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Background: Ponatinib, a third generation BCR-ABL inhibitor, has shown relevant activity against native and mutant forms of BCR-ABL, including the T315I mutant. The aim of this compassionate protocol was to confirm the efficacy and the safety of the compound in patients with advanced Ph+ ALL and CML. Design and Methods: Ponatinib was obtained through a compassionate use named patient program, approved by ARIAD Pharmaceuticals and by the Bologna Ethical Committee. After informed consent was signed, 17 patients (M/F=8/9) have been treated (45 mg orally, once daily) between February 2012 and July 2013, including 14 Ph+ ALL and 3 blast phases of CML (11 p190, 5 p210, 1 p230). The median age of the patients was 64 years (range 23 -77). The median time from diagnosis was 2 years (range 0.2-6). Five patients (29%) had previously received an allogenic stem cell transplantation. All the patients were resistant or intolerant to previous TKIs (11 patients received >=2 TKIs). Median Hb, PLTs and WBC values were 10,1 g/dl (range 8.3-13.9), 100000/mmc (range 14000-325000) and 4400/mmc (range 1700-17000), respectively. In 6 out of 17 patients (35%), additional cytogenetic alterations were revealed. Mutational analysis showed the presence of T315I mutation (8 pts), G250E (1 pt), T315I and Y253H (1 pt), T315I and Y253A (1 pt), V299L (1 pt). Results: The median treatment duration was 153 days (range 42-594+). With a median follow up of 8 months (range 2-21+), a maHR was obtained in 12/17 patients (71%). Among these, 6 were T315I mutated. After one month of treatment, a reduction of BCR ABL fusion transcript to undetectable level was observed in 3/17 patients (18%), which increased to 29% (5/17) after two additional cycles. The progression free survival (PFS) at 12 months was 35% (median 57 days), without differences between patients with T315I mutations and patients harboring other mutations. Furthermore, we observed that, in responder patients, mutations disappeared in all except one case. In contrast, in resistant patients, a specular mutational profile before and after treatment was detected. Currently, 6/17 patients are still on study (35%). Six patients died due to progression disease. In five cases, the response allowed the patients to proceed to a savage allogenic stem cell transplantation. The drug was well tolerated. No SAEs were detected and no thrombotic arterial/venous events occurred. Conclusion: In our experience, the activity of Ponatinib in advanced Ph+ leukemias was confirmed.No treatment-related deaths occurred. The understanding of molecular mechanisms responsible for resistance or lack of response to the drug will be necessary in order to identify patients who could take advantage of this treatment. Acknowledgments: Work supported by European LeukemiaNet, AIRC, AIL, PRIN 2010-2011, University of Bologna, FP7 NGS-PTL project. Citation Format: Cristina Papayannidis, Caterina De Benedittis, Simona Soverini, Ilaria Iacobucci, Maria Chiara Abbenante, Chiara Sartor, Maria Teresa Bochicchio, Anna Ferrari, Claudia Venturi, Valentina Robustelli, Andrea Ghelli Luserna di Rorà, Viviana Guadagnuolo, Emanuela Ottaviani, Nicoletta Testoni, Carmen Baldazzi, Simona Luatti, Sarah Parisi, Stefania Paolini, Alberto Conficoni, Federica Frabetti, Elisa Lani, Silvia Piccari, Paolo Di Bartolomeo, Roberto Di Lorenzo, Renato Fanin, Giuseppe Cimino, Fabio Ciceri, Giovanni Martinelli. Ponatinib is well tolerated and active in patients with relapsed/refractory philadelphia positive leukemias: The Bologna experience. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT312. doi:10.1158/1538-7445.AM2014-CT312

Unrelated cord blood transplantation (UCBT) and Haploidentical T-cell depleted peripheral blood stem cell transplantation (Haplo) are alternative options to treat patients with high risk acute leukaemia. With the aim to compare the outcomes of both strategies we have analysed retrospectively adults patients with ALL or AML receiving either UCBT or Haplo performed in EBMT centers from 1998–2002. One hundred forty four patients had ALL (Haplo=75 and UCBT=73) and 220 had de novo AML (Haplo=154, UCBT=66). In the ALL group, UCBT patients were younger and received less TBI than Haplo recipients. The frequency of patients with advanced phase of the disease at transplant was 45% in Haplo and 51% in UCBT (p=0.79). Cytogenetics and interval from diagnosis to transplant were not statistically different between the 2 groups. In the AML group, UCBT recipients were younger than Haplo recipients. Many patients were transplanted in advanced phase of the disease in both groups (58% of Haplo recipient and 59% in UCBT group), other disease-related factors were not significantly different. Unadjusted outcomes in both groups are reported in table 1. After statistical adjustment for differences between the 2 groups, in both analysis (ALL and AML), UCBT recipients had delayed neutrophil recovery and higher incidence of acute GVHD (II–IV) compared to Haplo recipients. In the AML group, relapse incidence, TRM and LFS were not statistically different after UCBT or Haplo, however in ALL group, LFS were superior and relapse incidence decreased after UCBT compared to Haplo transplants. In conclusion, in this based registry retrospective analysis, UCBT and Haplo showed similar TRM, relapse and LFS for adults with AML, however LFS were superior after UCBT for patients with ALL due to decreased incidence of relapse. ALL Cumulative incidence of aGvHD Cumulative incidence of 2y-RI Cumulative incidence of 2y-TRM Kaplan Meyer estimate 2y-LFS Haplo (n=75) 8+/−3% 38+/−5% 49+/−6% 13+/−4% UCBT (n=73) 26+/−5% 23+/−4% 41+/−6% 36+/−6% p value 0.004 0.07 0.55 0.01 AML Haplo (n=154) 5+/−5% 18+/−3% 58+/−4% 24+/−4% UCBT (n=66) 23+/−5% 24+/−5% 46+/−2% 30+/−6% p value

International audience; When describing known places from memory, patients with left spatial neglect may mention more right- than left-sided items, thus showing representational, or imaginal, neglect. This suggests that these patients cannot either build or explore left locations in visual mental imagery. However, in place description there is no guarantee that patients are really employing visual mental imagery abilities, rather than verbal-propositional knowledge. Thus, patients providing symmetrical descriptions might be using other strategies than visual mental imagery. To address this issue, we devised a new test which strongly encourages the use of visual mental imagery. Twelve participants without brain damage and 12 right brain-damaged patients, of whom 7 had visual neglect, were invited to conjure up a visual mental image of the map of France. They subsequently had to state by pressing a left- or a right-sided key whether auditorily presented towns or regions were situated to the left or right of Paris on the imagined map. This provided measures of response time and accuracy for imagined locations. A further task, devised to assess response bias, used the words “left” or “right” as stimuli and the same keypress responses. Controls and non-neglect patients performed symmetrically. Neglect patients were slower for left than for right imagined locations. On single-case analysis, two patients with visual neglect had a greater response time asymmetry on the geographical task than predicted by the response bias task, but with symmetrical accuracy. The dissociation between response times and accuracy suggests that, in these patients, the left side of the mental map of space was not lost, but only “explored” less efficiently.

Intraoperative electrical stimulation, which temporarily inactivates restricted regions during brain surgery, can map cognitive functions in humans with spatiotemporal resolution unmatched by other methods. Using this technique, we found that stimulation of the right inferior parietal lobule or the caudal superior temporal gyrus, but not of its rostral portion, determined rightward deviations on line bisection. However, the strongest shifts occurred with subcortical stimulation. Fiber tracking identified the stimulated site as a section of the superior occipitofrontal fasciculus, a poorly known parietal-frontal pathway. These findings suggest that parietal-frontal communication is necessary for the symmetrical processing of the visual scene.

International audience; OBJECTIVES: Comparatively little research has been conducted on right neglect after left brain damage. The authors sought to assess contralateral neglect in subacute left hemisphere stroke patients using a comprehensive test battery validated in a large control group after right hemisphere stroke. METHODS: Seventy-eight left hemisphere stroke patients were assessed. The test battery included a preliminary assessment of anosognosia and visual extinction, a clinical assessment of gaze orientation and personal neglect, and paper-and-pencil tests of spatial neglect in the peripersonal space. Only nonverbal tests were used. RESULTS: Drawing and cancellation tasks revealed neglect in 10 to 13% of patients. The combined battery was more sensitive than any single test alone. A total of 43.5% of patients showed some degree of neglect on at least one measure. Anatomic analyses showed that neglect was more common and severe when the posterior association cortex was damaged. CONCLUSIONS: The frequency of occurrence of right neglect was, as expected, much lower than that reported in a study using the same assessment battery in right brain damage stroke patients. Nevertheless, neglect was found in a substantial proportion of patients at a subacute stage, suggesting that it should be considered in the rehabilitation planning of left brain damage stroke patients.

Eighty blindfolded healthy female subjects participated in an active and a passive straight-ahead pointing task to study the estimation of the subjective sagittal middle in the presence or absence of an active haptic exploration. Subjects were to point straight-ahead with their left or right index finger starting from different right- or left-sided locations, while performing either an active movement or with the hand being passively moved by the examiner. Results showed: (i) a significant effect of the hand used only on the active straight-ahead pointing task performance; (ii) a significant effect of the starting position both on the active and passive pointing performance; (iii) a significant correlation between the two protocols only in terms of spatial bias (algebraic error) but not in terms of precision (absolute errors). These results are discussed with regards to normal and neuropsychological studies of the egocentric frame of reference.

Previous research on patients with left tactile extinction has shown that crossing of hands, so that each hand is on the opposite side of the body midline relative to the other, improves detection of stimuli given to the left hand.To study the influence of the spatial position of limbs on left tactile extinction, and its relations with left visual neglect.Normal participants and patients with right cerebral hemisphere damage and left tactile extinction were asked to detect single or double light touch stimuli applied to their cheeks, hands, or knees with their arm and legs either in anatomical or in crossed position, increasing the attentional load of the task.In patients with left extinction, limb crossing caused a deterioration in performance for stimuli applied to right body parts, with only a tendency to an improvement in detection for left body parts (only two of 24 patients showed substantial (20%) improvement in left extinction after limb crossing). After crossing, left limb detections of double stimuli decreased with increasing degrees of visual neglect.In conditions of high attentional load, limb crossing may impair tactile detection in most patients with left extinction, and particularly in those showing signs of left visual neglect. These results underline the importance of general attentional capacity in determining tactile extinction. Attentional and somatotopic mechanisms of extinction may assume different weights in different patients.

Halligan and Marshall [Cortex 27 (1991) 623] devised a new test to evaluate the hypothesis that in visual neglect, left space is systematically compressed rightwards. In the critical condition of the original study, rows of horizontally arranged numbers with a target arrow pointing to one of them from the opposite margin of the display were presented. When asked to verbally identify the number indicated by the arrow, a right brain-damaged patient with left neglect and hemianopia often indicated a number to the right of the target. The more the target was located on the left, the greater the response shift rightward, as if rightward compression were linearly proportional to the co-ordinates of Euclidian space. However, a possible alternative account could be that the patient’s attention was attracted by the numbers located to the right of the target digit, thus biasing her responses toward numbers on the right. To explore this hypothesis, we asked normal participants and patients with right hemisphere lesions, with and without neglect or hemianopia, to mark on the margin of a sheet the approximate location indicated by an arrow situated on the opposite margin. In three different conditions, the arrow indicated either one of several numbers or lines in a row, or a blank location on the sheet margin. Only patients with left neglect, and especially those with associated hemianopia, deviated rightward, and then crucially only on those conditions where visible targets were present, consistent with the attentional bias account.

Inhibition of return (IOR) is thought to reflect a bias against returning attention to previously attended locations. According to this view, IOR should occur only if attention is withdrawn from the target location prior to target appearance. In the present study, endogenous attention and exogenous cueing were manipulated orthogonally. IOR was observed both when a target appeared at an unexpected location, and when a target appeared at the expected location. A similar pattern of results was obtained in a reanalysis of data from a study with Neglect patients. These results suggest that IOR is independent of endogenous orienting.

When two visual events appear consecutively in the same spatial location, our response to the second event is slower than to the first. This inhibition for repeated events may reflect a bias toward sampling novel locations, a bias useful for exploring visual space. It has been shown that the left hemisphere is more specialized in selective attentional processes than the right one. The aim of the present experiment was to test if this hemispheric specialization for selective attention may also affect the inhibition for repeated events. For this purpose, we asked 11 normal subjects to perform an identity-based discrimination task in which the target to be detected could appear alone or surrounded by flanking letters, in the left or in the right visual field. Results show that inhibition for repeated events is present only when selective attention is required and when the task is performed in the right specialized visual field.

We studied reading performance for words and for isolated letters in a pure alexic patient. She performed reasonably well when naming isolated letters but was slower in reading letters than a control subject when reaction times (RTs) were recorded. When the patient read isolated letters, RTs were slower for a subset of letters that cannot be recognized from their left part alone (e.g. "b", an ambiguous letter, could be read "b" "h" "l" or "k" whereas "a" has no predictable confounders). We observed a significant positive correlation between the RTs for reading a word and the mean RTs for reading each of its composing letters before its uniqueness point (i.e. the point, when reading from the left to the right, where a word cannot be a word other than the one it is). This result suggests that, in our patient, the letter identification deficit can account for the slow, letter-by-letter reading behaviour, insofar as each letter represents a perceptual problem. Our findings can be accounted for by a deficit in the parallel processing of the left and right parts of each letter, compounded with a bias to process first the left part of the letter, and may thus reconcile the hypotheses of spatially-based deficit (Rapp and Caramazza, 1991) and of a perceptual deficit occurring at the letter identification level (Behrmann and Shallice, 1995; Perri et al., 1996).

Visual perception and visual mental imagery, the faculty whereby we can revisualise a visual item from memory, have often been regarded as cognitive functions subserved by common mechanisms. Thus, the leading cognitive model of visual mental imagery holds that visual perception and visual imagery share a number of mental operations, and rely upon common neural structures, including early visual cortices. In particular, a single visual buffer would be used "bottom-up" to display visual percepts and "top-down" to display internally generated images. The proposed neural substrate for this buffer consists of some cortical visual areas organised retinotopically, that is, the striate and extrastriate occipital areas. Empirical support for this model came from the report of brain-damaged patients showing an imagery deficit which parallels a perceptual impairment in the same cognitive domain. However, recent reports of patients showing double dissociations between perception and imagery abilities challenged the perception-imagery equivalence hypothesis from the functional point of view. From the anatomical point of view, the available evidence suggests that occipital damage is neither necessary nor sufficient to produce imagery deficits. On the other hand, extensive left temporal damage often accompanies imagery deficits for object form or colour. Thus, visual mental imagery abilities might require the integrity of brain areas related to vision, but at an higher level of integration than previously proposed.

Patients with unilateral brain damage may show slowed or hypometric arm movements toward the contralesional space, as compared to movements directed towards the side of the brain lesion. The present article describes a reaction time paradigm devised to study accuracy and latency of directional arm movements in normal human subjects and brain-damaged patients. Experimental paradigms hitherto used to explore directional motor disorders often do not reliably disentangle between perceptual and motor factors, because they employ lateralized perceptual stimuli. The traffic light paradigm, instead, consists of visual stimuli presented on the vertical midline (like a traffic light) and hand responses to be produced in either hemispace. Thus, participants have to produce lateralized arm responses to central visual stimuli. Performance on this ‘motor’ paradigm can be contrasted with performance on a ‘perceptual’ reaction time task, consisting of similar, but lateralized visual stimuli and central motor responses. Results obtained with these paradigms on normal participants and brain-damaged patients are presented and discussed. These results give empirical support to the claim that the traffic light paradigm is suitable to study directional motor disorders in relative isolation from perceptual biases.

After right posterior brain damage, patients may ignore events occurring on their left, a condition known as unilateral neglect. Although deficits at different levels of impairment may be at work in different patients, the frequency and severity of attentional problems in neglect patients have been repeatedly underlined. Recent advances in the knowledge of the mechanisms of spatial attention in normals may help characterizing these deficits. The present review focuses on studies exploring several aspect of attentional processing in unilateral neglect, with particular reference to the dichotomy between 'exogenous', or stimulus-related, and 'endogenous', or strategy-driven, orienting of attention. A large amount of neuropsychological evidence suggests that a basic mechanism leading to left neglect behavior is an impaired exogenous orienting toward left-sided targets. In contrast, endogenous processes seem to be relatively preserved, if slowed, in left unilateral neglect. Other component deficits, such as a general slowing of the operations of spatial attention, might contribute to neglect behavior. These results are presented and discussed, and their implications for hemispheric specialization in attentional orienting and for the mechanisms of visual consciousness are explored.

If, as Tulving1 asserts, “consciousness as an object of intellectual curiosity is the philosopher’s joy and a scientist’s nightmare”, this is due to the fact that it does not seem to answer the prerequisites of the Galilean method of scientific research. Indeed it is difficult to find a definition of consciousness which allows us to narrow down the field of inquiry, just as it is difficult to “measure” it and interpret the results of its possible measurement. The fact that consciousness has always more or less implicitly been considered a unitarian entity is largely responsible for most of these problems. From this point of view, the only possibility of defining consciousness lies in distinguishing it from the unconscious: consciousness is that which is not unconscious. This is where all the unresolved and unresolvable questions that have excluded consciousness from any line of inquiry stem from. But a definition of consciousness is in itself impossible, if by definition you mean an arbitrary definition of the meaning of consciousness, or of how the term should be used. It is equally impossible to limit a priori the field of concepts which make reference to consciousness. This is not because this type of descriptive process is in itself wrong. Indeed, it is quite easy to define a “glass” either by deciding arbitrarily that it is an object that usually contains liquids and which is used to drink from, or by seeing all or part of a series of concepts which concern the idea of drinking something from an object as leading back to glass.

Patients with unilateral spatial neglect due to right-hemisphere lesions typically fail to attend to and explore left-sided stimulus objects [32] . It has been postulated that in right-brain damaged (RBD) patients an ipsilesional displacement of the egocentric frame of reference (ER), whether visual or tactile, may be responsible for a contralesional supramodal spatial bias causing their left neglect behavior [39] . However, this hypothesis had been proposed without testing, in the same patients, the position of the ER or their performance in the visual and tactile modalities. Thus, the aim of the present study was to test the hypothesis that an ipsilateral shift of the ER is responsible for a supramodal spatial bias in neglect. For this purpose, a within-subject design is required. Consequently, 12 left neglect patients and 12 control subjects were asked to perform a proprioceptive straight-ahead pointing task while blindfolded, as well as visual and tactile bisection tasks. In the left neglect patients, we found: (i) no systematic deviation of the ER on the ipsilesional right side; (ii) a significant rightward bias in visual bisection, and normal performance in tactile bisection; (iii) no correlation among the three tasks; (iv) that only visual bisection correlated with the severity of neglect. These results are discussed with regard to the egocentric and attentional hypothesis of neglect.

In agreement with some of the ideas expressed by Perruchet & Vinter (P&V), we believe that some phenomena hitherto attributed to “unconscious” processing may in fact reflect a fundamental distinction between direct and reflexive forms of consciousness. This dichotomy, developed by the phenomenological tradition, is substantiated by examples coming from experimental psychology and lesion neuropsychology.

We describe a patient, VSB, whose reading was impaired as a consequence of a left temporal- parietal lesion, whereas writing was relatively preserved. At variance with other pure alexic patients described in the literature, VSB claimed to have become unable to mentally visualise letters and words. Indeed, his performance on a series of tests tapping visual mental imagery for orthographic material was severely impaired. However, performance on the same tests was dramatically ameliorated by allowing VSB to trace each item with his finger. Visual mental imagery for non-orthographic items was comparatively spared. The pattern of dissociation shown by VSB between impaired visual mental imagery and relatively preserved motor-based knowledge for orthographic material lends support to the view that separate codes, respectively based on visual appearance and on motor engrams, may be used to access knowledge of the visual form of letters and words.

Signs of unilateral neglect for events occurring in one hemispace most often result from right hemisphere lesions. Right unilateral neglect after left hemisphere damage is much rarer, and has received less attention. The present study explores the relationships between right unilateral neglect and asymmetries in producing laterally directed arm movements in the horizontal plane in left brain-damaged (LBD) patients. Participants produced right- or left-directed arm movements with their left arm in response to centrally located visual stimuli. Results showed that LBD patients with signs of right unilateral neglect were consistently slowed when producing arm movements toward the right (neglected) side, as compared to left-directed movements. Taking into account patients with and without signs of neglect, this directional asymmetry positively correlated with a reaction-time measure of perceptual spatial bias. These findings stand in contrast with previous results obtained with the same experimental paradigm in right brain-damaged patients, in whom a consistent slowing of leftward-directed movements was rare and apparently unrelated to the presence and severity of left neglect. These conflicting results are discussed with respect to the hypothesis that different mechanisms may underlie left and right unilateral neglect.

Introduction Allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed B-cell lymphomas. Different studies have shown that Rituximab (R) is implicated in the pathophysiology of acute and chronic GVHD. Methods: We analyzed 153 adult patients who received alloSCT for relapsed/refractory B-cell lymphomas. All patients received the same preparative conditioning consisting of thiotepa/cyclophosphamide/fludarabine, and GVHD prophylaxis consisting in cyclosporine and short course methotrexate. ATG (7 mg/kg) was added to patients allografted from class I antigen mismatched sibling or unrelated donors. Eighty-two patients (group A) received high-dose Rituximab (R 500 mg/ms on day -6) and were enrolled in a prospective multicenter study, whereas 71 consecutive patients (group B, control group) were part of a previous study without R. The two groups were not significantly different in terms of diagnosis (p=0.10), donor types (p=0.74), rate of complete remission at transplant (p=0.51). Results: The cumulative incidence (CI) of non-relapse mortality (NRM) at 2-years was 16% in group A and 18% in group B (p=0.84). Main cause of death were infections without GVHD in group A (7/13) and extensive GVHD in group B (6/14). Deaths associated to acute or chronic GVHD were significantly lower in group A (5 of 13) as compared to group B (13 of 14) (p=0.004). The CI of grade II-IV and III-IV acute GVHD was 23% versus 35% (p=0.11) and 7% versus 14% (p=0.11) in group A versus B, respectively. The CI of chronic GVHD was 48% versus 47% (p=0.73) in group A versus group B, respectively. The CI of acute GVHD and chronic GVHD in unrelated recipients was 20% versus 31% (p=0.41) and 32% versus 40% (p=0.83) in patients who received R in the conditioning comparing to group B. A delayed immune reconstitution of B-cells was still evident at 2 years after alloSCT in group A versus B [median value CD19+: 126/µL versus 300/µL with a significant higher percent of IgD+CD27- in group A and reduced immunoglobulin production: 502 versus 778 mg/dL of IgG (p=0.04)]. Progression free survival (PFS) and overall survival (OS) at 3-years were similar in group A and group B [PFS: 54% versus 58% (p=0.50); OS: 64% versus 67% (p=0.51)]. PFS at 3-years in indolent and aggressive lymphomas was 66% versus 75% and 42% versus 43% with and without R; OS at 3-years in indolent and aggressive lymphomas was 74% versus 78% and 55% versus 57% with and without R. In multivariate analysis, acute GVHD, extensive chronic GVHD and aggressive hystotype were associated to a lower OS [HR=3.6, p=0.0003; HR=2.3,p=0.03;HR=2.1,p=0.01] and only acute GVHD and aggressive hystotype to lower PFS [HR=2.7, p=0.002; HR=2.3, p=0.001]. Rituximab in the conditioning regimen, year of transplant and donor type did not influence the outcome. Conclusions: Rituximab administration in the setting of alloSCT is associated with reduced GVHD-related deaths and increased infection-related deaths, likely due to delayed B-cell immune-reconstitution. Disclosures: No relevant conflicts of interest to declare.

Background The incidence of acute myeloid leukemia (AML) increases with age. In elderly AML patients, intensive chemotherapy has been associated with complete remission (CR) rates of approximately 45%, considerably lower than in younger patients; the duration of remission is shorter and the early treatment-related mortality is high, 30% to 50%, which partially explains a median survival of 7 to 12 months. Several studies have suggested that maintenance therapy may improve CR duration and long-term, disease-free survival (DFS). Grovdal et al (2010) treated 60 elderly patients with high-risk myelodysplastic syndrome (MDS) or AML with cytarabine-based induction therapy resulting in CR in 24 patients who continued on to 5-Azacitidine (5-Aza) maintenance therapy. The median duration of complete response was 13.5 months. The median OS for the 5-Azacitidine-treated group was 20 months. Aims The present phase III, prospective, randomized, open-label, multicenter trial is designed to assess the efficacy of post-remission treatment with 5-Aza versus best supportive care in a cohort of subjects of > 60 years of age with AML, and in CR after conventional induction (“3+7”) and consolidation chemotherapy. Primary objectives are to evaluate overall survival overall survival and DFS at 2 years; secondary objectives are to evaluate the number and length of hospitalizations in the 2 arms in the 2-year post-remission period. Methods Approximately 95 patients with the following criteria: newly diagnosed AML with > 30% myeloid marrow blasts, either “de novo” or evolving from a MDS not previously treated with chemotherapeutic agents; no contraindications for intensive chemotherapy and performance status Results At the time of the present report 58 patients have been included in the study. Median age at diagnosis was 72, interquartile range (IQR) 65-75 years, M/F 34/24. During induction-consolidation chemotherapy, 16 patients were relapsed/refractory, 9 patients died, 3 patients were excluded for protocol violation, 3 refused to continue and 8 have not yet reached consolidation treatment. Nineteen patients have been randomized; characteristics of patients are shown in the table. Eighteen patients have reached at least a 4 week follow-up. Amongst these, 11 patients are still in CR at a median observation time of 25.4, IQR 12.9-47.4 weeks. Five patients in the BSC arm have experienced AML recurrence at 7, 8, 13, 21, 49 weeks, respectively, verus 2 patients in the 5-Aza arm at 42 and 47 weeks. DFS is longer in the 5-Aza arm (Figure). Grade 3-4 adverse events included neutropenia in 2 cases in the 5-Aza arm and in 1 case in the BSC arm. There were no hospitalizations related to the adverse events in either arm. Conclusions Preliminary results suggest that in elderly AML patients receiving standard induction-consolidation chemotherapy, 5-Aza post-CR is well-tolerated and may prolong survival. Disclosures: Oliva: Celgene: Consultancy. Off Label Use: Azacitidine is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with: • intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), • chronic myelomonocytic leukaemia (CMML) with 10-29 % marrow blasts without myeloproliferative disorder, • acute myeloid leukaemia (AML) with 20-30 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification.

Background Ponatinib, a potent third generation pan BCR-ABL inhibitor, has recently shown relevant activity against native and mutant forms of BCR-ABL, including the TKI resistant T315I mutant. The aim of this compassionate protocol was to confirm and evaluate the efficacy and the safety of the compound in patients with advanced Ph+ ALL and CML. Design and Methods Ponatinib was obtained through a compassionate use named patient program, approved by ARIAD Pharmaceuticals and by the Bologna Ethical Committee. After informed consent was signed, 17 patients (M/F: 8/9) have been treated with Ponatinib (45 mg orally, once daily) between February 2012 and July 2013, including 14 Ph+ ALL (10 p190, 4 p210) and 3 blast phases of CML (2 Myeloid and 1 Lymphoid, p210). The median age of the patients was 64 years (range 23 -77). The median time from diagnosis was 754 days (range 46-2264). All the patients were resistant or intolerant to previous TKIs (median number of previous TKIs: 2; range 1-3). Standard chemotherapy was previously performed in 7/17 patients (41%). Four patients (23%) had previously received allogeneic stem cell transplantation. At the time of enrolment, median Hb, PLTs and WBC values were 10,9 g/dl (range 8.6-13.9), 139000/mmc (range 14000-325000) and 4300/mmc (range 1700-17000), respectively. In 6 out of 17 patients, additional cytogenetic alterations were revealed. Mutational analysis showed the presence of T315I mutation (9 pts), G250E (1 pt), T315I and Y253H (1 pt), T315I and Y253A (1 pt), V299L (1 pt). No mutations were detected in 4 patients. Results The median treatment duration was 139 days (range 14-540+). Causes of treatment stop were: progression disease (5 patients), savage allogenic stem cell transplantation (6 patients), drug intolerance (1 patient), consisting in grade III headache. With a median follow up of 284 days (range 8-540+), a maHR was obtained in 13/17 patients (76%). After one month of treatment, a reduction of BCR-ABL fusion transcript level was observed in 9/15 patients (60%). For two patients the follow up is too short to be evaluable. The level became undetectable in 4 patients (3 presenting with T315I mutation). After treatment, T315I mutation disappeared in 6 out of the 9 patients who showed this molecular alteration at the beginning of therapy. At the time of this report, 6/17 patients are still on study (35%). Five patients died due to progression disease. As expected, the drug was well tolerated. Non-hematologic adverse events were described in 7/17 patients (grade >III skin rash in 3 patients; grade>II serum lipase increase in 2 patients; grade>II myalgia in 1 patient; grade III headache). Conclusion In our experience, the activity of Ponatinib in advanced Ph+ leukemias, mainly in T315I mutated patients, was confirmed. No treatment-related deaths occurred. The understanding of molecular mechanisms responsible for resistance or lack of response to the drug will be necessary in order to identify patients early on who could take advantage of this treatment. Acknowledgments Work supported by European LeukemiaNet, AIRC, PRIN 2010-2011, University of Bologna and BolognAIL. Disclosures: Soverini: Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Martinelli:NOVARTIS: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; PFIZER: Consultancy; ARIAD: Consultancy.

In the absence of a fully matched donor, adult patients with Acute Leukemia (AML and ALL) in CR are nowadays usually offered, as a first choice, an allogeneic transplant from an alternative donor (haplomismatch donor or cord blood cells), but there has been thus far no demonstration that outcome when using an alternative donor is superior to outcome following an autologous stem cell transplantation (ASCT). We reported last year on a matched pair analysis comparing 113 AML patients transplanted in CR1 with an haplo-mismatch family donor to 226 autologous stem cell transplantations done in the period from January 2000 to December 2010 ( Blood 2013, 3093a). Improvements in both transplant approaches may have changed the outcome, justifying a new analysis. In the present study, we considered the more recent period from January 2007 to December 2011 and we collected information on patients with AML and ALL transplanted in first (CR1) and second CR (CR2). Also, we considered only T repleted haplo mismatch transplants. During this period a total of 193 fully documented haplomismatch and 2252 ASCT were reported to the EBMT registry. We used patient age, diagnosis, status at transplant and interval from diagnosis to transplant (< > 6 months for CR1; < > 18 months for CR2) as matching factors. Collection of data on cytogenetics and molecular biology is still in progress. The pair match analysis was done on 184 haplo versus 359 ASCT. The median follow up was 13 months (range, 2-66) for haplo and 14 months (1-72) for ASCT(p=0.9). Patients allografted were transplanted more recently (median year of transplant : 2010 vs 2009, p Following an haplo mismatch transplantation : - The percentage of acute GVHD grade II+ was 33% - the incidence of chronic GVHD and extensive GVHD were respectively: 32+/- 3 and 14+/-3%. By Cox regression analysis introducing age, year of transplantation, diagnosis, status at transplant, TBI in conditioning and the nature of the transplant, ASCT was associated with a better LFS (p=0.05, HR=0.76, 95%CI: .58-.99) and OS (p =10-4 , HR=.53, 95% CI: .40 -.72) than haplomismatch transplant, and a lower non relapse mortality (p< 10-4 ; HR = .27, 95% CI: .17 - .44). Though this study did not account for cytogenetics and molecular markers (data collection is ongoing), these results suggest that the outcome following ASCT may be better compared to the outcome following a haplo-mismatch transplantation and at least is not inferior. We feel this study support a randomized controlled trial comparing the two transplant modalities in a specific patient population with Acute Leukemia to be defined. Disclosures: No relevant conflicts of interest to declare.

Paroxysmal nocturnal hemoglobinuria (PNH) derives from a non malignant clonal expansion of hematopoietic stem cells (HSCs) harbouring somatic mutations of the X-linked PIG-A gene, leading to the complete or partial loss of glycosylphosphatidylinositol membrane-anchored proteins (GPI-APs) from the cell surface of the HSCs and of their mature progeny. The resulting intravascular hemolysis is caused by uncontrolled activation of the complement cascade and determines hemoglobinuria, anemia, fatigue, renal impairment, pulmonary hypertension, smooth muscle dystonias and thromboembolism, with a bad quality of life. Moreover PNH is usually embedded with a various degree of bone marrow (BM) failure syndromes, from mild cytopenias up to aplastic anemia.We describe 5 PNH patients: 3 males and 2 females; median age was 36 year (18-54). All developed PNH after other haematologic disorders. The first one was a rare case occurring after autologous stem cell transplantation(ASCT) for relapsing non-Hodgkin’s lymphoma; the second had experienced an aplastic anemia, successfully treated with immunosuppressive therapy; two were affected by anemia and thrombocytopenia of unspecified nature; in the fifth young patient (18 ys), hereditary spherocytosis had been diagnosed 2 years before, based on erythrocyte membrane protein analysis and splenectomy had been performed. All patients had strong intravascular hemolysis (reticulocytosis, elevated LDH, gross hemosiderinuria); the flow cytometry immunophenotyping study of GPI-APs expression on peripheral blood cells showed large cellular populations of erythrocytes, granulocytes and monocytes which had undetectable expression of GPI-APs, suggesting PNH. According to the previous hematological disorders or therapy (ASCT) in the mentioned series of patients, PNH occurred after 2, 5, 9, 1 and 2 years respectively. Three patients were transfusion dependent. After unsuccessful therapy with prednisone, folate and even cycles of steroid therapy, the terminal complement inhibitor eculizumab (EC) was started. All the patients received vaccination against Neisseria meningitides. EC was infused according to the standard schedule, 600 mg weekly for 4 weeks, followed by 900 mg every other week. EC was started respectively after 7 months, 24 months and 8 years from PNH diagnosis in the first three patients and after 4 months from PNH diagnosis in in the last 2 patients. The intravascular hemolysis was completely controlled in all patients. Only one patient continued but reduced erythrocyte transfusions; she shows significant extravascular hemolysis, building up GPI- C3d coated erythrocytes (DAT ++), and is candidate for splenectomy. Despite the different haematological response all 5 patients experienced a dramatic clinical improvement in the quality of life. In the transplant patient the cytometry showed a progressive reduction and ultimately extinction of the pathological clone; this provided the unique possibility to discontinue treatment after 12 months, then maintaining remission for some years. Probably in this case, EC did not play any direct role in the kinetics of the PNH clone, while the conditions which led to expansion of the clone were somehow unique and possibly related to the ASCT and resulted transient. Our small series, including even 2 rare cases (one pediatric PNH patient and one occurred after ASCT) shows how variable are the clinical and biological spectrum of manifestations in this strange and fascinating disease; moreover its clinical evolution in each single patient remains frequently unpredictable. Disclosures: No relevant conflicts of interest to declare.

P055-e Interaction between postural and cognitive performances in right brain damaged patients: A dual task study C. Bourlon , L. Lehenaff , C. Batifoulier , A. Bordier , A. Chatenet , E. Desailly , C. Fouchard , M. Marsal , M. Martinez , F. Rastelli , A. Thierry , P. Bartolomeo , C. Duret a a Clinique Les Trois Soleils, 19, rue du Château, 77310 Boissise-le-Roi, France Fondation Ellen Poidatz, France c Inserm-UPMC UMRS 975, hopital de la Salpetriere, France E-mail address: c.bourlon@gmail.com

frein au retour a l’emploi et ont un impact personnel et de sante publiquemajeur. L’objectif principal de cette etude est d’evaluer l’existence de facteurs associes au retour a l’emploi, afin d’aider au mieux ces patients. Methode.– Il s’agit d’une etude transversale portant sur 285 patients âges 60 ans hospitalises en unite neurovasculaire au CHU d’Amiens en 2010 ou 2011. Nous leur avons envoye un questionnaire et effectue un recueil de donnees sociodemographiques, professionnelles, cliniques et d’imagerie. A l’arrivee, 106 patients en activite (82 avec AVC et 24 avec AIT) avaient repondu. Resultats.– Soixante-trois pour cent des patients avaient repris le travail avec un delai moyen de 101 jours apres l’AVC. Grâce a une analyse multi-variee, nous avons isole trois variables : le scoreNIHSS initial, le caractere depressif a distance de l’AVCvia l’echelle de depressionHADet la reprise de la conduite automobile. Nous avons trouve de nombreux facteurs predictifs limitant : etiologie indeterminee, scores NIHSS et Rankin de sortie, et des signes cliniques, souvent subjectifs. De plus, a ete retrouvee une association significative positive avec une consultation de medecine du travail. Enfin, on s’est etonne des difficultes professionnelles de quelques patients ayant presente un AIT. Conclusion.– Cette etude suggere l’implication de nombreux facteurs : medicaux, socioculturels. . . La phase de rehabilitation post AVC est une part non negligeable de la prise en charge globale de la sante et du bien-etre du patient impliquant la participation des differents medecins et appelant peut-etre de nouvelles approches, dans lesquelles le medecin de MPR a un role.

We asked 16 right-brain damaged patients with left unilateral neglect, 9 right-brain damaged patients without neglect and 11 healthy control subjects to bisect horizontal lines or to extend them rightward or leftward. Although in the line bisection task patients with neglect showed the typical rightward deviation of the subjective line midpoint, they did not show any significant difference when compared to the other two experimental groups in both rightward and leftward line extension tasks. These results suggest that neglect for the left side of space is usually observed in tasks requiring an automatic lateral orienting of attention, but not in tasks in which this lateral orienting is submitted to a continuous intentional control.

Background: Contradictory interpretations of left unilateral neglect suggest that it reflects either decreased attention toward the left or increased attention toward the right. According to the right-hyperattention postulate, increasing severity of neglect should result from an increasingly stronger bias toward the right. Thus, response times to right-sided targets should become progressively faster as neglect increases in severity across patients. The left-hypoattention postulate predicts that as neglect increases, progressively less-attentional resources are deployed in both hemispaces. Thus, response times to right targets should progressively increase with increasing neglect. Methods: We analyzed the distribution of manual response times to left- and right-sided targets in 24 patients with right hemisphere lesions and varying degrees of left neglect. Results: Not only the responses to left targets but also those to right targets became progressively slower as neglect increased, consistent with the hypoattention account. However, the two regression lines were not parallel. With increasing neglect, responses to left targets increased more steeply than those to right targets did. Conclusions: A rightward attentional bias is present in patients with left neglect, together with left hypoattention. However, this rightward bias is one of defective, and not enhanced, attention.

When two visual events appear consecutively in the same spatial location, our response to the second event is slower than that to the first. This inhibition for repeated events may reflect a bias toward sampling novel locations, a bias useful for exploring the visual space. Patients with right hemisphere damage and left neglect explore asymmetrically a visual scene. They are initially attracted by right-sided items and become stuck to them, being unable to reorient their attention toward the left. Here we show that neglect patients show facilitation instead of inhibition for repeated events on the right, non-neglected side. Patients without neglect showed normal inhibition. Our observation may explain why neglect patients' exploration of space cannot extend beyond a few right-sided objects.

The reference shift hypothesis of unilateral neglect holds that spatial bias in left neglectstems from a rightward deviation of patients egocentric frame of reference (ER). Twenty fiveunselected right brain-damaged patients participated in a straight-ahead pointing task to assessthe position of their ER (Experiment 1). A rightward ER shift emerged only in the subgroup ofpatients with extensive parietal lesions. In Experiment 2, we found that the position of the ER didnot predict the outcome of various visuospatial neglect tests ( r = 0.07 to 0.27). In Experiment 3,no significant positive correlation emerged between the ER position and visual ( r = 0.26) ortactile ( r = −0.48) extinction. Two further experiments examined the relationships between theER position and patients performance on a reaction time test of directional motor bias(Experiment 4), and on a test of response times to lateralised visual stimuli (Experiment 5).Results showed that the ER position did not predict the distribution of accuracy scores orresponse times in either task (Experiment 3: accuracy: r = 0.06; response times: r = 0.16;Experiment 4: accuracy: r = 0.09; response times: r = 0.04). We concluded that the position ofthe ER plays no crucial role in the behavioural consequences of spatial bias induced by righthemisphere lesions.

We asked 12 right-brain-damaged patients (6 with left neglect signs and 6 without left neglect signs) to perform a straight ahead pointing task and a visual detection task with lateralized motor response, in order to investigate the relationship between the position of the egocentric reference and response time and accuracy in producing lateralized arm movements. Results showed that there was no correlation between the position of the egocentric reference and neglect signs, nor between the position of the egocentric reference and the latencies to direct a motor response toward either side of space. These findings were interpreted within the context of egocentric hypotheses of neglect. In particular, it was suggested that attentional or intentional neglect signs cannot be considered as a direct consequence of an ipsilesional deviation of the egocentric reference.

A brain-damaged patient is described whose pattern of performance provides insight into both the functional mechanisms and the neural structures involved in visual mental imagery. The patient became severely agnosic, alexic, achromatopsic and prosopagnosic following bilateral brain lesions in the temporo-occipital cortex. However, her mental imagery for the same visual entities that she could not perceive was perfectly preserved. This clear-cut dissociation held across all the major domains of high-level vision: object recognition, reading, colour and face processing. Our findings, together with other reports on domain-specific dissociations and functional brain imaging studies, provide evidence to support the view that visual perception and visual mental imagery are subserved by independent functional mechanisms, which do not share the same cortical implementation. In particular, our results suggest that mental imagery abilities need not be mediated by early visual cortices.

A 74-year-old woman became a letter-by-letter reader after the occurrence of a left occipito-temporal hematoma. Seven months later, she suffered a second, mirror-image hematoma in the right hemisphere. After this second lesion, her residual reading capacity deteriorated dramatically in terms of both accuracy and reading latencies for words and isolated letters. Our findings support the hypothesis that the right hemisphere contributes to the residual reading capacities of pure alexic patients.

Sixty normal dextrals (30 left-to-right and 30 right-to-left readers) and two left unilateral neglect patient with opposite reading habits performed a passive line bisection task. In order to study the effect of scanning direction on performance, subjects had to stop a mark moving on the to-be-bisected line either from the left to the right or in the opposite direction. Results showed that the position of the subjective middle was dependent upon the scanning direction of the line for all the subjects. A leftward deviation appeared for left to right scanning, whereas a rightward shift occurred when the mark moved from the right to the left. These results emphasize the role of scanning direction in space organization and are discussed with respect to the explanatory hypotheses of unilateral neglect.

Hemispatial neglect is a neurological disorder which entails a spatial bias that penalizes events occurring in the hemispace contralateral to a brain lesion. Mechanisms operating upon various stages ranging from perception to action have been invoked to explain neglect. The present study explores the contribution of a defective programming of arm movements towards the neglected hemispace to neglect behaviour. Two reaction time tasks — a “perceptual” task and a “motor” task — were performed by right brain-damaged (RBD) patients with left hemispatial neglect, RBD patients without signs of neglect and control subjects. The perceptual task consisted of lateralized visual stimuli and central motor responses, whereas the motor task consisted of visual stimuli presented on the vertical midline and hand responses to be produced in either hemispace. Neglect patients showed a rightward bias on the perceptual task, but only two RBD patients (showing no signs of severe neglect) were consistently slowed in producing leftward motor responses. Different reference frames may thus be used in perceptual tasks and tasks involving arm movements. We conclude that hemispatial neglect commonly results from attentional impairments operating upon a visual perceptual frame of reference; additional deficits appear to be necessary to produce a directional motor disorder.

Sixteen control subjects and six right brain-damaged patients with left hemiparesis (three showing signs of left unilateral neglect, three with no signs of neglect) performed a straight-ahead pointing task with their right hand while blindfolded. The aim was to test the hypothesis that the egocentric reference shows significant ipsilesional deviation in left neglect patients. We found no correlation between the position of the egocentric reference and the presence of neglect signs. Neglect patients, like non-neglect patients, showed leftware, rightward or no significant deviation when pointing straight ahead. Results are discussed with reference to egocentric hypotheses of neglect and experimental remission of neglect.

In this study we report a patient, MG, who following rupture of left posterior communicating artery exhibited an amnesic-confabulatory syndrome. Neuropsychological examination showed severe impairment on episodic memory tasks, which were marred by florid but plausible and semantically appropriate confabulation. Performance on tasks involving various kinds of semantic knowledge was normal or only mildly impaired. Performance on tasks traditionally considered sensitive to frontal dysfunction was severely impaired with the exception of Cognitive Estimates where MG's performance was completely normal. There was no evidence of structural (CT scan) or metabolic (SPECT) damage to the frontal lobe. It is argued that tasks traditionally considered sensitive to frontal dysfunction are not specifically implemented by cognitive resources based on frontal structures. MG's confabulation is discussed in terms of a possible disruption of cognitive functions involved in the control of the subjective experience of feeling of remembering.

Left neglect patients, patients who had recovered from left neglect and control subjects performed a task of simple motor reaction times (RTs) to lateralised visual stimuli. Neglect and recovered patients were slower than controls on left-sided targets. To explore the time course of the allocation of attention across space, an analysis of responses as a function of the serial order of the trials was performed. While neglect patients' performance did not substantially change over time, recovered patients showed a stereotyped ‘novelty effect’, consisting of larger left/right RT differences at the beginning of the task than at the end of it. To explain this practice-related change, a trade-off is hypothesised between the process of learning the motor task and the mechanisms involved in recovery from neglect, such as the reorienting of attention toward the contralesional side following the initial ipsilesional orienting. A possible role is proposed for the prefrontal cortex as the crucial neural structure that mediates both processes

We describe a letter-by-letter patient who produced misreading errors in both letters in isolation and in words. All errors were visual in nature. We hypothesized an access deficit to the abstract visual representation of letters that prevents letter identification. This deficit could account for the patient's letter-by-letter behavior, since each letter constituted a potential identification problem. An access deficit, moreover, could also explain the patient's letter visual errors. In access processing, in fact, the letters sharing common structural features in their abstract representations were the ones more frequently mismatched.

Abstract 4094 Background: Telomeres are linear DNA structures at the ends of chromosomes that help to maintain genome stability. In the absence of effective telomere-protecting mechanisms, chromosomes lose a few base pairs (bp) of their telomeric DNA at each mitotic division and thus telomere length (TL) is also considered a marker of cell aging. In the hematopoietic system, TL of both early and committed progenitors progressively shortens with age, as in other highly replicating tissues. Moreover, many studies demonstrated that high proliferative stresses, including bone marrow (BM) regeneration after transplantation, cause a non-physiological TL shortening. Indeed, recent studies suggest that post-autograft TL correlates with TL of grafted material (Ruella et al, 2010). In order to address this issue, TL has been evaluated in a series of adult subjects engrafted with umbilical cord blood (UCB), a graft source characterized by cells harboring very long telomeres. Aim of the study was to verify whether despite the high replicative stress during engraftment, UCB hematopoietic stem cells may renew the recipient BM, maintaining the biologic characteristics of the graft. Patients and Methods: TL was evaluated on peripheral blood (PB) cells from 20 adult recipients of umbilical cord blood transplant (UCBT). They had been transplanted due to acute leukemia (n=12), multiple myeloma (n=2), non-Hodgkin's Lymphoma (n=3) or chronic myeloproliferative disease (=3). TL analysis was performed in absence of signs of the previous disease and at complete hematological recovery, at a median of 9 mos. (range 1–73) since UCBT. At TL analysis, cell blood counts revealed median values of 7,540 white blood cells/μL (range 2,870-18,800), 11.9 gr% of hemoglobin (range 8.3–14), and 144,000 platelets/μL (range 41,000–351,000). TL was evaluated on both whole PB cells and separated cell populations, i.e. MNC and granulocytes, obtained following Ficoll gradient cell separation. TL was also determined on a series of 47 UCB samples, including samples from cord blood units employed as graft material for four patients of the present series. TL was determined on DNA extracts by Southern blot analysis, according to well established procedures. Briefly, DNA fragments were separated by agarose gel electrophoresis. The Telomere Length Assay Kit (Roche Diagnostic) was used for the hybridization phase and for each telomere smear, mean terminal restriction fragment (TRF) lengths and the point of maximum signal intensity defining the highest concentration of telomere repeats were calculated using Quantity One software (Bio-Rad Laboratories, UK). Results: Overall, TL in PB cells following UCBT showed a rapid fall compared to TL values that characterize cord blood cells. In our series of 47 UCB samples, the median TL-TRF on MNC is 9,171 bp (range 6,573-13,695), whereas MNC from our UCBT recipients showed a median TL-TRF of 8,689 bp (range 5,982-11,149) (p=0,055). When values were distributed according to the age of UCBT recipients, TL remained higher than TL obtained from a large series of hundreds of normal control subjects. Indeed, median TL-TRF on MNC from healthy controls is 6,951 bp (range 4,375-10,467), significantly shorter compared to MNC from UCBT recipients, as shown in Figure 1. Similar results were obtained when TL was assessed on whole PB cells and on separated granulocytes. In fact, the most marked difference in TL between UCBT recipients and normal controls was observed on granulocytes. This was particularly clear among subjects aged >40 yrs. As shown in Figure 2, median TL-TRF on granulocytes from UCBT recipients aged 40–65 yrs. was 9,138 bp (range 7,644 – 11,138) compared to 6,857 bp (range 5,773 – 10,946) of granulocytes from age-matched normal controls. Overall, PB cells from subjects grafted with UCB showed a TL slightly longer than in the youngest control population of 0–20 yrs. of age. Lastly, no difference in TL was observed according to time elapsed since transplant, with analogous TL values in subjects evaluated at less or more than 6 months since UCBT. Conclusions: The results indicate that despite the high replicative stress during BM engraftment, UCBT regenerate a hematopoietic system characterized by long TL. This suggests that in the transplant setting the use of young donor cells such as UCB may replace patient BM with not only a healthy but also a biologically young hematopoietic system. Disclosures: Rambaldi: Hoffman-La Roche: Consultancy, Honoraria.

Objective: To identify white matter correlates of chronic right visuospatial neglect signs. Background The exact anatomical location of the lesions in the right hemisphere that lead to signs of visuospatial neglect is currently the object of an intense debate. The effect of confounding factors such as acute diaschisis and hypoperfusion, visual field defects and lesion size may account for conflicting results obtained by previous studies. Design/Methods: Here we present a detailed and comprehensive anatomical study of the white matter lesions in 77 patients with chronic vascular strokes in the right hemisphere and varying signs of visuospatial neglect based on a recently published atlas of the human brain connections. We took into account both lesion size and the presence of visual field defects. Results: White matter analyses confirmed the crucial role of damage to the second branch of the superior longitudinal fasciculus (SLF) in the determinism of chronic signs of visuospatial neglect with a sensitivity of 0.8 and a specificity of 0.84 (p= 0.002). Fronto-parietal disconnection was confirmed with DTI-tractography in a case-control study of two perfectly matched patients. Our analyses also revealed a small subgroup of neglect patients with no SLF damage, but with a focal lesion in the latero-dorsal portion of the thalamus connecting the premotor cortex and the inferior parietal lobule. Conclusions: These results provide a solution to the debate concerning the lesional bases of visuospatial neglect, by precisely identifying in a large sample of patients a cortico-subcortical network subserving aspects of spatial attention, whose dysfunction is crucial to the occurrence of neglect signs. Disclosure: Dr. Thiebaut De Schotten has nothing to disclose. Dr. Tomaiuolo has nothing to disclose. Dr. Bartolomeo has nothing to disclose. Dr. Doricchi has nothing to disclose.

Using a quantitative measure, we analyzed the relationship between visuospatial and representational neglect in right- and left-brain-damaged patients and found signs of representational neglect only in right-brain-damaged patients. Although representational neglect was always associated with visuospatial neglect, suggesting that the two forms share a common underlying mechanism, the most frequent finding in right-brain--damaged patients was that of visuospatial neglect in isolation. A strong influence of the phenomenon of attentional attraction toward space ipsilateral to the lesion in visuospatial, as opposed to imaginal, tasks can account for this finding.

Right brain-damaged patients with unilateral neglect, who ignore left-sided visual events, may also omit left-sided details when describing known places from memory. Modulating the orienting of visual attention may ameliorate imaginal neglect. A first step toward explaining these phenomena might be to postulate that space-related imagery is a cognitive activity involving attentional and intentional aspects.

Abstract 4546 Background: Reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed lymphomas. The present GITMO study is a prospective multicenter phase II trial for patients affected by relapsed CD20 positive lymphomas. Compared with the previous thiotepa/fludarabine/cyclophosphamide GITMO protocol (Leukemia 2007), the thiotepa dose is increased, and high-dose Rituximab is included in the regimen to improve the outcome and possibly modulate the incidence of acute GVHD. Aims: Primary end-point was 1-year progression-free survival; secondary endpoints were non-relapse mortality and incidence of acute and chronic GVHD. Methods: Fifty-seven patients (pts) were enrolled so far in the study and 49 are evaluable for analysis. Treatment plan consisted of high-dose R (500 mg/ms on day -6) followed by thiotepa (12 mg/kg), fludarabine (60 mg/kg) and cyclophosphamide (60 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and mini-methotrexate; ATG (7.5 mk/kg) was only added for pts allografted from one antigen mismatched sibling or unrelated donors. Histopathological subtypes included 24 aggressive (HG) (n= 17 diffuse large B-cell lymphomas, n= 7 mantle cell lymphomas) and 25 indolent lymphomas (LG) (n= 13 follicular lymphomas, n= 12 small lymphocytic/chronic lymphocytic leukemia). Patients were allografted from related siblings (SIB) (n= 32 matched, n=1 one single mismatched) or unrelated donors (UD) (n=11 matched, n=5 mismatched). All the pts had chemosensitive disease (n=20, 41% in complete remission) and 26 (53%) came from a failed autoSCT. Results: At a median follow-up of 13 months (range, 5–44 months), 36 pts are alive [n=27 (75%) in CR] and 13 died from any cause [n=6 for non-relapse mortality (NRM), n=7 for disease progression]. All the patients engrafted (94% had full donor chimerism at 3 months). The cumulative incidence (CI) of NRM was 13% at 1 year: 9% vs 19% for SIB and MUD (p=0.3), and 9% versus 16% for for LG and HG (p=0.3), respectively. In total only 11 of 49 pts had acute GVHD (n=8 grade II, n=3 grade III) with an estimated CI of 21% at 100 days. In the previous GITMO study the incidence was 35% with SIB only. Forty pts are evaluable for chronic GVHD with an estimated CI of 41% and 47% at 1 and 2 year, respectively (n=11 limited, n=3 extensive). Infections after engraftment requiring hospitalization or intravenous treatment were evaluable in 46 pts (n=3 excluded for early death). The overall incidence of infections was 58% (n=27) including 5 pts experienced sepsis and 10 pts pneumonia. Preliminary data on immune-reconstitution at 1 year showed: 1) low number of circulating B cells (median CD19+/ul: 129/ul) with an expansion of naive cells (IgD+, CD27-); 2) the median value of IgM was 89 mg/dl whereas IgG and IgA remained at low levels. The CI of relapse was 26% and 37% at 1 year and 2 years, respectively. In the indolent and aggressive groups, OS estimates at 2 years were 79% (95%CI, 52%-91%) and 61% (95 CI, 38%-77%) and PFS estimates were 53% (95%CI, 23%-76%) and 48% (95% CI, 27%-66%), respectively. Conclusions: The present data suggest that the administration of high-dose R is feasible and causes an unexpected reduction of the incidence of acute GVHD without increasing the NRM and the incidence of severe infections complications. Complete data evaluating the effects of R on immune reconstitution are ongoing. Disclosures: No relevant conflicts of interest to declare.