Severity-Dependent Interhemispheric White Matter Connectivity Predicts Poststroke Neglect Recovery.

Left-sided spatial neglect is a very common and challenging issue after right-hemispheric stroke, which strongly and negatively affects daily living behavior and recovery of stroke survivors. The mechanisms underlying recovery of spatial neglect remain controversial, particularly regarding the involvement of the intact, contralesional hemisphere, with potential contributions ranging from maladaptive to compensatory. In the present prospective, observational study, we assessed neglect severity in 54 right-hemispheric stroke patients (32 male; 22 female) at admission to and discharge from inpatient neurorehabilitation. We demonstrate that the interaction of initial neglect severity and spared white matter (dis)connectivity resulting from individual lesions (as assessed by diffusion tensor imaging, DTI) explains a significant portion of the variability of poststroke neglect recovery. In mildly impaired patients, spared structural connectivity within the lesioned hemisphere is sufficient to attain good recovery. Conversely, in patients with severe impairment, successful recovery critically depends on structural connectivity within the intact hemisphere and between hemispheres. These distinct patterns, mediated by their respective white matter connections, may help to reconcile the dichotomous perspectives regarding the role of the contralesional hemisphere as exclusively compensatory or not. Instead, they suggest a unified viewpoint wherein the contralesional hemisphere can - but must not necessarily - assume a compensatory role. This would depend on initial impairment severity and on the available, spared structural connectivity. In the future, our findings could serve as a prognostic biomarker for neglect recovery and guide patient-tailored therapeutic approaches.

Joint impact on attention, alertness and inhibition of lesions at a frontal white matter crossroad.

In everyday life, information from different cognitive domains-such as visuospatial attention, alertness and inhibition-needs to be integrated between different brain regions. Early models suggested that completely segregated brain networks control these three cognitive domains. However, more recent accounts, mainly based on neuroimaging data in healthy participants, indicate that different tasks lead to specific patterns of activation within the same, higher-order and 'multiple-demand' network. If so, then a lesion to critical substrates of this common network should determine a concomitant impairment in all three cognitive domains. The aim of the present study was to critically investigate this hypothesis, i.e. to identify focal stroke lesions within the network that can concomitantly affect visuospatial attention, alertness and inhibition. We studied an unselected sample of 60 first-ever right-hemispheric, subacute stroke patients using a data-driven, bottom-up approach. Patients performed 12 standardized neuropsychological and oculomotor tests, four per cognitive domain. A principal component analysis revealed a strong relationship between all three cognitive domains: 10 of 12 tests loaded on a first, common component. Analysis of the neuroanatomical lesion correlates using different approaches (i.e. voxel-based and tractwise lesion-symptom mapping, disconnectome maps) provided convergent evidence on the association between severe impairment of this common component and lesions at the intersection of superior longitudinal fasciculus II and III, frontal aslant tract and, to a lesser extent, the putamen and inferior fronto-occipital fasciculus. Moreover, patients with a lesion involving this region were significantly more impaired in daily living cognition, which provides an ecological validation of our results. A probabilistic functional atlas of the multiple-demand network was performed to confirm the potential relationship between patients' lesion substrates and observed cognitive impairments as a function of the multiple-demand network connectivity disruption. These findings show, for the first time, that a lesion to a specific white matter crossroad can determine a concurrent breakdown in all three considered cognitive domains. Our results support the multiple-demand network model, proposing that different cognitive operations depend on specific collaborators and their interaction, within the same underlying neural network. Our findings also extend this hypothesis by showing (i) the contribution of superior longitudinal fasciculus and frontal aslant tract to the multiple-demand network; and (ii) a critical neuroanatomical intersection, crossed by a vast amount of long-range white matter tracts, many of which interconnect cortical areas of the multiple-demand network. The vulnerability of this crossroad to stroke has specific cognitive and clinical consequences; this has the potential to influence future rehabilitative approaches.

The cost of attentional reorienting on conscious visual perception: an MEG study.

How do attentional networks influence conscious perception? To answer this question, we used magnetoencephalography in human participants and assessed the effects of spatially nonpredictive or predictive supra-threshold peripheral cues on the conscious perception of near-threshold Gabors. Three main results emerged. (i) As compared with invalid cues, both nonpredictive and predictive valid cues increased conscious detection. Yet, only predictive cues shifted the response criterion toward a more liberal decision (i.e. willingness to report the presence of a target under conditions of greater perceptual uncertainty) and affected target contrast leading to 50% detections. (ii) Conscious perception following valid predictive cues was associated to enhanced activity in frontoparietal networks. These responses were lateralized to the left hemisphere during attentional orienting and to the right hemisphere during target processing. The involvement of frontoparietal networks occurred earlier in valid than in invalid trials, a possible neural marker of the cost of re-orienting attention. (iii) When detected targets were preceded by invalid predictive cues, and thus reorienting to the target was required, neural responses occurred in left hemisphere temporo-occipital regions during attentional orienting, and in right hemisphere anterior insular and temporo-occipital regions during target processing. These results confirm and specify the role of frontoparietal networks in modulating conscious processing and detail how invalid orienting of spatial attention disrupts conscious processing.

Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults.

BACKGROUND: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment. METHODS: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment. RESULTS: Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%). CONCLUSIONS: A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).

Discriminative value of different combinations of tests to detect unilateral neglect in patients with right hemisphere damage.

BACKGROUND AND PURPOSE: This study was undertaken to assess the most sensitive combination of tests to detect peripersonal unilateral neglect (UN) after stroke. METHODS: The present study is a secondary analysis of a previously reported multicentric study of 203 individuals with right hemisphere damage (RHD), mainly subacute stroke, 11 weeks postonset on average, and 307 healthy controls. A battery of seven tests, providing 19 age- and education-adjusted z-scores, were given: the bells test, line bisection, figure copying, clock drawing, overlapping figures test, and reading and writing. Statistical analyses used a logistic regression and a receiver operating characteristic (ROC) curve after adjustment on demographic variables. RESULTS: A combination of four z-scores based on the following three tests provided good discrimination of patients with RHD from matched healthy controls: the starting point and the difference between the number of omissions on left and right sides from the bells test, rightward deviation in bisection of long lines (20 cm), and left-sided omissions in a reading task. The area under the ROC curve was 0.865 (95% confidence interval = 0.83-0.901), with sensitivity = 0.68, specificity = 0.95, accuracy = 0.85, positive predictive value = 0.90, and negative predictive value = 0.82. CONCLUSIONS: The most sensitive and parsimonious combination of tests to detect UN after stroke relies on four scores from three simple tests (bells test, line bisection, and reading). Future study is warranted to assess its ability to account for the functional difficulties of UN in daily life in the patient's actual environment.

Attentional distraction affects maintenance of information in visual sensory memory.

Classical theoretical models suggest that visual short-term memory can be divided in two main memory systems: sensory memory, a short-lasting but high-capacity memory storage and working memory, a long-lasting but low-capacity memory store. Whilst, previous research has systematically shown a strong interplay between attentional mechanisms and working memory, less clear is the role of attention in sensory memory. In the present study we approach this issue by asking whether withdrawing attentional resources by a dual task (Experiment 1) or by presenting task irrelevant information during memory maintenance (Experiment 2 and 3) similarly or differently affect sensory and working memory. Overall, results showed that sensory memory content was undermined not only by a simultaneous high-demanding cognitive task but even when purely task-irrelevant and non-masking visual distractors were presented during maintenance. Our data provide support against theories that consider sensory memories as a case of visual awareness free of attention.

Color Naming and Categorization Depend on Distinct Functional Brain Networks.

Naming a color can be understood as an act of categorization, that is, identifying it as a member of a category of colors that are referred to by the same name. But are naming and categorization equivalent cognitive processes and consequently rely on same neural substrates? Here, we used task and resting-state functional magnetic resonance imaging as well as behavioral measures to identify functional brain networks that modulated naming and categorization of colors. We first identified three bilateral color-sensitive regions in the ventro-occipital cortex. We then showed that, across participants, color naming and categorization response times (RTs) were correlated with different resting state connectivity networks seeded from the color-sensitive regions. Color naming RTs correlated with the connectivity between the left posterior color region, the left middle temporal gyrus, and the left angular gyrus. In contrast, color categorization RTs correlated with the connectivity between the bilateral posterior color regions, and left frontal, right temporal and bilateral parietal areas. The networks supporting naming and categorization had a minimal overlap, indicating that the 2 processes rely on different neural mechanisms.

Tongue cancer following hematopoietic cell transplantation for Fanconi anemia.

OBJECTIVES: The aim of this retrospective study was to determine the incidence and the clinical outcome of tongue cancer (TC) in patients affected by Fanconi anemia (FA) who received an allogeneic hematopoietic cell transplantation (HCT). MATERIALS AND METHODS: The patient database from the Bone Marrow Transplant Center of Pescara was reviewed to enroll FA patients. Patients', donors', HCT's, and screening's data were collected as well to look for the incidence and the treatment of TC. RESULTS: Twelve patients affected by FA were identified. Three patients died for transplant-related causes. Five of nine surviving patients were diagnosed with TC at a median of 21.7 years since transplantation and at a median age of 32.10 years. Interestingly, no patient manifested graft-versus-host-disease (GvHD). The 28-year cumulative incidence function of TC was 46.9% (95% CI, 36.9-56.9%). Two patients were treated with chemotherapy alone, two patients were treated with surgery alone, and one with surgery followed by chemotherapy. Overall, 4 patients with TC showed a clinical course characterized by a marked aggressiveness of the tumor disease which led to death due to cancer progression between 2 and 13 months. One patient is surviving 8 months after diagnosis of TC. CONCLUSIONS: Our study confirms the high incidence of tumors and in particular tongue tumors in allotransplanted FA patients. A careful screening has to be life-long maintained. CLINICAL RELEVANCE: Considering the rarity of FA and the frailty of FA patients, this study may add important information for the cancer management of these patients.

Quantitative Assessment of Motor Neglect.

Background and Purpose: We used differential actigraphy as a novel, objective method to quantify motor neglect (a clinical condition whereby patients mimic hemiplegia even in the absence of sensorimotor deficits), whose diagnosis is at present highly subjective, based on the clinical observation of patients' spontaneous motor behavior. Methods: Patients wear wristwatch-like accelerometers, which record spontaneous motor activity of their upper limbs during 24 hours. Asymmetries of motor behavior are then automatically computed offline. On the basis of normal participants' performance, we calculated cutoff scores of left/right motor asymmetry. Results: Differential actigraphy showed contralesional motor neglect in 9 of 35 patients with unilateral strokes, consistent with clinical assessment. An additional patient with clinical signs of motor neglect obtained a borderline asymmetry score. Lesion location in a subgroup of 25 patients was highly variable, suggesting that motor neglect is a heterogenous condition. Conclusions: Differential actigraphy provides an ecological measure of spontaneous motor behavior, and can assess upper limb motricity in an objective and quantitative manner. It thus offers a convenient, cost-effective, and relatively automatized procedure for following-up motor behavior in neurological patients and to assess the effects of rehabilitation.

Color Vision Deficits.

PURPOSE OF REVIEW: Color provides important information about the identity of the objects we encounter. After early processing stages in the retinal cones, thalamus, and occipital cortex, retinal signals reach the ventral temporal cortex for high-level color and object processing, which links color perception with top-down expectations and knowledge. In the language-dominant hemisphere, some of these regions communicate with the language systems; by assigning verbal labels to percepts, these circuits speed up stimulus categorization, and permit fast and accurate inter-individual communication. This paper provides a review of color processing deficits, from dysfunction of wavelength discrimination in the retinal photoreceptors to deficits of high-level processing in the ventral temporal cortex. RECENT FINDINGS: Neuroimaging evidence defined the existence and localization of color-preferring domains in the ventral occipito-temporal cortex. Evidence from the performance of a brain-damaged patient with color anomia but preserved color categorization demonstrated the independence of color categorization from color naming in the adult brain. Evidence from patients with brain damage suggests that high-level color processing may be divided into at least three functional domains: perceptual color experience, color naming, and color knowledge.

E-TAN, a technology-enhanced platform with tangible objects for the assessment of visual neglect: A multiple single-case study.

Visual neglect is a frequent and disabling consequence of right brain damage. Traditional paper-and pencil tests of neglect have limited sensitivity and ecological validity. The Baking Tray Task (BTT), instead, approaches real-life situations, because it requires participants to place 16 physical objects on a board. The number of objects placed on the left and right portions of the board provides a clinical index of visual neglect. Here we present E-TAN, a technology-enhanced platform for BTT (E-BTT). E-BTT automatically determines the object locations on the board, and also records the sequence and timing of their placement. We used E-BTT to test 9 patients with right hemisphere damage and compared their performance with that obtained by 115 healthy participants. To this end, we developed a new method of analysis of participants' performance, based on the use of the convex hull described by the objects on the board. This measure provides an estimate of the portion of space processed by each participant and can effectively discriminate neglect patients from patients without neglect. E-TAN allows clinicians to assess visuospatial performance by using a convenient, fast, and relatively automatized procedure, that patients can even perform at home to follow-up the effects of rehabilitation.

When colours split from objects: The disconnection of colour perception from colour language and colour knowledge.

We investigated object-colour knowledge in RDS, a patient with impaired colour naming after a left occipito-temporal stroke. RDS's colour perception, object naming and verbal colour-knowledge (the ability to verbally say the typical colour of an object) were relatively spared. RDS was also able to state if an object was appropriately coloured or not. However, he could neither match colour names to coloured objects, nor match colour patches to grey-scale objects. Thus, RDS's colour-naming deficit was associated with an impaired ability to conceptually relate visually presented object shapes and colours. These results suggest that objects in their typical colour are processed holistically in the visual modality, and that abilities important for colour naming may also be involved in abstracting colours from visual objects. We discuss these findings in the context of developmental psychology and linguistic anthropology, and propose a model of neuro-functional organization of object-colour knowledge.

Family Mismatched Allogeneic Stem Cell Transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of European Society for Blood and Marrow Transplantation.

This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34+ cell dose was 4.8 × 106/kg (range, 1.7 to 22.9; n = 43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28days was 82% (range, 70% to 93%), at a median of 21days (range, 19 to 23). At 2years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion.

Working memory in posterior cortical atrophy.

We used an ad hoc created neuropsychological battery to evaluate in details both verbal and visuospatial working memory (WM) in patients with posterior cortical atrophy (PCA, n = 5). PCA is a rare, early-onset neurodegenerative dementia, often due to Alzheimer's disease (AD) pathology. Clinically, PCA patients present with visual, visuospatial, and visuomotor deficits, and no memory complaints. PCA patients' patterns of performance were compared with those of 11 typical, amnestic AD patients matched for disease severity, as well as with 17 age-matched healthy controls. Both groups of patients had impaired WM performance compared to controls. However, PCA patients were more impaired than typical AD patients for both verbal and visuospatial WM. Moreover, PCA patients showed a more consistent impairment of visuospatial WM, as compared with verbal WM. Systematic WM evaluation should be part of the standard assessment in PCA. WM deficits affect patients' quality of life and can be detrimental to rehabilitation programs.

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy.

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34+ cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft.

Different patterns of confabulation in left visuo-spatial neglect.

Confabulating patients produce statements and actions that are unintentionally incongruous to their history, background, present and future situation. Here we present the very unusual case of a patient with right hemisphere damage and signs of left visual neglect, who, when presented with visual stimuli, confabulated both for consciously undetected and for consciously detected left-sided details. Advanced anatomical investigation suggested a disconnection between the parietal and the temporal lobes in the right hemisphere. A disconnection between the ventral cortical visual stream and the dorsal fronto-parietal networks in the right hemisphere may contribute to confabulatory behaviour by restricting processing of left-sided stimuli to pre-conscious stages in the ventral visual stream.

Clinical-Grade-Expanded Regulatory T Cells Prevent Graft-versus-Host Disease While Allowing a Powerful T Cell-Dependent Graft-versus-Leukemia Effect in Murine Models.

We developed a good manufacturing practices-compatible expansion protocol to improve number and purity of regulatory T cells (Tregs) available for clinical trials. Six clinical-grade separation procedures were performed, followed by expansion with high-dose interleukin (IL)-2, anti-CD3/anti-CD28 TCR stimulation, and rapamycin for 19 days achieving a median of 8.5-fold (range, 6.25 to 13.7) expansion. FOXP3 expression was stably maintained over the culture period, while the percentage of CD127 was significantly reduced. The in vitro suppression assay showed a strong Mixed Lymphocytes Reaction inhibition. In vitro amplification did not induce any karyotypic modification. To evaluate the graft-versus-host disease (GVHD)/graft-versus-leukemia (GVL) bifunctional axis, expanded Tregs and conventional T cells (Tcons) were tested in NOD/SCID/IL2Rgnull mice injected with primary acute myeloid leukemia (AML) cells, AML cell line, acute lymphoid leukemia Philadelphia cell line, or Burkitt-like lymphoma cell line. All mice that received leukemia cells together with expanded Tregs and Tcons were rescued from leukemia and survived without GVHD, showing that Treg expansion procedure did not compromise GVHD control and the strong Tcon-mediated GVL activity. This report might represent the basis for treating high-risk leukemia and/or relapsed/refractory leukemia patients with high-dose Treg/Tcons.

Cortico-thalamic disconnection in a patient with supernumerary phantom limb.

Supernumerary phantom limb (SPL) designates the experience of an illusory additional limb occurring after brain damage. Functional neuroimaging during SPL movements documented increased response in the ipsilesional supplementary motor area (SMA), premotor cortex (PMC), thalamus and caudate. This suggested that motor circuits are important for bodily related cognition, but anatomical evidence is sparse. Here, we tested this hypothesis by studying an extremely rare patient with chronic SPL, still present 3 years after a vascular stroke affecting cortical and subcortical right-hemisphere structures. Anatomical analysis included an advanced in vivo reconstruction of white matter tracts using diffusion-based spherical deconvolution. This reconstruction demonstrated a massive and relatively selective disconnection between anatomically preserved SMA/PMC and the thalamus. Our results provide strong anatomical support for the hypothesis that cortico-thalamic loops involving motor-related circuits are crucial to integrate sensorimotor processing with bodily self-awareness.