Evidence for a radiation belt around a brown dwarf.

Ultracool dwarfs (UCDs) are a category of astronomical objects that includes brown dwarfs and very-low-mass stars. Radio observations of UCDs have measured their brightness as a function of time (light curves) and spectral energy distributions, providing insight into their magnetic fields. We present spatially resolved radio observations of the brown dwarf LSR J1835+3259 using very-long-baseline interferometry showing extended radio emission. The detected morphology is consistent with the presence of a radiation belt. Comparison with models indicates that the radiation belt contains energetic particles confined by magnetic mirroring. We contend that radio-emitting UCDs have dipole-ordered magnetic fields with radiation belt-like morphologies and aurorae that are similar to those of Jupiter.

Do cone age and heating mode determine the opening of serotinous cones during wildfires? A new bench scale approach applied to Pinus halepensis Mill.

Serotiny is a well-known fire adaptive trait in some species, as the Mediterranean conifer Pinus halepensis. However, information about cone opening mechanisms during wildfires and consequences on post fire dispersal is scarce. In addition, standardized methods allowing a realistic simulation of heating modes at bench-scale are not available. In this study, we address for the first time the interacting effects of radiation, convection and direct flame on the opening and seed release of serotinous cones, following a novel repeatable methodology. Using a Mass Loss Calorimeter (MLC) device and a wide range of heat exposures (between 5 and 75 kW m-2) with or without ignition, we intended to simulate realistic cone heating during surface and crown fires in laboratory conditions. Additionally, we included the effect of contrasting serotinous cone ages interacting with heating mode and considering the random individual variation. The proposed methodology has shown a high potential to simulate the complex process of crown fires in relation to cone opening under controlled conditions, detecting a threshold of heat exposure (25-30 kW m-2) for cone opening. We confirmed that heating mode had a highly significant effect in cone opening, interacting with cone age, while cone age effect on its own was marginal. Particularly, ignition significantly increased the efficacy of cone opening and seed release. Moreover, young and old cones behave differently in seed release, both in surface and crown fire simulations. Implementing and adjusting this methodology in other species will allow more realistic and reliable quantitative comparisons than previously attained.

Functional relationships between leaves and stem across canopy layers in two contrasting clones of Populus nigra L.

Populus nigra L. represents a model system for plant biology and has a productive interest in breeding for short rotation forestry. The growth potential and adaptive capacity of this species are well characterized, but the canopy effect is poorly investigated. We analyzed morphological and functional leaf traits across a multilayer canopy profile in two contrasting clones of this species, 58-861 and Poli, respectively from northern and southern Italy, grown in field plantation. The results revealed how the variation of leaf functional traits was structured within the canopy. The two clones showed differences in leaf morphology and water use efficiency, but organized a similar functional canopy structure along a vertical profile, related to a gradient of light radiation. An acropetal enrichment gradient of carbon stable isotope was found both in leaves and stem wood across a vertical canopy profile and a tight correlation was found between carbon stable isotopes of leaves and of the respective stem section. Such a functional relationship indicates that substrates for stem growth were sourced from leaf assimilates of the closest canopy layer. These results characterize the physiology of black poplar under micro-environmental conditions at intra-canopy scale and contribute to clarify the canopy effect in young trees.

[Ionizing radiation received by patients with osteosarcoma during intra-arterial chemotherapy treatment]. / Radiación ionizante recibida por pruebas de radiología intervencionista durante el tratamiento con quimioterapia intraarterial en pacientes afectos de osteosarcoma.

BACKGROUND: Osteosarcoma paediatric patients are usually treated with intra-arterial chemotherapy (QTia) which is admi-nistered directly to the tumour. This procedure exposes patients to ionizing radiation. Paediatric patients are especially sensitive to this exposure. METHODS: The total amount of ionizing radiation received from QTia administration was quantified in a group of 16 osteo-sarcoma paediatric patients from the Clínica Universidad de Navarra. RESULTS: The median of the total radiation received per patient was 33.4 Gy·cm2 (IQR: 43.33 Gy·cm2), and the median number of procedures performed per subject was 10 (IQR: 6.5). CONCLUSIONS: The study highlights the importance of quantifying the radiation received by a group of children and adoles-cents affected by osteosarcoma during treatment with QTia. Long-term side effects of this radiation should be considered in pae-diatric patients. Currently, there are no previous studies that provide data of the amount of ionizing radiation received through this procedure.

ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA.

Long-term survival remains low for most patients with glioblastoma (GBM), which reveals the need for markers of disease outcome and novel therapeutic targets. We describe that ODZ1 (also known as TENM1), a type II transmembrane protein involved in fetal brain development, plays a crucial role in the invasion of GBM cells. Differentiation of glioblastoma stem-like cells drives the nuclear translocation of an intracellular fragment of ODZ1 through proteolytic cleavage by signal peptide peptidase-like 2a. The intracellular fragment of ODZ1 promotes cytoskeletal remodelling of GBM cells and invasion of the surrounding environment both in vitro and in vivo. Absence of ODZ1 by gene deletion or downregulation of ODZ1 by small interfering RNAs drastically reduces the invasive capacity of GBM cells. This activity is mediated by an ODZ1-triggered transcriptional pathway, through the E-box binding Myc protein, that promotes the expression and activation of Ras homolog family member A (RhoA) and subsequent activation of Rho-associated, coiled-coil containing protein kinase (ROCK). Overexpression of ODZ1 in GBM cells reduced survival of xenografted mice. Consistently, analysis of 122 GBM tumour samples revealed that the number of ODZ1-positive cells inversely correlated with overall and progression-free survival. Our findings establish a novel marker of invading GBM cells and consequently a potential marker of disease progression and a therapeutic target in GBM.

Radiation dose produced by patients during radiopharmaceutical incorporation in nuclear medicine diagnostic procedures.

OBJECTIVES: The aim of this study was to assess the dose received by members of the public due to close contact with patients undergoing nuclear medicine procedures during radiopharmaceutical incorporation, and comparing it with the emitted radiation dose when the test was complete, in order to establish recommendations. MATERIAL AND METHODS: A prospective study was conducted on 194 patients. H*(10) dose rates were measured at 0.1, 0.5, and 1.0m after the radiopharmaceutical administration, before the image acquisition, and at the end of the nuclear medicine procedure. Effective dose for different close contact scenarios were calculated, according to 95th percentile value (bone scans) and the maximum value (remaining tests). RESULTS: During the radiopharmaceutical incorporation, a person who stays with another injected patient in the same waiting room may receive up to 0.59 mSv. If the patient had a medical appointment, or went to a restaurant or a coffee shop, members of the public could receive 23, 43, and 22 µSv, respectively. After finishing the procedure, these doses are reduced by a factor 3. In most of the studies, the use of private instead of public transport may reduce the dose by more than a factor 6. CONCLUSION: It is recommended to increase the distance between the patients during the radiopharmaceutical incorporation and to distribute them according to the diagnostic procedure. Patients should be encouraged to use private instead of public transport. Depending on the number of nuclear medicine outpatients per year attended by a physician, it could be necessary to apply restrictions.

Radiation dosimetry and biodistribution in non-human primates of the sodium/iodide PET ligand [(18)F]-tetrafluoroborate.

BACKGROUND: [(18)F]-tetrafluoroborate is a PET radiotracer taken up by the sodium/iodide symporter (NIS). Albeit the in vivo behavior in rodents is similar to the (99m)Tc-pertechnetate, no studies exist in primates or in humans. The aims of this study were to evaluate the biodistribution of [(18)F]-tetrafluoroborate in non-human primates with PET and to estimate the absorbed dose in organs. METHODS: Whole-body PET imaging was done in a Siemens ECAT HR+ scanner in two male Macaca fascicularis monkeys. After an i.v. injection of 24.93 ± 0.05 MBq/kg of [(18)F]-tetrafluoroborate, prepared by isotopic exchange of sodium tetrafluoroborate with [(18)F]-fluoride under acidic conditions, eight sequential images from the head to the thigh (five beds) were collected for a total duration of 132 min. The whole-body emission scan was reconstructed applying attenuation and scatter corrections. After image reconstruction, three-dimensional volumes of interest (VOIs) were hand-drawn on the PET transaxial or coronal slices of the frame where the organ was most conspicuous. Time-activity curves for each VOI were obtained, and the organ residence times were calculated by integration of the time-activity curves. Human absorbed doses were estimated using the OLINDA/EXM software and the standard human model. RESULTS: [(18)F]-tetrafluoroborate was able to discriminate clearly the thyroid gland with an excellent signal-to-noise ratio. Most of the radiotracers (residence time) are localised in the organs that express NIS (stomach wall, salivary glands, thyroid, olfactory mucosa), are involved in excretion (kidneys and bladder), or reflect the vascular phase (heart and lungs). Considering the OLINDA source organs, the critical organs were the stomach wall, thyroid and bladder wall, with absorbed doses lower than 0.078 mGy/MBq. The effective dose was 0.025 mSv/MBq. CONCLUSIONS: [(18)F]-tetrafluoroborate is a very useful radiotracer for PET thyroid imaging in primates, with a characteristic biodistribution in organs expressing NIS. It delivers an effective dose slightly higher than the dose produced by (99m)Tc-pertechnetate but much lower than that produced by radioiodine in the form of (131)INa, (123)INa, or (124)INa.

Horizontal gene transfer from a flowering plant to the insular pine Pinus canariensis (Chr. Sm. Ex DC in Buch).

Horizontal gene transfer (HGT) is viewed as very common in the plant mitochondrial (mt) genome, but, to date, only one case of HGT has been found in gymnosperms. Here we report a new case of HGT, in which a mt nad5-1 fragment was transferred from an angiosperm to Pinus canariensis. Quantitative assay and sequence analyses showed that the foreign nad5-1 is located in the mt genome of P. canariensis and is nonfunctional. An extensive survey in the genus Pinus revealed that the angiosperm-derived nad5-1 is restricted to P. canariensis and present across the species' range. Molecular dating based on chloroplast DNA suggested that the HGT event occurred in the late Miocene after P. canariensis split from its closest relatives, and that the foreign copy became fixed in P. canariensis owing to drift during its colonization of the Canary Islands. The mechanism of this HGT is unclear but it was probably achieved through either direct cell-cell contact or external vectors. Our discovery provides evidence for an important role of HGT in plant mt genome evolution.

KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype.

To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.

[¹8F]fluorothymidine-positron emission tomography in patients with locally advanced breast cancer under bevacizumab treatment: usefulness of different quantitative methods of tumor proliferation.

OBJECTIVES: To investigate quantitative methods of tumor proliferation using 3'-[(18)F]fluoro-3'-deoxythymidine ([(18)F]FLT) PET in patients with breast cancer (BC), studied before and after one bevacizumab administration, and to correlate the [(18)F]FLT-PET uptake with the Ki67 index. MATERIAL AND METHODS: Thirty patients with newly diagnosed, untreated BC underwent a [(18)F]FLT-PET before and 14 days after bevacizumab treatment. A dynamic scan centered over the tumor began simultaneously with the injection of [(18)F]FLT (385 ± 56 MBq). Image derived input functions were obtained using regions of interest drawn on the left ventricle (LV) and descending aorta (DA). Metabolite corrected blood curves were used as input functions to obtain the kinetic Ki constant using the Patlak graphical analysis (time interval 10-60 min after injection). Maximum SUV values were derived for the intervals 40-60 min (SUV40) and 50-60 min (SUV50). PET parameters were correlated with the Ki67 index obtained staining tumor biopsies. RESULTS: [(18)F]FLT uptake parameters decreased significantly (p<0.001) after treatment: SUV50=3.09 ± 1.21 vs 2.22 ± 0.96; SUV40=3.00 ± 1.18 vs 2.14 ± 0.95, Ki_LV(10-3)=52[22-116] vs 38[13-80] and Ki_DA(10-3)=49[15-129] vs 33[11-98]. Consistency interclass correlation coefficients within SUV and within Ki were high. Changes of SUV50 and Ki_DA between baseline PET and after one bevacizumab dose PET correlated with changes in Ki67 index (r-Pearson=0.35 and 0.26, p=0.06 and 0.16, respectively). CONCLUSIONS: [(18)F]FLT-PET is useful to demonstrate proliferative changes after a dose of bevacizumab in patients with BC. Quantification of tumor proliferation by means of SUV and Ki has shown similar results, but SUV50 obtained better results. A correlation between [(18)F]FLT changes and Ki67 index was observed.

[Validation of segmentation techniques for positron emission tomography using ex-vivo images of oncological surgical specimens]. / Validación de técnicas de segmentación para la tomografía por emisión de positrones mediante imágenes ex-vivo de piezas quirúrgicas oncológicas.

OBJECTIVE: To design a novel ex-vivo acquisition technique to establish a common framework to validate different segmentation techniques for oncological PET images. To evaluate several automatic segmentation algorithms on this set of images. MATERIAL AND METHODS: In 15 patients with cancer, ex-vivo PET studies of surgical specimens removed during surgery were performed after injection of (18)F-FDG. Images were acquired in two scanners: a clinical PET/CT and a high-resolution PET scanner. Real tumor volume was determined in each patient, and a reference image was generated for segmentation of each tumor. Images were segmented with 12 automatic algorithms and with a standard method for PET (relative threshold at 42%) and results were evaluated by quantitative parameters. RESULTS: It has been possible to demonstrate by segmentation of PET images of surgical specimens that on high resolution PET images, 8 out of 12 evaluated segmentation techniques outperformed the standard method, whose value is 42%. However, none of the algorithms outperformed the standard method when applied on images from the clinical PET/CT. Due to the great interest of this set of PET images, all studies have been published on the Internet in order to provide a common framework for validation and comparison of different segmentation techniques. CONCLUSIONS: We have proposed a novel technique to validate segmentation techniques for oncological PET images, acquiring ex-vivo PET studies of surgical specimens. We have demonstrated the usefulness of this set of PET images by evaluating several automatic segmentation algorithms.

Plasticity in reproduction and growth among 52 range-wide populations of a Mediterranean conifer: adaptive responses to environmental stress.

A plastic response towards enhanced reproduction is expected in stressful environments, but it is assumed to trade off against vegetative growth and efficiency in the use of available resources deployed in reproduction [reproductive efficiency (RE)]. Evidence supporting this expectation is scarce for plants, particularly for long-lived species. Forest trees such as Mediterranean pines provide ideal models to study the adaptive value of allocation to reproduction vs. vegetative growth given their among-population differentiation for adaptive traits and their remarkable capacity to cope with dry and low-fertility environments. We studied 52 range-wide Pinus halepensis populations planted into two environmentally contrasting sites during their initial reproductive stage. We investigated the effect of site, population and their interaction on vegetative growth, threshold size for female reproduction, reproductive-vegetative size relationships and RE. We quantified correlations among traits and environmental variables to identify allocation trade-offs and ecotypic trends. Genetic variation for plasticity was high for vegetative growth, whereas it was nonsignificant for reproduction. Size-corrected reproduction was enhanced in the more stressful site supporting the expectation for adverse conditions to elicit plastic responses in reproductive allometry. However, RE was unrelated with early reproductive investment. Our results followed theoretical predictions and support that phenotypic plasticity for reproduction is adaptive under stressful environments. Considering expectations of increased drought in the Mediterranean, we hypothesize that phenotypic plasticity together with natural selection on reproductive traits will play a relevant role in the future adaptation of forest tree species.

Automated analysis of FDG PET as a tool for single-subject probabilistic prediction and detection of Alzheimer's disease dementia.

PURPOSE: To introduce, evaluate and validate a voxel-based analysis method of ¹8F-FDG PET imaging for determining the probability of Alzheimer's disease (AD) in a particular individual. METHODS: The subject groups for model derivation comprised 80 healthy subjects (HS), 36 patients with mild cognitive impairment (MCI) who converted to AD dementia within 18 months, 85 non-converter MCI patients who did not convert within 24 months, and 67 AD dementia patients with baseline FDG PET scan were recruited from the AD Neuroimaging Initiative (ADNI) database. Additionally, baseline FDG PET scans from 20 HS, 27 MCI and 21 AD dementia patients from our institutional cohort were included for model validation. The analysis technique was designed on the basis of the AD-related hypometabolic convergence index adapted for our laboratory-specific context (AD-PET index), and combined in a multivariable model with age and gender for AD dementia detection (AD score). A logistic regression analysis of different cortical PET indexes and clinical variables was applied to search for relevant predictive factors to include in the multivariable model for the prediction of MCI conversion to AD dementia (AD-Conv score). The resultant scores were stratified into sixtiles for probabilistic diagnosis. RESULTS: The area under the receiver operating characteristic curve (AUC) for the AD score detecting AD dementia in the ADNI database was 0.879, and the observed probability of AD dementia in the six defined groups ranged from 8% to 100% in a monotonic trend. For predicting MCI conversion to AD dementia, only the posterior cingulate index, Mini-Mental State Examination (MMSE) score and apolipoprotein E4 genotype (ApoE4) exhibited significant independent effects in the univariable and multivariable models. When only the latter two clinical variables were included in the model, the AUC was 0.742 (95% CI 0.646 - 0.838), but this increased to 0.804 (95% CI 0.714 - 0.894, bootstrap p=0.027) with the addition of the posterior cingulate index (AD-Conv score). Baseline clinical diagnosis of MCI showed 29.7% of converters after 18 months. The observed probability of conversion in relation to baseline AD-Conv score was 75% in the high probability group (sixtile 6), 34% in the medium probability group (merged sixtiles 4 and 5), 20% in the low probability group (sixtile 3) and 7.5% in the very low probability group (merged sixtiles 1 and 2). In the validation population, the AD score reached an AUC of 0.948 (95% CI 0.625 - 0.969) and the AD-Conv score reached 0.968 (95% CI 0.908 - 1.000), with AD patients and MCI converters included in the highest probability categories. CONCLUSION: Posterior cingulate hypometabolism, when combined in a multivariable model with age and gender as well as MMSE score and ApoE4 data, improved the determination of the likelihood of patients with MCI converting to AD dementia compared with clinical variables alone. The probabilistic model described here provides a new tool that may aid in the clinical diagnosis of AD and MCI conversion.

[Contribution of time of flight and point spread function modeling to the performance characteristics of the PET/CT Biograph mCT scanner]. / Aportación del tiempo de vuelo y de la modelización de la respuesta a una fuente puntual a las características de funcionamiento del tomógrafo PET/TAC Biograph mCT.

OBJECTIVE: To characterize the performance of the Biograph mCT PET/CT TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. MATERIAL AND METHODS: The PET/CT scanner combines a 64-slice CT and PET scanner that incorporates in the reconstruction the TOF and PSF information. PET operating characteristics were evaluated according to the standard NEMA NU 2-2007, expanding some tests. In addition, different reconstruction algorithms were included, and the intrinsic radiation and tomographic uniformity were also evaluated. RESULTS: The spatial resolution (FWHM) at 1 and 10cm was 4.4 and 5.3mm, improving to 2.6 and 2.5mm when PSF is introduced. Sensitivity was 10.9 and 10.2 Kcps/MBq at 0 and 10cm from the axis. Scatter fraction was less than 34% at low concentrations and the noise equivalent count rate (NECR) was maximal at 27.8 kBq/mL with 182 Kcps, the intrinsic radiation produced a rate of 4.42 true coincidences per second. Coefficient of variation of the volume and system uniformity were 4.7 and 0.8% respectively. The image quality test showed better results when PSF and TOF were included together. PSF improved the hot spheres contrast and background variability, while TOF improved the cold spheres contrast. CONCLUSIONS: The Biograph mCT TrueV scanner has good performance characteristics. The image quality improves when the information from the PSF and the TOF is incorporated in the reconstruction.

Intraoperative monitoring of carotid endarterectomy by transcranial motor evoked potential: a multicenter study of 600 patients.

OBJECTIVE: This study was to investigate the utility of motor evoked potential monitoring elicited by transcranial electrical stimulation (tcMEP) during CEA in addition to the established median nerve somatosensory evoked potentials (mSSEPs). METHODS: We retrospectively reviewed data from 600 patients undergoing CEA under general anesthesia with monitoring of mSSEPs and tcMEPs in a multicenter study. MSSEP and tcMEP parameters were recorded during internal carotid artery (ICA) cross clamping and compared with the postoperative motor outcome, demographic and patient history data. RESULTS: The intraoperative monitoring of tcMEPs was successful in 594 of the patients (99%) and selective shunt was performed in 29 of them (4.83%). Nine of the patients showed a transient contralateral loss of tcMEPs, without changes in mSSEPs and required intervention (1.5% "false-negative"). Three of them showed postoperative motor deficits. The time period from tcMEP loss to intervention was significantly longer (p = 0.01) in this group compared to the patients without postoperative motor deficit. CONCLUSION: TcMEPs during CEA may be an adjunct to mSSEP monitoring to avoid "false-negative" mSSEP results, as mSSEPs seem to lack specificity for detecting isolated ischemia of corticospinal pathway. SIGNIFICANCE: TcMEPs seem to improve postoperative outcome, especially in case of a timely correction of cerebral ischemia.

Genetic differentiation for size at first reproduction through male versus female functions in the widespread Mediterranean tree Pinus pinaster.

BACKGROUND AND AIMS: The study of local adaptation in plant reproductive traits has received substantial attention in short-lived species, but studies conducted on forest trees are scarce. This lack of research on long-lived species represents an important gap in our knowledge, because inferences about selection on the reproduction and life history of short-lived species cannot necessarily be extrapolated to trees. This study considers whether the size for first reproduction is locally adapted across a broad geographical range of the Mediterranean conifer species Pinus pinaster. In particular, the study investigates whether this monoecious species varies genetically among populations in terms of whether individuals start to reproduce through their male function, their female function or both sexual functions simultaneously. Whether differences among populations could be attributed to local adaptation across a climatic gradient is then considered. METHODS: Male and female reproduction and growth were measured during early stages of sexual maturity of a P. pinaster common garden comprising 23 populations sampled across the species range. Generalized linear mixed models were used to assess genetic variability of early reproductive life-history traits. Environmental correlations with reproductive life-history traits were tested after controlling for neutral genetic structure provided by 12 nuclear simple sequence repeat markers. KEY RESULTS: Trees tended to reproduce first through their male function, at a size (height) that varied little among source populations. The transition to female reproduction was slower, showed higher levels of variability and was negatively correlated with vegetative growth traits. Several female reproductive traits were correlated with a gradient of growth conditions, even after accounting for neutral genetic structure, with populations from more unfavourable sites tending to commence female reproduction at a lower individual size. CONCLUSIONS: The study represents the first report of genetic variability among populations for differences in the threshold size for first reproduction between male and female sexual functions in a tree species. The relatively uniform size at which individuals begin reproducing through their male function probably represents the fact that pollen dispersal is also relatively invariant among sites. However, the genetic variability in the timing of female reproduction probably reflects environment-dependent costs of cone production. The results also suggest that early sex allocation in this species might evolve under constraints that do not apply to other conifers.

Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.

Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.

Quantitative volumetric analysis of gliomas with sequential MRI and ¹¹C-methionine PET assessment: patterns of integration in therapy planning.

PURPOSE: The aim of the study was to evaluate the volumetric integration patterns of standard MRI and (11)C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade. METHODS: We studied 23 patients with suspected or previously treated glioma who underwent preoperative (11)C-methionine PET because MRI was imprecise in defining the surgical target contour. Images were transferred to the treatment planning system, coregistered and fused (BrainLAB). Tumour delineation was performed by (11)C-methionine PET thresholding (vPET) and manual segmentation over MRI (vMRI). A 3-D volumetric study was conducted to evaluate the contribution of each modality to tumour target volume. All cases were surgically treated and histological classification was performed according to WHO grades. Additionally, several biopsy samples were taken according to the results derived either from PET or from MRI and analysed separately. RESULTS: Fifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high (11)C-methionine uptake without correspondence in MRI showed tumour proliferation, including infiltrative zones, distinguishing them from dysplasia and radionecrosis. Two main PET/MRI integration patterns emerged after analysis of volumetric data: pattern vMRI-in-vPET (11/23) and pattern vPET-in-vMRI (9/23). Besides, a possible third pattern with differences in both directions (vMRI-diff-vPET) could also be observed (3/23). There was a statistically significant association between the tumour classification and integration patterns described above (p < 0.001, κ = 0.72). GBM was associated with pattern vMRI-in-vPET (9/10), low-grade with pattern vPET-in-vMRI (7/8) and anaplastic with pattern vMRI-diff-vPET (3/5). CONCLUSION: The metabolically active tumour volume observed in (11)C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in (11)C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas.