Confounding factors affecting the National Institutes of Health (NIH) chronic Graft-Versus-Host Disease Organ-Specific Score and global severity.

The 2005 NIH chronic GVHD (cGVHD) organ severity is based on the assessment of current status regardless of whether abnormalities are due to GVHD. The score assignment does not require knowledge of past manifestations, attribution or whether cGVHD is still active. The aim of this study is to describe confounding factors affecting organ scores in patients with cGVHD. The study included 189 consecutive cGVHD patients evaluated at our center in 2013. Providers completed the NIH 0-3 organ-specific scoring evaluation with two questions added for each organ to identify abnormalities that were (i) not attributed to cGVHD or (ii) attributed to cGVHD plus other causes. Abnormalities attributed to causes other than GVHD were recorded. Eighty (14%) abnormalities were not attributed to cGVHD in at least one organ, and 41 (7%) abnormalities were attributed to cGVHD plus other causes in at least one organ. A total of 436 (78%) abnormalities were attributed only to cGVHD. Abnormalities not attributed to cGVHD were observed most frequently in the lung, gastrointestinal tract and skin. Most common abnormalities included pre-transplant condition, sequelae from GVHD, deconditioning, infections and medications. Our results support the 2014 NIH consensus recommendation to consider attribution when scoring organ abnormalities.

Investigator feedback about the 2005 NIH diagnostic and scoring criteria for chronic GVHD.

The 2005 National Institutes of Health (NIH) consensus criteria for chronic GVHD have set standards for reporting. Many questions, however, have arisen regarding their implementation and utilization. To identify perceived areas of controversy, we conducted an international survey on diagnosis and scoring of chronic GVHD. Agreement was observed for 50-83% of the 72 questions in 7 topic areas. There was agreement on the need for modifying criteria in six situations: two or more distinctive manifestations should be enough to diagnose chronic GVHD; symptoms that are not due to chronic GVHD should be scored differently; active disease and fixed deficits should be distinguished; a minimum threshold body surface area of hidebound skin involvement should be required for a skin score of 3; asymptomatic oral lichenoid changes should be considered a score 1; and lung biopsy should be unnecessary to diagnose chronic GVHD in a patient with bronchiolitis obliterans as the only manifestation. The survey also identified 26 points of controversy. Whenever possible, studies should be conducted to confirm the appropriateness of any revisions. In cases where data are not available, clarification of the NIH recommendations by consensus is necessary. This survey should inform future research in the field and revisions of the current consensus criteria.

Characteristics of chronic GVHD after cord blood transplantation.

Most reports of chronic GVHD after cord blood transplantation (CBT) have utilized traditional diagnostic criteria. We used traditional criteria and National Institutes of Health (NIH) criteria prospectively to evaluate chronic GVHD in a cohort of 87 adult and pediatric recipients of single or double unrelated CBT for treatment of hematologic malignancies. Fifty-four patients developed traditionally defined chronic GVHD, for an estimated 2-year probability of 64%. Among 54 patients, 25 (46%) met the NIH criteria for persistent, recurrent or late acute GVHD at onset. Twenty-four (44%) had overlap chronic GVHD, including one who presented initially with late acute GVHD, and only seven (13%) had classic chronic GVHD, including one who also presented initially with late acute GVHD. Among patients who successfully discontinued all systemic immunosuppression (SI), the median time to discontinuation of corticosteroid treatment was 315 days (range 28-977), and the median time to discontinuation of all SI was 353 days (range 67-977). Chronic GVHD diagnosed by traditional criteria after CBT had a predominance of acute GVHD clinical features.

High prevalence of metabolic syndrome after allogeneic hematopoietic cell transplantation.

We conducted a cross-sectional study to estimate the prevalence of metabolic syndrome, a clustering of risk factors associated with cardiovascular disease, among 86 adults who had allogeneic hematopoietic-cell transplant (HCT) as compared with 258 age- and gender-matched US population controls selected from the 2005-2006 National Health and Nutrition Examination Survey database. The median age at study enrollment was 50 years (range, 21-71), and patients were at a median of 3 years (range, 1-21) from HCT. The prevalence of metabolic syndrome was 49% (95% confidence intervals (CI), 38-60%) among HCT recipients, a 2.2-fold (95% CI, 1.3-3.6, P=0.002) increase compared with controls. The prevalence rates of elevated blood pressure and hypertriglyceridemia were significantly higher among HCT recipients than among controls, but the prevalence rates of abdominal obesity, elevated blood glucose and low high-density lipoprotein cholesterol were not. HCT survivors with metabolic syndrome were more likely to have microalbuminuria (43 vs 10%) and elevated creatinine (31 vs 11%). No patient, donor or transplant characteristics were associated with the diagnosis of metabolic syndrome. We conclude that metabolic syndrome occurs frequently among allogeneic HCT survivors who are seen by transplant physicians. Approaches to screening, prevention and management of metabolic syndrome should be developed for HCT recipients.

Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia.

Allogeneic bone marrow transplantation (BMT) may offer the only chance of cure for children with acute myeloid leukemia (AML) in second complete remission (CR2) or with relapsed disease, but the outcome of these patients has not been clearly defined. We conducted a retrospective study of 58 children, median age 7.4 years (range 0.8-17.3), who received matched related or unrelated BMT at our institution for AML in CR2 (n = 12), in untreated first relapse (n = 11) or with refractory disease (n = 35), to identify risk factors associated with disease-free survival (DFS). Life threatening to fatal regimen-related toxicity was observed in 22% of patients. Estimates of DFS at 5 years (95% confidence interval) for patients in CR2, with untreated first relapse and refractory disease were 58% (27-80%), 36% (11-63%) and 9% (2-21%), respectively. Non-relapse mortality estimates were 0%, 27% (0-54%) and 17% (5-30%), and relapse estimates were 42% (14-70%), 36% (8-65%) and 74% (60-89%), respectively. Advanced disease phase and cytogenetic abnormalities at the time of transplantation were each associated with decreased DFS and increased relapse in multivariable regression models. Survival for children transplanted in CR2 or untreated first relapse is higher than that previously reported, but relapse remains the major cause of treatment failure regardless of disease stage.

Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience.

The purpose of this study was to evaluate the role of allogeneic bone marrow transplantation (BMT) in children with myelodysplastic syndrome (MDS). In total, 94 consecutive pediatric patients with MDS received an allogeneic BMT from 1976 to 2001 for refractory anemia (RA) (n=25), RA with ringed sideroblasts (RARS) (n=2), RA with excess blasts (RAEB) (n=20), RAEB in transformation (RAEB-T) (n=14), juvenile myelomonocytic leukemia (JMML) (n=32) or chronic myelomonocytic leukemia (CMML) (n=1). The estimated 3-year probabilities of survival, event-free survival (EFS), nonrelapse mortality and relapse were 50, 41, 28 and 29%, respectively. Patients with RA/RARS had an estimated 3-year survival of 74% compared to 68% in those with RAEB and 33% in patients with JMML/CMML. In multivariable analysis, patients with RAEB-T or JMML were 3.9 and 3.7 times more likely to die compared to those with RA/RARS and RAEB (P=0.005 and 0.004, respectively). Patients with RAEB-T were 5.5 times more likely to relapse (P=0.01). The median follow-up among the 43 surviving patients is 10 years (range 1-25). We conclude that allogeneic BMT for children with MDS is well tolerated and can be curative.

Baseline conditions and subtractive logic in neuroimaging.

Discrepancies in the patterns of cortical activation across studies may be attributable, in part, to differences in baseline tasks, and hence, reflect the limits of the subtractive logic underlying much of neuroimaging. To assess the extent of these effects, three of the most commonly used baseline conditions (rest, tone monitoring, and passive listening) were compared using phoneme discrimination as the experimental task. Eight participants were studied in a fMRI study with a 4.1 T system. The three baseline conditions systematically affected the amount of activation observed in the identical phoneme task with major affects in Broca's area, the left posterior superior temporal gyrus, and the left and right inferior parietal regions. Two central findings were: 1) a differential effect of baseline within each region, with the rest baseline condition producing the greatest amount of activation and the passive listening condition producing the least, and 2) systematic baseline task activation in the inferior parietal regions. These results emphasize the relativity of activation patterns observed in functional neuroimaging, and the necessity to specify the baseline processes in context to the experimental task processes.

Mental rotation of objects retrieved from memory: a functional MRI study of spatial processing.

This functional MRI study examined how people mentally rotate a 3-dimensional object (an alarm clock) that is retrieved from memory and rotated according to a sequence of auditory instructions. We manipulated the geometric properties of the rotation, such as having successive rotation steps around a single axis versus alternating between 2 axes. The latter condition produced much more activation in several areas. Also, the activation in several areas increased with the number of rotation steps. During successive rotations around a single axis, the activation was similar for rotations in the picture plane and rotations in depth. The parietal (but not extrastriate) activation was similar to mental rotation of a visually presented object. The findings indicate that a large-scale cortical network computes different types of spatial information by dynamically drawing on each of its components to a differential, situation-specific degree.

Interdependence of nonoverlapping cortical systems in dual cognitive tasks.

One of the classic questions about human thinking concerns the limited ability to perform two cognitive tasks concurrently, such as a novice driver's difficulty in simultaneously driving and conversing. Limitations on the concurrent performance of two unrelated tasks challenge the tacitly assumed independence of two brain systems that seemingly have little overlap. The current study used fMRI (functional magnetic resonance imaging) to measure cortical activation during the concurrent performance of two high-level cognitive tasks that involve different sensory modalities and activate largely nonoverlapping areas of sensory and association cortex. One task was auditory sentence comprehension, and the other was the mental rotation of visually depicted 3-D objects. If the neural systems underlying the two tasks functioned independently, then in the dual task the brain activation in the main areas supporting the cognitive processing should be approximately the conjunction of the activation for each of the two tasks performed alone. We found instead that in the dual task, the activation in association areas (primarily temporal and parietal areas of cortex) was substantially less than the sum of the activation when the two tasks were performed alone, suggesting some mutual constraint among association areas. A similar result was obtained for sensory areas as well.

fMRI investigation of sentence comprehension by eye and by ear: modality fingerprints on cognitive processes.

The neural substrate underlying reading vs. listening comprehension of sentences was compared using fMRI. One way in which this issue was addressed was by comparing the patterns of activation particularly in cortical association areas that classically are implicated in language processing. The precise locations of the activation differed between the two modalities. In the left inferior frontal gyrus (Broca's area), the activation associated with listening was more anterior and inferior than the activation associated with reading, suggesting more semantic processing during listening comprehension. In the left posterior superior and middle temporal region (roughly, Wernicke's area), the activation for listening was closer to primary auditory cortex (more anterior and somewhat more lateral) than the activation for reading. In several regions, the activation was much more left lateralized for reading than for listening. In addition to differences in the location of the activation, there were also differences in the total amount of activation in the two modalities in several regions. A second way in which the modality comparison was addressed was by examining how the neural systems responded to comprehension workload in the two modalities by systematically varying the structural complexity of the sentences to be processed. Here, the distribution of the workload increase associated with the processing of additional structural complexity was very similar across the two input modalities. The results suggest a number of subtle differences in the cognitive processing underlying listening vs. reading comprehension.

The neural bases of sentence comprehension: a fMRI examination of syntactic and lexical processing.

One of the challenges to functional neuroimaging is to understand how the component processes of reading comprehension emerge from the neural activity in a network of brain regions. In this study, functional magnetic resonance imaging (fMRI) was used to examine lexical and syntactic processing in reading comprehension by independently manipulating the cognitive demand on each of the two processes of interest. After establishing a consistency with earlier research showing the involvement of the left perisylvian language areas in both lexical access and syntactic processing, the study produced new findings that are surprising in two ways: (i) the lexical and syntactic factors each impact not just individual areas, but they affect the activation in a network of left-hemisphere areas, suggesting that changing the computational load imposed by a given process produces a cascade of effects in a number of collaborating areas; and (ii) the lexical and syntactic factors usually interact in determining the amount of activation in each affected area, suggesting that comprehension processes that operate on different levels of language may nevertheless draw on a shared infrastructure of cortical resources. The results suggest that many processes in sentence comprehension involve multiple brain regions, and that many brain regions contribute to more than one comprehension process. The implication is that the language network consists of brain areas which each have multiple relative specializations and which engage in extensive interarea collaborations.

Non-Fc receptor-binding humanized anti-CD3 antibodies induce apoptosis of activated human T cells.

Human trials in organ allografts have demonstrated that murine anti-CD3 mAbs are immunosuppressive. By mimicking Ag, anti-CD3 can produce T cell activation, anergy, or death. Activation of resting T cells in vivo results in dose-limiting cytokine release and is caused by Ab-mediated cross-linking of T cells and Fcgamma receptor (FcR)-bearing cells. With the goal of minimizing cytokine-induced toxicity, anti-CD3 have been engineered to lower Fc binding avidity. Preclinical murine studies have indicated that non-FcR-binding anti-CD3 can induce apoptosis of Ag-activated T cells. Since induction of T cell apoptosis may be an important mechanism of immunosuppression by anti-CD3, we tested whether Fc mutations affect the ability of anti-human CD3 to induce apoptosis of activated T cells. We compared wild-type murine anti-CD3, M291, and OKT3 and their humanized, FcR- and non-FcR-binding structural variants in quantitative assays of T cell apoptosis. Non-FcR-binding variants produced more sustainable phosphorylation of extracellular signal-regulated kinase-2, greater release of IFN-gamma, and more effectively caused activation-dependent T cell apoptosis. Non-FcR-binding variants dissociated more quickly from the T cell surface and caused less internalization of the TCR, which then remained available in greater abundance on the cell surface for signaling. Cross-linking of non-FcR-binding variants by antiglobulin enhanced TCR internalization and minimized induction of T cell apoptosis. We conclude that non-FcR-binding, humanized anti-CD3 have improved ability to induce apoptosis of activated T cells, presumably by allowing durable expression of the TCR and sustained signaling.

The neural bases of strategy and skill in sentence-picture verification.

This experiment used functional Magnetic Resonance Imaging to examine the relation between individual differences in cognitive skill and the amount of cortical activation engendered by two strategies (linguistic vs. visual-spatial) in a sentence-picture verification task. The verbal strategy produced more activation in language-related cortical regions (e.g., Broca's area), whereas the visual-spatial strategy produced more activation in regions that have been implicated in visual-spatial reasoning (e.g., parietal cortex). These relations were also modulated by individual differences in cognitive skill: Individuals with better verbal skills (as measured by the reading span test) had less activation in Broca's area when they used the verbal strategy. Similarly, individuals with better visual-spatial skills (as measured by the Vandenberg, 1971, mental rotation test) had less activation in the left parietal cortex when they used the visual-spatial strategy. These results indicate that language and visual-spatial processing are supported by partially separable networks of cortical regions and suggests one basis for strategy selection: the minimization of cognitive workload.

Collaborative activity between parietal and dorso-lateral prefrontal cortex in dynamic spatial working memory revealed by fMRI.

Functional MRI was used to determine how the constituents of the cortical network subserving dynamic spatial working memory respond to two types of increases in task complexity. Participants mentally maintained the most recent location of either one or three objects as the three objects moved discretely in either a two- or three-dimensional array. Cortical activation in the dorsolateral prefrontal (DLPFC) and the parietal cortex increased as a function of the number of object locations to be maintained and the dimensionality of the display. An analysis of the response characteristics of the individual voxels showed that a large proportion were activated only when both the variables imposed the higher level of demand. A smaller proportion were activated specifically in response to increases in task demand associated with each of the independent variables. A second experiment revealed the same effect of dimensionality in the parietal cortex when the movement of objects was signaled auditorily rather than visually, indicating that the additional representational demands induced by 3-D space are independent of input modality. The comodulation of activation in the prefrontal and parietal areas by the amount of computational demand suggests that the collaboration between areas is a basic feature underlying much of the functionality of spatial working memory.

Working memory and executive function: evidence from neuroimaging.

Traditional theories of working memory and executive function, when mapped in straightforward ways into the neural domain, yield predictions that are only partly supported by the recent neuroimaging studies. Neuroimaging studies suggest that some constituent functions, such as maintaining information in active form and manipulating it, are not discretely localized in prefrontal regions. Some hypothesized executive processes, such as goal management, have effects in several cortical regions, including posterior regions. Such results suggest a more dynamic and distributed view of the cortical organization of working memory and executive functions.

Computational modeling of high-level cognition and brain function.

This article describes a computational modeling architecture, 4CAPS, which is consistent with key properties of cortical function and makes good contact with functional neuroimaging results. Like earlier cognitive models such as SOAR, ACT-R, 3CAPS, and EPIC, the proposed cognitive model is implemented in a computer simulation that predicts observable variables such as human response times and error patterns. In addition, the proposed 4CAPS model accounts for the functional decomposition of the cognitive system and predicts fMRI activation levels and their localization within specific cortical regions, by incorporating key properties of cortical function into the design of the modeling system.

Time course of fMRI-activation in language and spatial networks during sentence comprehension.

Functional neuroimaging previously has been considered to provide inadequate temporal resolution to study changes of brain states as a function of cognitive computations; however, we have obtained evidence of differential amounts of brain activity related to high-level cognition (sentence processing) within 1.5 s of stimulus onset. The study used an event-related paradigm with high-speed echoplanar functional magnetic resonance imaging (fMRI) to trace the time course of the brain activation in the temporal and parietal regions as participants comprehended single sentences describing a spatial configuration. Within the first set of images, on average 1 s from when the participant begins to read a sentence, there was significant activation in a key cortical area involved in language comprehension (the left posterior temporal gyrus) and visuospatial processing (the left and right parietal regions). In all three areas, the amount of activation during sentence comprehension was higher for negative sentences than for their affirmative counterparts, which are linguistically less complex. The effect of negation indicates that the activation in these areas is modulated by the difficulty of the linguistic processing. These results suggest a relatively rapid coactivation in both linguistic and spatial cortical regions to support the integration of information from multiple processing streams.

Modeling the mind: very-high-field functional magnetic resonance imaging activation during cognition.

This article describes how fMRI can be used to examine the large-scale networks of cortical areas that subserve high-level cognition, such as sentence comprehension and visual thinking. The findings from a number of studies show that the qualitative and quantitative nature of the cognitive processes determines which cortical areas are activated (the network constituency) and the degree to which each network member is activated. For example, during sentence comprehension, activation in the left posterior temporal region and the inferior frontal gyrus, as well as their right hemisphere homologs, increases as a function of the linguistic complexity of the sentence. Such findings indicate that cognition emerges from the collaboration among the multiple cortical areas that compose the large-scale networks, rather than from the aggregate of autonomously functioning modules. The patterns of activation also show systematic shifts in the activity of a network during the spontaneous recovery of function by stroke patients, demonstrating cortical plasticity in adults. Finally, the article describes some simulation models that relate the information processing activity of a computational system to its resource consumption. This construct enables a mapping from the functional properties of the cognitive systems to the biological substrate that is reflected in fMRI.