below the suggested QI threshold of 45 % for pneumothorax. There was a negative association between number of cores obtained and risk of AE (AE vs no AE mean cores = 3.5 vs 4.8). After adjusting for the number of cores and smoking history, RO vs CI + CT lung biopsies had a higher risk of AEs (adjusted relative risk [aRR] = 2.44, 1.08-5.55, p = 0.03 vs non-lung aRR = 0.86, 0.10-7.09, p = 0.89). CONCLUSION: CNBs performed for research purposes do not have a significantly increased risk of AEs when compared to those performed for clinical trials and/or when clinically indicated. However, AEs were most frequent in lung biopsies. When performing research biopsies, a target other than lung may be preferred when clinically appropriate.

Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition.

Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits.

Widespread white matter and conduction defects in PSEN1-related spastic paraparesis.

The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different, and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white-matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutation's effect on amyloid precursor protein processing and amyloid deposition.

Abnormal activity-dependent brain lactate and glutamate+glutamine responses in panic disorder.

BACKGROUND: Prior evidence suggests panic disorder (PD) is characterized by neurometabolic abnormalities, including increased brain lactate responses to neural activation. Increased lactate responses could reflect a general upregulation of metabolic responses to neural activation. However, prior studies in PD have not measured activity-dependent changes in brain metabolites other than lactate. Here we examine activity-dependent changes in both lactate and glutamate plus glutamine (glx) in PD. METHODS: Twenty-one PD patients (13 remitted, 8 symptomatic) and 12 healthy volunteers were studied. A single-voxel, J-difference, magnetic resonance spectroscopy editing sequence was used to measure lactate and glx changes in visual cortex induced by visual stimulation. RESULTS: The PD patients had significantly greater activity-dependent increases in brain lactate than healthy volunteers. The differences were significant for both remitted and symptomatic PD patients, who did not differ from each other. Activity-dependent changes in glx were significantly smaller in PD patients than in healthy volunteers. The temporal correlation between lactate and glx changes was significantly stronger in control subjects than in PD patients. CONCLUSIONS: The novel demonstration that glx responses are diminished and temporally decoupled from lactate responses in PD contradicts the model of a general upregulation of activity-dependent brain metabolic responses in PD. The increase in activity-dependent brain lactate accumulation appears to be a trait feature of PD. Given the close relationship between lactate and pH in the brain, the findings are consistent with a model of brain metabolic and pH dysregulation associated with altered function of acid-sensitive fear circuits contributing to trait vulnerability in PD.

A match made by modafinil: probability matching in choice decisions and spatial attention.

When predicting where a target or reward will be, participants tend to choose each location commensurate with the true underlying probability (i.e., probability match). The strategy of probability matching involves independent sampling of high and low probability locations on separate trials. In contrast, models of probabilistic spatial attention hypothesize that on any given trial attention will either be weighted toward the high probability location or be distributed equally across all locations. Thus, the strategies of probabilistic sampling by choice decisions and spatial attention appear to differ with regard to low-probability events. This distinction is somewhat surprising because similar brain mechanisms (e.g., pFC-mediated cognitive control) are thought to be important in both functions. Thus, the goal of the current study was to examine the relationship between choice decisions and attentional selection within single trials to test for any strategic differences, then to determine whether that relationship is malleable to manipulations of catecholamine-modulated cognitive control with the drug modafinil. Our results demonstrate that spatial attention and choice decisions followed different strategies of probabilistic information selection on placebo, but that modafinil brought the pattern of spatial attention into alignment with that of predictive choices. Modafinil also produced earlier learning of the probability distribution. Together, these results suggest that enhancing cognitive control mechanisms (e.g., through prefrontal cortical function) leads spatial attention to follow choice decisions in selecting information according to rule-based expectations.

Excessive contralateral motor overflow in schizophrenia measured by fMRI.

Schizophrenia is characterized by significant problems in control of behavior; however, the disturbances in neural systems that control movement remain poorly characterized. We used functional magnetic resonance imaging (fMRI) to evaluate the origin of motor overflow in schizophrenia. Twenty-seven clinically stable medicated outpatients with Diagnostic and Statistical Manual, 4th edition, text revision (DSM-IV-TR)-defined schizophrenia (SZ), and 18 healthy control (HC) subjects, all right-handed, performed a dominant-handed, single-choice visual sensorimotor reaction time paradigm during fMRI. Voxel-wise analyses were conducted within sensorimotor cortical and striatal regions on general linear model (GLM)-derived measures of blood oxygen level-dependent (BOLD) signal change. The SZ group was not different from the HC group in reaction time, activation in somatosensory or motor cortices ipsilateral to the active (intended) descending corticospinal tract, nor visual cortex. However, in the right hemisphere (contralateral to the active M1), the SZ group showed significantly higher activation in primary motor cortex and adjacent premotor and somatosensory cortices (right Brodmann areas (BA) 1 through 4, and 6), and significantly lower activation in bilateral basal ganglia. Right BA 4 activation was strongly related to disorganization and poverty symptoms (and unrelated to medications) in the patient group. This study provides evidence in SZ of excessive neural activity in motor cortex contralateral to the intended primary motor cortex, which may form the basis for altered motor laterality and motor overflow previously observed, and disorganized behavior. This pathological motor overflow may be partly due to altered modulation of intended movement within the basal ganglia and premotor cortex.

An interactive teaching device simulating intussusception reduction.

Intussusception is relatively uncommon, occurring in 0.5 to 2.3 cases per 1,000 live births in the USA. Radiology residents, therefore, have few opportunities to participate in intussusception reduction during training, and practicing radiologists encounter it infrequently. Training is essential, as successful reduction avoids surgery. The judgment involved in reducing an intussusception is best gained with experience. We developed a training device that simulates fluoroscopic intussusception reduction with air. The device consists of a doll that contains a cylinder with similar stress and strain characteristics to the human colon. The trainee pumps air into the cylinder through a rectal tube using a standard hand-held air reduction pump. A sensor measures the pressure within the chamber and transmits readings to a computer, which displays images from actual intussusception reductions based on the pressure maintained within the device. A random component in the software gives the user a new experience each time and models uncertainties in the actual reduction process, including perforation. This intussusception reduction simulator can enhance resident education, giving residents the opportunity to practice this technique before employing it on a real patient. The simulator can also help practicing radiologists become more comfortable with intussusception air reduction.